COGNITIVE AND NEURAL PROCESSES OF ...

COGNITIVE AND NEURAL PROCESSES OF AUDITORY-VERBAL HALLUCINATIONS IN SCHIZOPRENIA:

Evidence from Behavioral and Neuroimaging Experiments

Ans Vercammen

Paranimfen:

Marte Swart Marjolijn Hoekert

Printing:

Ridderprint Offsetdrukkerij B.V.

Financial Support:

University of Groningen (Ubbo Emmius Grant 180/800514) BCN Graduate School

Cover illustration courtesy of Phillippa King http://www.loadedbrush.me.uk

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RIJKSUNIVERSITEIT GRONINGEN

COGNITIVE AND NEURAL PROCESSES OF AUDITORY-VERBAL HALLUCINATIONS IN SCHIZOPHRENIA: Evidence from behavioral and neuroimaging experiments

Proefschrift

ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op maandag 5 oktober 2009 om 16.15 uur

door

Ans Vercammen

geboren op 10 februari 1982 te Herentals, België

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Promotor:

Prof. Dr. A. Aleman

Copromotor:

Dr. H. Knegtering

Beoordelingscommissie

Prof. Dr. R.J. van den Bosch Prof. Dr. G. Vingerhoets Prof. Dr. W.H. Brouwer Prof. Dr. D.J. Veltman

ISBN: 978-90-367-3908-5

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CONTENTS

PART I: Introduction 1.

Auditory-verbal hallucinations (AVH): Definition, phenomenology, and (neuro-) psychological determinants.

2.

Perspective of the current thesis

3.

Overview and rationale of the experiments

Part II: Empirical Studies 4. Cognitive basis of AVH 4.1. Semantic expectations can induce false perceptions in hallucination-prone subjects. 4.2. Hearing a voice in the noise: Auditory hallucinations and speech perception. 5. Neural basis of AVH 5.1. Structural covariance in the hallucinating brain: A voxel-based morphometry study. 5.2. Perceptual characteristics of auditory-verbal hallucinations are associated with activation of the inner speech processing network. 6. Intervention with Transcranial Magnetic Stimulation (TMS) 6.1. Effects of bilateral repetitive Transcranial Magnetic Stimulation on treatment resistant auditory-verbal hallucinations in schizophrenia: A randomized controlled trial. 6.2. Functional connectivity of the temporoparietal region in schizophrenia: Associations with auditory-verbal hallucinations and modulations induced by rTMS treatment.

PART III: General Discussion and Conclusions

References Nederlandse Samenvatting Dankwoord Curriculum Vitae List of Publications

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PART I: INTRODUCTION

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1.

Auditory-verbal hallucinations (AVH): Definition, phenomenology, and (neuro-) psychological determinants

1.1.

Historical background and definition

The word hallucination derives from the Latin ‘hallucinare’, which means ‘to wander through the mind’. It is most likely that hallucinations are as old as mankind. The phenomenon has already been described during ancient times. Socrates (4th century B.C.) reportedly heard voices that guided and assisted him in making important decisions. A number of other historical figures are known to have experienced hallucinations. One of the most famous cases is probably Joan of Arc, who led the French troups against the English, guided by the divine intervention of God and the Archangel Michael, who spoke to her in voices. Ancient Chinese texts recount the power of hemp, thought to lead to “seeing of devils”, when consumed in large quantities. Although “visions” and hallucinatory phenomena are ubiquitous in medieval literature, it was not until the 19

th

century that the first scientific studies on

hallucinations were reported. During this period the concept of “hallucinations” was introduced as a generic term, describing a host of experiences that could bear upon each of the different senses. It was the French psychiatrist Esquirol who coined the term hallucinations as we know it today. Esquirol differentiated between illusions and hallucinations, with a hallucination described as “a strong conviction of a sensory experience, when there is no external stimulus affecting the senses in a corresponding manner”. An illusion on the other hand concerns a faulty interpretation of an actual external stimulus. Despite the long standing fascination of writers and scientists with hallucinations, to this day, the very nature of the inherently elusive and subjective phenomenon complicates an encompassing description or definition, as hallucinations may take on many different forms, may occur in all sensory modalities, and may or may not be linked to mental or physical illness. Perhaps the most appropriate modern definition comes from David (2004), who states that a hallucination can be characterized as ‘a

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sensory experience, occurring in the absence of corresponding stimulation of the relevant sensory organ”. Aleman & Larøi (2008) have added to this description that a hallucination occurs during the awake state, thereby setting it apart from lucid dreams, for instance. Furthermore Aleman & Larøi (2008) add that a hallucination should have a sufficient sense of reality, such that it resembles an actual perception, and the perceiver feels he/she has no voluntary control over its occurrence. This definition encompasses what happens when an 80 year old woman with Charles Bonnet Syndrome sees Scottish highland cattle grazing through her living room, although in reality, luckily, none are present. She can clearly perceive the animals, although no corresponding stimuli reach the retina, and she realizes they could not actually be there. The word ‘corresponding’ is instrumental here, since the eye does receive sensory input from other sources. In the case of Charles Bonnet Syndrome, hallucinations are thought to be caused by the brain ‘filling in’ information in a top-down manner, in the context of a loss of sensory input, due to damage to the peripheral sensory organ, i.e. the eye or optic pathways. Although sometimes disturbing, because they may interfere with daily life, these hallucinations are mostly met with indifference from the perceiver, as he or she has insight their origin. Hallucinations in mental illness present an entirely different situation. The patient with schizophrenia who hears incessant voices, commanding him to act a certain way against his own will, will frequently find this experience very disturbing, and the hallucinations may contribute to serious disability. Additionally, lack of insight into symptoms will hamper the ability to cope with them. In both described cases however, the hallucination is characterized by a perceptual ‘realness’, that is, the woman with Charles Bonnet Syndrome really sees the cows, life size and full color, and the patient with schizophrenia hears a voice with a particular accent, gender and tone. From the aforementioned situational sketches it becomes clear that hallucinations represent a complex and variable phenomenon. Despite the fact that the above mentioned definition manages to outline the defining characteristics of the hallucinatory experience, setting it apart from vivid imagination of dream-like states, large differences in phenomenology exist. Importantly, these variants may be linked to divergent biological and psychological mechanisms.

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1.2.

Modalities of hallucinations

A rich literature bears evidence of the phenomenological heterogeneity of hallucinations. They can occur in all sensory modalities, and thus be of an olfactory, visual, auditory, tactile or gustatory nature. Furthermore, multimodal hallucinations have been described, where the hallucination is simultaneously expressed in different senses. Although auditory hallucinations are considered to be most prevalent, especially in psychotic disorders, evidence suggests that hallucinations in the other modalities may be underreported in the literature (Aleman & Laroi, 2008). Auditory hallucinations may present as primitive sounds, such as whistles, tones or knocking sounds or may take on a more elaborate form, consisting of voices laughing, talking or whispering. In the case of auditory-verbal hallucinations, the perceiver will often hear his own thoughts spoken out loud, a foreign voice commenting on his actions or thoughts, or a group of voices talking about him in the third person (Nayani & David, 1996). In some cases the voices will address the voicehearer directly and command the performance of certain actions. These commands may be relatively benign (repeatedly washing one’s hands), but may also elicit socially inappropriate behavior (masturbating in public) or outright harmful and dangerous actions (jumping in front of a train) (Trower et al., 2004). A recent study conducted in a sample of 100 psychiatric patients attempted to objectively define the structure of auditory-verbal hallucinations (Stephane, Thuras, Nasrallah, & Georgopoulos, 2003). From structured interviews, twenty phenomenological variables were identified. A multi-dimensional scaling technique was applied, which revealed three underlying dimensions: (1) linguistic complexity, from low (single words), over intermediate (phrases) to high (entire conversations), (2) self-other distinction, indicating the attribution of the voice to the self (perceiving one’s own inner voice out loud) or to a foreign agent (hearing someone else talking to you), and (3) spatial localization, either internal (coming from inside one’s head) or external (perceiving the voice via one’s ears). Within the auditory hallucinations, musical hallucinations, or the perception of melodies, rhythms and timbres, take up their own place. They are most prevalent in pathologies of the auditory pathway (Tanriverdi, Sayilgan, & Ozcurumez, 2001),

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neurological disorders (Terao & Tani, 1998), toxic effects and as side effects of antidepressant treatment (Terao, 1995). Especially women and elderly persons appear particularly prone to develop this form of auditory hallucinations (Berrios, 1990). Visual hallucinations are reputed to occur in very divergent populations and disorders, such as acquired brain damage (Berrios & Brook, 1985), different neurodegenerative diseases (Brasic, 1998) , but also in psychiatric disorders, including schizophrenia. In the latter case, these hallucinations are typical in the so called lateonset subtype, characterized by the first emergence of symptoms during middle age, rather than adolescence. Visual hallucinations in neurodegenerative disorders are often simple in form (i.e. seeing shapes and light flashes), whereas in psychiatric conditions, they more often take on humanoid forms, and are elicited during times of stress, fatigue, loneliness or social/relational problems (Gauntlett-Gilbert & Kuipers, 2003). Multimodal hallucinations are hallucinations affecting different sensory modalities in unison, producing an integrated, complex and holistic perception. Silbersweig et al. (1995), for instance, describe the case of a patient experiencing simultaneous auditory and visual hallucinations. He observed moving, colored scenes, consisting of rolling, bodiless heads, talking, and giving him instructions. One category of hallucinations that deserves a separate mention, are the hypnagogic and hypnopompic hallucinations, referring to hallucinations that occur just before falling asleep or upon waking, respectively. Again, these hallucinations may affect any of the senses, but most typically are characterized by sensations of falling, floating, or leaving one’s body, the sensation of a presence, and seeing and/or hearing people or scenes. Although they occur in the general population, i.e. in otherwise healthy individuals, there seems to be an association with sleep disorders such as narcolepsy, cataplexy, sleep paralysis and excessive daytime sleepiness (Ohayon, Priest, Caulet, & Guilleminault, 1996).

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1.3.

‘Clinical’ versus ‘non-clinical’ hallucinations

Hallucinations as an intrinsically variable and ubiquitous phenomenon are associated with disorders of both psychiatric and non-psychiatric nature. Additionally, they may be elicited in otherwise healthy individuals, often under special circumstances such as sensory deprivation, isolation or bereavement. Within the clinical hallucinations (i.e. those occurring in the context of disease), typically three categories are distinguished: (1) substance induced hallucinations, (2) hallucinations in the context of neurological, neurodegenerative and sensory disorders, and (3) hallucinations in the context of psychiatric disorders.

1.3.1.

Hallucinations in clinical populations

1.3.1.1. Substance induced hallucinations A number of chemical substances, both natural and synthetic, have hallucinogenic properties. Among these are lysergic acid diethylamide (LSD), cannabis, opiates, gamma-hydroxybutyric acid (GHB), phencyclidine (PCP or ‘angel dust’), amphetamines, mescaline, cocaine (Watkins, 1998), and psylocybine and psylocine-containing mushrooms (‘shrooms’). Hallucinogenic substances may induce reliving of perceptual experiences one had while under the influence of the drug. These so called flashbacks may consist of visual and auditory experiences, usually lasting only a few seconds. Tactile hallucinations (e.g. a sensation of crawling bugs under the skin) are less common and mostly associated with cocaine or methamphetamine intoxications. Interestingly, the effect of the drug may differ greatly depending on the individual, the his or her emotional and physical condition, social circumstances and dosage (Asaad & Shapiro, 1986). Phenomenologically, these substance induced hallucinations can be differentiated from spontaneous hallucinations (Bentall, 2003). Visual hallucinations under intoxication often consist of rotating, pulsing or explosive perceptions of color that are enhanced with the eyes closed, or in a dark environment. Auditory hallucinations are mostly vague and

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unstructured, and thus quite different from for instance the ‘voices’ observed by a patient with schizophrenia. Withdrawal from drugs and alcohol may also engender hallucinatory experiences. In some cases, individuals will develop an abstinence syndrome with delirium, prominently characterized by auditory, visual and tactile hallucinations. These hallucinations however are transient, lasting on average just a few days.

1.3.1.2. Hallucinations in non-psychiatric disorders 1.3.1.2.1. Neurological disorders A number of neurological ailments, including brain tumors, epilepsy, cerebrovascular infarctions, migraine, and narcolepsy have known associations with the occurrence of different types of hallucinations (Brasic, 1998). Auditory hallucinations are often observed in epilepsy, especially when the epileptic focus originates in the temporal lobe, after resection of (part of the) temporal lobe, and in brain tumors of the temporal lobe, the diencephalon or midbrain. Visual hallucinations are more frequent in cases of viral encephalitis, vascular embolism, thrombosis, migraine, and cortical lesions in occipital or temporo-parietal regions. Olfactory and gustatory hallucinations may also result from brain tumors of the temporal lobe, epilepsy, meningiomas, and migraine attacks.

1.3.1.2.2. Neurodegenerative disorders In recent years, in addition to the well-described cognitive deficits, researchers have become aware of the presence of non-cognitive problems in the dementias. In 1996, the International Psychogeriatric Association officially termed these problems “behavioral and psychological signs and symptoms of dementia” (Finkel, Costa, Cohen, Miller, & Sartorius, 1996). Behavioral problems included eating and sleeping disorders, agitation, aggression, abnormal vocalizations, wandering, overactivity, (sexual) disinhibition, and apathy. Symptoms in the psychological domain were described as euphoria, depression and psychotic experiences. The latter were subdivided into delusions (false ideas held with unshakable conviction), delusional misidentifications (misperceptions of oneself, other people places or objects) and

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hallucinations. Dementia of the Alzheimer type is characterized by a relatively high prevalence of hallucinations, with estimates ranging from 12% to 53% (Holroyd, 1996). This group of patients most often reports hallucinations in the visual modality, with simple forms or shapes predominating, although sporadically complex multimodal hallucinations are observed. Hallucinations tend to occur in the moderate to the moderately severe stages of the illness, but not in the very advanced phase. This appears to indicate that a specific deficit in cognitive and/or perceptual processes is required for the production of hallucinations, but that a severely atrophied and diseased brain no longer has the capacity to generate such phenomena. In Lewy Body dementia, which is the second most frequent form of dementia, cognitive and motor symptoms, as well as recurring visual hallucinations are central to the illness. Given this fact, it is no surprise that the literature bears evidence of high rates of prevalence of hallucinations in these patients. For instance, (McKeith, Perry, Fairbairn, Jabeen, & Perry, 1992) observed hallucinations in 46% of patients. Hallucinations are often rich, detailed and personally relevant, as they involve family members, and personal experiences. Although visual hallucinations are most common, auditory or complex hallucinations, and even - although decidedly more rare - olfactory and tactile hallucinations have been observed. The experience can invoke highly variable affective responses that may range from amusement to fear or indifference. In general, they occur in the early phases of the disease and patients often have a certain degree of insight into their symptoms. Hallucinations are also relatively common in Parkinson’s disease. Aarsland et al. (1999) report a prevalence of 27% in a group of patients drawn from a community sample. In the group examined by (Fenelon, Mahieux, Huon, & Ziegler, 2000), 39,8% even indicated that they had experienced hallucinations in the last three months. This relatively higher rate of occurrence is probably due to the fact that the latter study also included minor forms of hallucinations, including for instance the sensation of the presence of a person or an object. When auditory, olfactory or tactile hallucinations occur in the course of Parkinson’s disease, they seldom do so in isolation, but rather in association with visual hallucinations (Henderson & Mellers, 2000). Generally the experiences are quite benign, not threatening and emotionally neutral. Patients may

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even be amused by their hallucinations, and often retain adequate insight throughout the course of the illness. Finally, hallucinations tend to occur in the later phases of the illness. It is possible that psychotic-like experiences are underreported in samples of patients with neurological or neurodegenerative disorders. Most studies are based on reports from informants rather than from the patients themselves, and thus should be interpreted with caution. Informants (usually close family members) may wish to protect the integrity of the patient, which may lead to behavior observed as bizarre and disturbed or indicative of mental illness being omitted from reports. Secondly, it is important to realize that although biological factors underlying the neurodegenerative process and the employment of pharmacological agents play an important part in the genesis of hallucinations, these factors are not fully explanatory. For instance, Sweet et al. (2000) compared a group of patients with Parkinson’s disease and psychotic symptoms (including hallucinations) to a group of patients who did not show such symptoms. In terms of neuropathology, no differences emerged between the two groups. In addition, not all patients diagnosed with a neurodegenerative

disorder

develop

hallucinations

of

other

psychotic-like

phenomena, which suggests that other factors in the domain of personality, cognitive and sensory deficits, and social or environmental processes must play an important role.

1.3.1.3. Hallucinations in psychiatric disorders Hallucinations have been described in a great number of psychiatric conditions, and are therefore not limited to a specific diagnostic category. Those psychiatric disorders in which hallucinations are fairly common and well documented in the literature include schizophrenia, affective disorders (e.g. bipolar disorder), posttraumatic stress disorder, postpartum psychosis, alcoholic hallucinosis, and borderline personality disorder. A multinational study of the World Health Organization estimated that approximately 70% of all patients meeting the diagnostic criteria for schizophrenia have hallucinations at some point during the course of the illness (Sartorius, Shapiro,

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& Jablensky, 1974). Andreasen & Flaum (1991) report similar base rates for auditory hallucinations in two samples from the state of Iowa in the United States. Auditory hallucinations are the most common form among patients with schizophrenia, followed by visual hallucinations. Olfactory, gustatory or tactile hallucinations may occur, but are much less frequently reported. Severe depression may also be accompanied by hallucinations. It has been estimated that as many as a quarter of all depressed patients may be suffering from a depression with psychotic symptoms, like delusions or hallucinations (Schatzberg & Rothschild, 1992). The hallucinations are often auditory-verbal in nature, usually transient and limited to brief utterances of single words or short phrases, expressing mood-consistent messages. A psychotically depressed subject typically hears voices that are mocking, humiliating and criticizing, and thus personally referent. They may also be ordered to make up for perceived wrongdoings by performing self-mutilating acts or even committing suicide (Watkins, 1998). Patients with bipolar disorder may also experience hallucinations. One study reported that 47% of adult bipolar patients have had hallucinations during the course of their illness (Hammersley et al., 2003), with auditory and visual hallucinations being roughly equally prevalent. Hallucinations may occur both in the depressed and the manic phase of the disorder (Taylor & Abrams, 1975). In the manic phase, they usually consist of voices speaking directly to the subject, with the content congruent with the abnormally elevated mood. Posttraumatic stress disorder (PTSD) is a psychiatric condition that an individual may develop as a result of exposure to a traumatic event, during which the subject’s life or wellbeing was (subjectively perceived to be) in danger, and he or she suffered feelings of helplessness and intense fear. Typically symptoms involve emotional blunting, avoidance of stimuli reminiscent of the event, increased arousal and reliving of the event in the form of flashbacks. These flashbacks often take the form of auditory, visual, tactile and/or olfactory hallucinations, or a combination of these (Morrison, Frame, & Larkin, 2003). There are marked similarities between PTSD and symptoms of schizophrenia (Muenzenmaier et al., 2005). Combat veterans with PTSD are more likely to report schizophrenia-like symptoms, particularly hallucinations and

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paranoia, compared with those who did not develop PTSD following wartime experiences (Butler, Mueser, Sprock, & Braff, 1996; Mueser & Butler, 1987). In some cases, the hallucinations may relate to a specific event that occurred during battle. Other trauma related psychopathology may also conjoin with hallucinations. There is evidence of a specific association between the traumatic event of childhood sexual abuse and the occurrence of auditory hallucinations, both in clinical (Read & Argyle, 1999) and non-clinical samples (Startup, 1999). Postpartum disorders refer to a range of disturbances that women may develop shortly after giving birth, depression being the most common disorder. In some cases the postpartum disorder has psychotic features such as hallucinations, although this is quite rare, occurring in only 1-2 out of every 1000 deliveries (Kaplan & Sadock, 1981). Symptoms usually center on the woman’s feelings towards the new baby, and her role as a mother. Hallucinations may take the form of voices commanding the new mother to kill or harm her child, or commenting on her competence as a mother. In contrast, some women may present with more benign forms, such as hearing their child crying. A rare complication of chronic alcoholism is alcoholic hallucinosis, which may occur during intoxication as well as during withdrawal from alcohol. In the DSM-IV the older term has now been replaced by ‘substance-induced psychotic disorder with hallucinatory features’. The syndrome is characterized by hallucinations (typically auditory, but visual and tactile hallucinations may occur), delusions, misidentification, psychomotor and affective disturbances. The hallucinatory state may be as brief as a few hours, but may also persist over the course of several months, and in some cases may take a chronic form. Many patients diagnosed with a borderline personality disorder report hallucinations. A multiple case study of (Yee, Korner, McSwiggan, Meares, & Stevenson, 2005) reported on a total of 117 patients, of which 29.2% reported hearing voices on the Symptom Checklist 90. A closer examination of ten cases further revealed that a large majority of patients experienced the hallucinations as very distressing. They occurred with great frequency over prolonged periods, typically invoked self-harming behaviour, and had a critical content. Although the majority of hallucinations were auditory, visual and olfactory hallucinations were also reported.

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1.3.2.

Hallucinations in non-clinical populations

Non-clinical hallucinations are those forms of hallucinatory experiences occurring in otherwise healthy individuals, without a history of neurological or psychiatric disorder. They may manifest spontaneously, but are often associated with exceptional circumstances, such as bereavement, social isolation or sensory deprivation and particularly stressful life events.

1.3.2.1. Prevalence A number of studies suggest that a substantive proportion of the general population have experienced or regularly experience hallucinations. Tien (1991) investigated for the first time the occurrence of hallucinations in a very comprehensive sample of 18.572 subjects from the general American public, observing a prevalence of 10% in males and 15% in females. Similar rates were found in comparable studies conducted in France (Verdoux et al., 1998) and New-Zealand (Poulton et al., 2000). Another large study (Ohayon, 2000) examined a representative sample from three different nations (the United Kingdom, Italy and Germany), by conducting telephone interviews. The investigators petitioned diverse types of hallucinations. 38.7% of the interviewees indicated that they had had at least one hallucinatory experience in their life, although the proportion of subjects having regular hallucinations was limited (2.7% having them once a week, 2.4% having multiple occurrence per week). In the Netherlands, van Os, Hanssen, Bijl & Ravelli (2000) carried out psychiatric interviews in 7.067 subjects selected randomly from the general population. 1.7% reported ‘true’ hallucinations, i.e. those not brought on by illness or substance (ab)use. Another 6.2% of the subjects had hallucinations considered to be non-clinically relevant, as they were not associated with any distress or discomfort.

1.3.2.2. Contextual influences There are a number of situations particularly engendering towards hallucinations, both in clinical and non-clinical groups. States of deprivation from sleep, inadequate

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nourishment, lack of sensory input, as well as extreme fatigue, stress, bereavement, (sexual) abuse, life threatening situations, and religious or spiritual activities are known to be conducive to the emergence of hallucinations. Sensory (over-)stimulation or in contrast, sensory deprivation are the most common external factors leading to hallucinations. People may report hallucinatory phenomena in situations where external stimulation is increased, such as busy crowds, or repetitive machine sounds, or decreased, such as during a long solitary sailing trip. Reduced input due to a sensory deficit may also lead to the emergence of hallucinations. Associations have been established between deafness and auditory hallucinations, especially in the elderly (David, 1999). Similarly, in the visual domain, hallucinations within a scotoma have long been recognized (Brown, 1985). Lesions of the optic tract may also result in hallucinations (Kolmel, 1985), and 10 to 30% of people who are blind experience hallucinations (Lepore, 1990). It appears that the loss of input from the external world is associated with the generation of internal perceptual experiences and that distinguishing between internally and externally derived stimulation may be hampered by a history of inadequate sensory stimulation. Stress is another common eliciting factor. Evidence from case studies point to the potential for hallucinations to arise in violent and/or life threatening situations such as mining accidents (Comer, Madow, & Dixon, 1967), military operations (Belenky, 1979), and terrorist attacks (Siegel, 1984). A study (Laroi & Van der Linden, 2005a) investigating hallucinations in healthy subjects found that in approximately one fourth of the individuals reporting hallucinations, the first such experience occurred in the context of a particularly stressful life event. Loss of a loved one and the associated period of mourning may also provide a context for hallucinations. The bereaved often report seeing or hearing the deceased, and may experience a sensation of their presence. A detailed investigation in a group of 293 recently widowed women revealed that almost half had experienced hallucinations relating to the loss of their spouse. These hallucinations endured in a considerable subset of the women, such that half of the women still reported having hallucinations after ten years, and after forty years the hallucinations had persisted in approximately one third. These bereavement-induced hallucinations were more likely in elderly subjects,

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compared to women who were widowed at a younger age, and a long, happy marriage was a reliable predictor for their occurrence. Interestingly, most women had positive attitudes with regard to the experiences, and felt generally comforted by them during the difficult period of mourning. Subsequent research by Grimby (1993) mainly confirmed the prior findings, and added the observation that this type of hallucination is more prevalent in women then in men.

1.3.2.3. Hallucinations and the association with risk factors Although the occurrence of hallucinations is not necessarily indicative of psychopathology, it appears that there may be link with certain risk factors for and the actual development of psychological problems. Johns et al. (2004) for instance found an association between hallucinations and neurotic traits, victimization experiences, average or below-average intelligence, alcohol dependence and the female gender. Larøi, DeFruyt, van Os, Aleman & Van der Linden (2005) examined the association between hallucination-proneness and personality structure in both young and elderly subjects. In the young sample, neuroticism was significantly associated with the presence of both auditory hallucinations and vivid daydreaming. It has often been reported that hallucinations are more prevalent in individuals with a history of (psychological) trauma, such as sexual abuse (Read & Hammersley, 2005; Read, Agar, Argyle, & Aderhold, 2003). From a number of studies it has become clear that emotional disturbances, in particular feelings of depression and anxiety, are related to hallucinations in non-clinical populations. Allen et al. (2005) for instance observed that higher levels of self-reported anxiety, self-focus and extreme responding were associated with hallucinatory predisposition. The risk for the development of psychosis in non-clinical subjects with occasional hallucinations may be mediated by depressed mood and the formation of delusional ideas (Krabbendam & van Os, 2005; Krabbendam et al., 2005; Krabbendam et al., 2004). In a Dutch study, Sommer et al. (2008a) used a public website to recruit subjects from the general population, who reported a history of auditory hallucinations. The goal was to assess whether these hallucinations occurred as an isolated phenomenon, or whether they were associated with a specific sensitivity for psychosis. Psychiatric interviews were conducted in 103

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voice hearers, and the subjects filled out a number of self-report questionnaires. In addition, sixty control subjects were recruited, matched for age, education level and gender. The voice hearers could not be distinguished from the controls in terms of clinically relevant characteristics, such as delusions, disorganized, negative or catatonic symptoms, and showed no evidence of personality disorders. It was however evident that traumatic childhood experiences, and a family history of Axis I disorders were more prevalent in the group of subjects with hallucinations. The level of everyday global functioning was slightly lower in this group, and their scores on two measures of schizotypal characteristics and delusional formation were remarkably elevated. More detailed analyses revealed that these mediating variables, (i.e. schizotypal traits, lower education level, and a family history of mental illness) were particularly predictive towards reduced global functioning, rather than the presence of voices itself. This led to the conclusion that hallucinations in otherwise healthy subjects are related to a more general sensitivity for disorders in the psychosis spectrum. Longitudinal investigations of the occurrence of ‘psychotic’ symptoms in pediatric populations allow the inventory of their predictive value towards the development of true psychotic disorders in later life. A number of studies have attempted to link the characteristics of hallucinations in children and adolescents to clinical variables. Interviews conducted in the Dunedin birth cohort (McGee, Williams, & Poulton, 2000) revealed that 8% of 11-year olds had occasional hallucinations. These children also scored higher on measures of anxiety and depression, as well as attention deficit/hyperactivity. Of the children showing ‘strong signs of psychotic symptoms’ at the age of 11, 25% had developed schizophreniform disorder at the age of 26 (Poulton et al., 2000). A Japanese study (Yoshizumi, Murase, Honjo, Kaneko, & Murakami, 2004) based on self-report scales in a sample of 761 children aged 11-12 found hallucinations in 21%. Those presenting with a combination of visual and auditory hallucinations also had increased rates of anxiety and dissociative traits. In the Netherlands, Dossche, Ferdinand, Van der Ende, Hofstra & Verhulst (2002) found a prevalence of 2% and 5% for visual and auditory hallucinations, respectively, in a sample of 914 adolescents. The presence of hallucinations was related to a score in

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the clinical range on the Youth Self-Report (YSR), indexing self-ratings for 20 competence and problem items paralleling those of the Child Behavior Checklist (CBCL). The study failed to find an association with the development of psychosis, but did disclose an elevated risk for affective disorders and substance abuse at follow-up eight years later. Escher, Romme, Buiks, Delespaul, & van Os (2002) followed a group of 80 children who heard voices, of which approximately half were not receiving mental health care, and collected data on hallucination characteristics, coping mechanisms, significant life events, psychopathology scores, and requests for professional (mental health) care. At the follow-up assessment after three years, 60% of the children were no longer hearing voices. Variables that contributed to the continuation of the voices included severity and frequency of the hallucinations, associated depression and anxiety, and the absence of specific triggering events in time or place. The need for professional assistance was more related to the appraisal of omnipotence and intrusiveness of the hallucinated voices, rather than the perception itself or the presence of a specific diagnosis. A recent large Australian study (Scott et al., 2009) examined the prevalence of hallucinations based on selfreports and parental assessments and additionally took into account psychosocial factors. A hallucination prevalence of 8.4% was established in this sample of adolescents. Hallucinations were more frequent in adolescents from single-parent or blended families. Adolescents who heard voices also scored significantly higher on a checklist indicating behavioral and emotional problems. Their self-reports revealed higher rates of depressed feelings and an association with prior cannabis use. The same authors recently reported follow-up data from a 21-year birth cohort study, in which psychopathology was measured at 5 and 14 years of age, using the CBCL, and at 14 using the YSR. Delusional experiences were assessed at 21 years of age with the Peters Delusion Inventory (PDI). Adolescent-onset psychopathology and continuous psychopathology throughout both childhood and adolescence strongly predicted delusional thinking in young adulthood, as was evident form the relationship between delusion-like experiences at age 21 and high CBCL scores at ages 5 and 14 and high scores on the YSR at age 14. Hallucinations at age 14 were also significantly associated with delusions. Interestingly, the general pattern of associations persisted when

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adjusted for previous drug use or the presence of non-affective psychoses at age 21. From these studies in children and adolescents it has become evident that a fair number of children and adolescents may have auditory-verbal hallucinations, be it regularly or sporadically. The presence of these hallucinations may be related to the development of different psychopathologic symptoms during childhood and adolescence, and later on in adult life. It is however likely that there are mediating factors in this relationship, such as (traumatic) life events which can act as triggers, and other psychosocial and environmental determinants. Importantly, in a great number of cases, the hallucinations are a transient phenomenon, and the majority of children who hear voices will have a benign outcome and will not develop a psychotic disorder. Laurens et al. (2007) furthermore suggest that in order to adequately predict the risk for psychosis, one should not only assess the presence of psychotic-like experiences, but also screen for other developmental disorders in speech, cognition, motor control, behavior and affect.

1.3.3.

Conclusions form hallucinations in clinical and non-clinical populations: The

continuum hypothesis

The occurrence in clinical as well as non-clinical groups suggests that hallucinations may not be nominally different from normal experiences. This line of reasoning has become known as the ‘continuum hypothesis’ of psychopathological symptoms, and argues that the difference between a ‘clinical’ and a ‘non-clinical’ hallucination is quantitative, rather than qualitative. Furthermore, supporters of this thesis suggest that it is not the nature of the hallucinatory experience itself which determines whether the subject becomes a psychiatric patient, but the way the subject responds to it. This view thus challenges the concept of psychiatric symptoms as discrete entities. Four assumptions underlying the continuum hypothesis may be identified: (1) the distributional component: hallucinations should be present not only in clinical cases, but also in the general population. In addition, the hallucination

24

phenotype is expected to be far more prevalent than the clinical hallucination as defined by narrow medical criteria; (2) the phenomenological component: there should be considerable inter-group similarity, as well as intra-group variability, in terms of phenomenological characteristics (degree of control, affective response, insight, rates of occurrence, etc.), resulting in considerable overlap between clinical and non-clinical groups; (3) the developmental component: factors that are important demographical or psychosocial determinants in clinical cases (e.g. urbanicity, lower income, lower level of functioning, unemployment, single marital status, etc.) should be paralleled in nonclinical cases, which is suggestive of a general developmental mechanism underlying hallucination genesis; and (4) the etiological component: clinical and non clinical hallucinations should have similar underlying mechanisms. These etiological determinants are to be found at the biological

(e.g.

genetic),

psychological

(e.g.

cognitive

deficits),

and

social/environmental (e.g. adverse life events). The idea of a continuum between normality and psychopathology does not contradict the observation that hallucinations as a general phenomenon may refer to a host of heterogeneous experiences. The different types of hallucinations may consequently have diverging biological and psychological/cognitive antecedents. For instance, neuroimaging studies have revealed that hallucinations occurring in a specific modality are associated with activation in brain areas known to be involved in the processing of external sensory information in that modality. Primary and secondary auditory cortex has been found to be activated during auditory verbal hallucinations (Dierks et al., 1999; van de Ven et al., 2005) and visual hallucinations are associated with occipital activation (Ffytche et al., 1998). The current thesis focuses on one particular type of hallucination, namely auditory-verbal hallucinations (AVH). More specifically, the main research subject will be AVH occurring in patients with schizophrenia. AVH are considered to be one of the core symptoms of the disorder and have been linked to considerable disability in the daily life of patients. In addition, in line with the continuum hypothesis, investigations in subjects from the general population, who are prone to experience hallucinations,

25

are used as a proxy for clinical hallucinations. Studying non-clinical samples has the distinct advantage that the results are unbiased by other disease-related variables such as duration of illness, hospital admission, general cognitive decline and medication effects. However, as the continuum-hypothesis suggests, the psychological and neurobiological underpinnings of AVH may be similar in patients with schizophrenia and in people with AVH in the general population and thus informative towards the clinical variant of hallucinations. Eventually, a better understanding of the internal workings of AVH at the cognitive and neural level may lead the way towards important new avenues for therapeutic interventions.

1.4.

Auditory-verbal hallucinations in schizophrenia

1.4.1.

Schizophrenia

Schizophrenia is one of the most severe psychiatric disorders. The lifetime population prevalence of schizophrenia is 1.0-1.5%, with an estimated annual incidence rate of 0.16-0.42 per 1000 persons (Jablensky, 1995). It is typically characterized by a loss of contact with reality. Schizophrenia affects the ability to think clearly, to show and experience emotions in an adaptive fashion, and to interact with others in socially appropriate ways. As a result, the individual will suffer disadvantage in performing his or her occupational and social roles in daily life. The effects are especially devastating as the disorder tends to occur fairly early in life, usually between the ages of 17 to 35, during a period of important developments in social, educational, professional and relational domains.

1.4.2.

Auditory-verbal hallucinations (AVH) in schizophrenia

As can be derived from the DSM-IV criteria, and as mentioned earlier, hallucinations are a characteristic symptom of schizophrenia. It has been estimated that up to 70% of all schizophrenia patients experience hallucinations at some point during the course of their illness (WHO; Sartorius et al., 1974). Schneider (1959)

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defined a number of specific forms of hallucinations and delusions as most characteristic for schizophrenia. These symptoms are known as the classical ‘first rank symptoms’. Hallucinations in schizophrenia are mostly auditory-verbal, and according to Schneider may be subdivided in three categories: (1) voices with running commentary on the patient’s behavior and thoughts (2) voices conversing in the third person (3) the patient’s own thoughts spoken out loud Although the specific form and content of the AVH may vary from one patient to the next, the assumption is that similar processes are at work at the cognitive and neural level. In the following sections, an overview will be provided of the cognitive theories on AVH. Each of these theories attempts to explain the symptom by relating it to deficits or abnormalities in normal cognitive processes, such as speech perception, attention, inner speech, self-monitoring and verbal working memory. Secondly, studies employing structural and functional neuroimaging methods in the investigation of the underlying mechanisms of AVH at the neuronal level will be reviewed. Finally, a concise description of the currently available and prevailing treatments AVH will be given.

1.4.3.

Cognitive theories of AVH

1.4.3.1. Mental imagery One of the oldest theories on AVH centered on the notion of abnormal mental imagery. The basic idea was that when mental imagery is especially vivid, or has a heightened sense of ‘realness’, it may be difficult to distinguish internally generated mental images from externally derived perceptions. Mintz & Alpert (1972) tested this hypothesis in a classical study. Subjects were asked to take place in a silent room, and were told that a tape with the familiar song “White Christmas” would be played at irregular intervals. In reality, the tape being played contained only noise. Compared to subjects who were not prone to hallucinations, a larger number of subjects with high scores on a hallucination proneness measure reported actually having heard the tune. Recently, a similar investigation was reported by (Knobel & Sanchez, 2009). In this

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case, the authors explicitly attempted to manipulate the focus of attention. Sixty-six healthy subjects were tested in the completely silent environment of a soundproofed booth, under different attentional conditions. During performance of a relatively taxing cognitive task, 10% reported some form of auditory perceptions. This rate decreased to 6% when subjects were instructed to focus their attention on visual perception (i.e. they were told there might be a change in ambient lighting), and increased to 36% in the auditory attention condition (i.e. they were told there might be a change in ambient sound). The fact that studies like these rely completely on selfreport and are particularly sensitive to effects of suggestibility pleads for a cautious interpretation of the findings. Other early studies investigating the link between mental imagery and hallucinations provided conflicting evidence. Seitz & Molholm (1947) found a negative relationship between hallucinations and preferred mode of imagery, leading them to argue that schizophrenic hallucinators are relatively deficient in imagery in the modality of their hallucinations. In addition, they compared vividness of reported mental imagery in patients to that of controls and found it to be weaker in the hallucinators. An occasionally occurring vivid image in the nonpreferred and weak modality could therefore be interpreted as none-self produced, and thus experienced as a hallucination. Slade (1976) employed two questionnaires measures of mental imagery and on one (the Betts Scale) schizophrenia patients were found overall to have more vivid imagery compared to controls. However, no difference could be detected between those with and without hallucinations. The other scale (the Gordon Scale of Mental Imagery Control) revealed no group differences at all. A number of other studies (Brett & Starker, 1977; Catts, Armstrong, Norcross, & McConaghy, 1980), using a very similar design failed to replicate this result. Although the findings with regard to mental imagery are discordant, studies such as these indicate that patients with schizophrenia are poor reality testers. Studies attempting to quantify this skill, or the lack thereof, have employed the so called Verbal Transformation Effect, discovered by Warren et al. (1961). The effect is elicited by playing a tape-loop of the same word or phrase, repeated at a fairly fast rate. A normal perception involves hearing phonetically related changes in the stimulus at regular intervals. An initial study (Slade, 1976) found schizophrenia

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patients with a history of hallucinations not to differ from controls in the frequency which they experienced stimulus transformations, but they did hear more bizarre words, phonetically less related to the original stimulus. In order to assess to what extent suggestibility rather than perceptual effects play a role in this effect, Haddock (1995) explicitly manipulated the task instructions. In one condition of the task, subjects were told they might observe a transformation of the stimulus, and in the highly suggestive condition, were told the stimulus would change form. Although no overall differences were observed between groups of hallucinating patients, psychiatric controls and healthy controls for the number of transformations or the latencies of transformations, the hallucinators reported significantly more transformations in the suggestion condition compared to the no suggestion condition. In addition, they identified a greater range of transformations. The results indicate that the auditory judgments of hallucinators are highly influenced by beliefs and expectations. Negative results from other studies however yield a mixed pattern of evidence. Catts et al. (1980) could not confirm the previous results, when comparing twelve non-hallucinating to twelve hallucinating patients, using a similar design to Slade (1976). Evans et al. (2000) tested patients with and without the propensity to hallucinate on five tasks involving the relationship between the ‘inner ear’ and ‘inner speech’, including a verbal transformation task. They found no evidence to suggest that patients with a hallucinatory predisposition are impaired or perform abnormally on any of the tests. However, as Haddock et al. (1995) suggest, the divergent results obtained from hallucinating patients may reflect the specific task demands, and especially the instructions employed in the experiments. In order to gain insight into the nature and impact of mental imagery processes in hallucinations, more objective behavioral measures are necessary. A potential approach entails a direct comparison of performance on a perceptual version of a simple task to an imagery version of the same task (Aleman, Nieuwenstein, Bocker, & de Haan, 1999; Aleman, Nieuwenstein, Bocker, & de Haan, 2000), the underlying conception being that stronger imagery capacity will convey more sensory, contextual and semantic detail to the mental image, making it more alike to an external percept. Hypothetically this would lead to a smaller performance gap between the perceptual

29

and the imagery version of the task. Bocker, Hijman, Kahn & de Haan (2000) compared patients with and without auditory hallucinations on two measures of auditory and visual perception and imagery. Although no group differences became apparent on the two versions of the tasks, patients with hallucinations had relatively stronger auditory imagery compared to visual imagery. A case study of a continuously hallucinating patient, reported by Aleman, de Haan, Bocker, Hijman & Kahn (2002) further illustrates enhanced imagery processing in the auditory, but not the visual modality. In a more elaborate investigation, Aleman, Bocker, Hijman, de Haan & Kahn (2003) asked subjects to form a mental image of one of two previously presented tones (a high versus a low tone). Subsequently, acoustic noise was presented, with either the imagined or the other tone embedded in the noise. Detection of the imagined tone in noise is typically enhanced, an effect known as ‘imagery gain’. This measure correlated with the severity of hallucinations in a patient sample, evidencing increased ‘imagery gain’ with more severe hallucinations. These findings fit with the idea that hallucinations may be related to increased impact of top-down influences on (auditory) perception. Perception is not a passive process, but a reconstructive effort (Kveraga, Ghuman, & Bar, 2007). Every percept is the result of an interaction of bottom-up information, flowing through the system from the peripheral sensory organs upward to primary, secondary and association cortices, and concurrent topdown processing, consisting of internal models of the (acoustic) environment, contextual cues and general world knowledge, which generate perceptual expectations. In a similar vein, Kot & Serper (2002) investigated auditory conditioning in hallucinating and non-hallucinating schizophrenia patients by repeatedly pairing a tone (unconditioned stimulus) with a light (conditioned stimulus), until presentation of the light alone elicits the ‘perception’ of the tone. If top-down processes mediate the occurrence of clinical hallucinations, one would expect hallucinating patients to be more susceptible to conditioning. Consistent with the auditory sensory-conditioning model, results indicated that hallucinating patients acquire sensory-conditioned hallucinations more quickly and are more resistant to extinction than their nonhallucinating counterparts.

30

Thus, in the case of schizophrenia with hallucinations, there may be a distorted balance between these bottom-up and top-down processing pathways, in such a way that a relatively higher priority is assigned to top-down factors in determining the final perception (Grossberg, 2000; Behrendt, 1998), possibly giving rise to perceptions without corresponding external origin (i.e. hallucinations). This fits with a conception of perception as a fundamentally subjective and reconstructive process. (Behrendt, 1998) for instance remarks that traditionally perception is thought to be a fairly accurate internal reflection of the outside world. However, this fails to account for hallucinations and perceptions in dream-states, which have all the richness of ‘true’ perceptions, but no external basis. He goes on to state rather evocatively that “perception should not be seen as an introjection of external reality. Rather, it is an entirely internal production that is projected outside […] everything that we are aware of is the mind, and what we regard as reality is nothing but an externalized part of the mind”. In general, perception is internally determined by mental factors, such as appetitive and emotional drives, expectations, and current needs, and secondly, externally restricted by sensory stimulation. Within this framework, hallucinations do not differ from perception in their reliance on the activation of internal representations, as normal perceptions do not completely acquire their content from external reality either. Hallucinations differ with respect to the balance between internal and external mental conditions of the process, in that they are underconstrained by sensory input. Similarly, Grossberg (2000) suggests that learned top-down expectations are essential in normal learning and memory. These expectations produce prototypes that assist in focusing attention on the relevant feature combinations that comprise conscious perceptual experiences. Top-down expectations may modulate or sensitize target cells to respond more effectively to matched sensory information that enters the perceiving system from the bottom-up. The modulating property of top-down expectations is achieved through a balance between top-down excitation and inhibition. Phasic volitional signals can shift the balance between excitation and inhibition to favor net excitatory activation. Such a volitionally mediated shift enables top-down expectations, in the absence of supportive bottom-up inputs, to cause conscious experiences of, for example,

31

imagery, inner speech, and dreams, and thereby to enable fantasy and planning activities to occur. If these volitional signals, which may or may not be consciously generated, become tonically hyperactive, the top-down expectations can give rise to conscious experiences in the absence of bottom-up inputs and volition. Indeed, it has been proposed that excessive top-down processing, particularly in the form of serial linguistic expectations, may lead to the generation of spontaneous perceptual experiences (Hoffman, Rapaport, Mazure, & Quinlan, 1999).

1.4.3.2.

Deficits in speech perception

AVH are by definition speech perceptions that are erroneously perceived in the absence of speech input. It is therefore understandable that a considerable number of investigations have focused on the integrity of perceptual processes in hallucinating individuals. In contrast to the top-down account of AVH, this approach assumes that deficits occur in the bottom-up processing pathway. Ample evidence from neurology and psychology supports the occurrence of hallucinations in association with sensory impairment and deprivation. For example, acquired deafness in old age has been associated with the emergence of AVH. Thewissen et al. (2009) prospectively investigated the onset of hallucinations and delusions in a general community sample. Of the subjects with deafness or hearing impairment at baseline, 10.1% displayed psychotic symptoms at follow-up, compared to only 2.9% in hearing subjects. Hallucinations arising from various forms of sensory impairments have been termed ‘release’ hallucinations. A lesion to cortical areas may cause loss of inhibition in other cortical areas, resulting in the release of cortical activity and subsequent hallucinatory perceptions. The evidence for sensory impairments in schizophrenia is however mixed. On the one hand, schizophrenia patients as a group do show sensory abnormalities, both in the auditory and visual domains (David, Malmberg, Lewis, Brandt, & Allebeck, 1995). In accordance with the prominent linguistic problems in schizophrenia, sensory deficits may be more pronounced in the language domain. Hoffman, Rapaport, Mazure & Quinlann (1999) observed a performance deficit in hallucinating patients, compared to non-hallucinating patients on a masked speech tracking task, using

32

different levels of superimposed phonetic noise. The task requires subjects to immediately repeat the speech stimuli, as they are listening to the auditory stream. Additionally, a sentence repetition task and an auditory continuous performance task were used to assess verbal working memory and non-language attentional processes. Results supported the hypothesis that hallucinated voices arise from disrupted speech perception and verbal working memory system rather than from non-language cognitive deficits. The fact that this deficit occurs at the level of linguistic processes, and not in more basic perceptual domains was confirmed in a study that tested 30 patients with schizophrenia and 32 controls subjects on verbal serial position tasks on the one hand and tone serial position tasks on the other hand (Stevens, Donegan, Anderson, Goldman-Rakic, & Wexler, 2000) Groups were matched on auditory acuity, such that performance deficits could not be ascribed to basic sensory differences. Remarkably, patients performed worse on all verbal tasks, but did not differ from controls on the tasks employing tones. McKay, Headlam & Copolov (2000) used a comprehensive battery of auditory tests in order to assess whether auditory hallucinations are associated with abnormalities in central auditory processing. Three groups of subjects were tested: 22 patients with psychosis and a recent history of auditory hallucinations, 16 patients with psychosis but no history of auditory hallucinations, and 22 normal subjects. The auditory assessments included auditory brainstem response, monotic and dichotic speech perception tests, and non-speech perceptual tests. There were no group differences on tests that were sensitive to low brainstem function. However, patients in general performed worse than controls on tests sensitive to higher brain stem and cortical function. Hallucinating patients differed from their non-hallucinating counterparts on particularly on a number of speech perception tests, e.g. filtered speech perception and dichotic listening tasks, on which stimuli are presented to both ears simultaneously, and attention should be directed to one ear. Hallucinating subjects performed worse than controls when stimuli presented in the left ear had to be reported. The authors concluded that AVH may be associated with dysfunctions in interhemispheric transfer or language processing of the right hemisphere, but that the deficit observed in hallucinating patients probably represents a greater degree of the same kind of language

33

abnormalities seen schizophrenia patients in general. Other studies utilizing the dichotic listening paradigm have likewise observed performance deficits in patients with AVH (for a review, see Hugdahl et al., 2007). In the Bergen dichotic listening paradigm (Tervaniemi & Hugdahl, 2003), the subject is presented with two consonant–vowel syllables simultaneously, one in each ear, and required to report the syllable identified best on each trial. The instruction emphasizes that the subject should provide only the syllable identified best on each trial. The idea is that this taps into an initial perceptual process and avoids confounding with memory. Moreover, the subject is not told that there are two different syllables on each trial, and is encouraged to “not to try to remember, or think about the stimulus, but just report what you initially hear”. Healthy controls typically show a right-ear-advantage (REA) in this paradigm. The neuroanatomical model suggested by Kimura (1961) is often advanced in explaining the REA, as it states that the contralateral auditory neural pathway is more preponderant than the ipsilateral one, and that the left hemisphere is dominant for speech perception. This should favor processing of the right ear stimulus because it has direct access through the contralateral auditory pathways to the speech processing areas in the left temporal lobe. As a group, patients with AVH show a reduced REA, and an inverse relationship exists between AVH severity and right ear performance, supporting the idea that hallucinations interfere with the perception of external speech stimuli, localized to the left temporal lobe. What is not clear from these results is whether this is caused by a direct interference by “active voices” or that the presence of AVH over a long time is associated with neuronal pathology at the level of the left peri-Sylvian region. Decision processes higher up in the processing stream may also affect speech perception ability. In a number of studies, a positive response bias was observed in patients with AVH, when reporting the detection of stimuli. Bentall and Slade (1985) constructed a task based on Signal Detection Theory (SDT), in which the word “who” had to be detected against a background of acoustic noise. On half of the trials only noise was presented. SDT allows the dissociation between perceptual sensitivity, i.e. the general efficiency of the perceptual system, and response bias, i.e. the individual’s private criterion for deciding that a perceived event is an actual stimulus. Two non-

34

clinical groups, consisting of hallucination prone subjects and non-hallucination prone subjects, as well as groups of schizophrenia patients with and without AVH completed the task. Hallucinators did not differ from non-hallucinators in terms of perceptual sensitivity. In contrast, hallucinators were more likely to indicate they observed the word in noise, when it was not present (i.e. a false alarm). Thus, it seems that the predisposition for hallucinations relates to changes in the perceptual criterion for speech stimuli. In opposition to the idea of a speech perception deficit, one could even posit that this response bias may actually lead to improved detection of stimuli under ambiguous circumstances, as it is characterized by a willingness to err on the side of false positives. Theoretically, the number of missed stimuli will decrease, as the decision criterion shifts (Dolgov & McBeath, 2005).

1.4.3.3. Meta-cognitive control processes Metacognition means “thinking about thinking”, or in other words, reflections about your own thought processes. This metacognitive attitudes and beliefs may be implicit, that is, the subject is not necessarily consciously aware of them. Recent cognitive models of hallucinations have focused on potential deficits in these processes, particularly in the attribution of internally generated experiences. The most prominent theories relate AVH to misattribution of inner speech, and problems with monitoring the source of mental events.

1.4.3.3.1. Misattributed inner speech Inner speech refers to the “inner voice”, which is a common human cognitive process that enables the regulation of behavior and emotions. It typically involves commenting to oneself about what is happening or issuing instructions about what to do. The idea that AVH occur when an individual misattributes this inner speech to an external source has considerable intuitive appeal, and in the literature a certain consensus exists in support of this view. In support of this theory, subvocal activation of the speech muscles has been observed during hallucinations, similar to the subvocalization present during normal inner speech in healthy adults (Gould, 1948; Gould, 1949). Similarly, some studies have found that verbal tasks that block

35

subvocalization also inhibit the occurrence of AVH (Gallagher, Dinan, & Baker, 1994). It is hypothesized that a breakdown in the monitoring of inner speech production is responsible for its misattribution to an external source. Frith (1987; 1989) formulated a theory of alien control symptoms in schizophrenia, explaining them in terms of failure in monitoring the intention to act. Deficits in self-monitoring may cause overt actions or mental actions to become isolated from the volitional signal. Applied to AVH, if one fails to recognize the intention associated with one’s inner speech, this would lead to the interpretation of the inner voice as an external one. This proposition is largely based on Feinberg’s (1978) idea that schizophrenia is associated with deficits in the efference-copy/corollary discharge system. Briefly, each action a person makes is assumed to be accompanied by an ‘efference copy’ of the action, which sends a signal to the sensory cortex. Here, a corollary discharge is produced, which primes the cortex for the impending sensory consequences of the action. This signals to the person that the sensations are linked to a self-generated act. During talking, for instance, the plan to speak sends an efferent signal to the auditory cortex, where it becomes a corollary discharge. Almost simultaneously, speech is initiated, and the sound reaches the auditory cortex. In the normal situation, an internal monitor matches the afferent input to the corollary discharge, and the sensory experience is reduced in its impact. In schizophrenia however, it is presumed that this efference copy does not produce a timely corollary discharge, which complicates the distinction between internal and external perceptual events. If this corollary discharge process fails during inner speech, a self-generated inner dialogue may be experience as coming from a non-self source.

1.4.3.3.2. Reality discrimination and reality monitoring Richard Bentall (1990) introduced an influential model that explains hallucinations in terms of a disruption in reality discrimination and/or monitoring, i.e. the ability to distinguish real from imagined events. Reality discrimination refers to the on-line judgment of whether an ongoing experience internally generated or is coming from an external (i.e. non-self) source. Reality monitoring then refers to memories regarding the internal or external source of an event. The theory suggests

36

that hallucinating individuals have specific externalizing bias, or the tendency to attribute their thoughts to an external source. This idea is obviously in accordance with the general idea underlying other theories of AVH, e.g. the inner speech model. A major advantage of this approach lies in the fact that it is based on a body of experimental work with a paradigm tapping into the more general ability of “source monitoring” (Johnson, Hashtroudi, & Lindsay, 1993). Source monitoring refers to the ability to discriminate different sources of information, e.g. whether you read something in the newspaper, or heard the story from a friend. Reality discrimination and monitoring can be seen as a subset of source monitoring processes, specifically relating to the internal/external distinction. In a typical source monitoring paradigm subjects are given a list of words to remember. During the encoding phase, half of the words will be read by the experimenter, and half by the subject herself. In the test phase, the subject has to indicate for each given word, whether it was self generated or read aloud by the experimenter, or whether it is a new distractor word. According to Bentall’s hypothesis, patients with hallucinations should make more errors indicating a self-generated word was spoken by the experimenter. A number of studies have found corroborating evidence (Bentall, Baker, & Havers, 1991; Morrison & Haddock, 1997; Brebion et al., 2000). Evidence of disturbances in reality monitoring in non-clinical participants was reported by Larøi, Van der Linden & Marcewski (2004). For every presented word, the subject was required to associate another word. Interestingly, the stimuli were varied in terms of emotional valence, and cognitive effort. High cognitive effort words were those for which longer latencies were required in finding an associate. After a delay, a series of stimuli was presented, including those generated by the experimenter, the associate words provided by the subject, and distractor words, and the subject was asked to identify the source of each word. Hallucination prone subjects made more errors for self-generated items, and this pattern of results was particularly marked in the high cognitive effort and emotionally charged material. This suggests that hallucination prone subjects have a deficit in the use of meta-cognitive cues, such as cognitive effort (typically, one is more likely to accept an experience as self-generated when it is associated with a

37

memory of the cognitive effort associated with the production of the event), and the effect of emotion on cognitive processes. However, not all studies have been able to endorse the specific link between hallucinations and source monitoring deficits. For instance, Keefe et al. (1999; 2002) report that patients without hallucinations, but with other positive symptoms, make the same errors. Costafreda et al. (2008) also found that external misattributions were more common than self-misattributions, especially for negatively valenced material, and that the bias was greater for patients with active positive symptoms relative to patients in remission. However, this association held up for both patients with hallucinations and delusions, and thus argues against the specificity of source monitoring deficits to the hallucination process. Another issue plaguing this theory is the fact that phenomenologically, the perceived voices are not necessarily externalised by hallucinating patients. A number of studies indicate that patients often experience their voices as coming from “inside their head”. In addition, some patients have difficulty distinguishing their own thoughts from their verbal hallucinations. Or, in other words, a subjective perceptual event does not need to be externalized in order to qualify as a hallucination.

1.4.4.

Neuroimaging of hallucinations

Are there observable alterations or deficits in the brain of an individual who hears voices when no one is speaking? Which brain areas are involved in the experience of hallucinations? With the use of modern imaging techniques, such as Positron Emission Tomography (PET) and (functional) Magnetic resonance Imaging (fMRI) researchers have attempted to answer these questions. Allen et al. (2008) provide an exhaustive review of structural and function imaging studies investigating the neural substrates of AVH. Here, we provide a brief summary of activation studies, which probe the immediate neural activity associated with the occurrence of AVH, cognitive interference studies, investigating the neural basis of cognitive processes involved in AVH, and studies mapping brain changes in terms of structure and connectivity.

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1.4.4.1. Structural neuroimaging The aim of these studies is to link structural changes in brain morphology to the presence and/or severity of AVH. In contrast to hallucinations caused by a specific pathological process, such as a tumor, hallucinations in psychiatric disorders are generally not observable in terms of consistent and evident brain changes at the individual level. However, when brain scans from larger samples of schizophrenia patients with AVH are averaged and compared with brain scans obtained from psychiatric controls and/or healthy subjects, structural alterations may be observed. Another option is a correlations approach, in which the relationship between symptom severity and neurobiological measures (e.g. volumes of particular brain regions) is explored. The first study comparing hallucinating schizophrenia patients with healthy controls revealed that patients had larger lateral ventricles, as well as reduced volume in the superior temporal gyrus (STG). In addition, the severity of AVH was negatively correlated with left STG volume, an area important for speech processing (Barta, Pearlson, Powers, Richards, & Tune, 1990). A number of other studies support this latter finding, and also report a link between STG volume and hallucinations severity (Flaum et al., 1995; Onitsuka et al., 2004). Structural changes in non-sensory brain regions have been reported in studies using advanced, automated techniques for the assessment of brain volumes (e.g. Voxel-Based Morphometry; VBM). Neckelmann et al. (2006) confirmed the association of AVH with the left STG, and in addition were able to link AVH to gray matter volume in the thalamus and cerebellum. Shapleske, Rossell, Simmons, David & Woodruff (2001) assessed the length of the Sylvian Fissure (SF) and the Planum Temporal (PT) volume in schizophrenia patients, and calculated both absolute measures and degree of lateralization. Although no asymmetry differences were observed between groups of patients with and without AVH and healthy controls, hallucination severity was correlated with greater leftward asymmetry of the PT. This relationship does not seem very specific however, as thought disorder also correlated with the asymmetry measure. A later study (Shapleske et al., 2002) did reveal a reduction of grey matter tissue in localized areas in the brains of schizophrenia patients. There were also reductions in white-matter

39

tissue, extending along much of the large anterior-posterior frontal tracts in the right hemisphere. Small regions of increased grey matter were also noted in the right inferior parietal lobe. When specifically contrasting patient groups with and without AVH, a single region of reduced grey-matter tissue was identified, affecting the left insula and adjacent temporal lobe. Most of these studies have relatively small sample sizes and divergent findings may be due to differences in methodology and sample characteristics. In order to overcome the limitations of conventional volumetric methods, Gaser et al. (2004) used deformation-based morphometry (DBM), a novel automated whole-brain morphometric technique, to assess local gray and white matter deficits in structural magnetic resonance images in a large sample of 85 schizophrenia patients. They found severity of auditory hallucinations to be significantly correlated with volume loss in the left transverse temporal gyrus of Heschl (i.e. the primary auditory cortex) and left inferior supramarginal gyrus, as well as middle/inferior right prefrontal gyri. These structural deficits in a distributed frontotemporal network appeared to be specific to auditory hallucinations which suggests that AVH may be associated with alterations in interconnected brain regions involved in the processing of auditory and linguistic information. Changes in speech processing areas could possibly lead to a loss of inhibition of inner speech. The volume loss in the prefrontal cortex potentially explains reduced volitional control over inner speech and auditory perception processes. Sumich et al. (2005) partially confirmed these findings. Stephane, Barton & Boutros (2001) conducted a review of studies investigating hallucinations and changes in speech processing areas. The authors warn against farreaching conclusions based on the available literature, as not all studies were able to confirm the link between AVH and structural deficits in auditory regions (e.g. (DeLisi, Hoff, Neale, & Kushner, 1994; Havermans et al., 1999)). Although older MRI studies have produced rather diverging results, recent, and methodologically more advanced studies seem to be more in agreement. Eight studies report volumetric reductions of the left temporal region, in association with AVH, whereas three failed to find a link. One study actually observed in increase in frontal and temporal gray and white matter (Shin et al., 2005). The patient group in this study was quite atypical however, as it consisted of young, unmedicated patients during a first psychotic break.

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Periventricular and ventricular changes were found in four of these studies. In all, it appears that the most consistent finding in hallucinating patients is a reduction in left STG volume. This concurs with lesion studies, which indicate that the localization of the lesion is expected to match the specific modality of the hallucination, i.e. language-related brain regions in the case of AVH.

1.4.4.2. Functional neuroimaging PET, fMRI and other functional neuroimaging methods are used to quantify and image changes in cerebral blood flow, metabolism and neurotransmission. With regard to the study of AVH two prevailing approaches can be distinguished. The first category of experiments can be described as “activation studies”. These studies are designed to measure AVH-related activity at the moment they occur. Either patients are scanned once during the active symptomatic phase and some time later when the symptoms have remitted, or, patients are scanned in a single imaging session, and simply asked to indicate (e.g. by means of a button press) the duration of the periods he or she is having a hallucination. In some instances concurrent auditory stimuli are presented, in order to assess conflicts between internal and external “auditory” information. The second category of studies are so called “cognitive interference” studies. Typically, groups of subjects with and without a (history of) hallucinations are compared in terms of behavioral performance and cerebral activity on a cognitive task. A particular task is chosen because it is thought to tap into specific cognitive processes underlying AVH (e.g. reality monitoring, inner speech processing, etc.). Both types of studies (activation studies and interferences studies) will be discussed in more detail hereafter.

1.4.4.2.1. Activation studies In the first study of its kind, McGuire, Shah & Murray (1993) scanned 13 patients with schizophrenia during a period in which they had active positive symptoms, including AVH. The same protocol was repeated in each of the patients, upon remission of the symptoms. A comparison of these scans revealed increased activity in

41

the left inferior frontal gyrus, i.e. Broca’s area, during the hallucinatory phase. This region has long been known to be involved in speech production. Additionally, but to a lesser extent, activity was observed in the left temporal cortex, which is important for speech perception, and the anterior cingulate gyrus, which controls attentional processes. Using the same general design, but a different imaging technique (SPECT), Suzuki, Yuasa, Minabe, Murata & Kurachi (1993) confirmed part of the latter findings, also observing left temporal cortex activation in 5 patients with AVH. Reporting data from a similarly small sample, Silbersweig et al. (1995) demonstrate AVH related activity in a much more distributed network of subcortical nuclei (thalamic, striatal), limbic structures (especially hippocampus), and paralimbic regions (parahippocampal and cingulate gyri, as well as orbitofrontal cortex). They also report a case study of a unique, drug-naive patient who had both visual and auditory hallucinations. This patient showed activity in visual and auditory/linguistic association cortices as part of a distributed cortical-subcortical network. Based on these findings, the authors suggested that activity in deep brain structures may generate or modulate hallucinations, whereas the particular neocortical regions entrained in individual patients may affect the specific perceptual content. Lennox, Park, Jones & Morris (1999) performed the first activation study with fMRI. They describe a single case of a patient with intermittent AVH. On average his AVH episodes lasted 26 seconds and were followed by hallucination free periods of approximately the same duration. The patient was asked to press a button when the hallucination started, and release it when the voices subsided. A comparison of these short AVH epochs revealed increased activity in the right middle temporal gyrus during AVH. In a follow-up study (Lennox, Park, Medley, Morris, & Jones, 2000) with four subjects, cerebral activation associated with auditory hallucinations was again mapped with fMRI. Group analysis demonstrated shared areas of activation in right and left superior temporal gyri, left inferior parietal cortex and left middle frontal gyrus. When the data were examined on an individual basis, the temporal and prefrontal cortices were activated during AVH in all four subjects. These findings support the theory that AVH reflect abnormal activation of normal auditory pathways. This conclusion was further supported by another fMRI study (Dierks et al., 1999), which, interestingly, found AVH-related

42

activation of the primary auditory cortex in three patients. In healthy subjects, inner speech or auditory imagery does not activate primary sensory areas. The possibility exists that in patients with AVH, there are abnormal feedback projections from higher order processing regions to primary auditory cortex, leading to concomitant activity, and the subjective experience of a “real” auditory stimulus with definitive perceptual characteristics. The case study describing a patient with AVH, that subsided when external sounds were presented again implicated primary auditory cortex in the process of AVH. Van de Ven et al. (2005) argued that the self-report method used in previous studies may not be sensitive enough to capture all neurophysiological signals related to hallucinations. They employed spatial independent component analysis (sICA) to extract the activity patterns associated with AVH in six patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. Bilateral auditory cortex activity, including Heschl's gyrus, was seen during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. This latter fact may have contributed to the somewhat divergent results among the self-report based studies. Additionally, when the subject is required to actively monitor for the presence of AVH and press a button when they occur, the resulting brain activity probably does not only reflect true AVH processes, but other (meta-)cognitive activity as well (e.g. sustained attention and vigilance, self-monitoring, response selection, and motor activity). Shergill, Brammer, Williams, Murray & McGuire (2000) attempted to bypass this methodological flaw by using a novel fMRI method that permitted the measurement of spontaneous neural activity without requiring subjects to signal when hallucinations occurred. Approximately 50 individual scans were acquired at unpredictable intervals in six patients while they were intermittently hallucinating. Immediately after each scan, subjects reported whether they had been hallucinating at that instant. AVH were associated with activation in the inferior frontal/insular, anterior cingulate, and temporal cortex bilaterally, with greater responses on the right. The right thalamus and inferior colliculus, and the left hippocampus and parahippocampal cortex were activated as well. The authors concluded that AVH

43

appear to be mediated by a distributed network of cortical and subcortical area and that prior neuroimaging studies may have identified different components of this network. One interesting aspect of this study was that it also provided information on the temporal course of AVH. Activity in the left frontal and right middle temporal cortex preceded the start of the AVH, whereas the superior temporal gyri and insula responded during AVH. This finding is consistent with the hypothesis that cortical areas associated with inner speech production become activated before speech perception areas are recruited. The most recent, and largest study to date, investigating on-line AVH activity in intermittent hallucinators was reported by Sommer et al. (2008b). Cerebral activation was measured using fMRI in 24 psychotic patients while they experienced AVH in the scanner and, in another session, while they silently generated words. Group analysis for AVH revealed activation in the right homologue of Broca's area, bilateral insula, bilateral supramarginal gyri and right superior temporal gyrus. The word generation task on the other hand yielded activation in the typical left hemisphere language areas (Broca's and Wernicke's area) and to a lesser degree their right-sided homologues, as well as the bilateral insula and anterior cingulate gyri. The lateralization of AVH-related activity did not correlate with language lateralization, but rather with the degree to which the content of the hallucinations had a negative emotional valence. These findings appear to indicate that the main difference between the neural processes of AVH and normal inner speech is the lateralization of activity. AVH predominantly engage the right inferior frontal region, which may also account for the low semantic complexity and negative emotional content typically associated with AVH. In sum, some variability exists in the particular brain regions identified by the different activation studies. It is likely that AVH recruit a distributed network of cortical and subcortical structures. Through methodological and sample variations, different studies may have exposed separate individual parts of this network. Some studies report activity in speech production areas, and others in speech perception areas, a minority including the primary auditory cortex. Most studies however do find that the temporal cortex, in particular the posterior superior and middle parts, is involved when subjects perceive hallucinated voices.

44

1.4.4.2.2. Cognitive interference studies The rationale behind cognitive interference is that a decreased neural response to external (auditory-verbal) stimulation in hallucinating patients, compared to nonhallucinating patients, indicates that the same neurophysiological resources are addressed by the perception of hallucinations and by the perception of external (“real”) stimuli. In its most simple version, external stimuli are presented in the same modality as the hallucinations experienced by the patient. David et al. (1996) studied one patient with AVH, and measured cortical activation in response to periodic exogenous auditory and visual stimulation. Functional brain images were obtained in each condition, both while the patient was on and off antipsychotic drugs. The response of the temporal cortex to exogenous speech stimuli was markedly reduced when the patient was experiencing hallucinating voices, regardless of medication. Visual cortical activation, however, was unaffected. This suggests that hallucinations coincide with activation of the sensory and association cortex, specific to the modality of the experience. Woodruff et al. (1997) confirmed these findings in a larger sample with different groups of subjects: eight currently asymptomatic patients with schizophrenia and a history of auditory hallucinations (trait-positive); seven patients without such a history (trait-negative); and eight healthy volunteers. In addition, seven patients with schizophrenia were examined on two occasions: while they were experiencing severe AVH and again after the AVH had remitted. Neural responses to external speech were diminished in the left superior temporal gyrus, but increased in the right middle temporal gyrus in the combined schizophrenia groups relative to the healthy controls. Thus, the trait-positive and trait-negative patients did not appear to differ in terms of brain response to external auditory stimuli. However, comparing patients in the hallucinatory state, to the remitted state, revealed that the neural response to external speech was reduced in the temporal cortex, especially the right middle temporal gyrus. These results suggest that speech perception may be abnormal in all schizophrenia patients, regardless of the predisposition towards hallucinations, but that the active hallucinatory state is particularly associated with reduced responsivity in temporal cortical regions, which normally process external speech. A more recent study (Plaze et al., 2006) also tested the hypothesis of an

45

inverse relationship between the clinical severity of hallucinations and local brain activity during external speech processing. Fifteen right-handed patients with schizophrenia and daily AVH were studied with event-related fMRI while listening to spoken sentences. AVH severity indeed showed a negative correlation with activity in the left temporal superior cortex when patients were listening to sentences as opposed to silence, again supporting the idea regarding neurophysiological competition between AVH and external speech processing. There is also some evidence that not only perceptual areas show aberrant response patterns to external stimulation. Copolov et al. (2003) used PET to scan hallucinating, non-hallucinating patients and as healthy controls. Perception of externally speech was associated with a consistent pattern of extensive bilateral auditory cortex activation in nonhallucinating patients and healthy controls. Hallucinating participants also activated bilateral auditory cortex, but in addition showed activation in left limbic regions, right medial frontal and right prefrontal regions. The authors contend that this pattern of neural responses is consistent with the idea that AVH represent the activation of misremembered episodic memories of speech. The above mentioned studies provide evidence in support of the idea that AVH are not simply externalized thoughts, but that they possess “sensory” qualities, as they activate brain areas involved in auditory perception. It is however unclear which processes are involved in the production of these aberrant perceptions. A number of studies have attempted to clarify this issue, by employing specific tasks that engage cognitive processes thought to be involved in AVH. These studies are designed to investigate the neural correlates of processes such as auditory imagery, inner speech, and self/source monitoring. In a PET study by McGuire et al. (1995) volunteers were asked to imagine speaking particular sentences in their own voice (inner speech task). Secondly, they were asked to imagine sentences spoken in another person’s voice (verbal imagery task), which is thought to engage inner speech monitoring processes to a larger extent. The latter task was associated with reduced activation in the left medial temporal gyrus and the rostral supplementary motor area in patients with AVH, compared to non-hallucinating patients and controls. The authors concluded that a predisposition to AVH is associated with a failure to activate areas implicated in

46

the normal monitoring of inner speech. In an analogous study using fMRI Shergill et al. (2001) schizophrenia patients with a history of prominent auditory hallucinations and a healthy control group were scanned while either generating inner speech or imagining external speech. Inner speech generation revealed no differences between the groups, but during verbal imagery patients with AVH did show an attenuated response in a distributed network of cortical and subcortical areas, including the posterior cerebellar cortex, hippocampi, lenticular nuclei, right thalamus, temporal cortex and left nucleus accumbens. These results were consistent with previous findings of reduced recruitment of inner speech monitoring regions, but suggested that a more distributed network may be involved. The same authors further investigated inner speech processing using a parametric design (Shergill et al., 2003). Subjects were trained to vary the rate of inner speech generation. When the rate of inner speech is increased, monitoring demands are thought to increase. Patients with schizophrenia and a history of prominent AVH showed a relatively attenuated response in the right temporal, parietal, parahippocampal and cerebellar cortex, compared to healthy controls, with increasing rate of inner speech. These findings were again interpreted as evidence for defective self-monitoring of inner-speech in patients experiencing hallucinations. A small number of studies have directly addressed neural correlates of explicit source monitoring. McGuire, Silbersweig & Frith (1996) implemented a verbal selfmonitoring task in a PET study with healthy volunteers. In the first condition volunteers were shown words and asked to read them aloud. In a second condition volunteers read the word silently, and the auditory feedback consisted of another person’s voice. On half of all the trials the speech that the volunteers heard was distorted by elevating the pitch. The speaker’s own distorted speech led to a bilateral activation of the lateral temporal cortex, with greater responses on the right. A similar pattern of activity was evident when the word they heard was spoken by someone else. These data suggest self generated and external speech are processed in similar regions of the temporal cortex. A subsequent fMRI study using the same task in a healthy control group confirmed these results (Fu et al., 2006). Furthermore, in this study the use of an event related design allowed correct and misattributed source

47

judgments trials to be isolated and analyzed separately. Correct source attributions for self-speech were associated with greater temporal activation than misattributions, which supports the idea that a mismatch between expected (signaled via a feed forward signal and leading to a corollary discharge) and perceived auditory feedback leads to greater temporal activation. Allen et al. (2007) studied the neural correlates of source misattribution in patients with and without AVH, compared to healthy controls. All subjects underwent fMRI, while listening to pre-recorded words. The source (self/non-self) and acoustic quality (undistorted/distorted) of the auditory feedback were varied across trials. The hallucinating group made more external misattributions and showed altered activation in the superior temporal gyrus and anterior cingulate compared to both other groups. The authors suggest that these abnormal neural responses may be related to impairments in the explicit evaluation of ambiguous auditory verbal stimuli. Few studies have paid particular attention to the content of the stimuli used in inner speech or self-monitoring experiments. However, hallucinations in psychotic disorders often have a distinct affective component, which suggests that it is pertinent to assess changes in the neuronal systems involved in emotion processing. A study by Sanjuan et al. (2007) evaluated neural responses to neutral and emotional words spoken by an actor, with affective prosody. The auditory paradigm was based on the most frequent words reported by psychotic patients with AVH. Cerebral activation was assessed with fMRI in 11 patients with schizophrenia with persistent hallucinations and 10 healthy subjects. Compared to controls, increased activity of the frontal lobe, temporal cortex, insula, cingulate, and amygdala (mainly right side) was observed in patients when listening to emotional words. These findings are consistent with other studies (Aleman & Kahn, 2005) suggesting a relevant role for emotional response in the pathogenesis of AVH.

1.4.4.2.3. Alterations in lateralization There is a long-standing hypothesis regarding the etiology of schizophrenia, which posits that reduced language lateralization is responsible for a number of typical symptoms, including AVH. A major proponent of this view, Crow (1998) argues

48

that symptoms of schizophrenia can be understood as a failure to establish language dominance in one hemisphere, with consequent disruption of the mechanisms that allow the speaker to distinguish thoughts from speech output. Several authors have asserted that AVH may arise from aberrant activation in the right hemisphere (Olin, 1999), a hypothesis that dates back to an influential book by Julian Jaynes (1979), “The origin of consciousness in the breakdown of the bicameral mind”. Jaynes contended that in ancient times human behavior was controlled by a ‘‘bicameral mind’’, consisting of the left hemisphere as the site for speech, and the right hemisphere, which mediated supernatural voices of gods and demons (i.e. hallucinations). Over the course of human evolution the hemispheres became integrated, but the bicameral mind would still be reflected in mental disorders such as schizophrenia. Although some studies have observed either bilateral or right hemisphere activation during AVH (Lennox et al., 2000; Shergill, Brammer, Williams, Murray, & McGuire, 2000; Sommer et al., 2008b), many studies implicate typical left hemisphere language areas in AVH, which argues against Jaynes’ hypothesis. However, lateralization of language functions, does appear to be abnormal in schizophrenia (see Sommer, Ramsey, Aleman, Bouma, & Kahn, 2001, for a metaanalysis), and a specific link to AVH has been observed as well. Severity of AVH shows a negative correlation with language lateralization (Sommer, Ramsey, & Kahn, 2001). Consistent with this, a study by Weiss et al. (2006) has also implicated aberrant asymmetry in AVH. During performance of a verbal fluency task, patients with schizophrenia showed reduced language lateralization in the frontal cortex, due to a more bilateral activation of Broca’s area compared to primarily left hemisphere activation in healthy controls. The decrease in lateralization was correlated with the severity of AVH. Stephane et al. (2006) used PET to scan eight patients with AVH , ten patients without AVH, and twelve healthy controls under different conditions: reading aloud English nouns and passively looking at English nouns. Reading aloud, compared to passive viewing was characterized by a reversed laterality index for the supplementary motor area in the group of patients with AVH. The authors suggest that this abnormal lateralization of brain activity may account for the failure to attribute speech generated by one's own brain to one's self. Angrilli et al. (2009)

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tested twelve schizophrenic patients treated with low levels of neuroleptics and twelve matched healthy controls in an Event-Related Potential (ERP) study. Subjects were required to match pairs of words in three tasks: phonological, semantic judgment and word recognition. Slow evoked potentials were recorded from 26 scalp electrodes, and a laterality index was computed for anterior and posterior regions during the inter stimulus interval. During phonological processing individuals with schizophrenia failed to achieve the left hemispheric dominance in anterior brain regions consistently observed in healthy controls. This study suggests that the deficit of lateralization in the schizophrenic brain is specific for the phonological component of language. This loss of hemispheric dominance would explain typical symptoms, e.g. when an individual's own thoughts are perceived as an external intruding voice.

1.4.4.2.4. Studies on anatomical and functional connectivity Although a number of neuroimaging studies have taken a localized approach to AVH, attempting to link the occurrence of hallucinations to abnormal activity in particular brain regions (e.g. superior temporal cortices involved in speech perception), recent models of schizophrenia favor a conception of the disorder in terms of a failure to integrate activity across distributed neural circuits (Andreasen et al., 1999; Stephan, Baldeweg, & Friston, 2006; Stephan, Friston, & Frith, 2009; Zhou et al., 2008; Liang et al., 2006). McGlashan & Hoffman (2000) for instance, formulated a pathophysiological model referred to as ‘developmentally reduced synaptic connectivity’. This model posits that schizophrenia arises from critically reduced synaptic connectedness as a result from developmental disturbances of synaptogenesis during gestation and early childhood, and a failure in synaptic pruning during adolescence. Advances in neuroimaging methods now allow detailed imaging of white matter tracts connecting spatially distinct brain regions, e.g. by means of Diffusion Tensor Imaging (DTI). DTI assesses the directionality of water diffusion (anisotropy), which is restricted by boundaries such as white matter fibers. Reduced anisotropy implies a loss of white matter integrity. Hubl et al. (2004) investigated integrity of white matter tracts in the brains of schizophrenia patients with and without AVH and a healthy

50

control group. Patients with AVH had significantly higher anisotropy values relative to both control groups in the lateral temporo-parietal section of the arcuate fasciculus. This white matter tract connects frontal language production areas (e.g. Broca’s area) with temporal auditory perception areas. The authors speculate that enhanced connectivity between these areas in patients with hallucinations may lead to dysfunctional coactivation of brain regions involved in acoustical processing of external stimuli. Another DTI study (Shergill et al., 2007) assessed integrity of the major white matter fasciculi connecting frontal, temporal and parietal cortices, as well as the corpus callosum which connects the two hemispheres. Across the entire group of patients there was reduced anisotropy in regions corresponding to the longitudinal fasciculi bilaterally and in the genu of the corpus callosum. However, within the group experiencing AVH, the propensity to hallucinate was related to relatively increased anisotropy in the superior longitudinal fasciculi and in the anterior cingulum, leading to the conclusion that schizophrenia is associated with altered white matter integrity in the tracts connecting the frontal cortex with the temporal and parietal cortices and with the contralateral frontal and temporal lobes. The severity of these changes may vary with the pattern of symptoms associated with the disorder. Seok et al. (2007) obtained DTI scans and structural MRI scans from schizophrenia patients with and without AVH, and a healthy control group. The three groups were compared on fractional anisotropy derived from DTI as well as white matter density derived from structural MRIs. In both the hallucinating and nonhallucinating groups, anisotropy of the white matter regions was significantly decreased in the left superior longitudinal fasciculus, whereas white matter density was significantly increased in the left inferior longitudinal fasciculus. AVH severity correlated positively with the mean anisotropy value of the left frontal part of the superior longitudinal fasciculus in the hallucinating patient group. The findings show that white matter changes were mainly observed in the frontal and temporal areas, suggesting that disconnectivity in the left fronto-temporal area may contribute to the pathophysiology of schizophrenia. Pathologic white matter changes in this region may also be an important step in the development of auditory hallucinations in schizophrenia. A study by Lee et al. (2009) conducted the first investigation of altered

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structural integrity in gray and white matter of the superior temporal gyrus (STG) in patients with chronic schizophrenia compared with healthy controls. MRIs and DTI were acquired in the two groups of subjects. Mean diffusivity and fractional anisotropy were measured within STG and correlational analyses were conducted to assess possible associations between DTI and clinical measures. Compared with controls, patients demonstrated reduced volume in bilateral STG gray matter, but not in white matter. For DTI measures, patients showed increased mean diffusivity, in bilateral STG gray matter, and in left STG white matter. In addition, mean diffusivity in left STG white matter was significantly correlated with auditory hallucinations and attentional impairments in patients. These findings suggest a disruption of tissue integrity in STG gray and white matter in schizophrenia. In addition, increased water diffusivity in left STG, which was associated with auditory hallucinations and attentional impairments, suggests the possibility of a disconnection among auditory/language processing regions. In addition to DTI studies, which describe anatomical connectivity, a number of reports are available on functional and effective connectivity, derived from fMRI data. Functional connectivity refers to covariation of neural responses over time between spatial remote brain regions, without making inferences with regard to the direction of the effect (Friston, Frith, Liddle, & Frackowiak, 1993). Studies of effective connectivity on the other hand aim to indicate the contributory influence of each region on another (Friston, Frith, Fletcher, Liddle, & Frackowiak, 1996; Bullmore et al., 2000). Schizophrenia with AVH appears to be characterized particularly by a disintegration of fronto-temporal connections. Disturbances in connectivity have been reported during a sentence completion task (Lawrie et al., 2002), in association with misattributions of speech stimuli (Mechelli et al., 2007), and during verbal working memory (Hashimoto, Lee, Preus, McCarley, & Wible, 2009). Recently, abnormal patterns of connectivity have also been observed in schizophrenia patients during the resting state (Zhou et al., 2008; Liu et al., 2006; Liang et al., 2006). This default mode of the brain is considered to reveal intrinsic activity involving selfreferenced processing. It has been suggested that this intrinsic activity may be at least as important as evoked activity in terms of overall brain function (Raichle & Gusnard,

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2005). However, it is unclear whether specific changes in the resting state can be linked to particular symptoms. AVH are inherently complex, involving perceptual, attentional, cognitive control, affective and memory processes, and accordingly recruit a distributed network of brain regions. Further development of methods for the investigation of structural and functional integration of language, emotion and attention networks will therefore be crucial to the understanding of the neural substrate of this intriguing phenomenon. Specifically, the combination of different imaging methodologies in the same subjects could be informative. For instance, the higher temporal resolution of EEG could shed some light the sequence of processes involved in the production of AVH, whereas fMRI measured concurrently could clarify the spatial origin.

1.4.5.

Treatment of AVH

A number of treatments are available for the management of AVH. At this time, the

primary

treatment

usually

consists

of

pharmacological

intervention.

Antipsychotics (also known as ‘neuroleptic drugs’, literally meaning ‘to take hold of one’s nerves’) are a group of psychoactive compounds that are largely effective in treating acute psychosis, and preventing relapse. The first antipsychotic drugs were happened upon largely by chance and were subsequently tested empirically for their effectiveness. Chlorpromazine, the first antipsychotic, was originally intended as a surgical anesthetic. It was used in psychiatric patients because of its powerful calming effect. Over time, a wide range of compounds have been developed. The first generation of drugs, now known as “typical” antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, now known as “atypical” antipsychotics, have been developed more recently. However, the first atypical antipsychotic, clozapine, was actually discovered in the 1950s, but introduced clinically in the 1970s. Both classes of medication tend to block dopamine D2 receptors in the brain, but antipsychotic drugs encompass a wide range of receptor targets, and the newer drugs tend to have more diverse receptor profiles, additionally targeting serotonergic and/or GABA-ergic neurotransmission. Compared to the typical drugs,

53

the second generation antipsychotics are reported to be more efficient in the treatment of negative symptoms, and seem to cause fewer undesired side effects (Stip, 2000), but do not necessarily lead to better management of positive symptoms. A third generation of antipsychotics has now seen the light, with the production of aripiprazole, which is a partial D2-agonist. At low dopamine levels, a partial agonist will stimulate dopamine receptors, and at high dopamine levels a partial agonist will inhibit dopamine receptors, which may serve to stabilize the dopamine imbalance associated with schizophrenia (Stahl, 2001a; 2001b). Pharmacotherapy has its limitations, as it was shown that in a significant number of patients symptoms persist to a certain extent. It has been estimated that between 10% and 60% of patients who adhere to treatment continue to experience psychotic symptoms (Curson, Patel, Liddle, & Barnes, 1988). In hallucinations, evidence suggest that in 25 to 50% of cases, the symptoms are not managed fully, even in face of adequate

levels

of

medication

(Pantelis

&

Barnes,

1996).

Furthermore,

pharmacotherapy is complicated by non-compliance. A meta-analysis of studies examining medication non-adherence in patients with schizophrenia reported a rates of 41% to 50% (Lacro, Dunn, Dolder, Leckband, & Jeste, 2002). One of the reasons for this non-compliance is the association of antipsychotics with important and potentially grave side effects, including weight gain and diabetes, agranulocytosis (an acute condition involving potentially lethal leucopenia associated with clozapine), extrapyramidal reactions, such as tardive dyskinesia (involuntary, repetitive movements), Parkinsonian symptoms, tachycardia and hypotension, and a decreased subjective wellbeing. All of this suggests that adjunctive treatments are warranted in the management of psychotic symptoms. Transcranial magnetic stimulation (TMS), in particular repetitive TMS potentially provides such an additional treatment strategy for patients with medication resistant hallucinations. In TMS, a magnetic field is generated by a very short current pulse sent through a coil of wire. The stimulator coil is placed over a certain scalp position, and the magnetic field passes unimpeded through the skull, inducing a current in the underlying brain tissue, which results in neuronal membrane depolarization and neural activation (Pascual-Leone, Davey, Rothwell, Wassermann, & Puri, 2002).

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Repetitive TMS then refers to the application of series of pulses at particular frequencies. At a frequency of 1 Hz or less, rTMS has inhibitory effects on cortical signal transmission. At higher frequencies of 5 Hz or more, rTMS has excitatory effects. The rationale in rTMS application in AVH is that hallucinations derive from overactivation of posterior temporal speech processing regions of (mainly) the left hemisphere. Hoffman et al. (2000) published the first report in this regard, finding a significant reduction in AVH after rTMS treatment, compared to sham stimulation, in a crossover design study in 12 patients with schizophrenia. Aleman, Sommer & Kahn (2007) recently conducted a meta-analysis of studies applying 1 Hz rTMS in the treatment of hallucinations in a randomized, placebo controlled design. The majority of studies employed very similar parameters: rTMS was focused mainly on the left temporo-parietal junction, with intensities of 80 to 100% of the resting motor threshold. Durations of the rTMS sessions and the total treatment varied somewhat, but were mostly confined to 15 to 20 minutes daily over a period of 4 to 10 days. The meta-analysis revealed a mean effect size of .76, providing rather compelling evidence of the efficacy of this treatment in reducing AVH severity. Another meta-analysis on the application of TMS in both negative and positive symptoms in schizophrenia confirmed the previous finding of a large and significant effect size in the treatment of AVH (Freitas, Fregni, & Pascual-Leone, 2009). Interestingly, the rTMS effect appears to be restricted to hallucinations and does not generalize to other positive symptoms or general psychopathology. Although rTMS is a promising technique, a number of unresolved issues need to be addressed. The mean effect sizes reported in both metaanalyses are impressive, but still not all studies report uniformly positive effects compared to sham stimulation (e.g. see Fitzgerald et al., 2005; Lee et al., 2005; McIntosh et al., 2004; Saba et al., 2006). Variations in treatment response could be due to significant interindividual variability in the neural substrate of AVH. Neuroimaging studies in fact point to the involvement of a network of speech, emotion and memory related processing regions in AVH. A potential solution to this issue is the application of individually tailored fMRI-guided rTMS. Areas of significant activation are first identified on individual fMRI scans, and neuronavigation may be employed to target specific brain regions showing hallucination-related activity.

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However, Sommer et al. (2007) did not find that this particular strategy improved rTMS treatment efficiency when compared to the traditional method of coil positioning based on the 10/20 international EEG positions. Jardri, Pins, Delmaire, Goeb & Thomas (2007) report a case study of an 11-year old boy with treatmentresistant AVH. fMRI guided rTMS of the left temporo-parietal area resulted in a significant improvement of his symptoms. A problem with this approach is that it is only applicable in a limited number of patients, as the determination of fMRI activation patters associated with AVH requires discrete AVH epochs and non-AVH epochs during the approximately 1 hour scan session. A more general limitation of all rTMS studies is that neither the cognitive nor the neural basis of the rTMS effect is well understood. In contrast to these more biologically oriented treatment strategies involving direct of indirect interventions at the level of neurotransmission, in recent years, it has become clear that psychological approaches may also be effective in the treatment of several symptom dimensions in patients with schizophrenia. For AVH in particular, three strategies have proven efficiency: (1) distraction or counter-stimulation, (2) focusing/concentrating on the AVH, and (3) cognitive behavior therapy. Exemplifying the first strategy, reading out loud seems to (temporarily) suppress the experience of hallucinated voices. Many patients notice that watching TV may have the same effect, potentially because these activities occupy the same cognitive resources as those responsible for the genesis of AVH. Such coping strategies tend to develop naturally in the majority of patients (Nayani et al., 1996; Carter, Mackinnon, & Copolov, 1996). The second strategy encourages the patient to focus on the AVH, and at the same time label to “voices” as non-real. Slade & Bentall (1988) remarked that this focusing probably works because the patient learns to identify the sensory characteristics associated with internally generated events, compared to external ones. Additionally, the conscious labeling of the experience as non-real may serve alter perceptual expectations, such that ambiguous sensory experiences are less likely to be observed as having an external origin. From a number of meta-analysis it has become clear that cognitive behavior therapy (CBT) is effective in alleviating positive psychotic symptoms (e.g. see Dickerson, 2000; Garety, Fowler, & Kuipers, 2000) . The

56

general aim of CBT is to reduce distress, disability and emotional disturbance caused by the symptoms, and to assist the patient in arriving at an understanding of psychosis, in order to promote active participation in the prevention of relapse. Cognitive behavioral techniques are employed to question the patients’ beliefs with regard to malevolence, power and omnipotence of the hallucinated voices. When patients attain a more indifferent attitude toward their AVH, associated anxiety and feelings of depressions diminish, improving daily global functioning, even though the AVH itself do not necessarily disappear (Valmaggia, van der Gaag, Tarrier, Pijnenborg, & Slooff, 2005). Group therapy has the additional advantage that patients, who are often socially isolated and experience feelings of loneliness, are encouraged to share their experiences with others, observe that their symptoms are mirrored in others with the same condition and may share intuitive coping strategies (Wykes, 2004). A recent study employing a randomized controlled trail design showed that although no effect was seen on the general severity of hallucinations, this form of therapy led to significant improvement in social functioning 6 months post treatment (Wykes et al., 2005). Hallucination-focused-Integrative Treatment (HIT) deserves a particular mention in this regard. This approach uses multiple modalities to maximize control of persistent AVH, combining CBT with supportive counseling, psychoeducation, training in coping strategies, crisis intervention and pharmacotherapy (Jenner, 2002). The intervention covers 20 sessions, over the course of a 6 to 12 month period. Several studies provide evidence for the efficiency of this integral approach in chronic patients (Jenner, Nienhuis, van de, & Wiersma, 2006), as well as adolescents with psychotic symptoms (Jenner & van de Willige, 2001). Effects lasted for up to 18 months.

2.

Perspective of the current thesis

Hallucinations are a relatively common and very variable phenomenon, occurring in a multitude of forms, modalities and situations, and may or may not be indicative of pathology. The current thesis will focus on one type of hallucinations, namely, auditory-verbal hallucinations (AVH) in the context of schizophrenia. AVH are a characteristic and particularly ubiquitous phenomenon in this disorder. The study

57

samples in the reported experiments thus mostly consist of patients with a diagnosis of schizophrenia. As mentioned earlier, however, the study of otherwise healthy individuals with a proneness towards hallucinations can be particularly informative. Investigations in healthy subjects are not hampered by potential confounding variables related to the disease process, such as general cognitive deficits, effects of medication, effects of hospitalization, etc. The underlying mechanisms are nevertheless thought to be similar, implying that investigations in clinical and nonclinical groups are complementary and may give a more thoroughgoing explanation of the precursors of AVH. As reviewed above, a body of research exists on the putative causes and processes involved in hallucinations. However, in the literature no general consensus exists with regard to the psychological, cognitive and (neuro-)physiological mechanisms of AVH. Although most researchers will agree that AVH represent internally generated events that are somehow misattributed to an external source, often acquiring particular attentional and affective salience, it is unclear just how this takes place, although a number of candidate processes have been put forward in the past, including defective self-monitoring, failing working memory, etc. (cf. supra). Findings from neuroimaging teach us that AVH are accompanied by activation in relevant sensory cortices, as well as brain regions involved in attention, memory, and emotion. Whether these aberrant neural processes are causative towards AVH is nevertheless unclear. Furthermore, AVH are complex cognitive-perceptual events and most likely not to be traced back to a single neurophysiological deficit in a particular brain region, but linked to dysfunction in a network of interrelated neural processes.

3.

Overview and rationale of the experiments

In this thesis, auditory-verbal hallucinations were investigated on different levels of explanation. The first part of the empirical studies focuses on cognitive processes thought to contribute to the genesis of AVH. In particular, AVH are hypothesized to relate to an imbalance in the normal processes involved in (speech) perception. When top-down influences, such as perceptual expectations take precedence over bottom-

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up inputs, particularly in the case when the input is degraded or ambiguous, subjective perceptions may arise that are uncoupled from reality. In Chapter 4.1. this hypothesis was tested in a sample of university students with differing scores on a questionnaire polling the experience of hallucinatory phenomena. Semantic expectations were induced by manipulating sentence context, and the influence of these expectations on subsequent auditory perception of words in acoustic noise was tested. In Chapter 4.2. the influence of top-down processes on perception was again tested, this time in a sample of patients with schizophrenia, with and without auditory-verbal hallucinations, in comparison to healthy, matched controls. In this speech discrimination task, the top-down influence was established on the level of phonological, rather than semantic processing. Participants had to decide whether a particular spoken word was identical to a previously presented speech stimulus, embedded in noise. Signal Detection Theory was employed on the data to reveal the underlying cognitive processes, which makes it possible to distinguish between deficits in perception and biases in responding. In the second part of the empirical studies neuroimaging methods were employed to elucidate the neural underpinnings of cognitive processes involved in AVH. In Chapter 5.1. structural abnormalities in the inner speech processing network were assessed. The literature suggests that there are abnormalities in this network, both in terms of function and structure. Regional volumes and covariation between regional volumes in separate brain areas were investigated using Voxel-based morphometry (VBM), and were correlated with severity of AVH in a sample of patients with schizophrenia. Chapter 5.2. describes a functional magnetic resonance (fMRI) study utilizing a Region-of-Interest approach to assess the relationship between perceptual characteristics of AVH and activity in brain regions associated with (inner) speech processing. Patients with schizophrenia and AVH performed a metrical stress evaluation task during fMRI, which is a task requiring the production of a words’ phonological code and the assessment of its sound characteristics, and filled out selfreport questionnaires on the perceptual characteristics of their hallucinations. It was hypothesized that if inner speech is involved in the production of AVH, activity in

59

know speech processing regions should correlate with the subjective characteristics that impart the perceptual quality of AVH , such as “loudness” and “sense of reality”. Although cognitive and neuroimaging studies have the potential to reveal processes that are related to AVH, the direction of the relationship is unclear, and the question remains whether the link is really causal. It could be that aberrant processes such as increasing reliance on top-down processes, or deficits in inner speech processing, arise from continuous abnormal, or unreliable perceptual experiences. Transcranial magnetic stimulation (TMS) is a technique that employs magnetic stimuli to either interfere with or stimulate neural activity in the cortex of the wakeful subject. As it allows direct interference with ongoing neural processes, it becomes possible to make causal inferences with regard to the role of the targeted brain area. Chapter 6.1. reports on a randomized controlled trial, in which 1 Hz repetitive TMS was applied to the temporo-parietal cortex of patients with medication resistant AVH. This area has been identified in previous neuroimaging studies to be hyperactive during the experience of AVH. Repetitive TMS, at frequencies of 1 Hz or less, has inhibitory influences on the underlying cortex, suggesting a potential therapeutic effect against this pathological hyperactivity. This study extended the existing literature on the effects of rTMS by including a treatment condition, in which the bilateral posterior superior temporal cortices were targeted by rTMS in the same session. The accompanying hypothesis is based on the evidence of decreased cerebral lateralization in schizophrenia, and accumulating evidence that the right hemisphere might have an important role in the non-linguistic aspects of speech/language processing, such as prosody perception, non-literal meaning and emotional significance. Therefore, targeting this hemisphere along with the traditional language areas of the left hemisphere was thought to lead to a more complete management of the AVH symptom, by influencing non-linguistic and emotional aspects of the experience. Outcome of the treatment consists of both clinical ratings and selfreported changes in AVH severity on a number of scales, polling perceptual and emotional characteristics of the AVH, as well as (delusional) belief systems regarding the hallucinated voices. In the final empirical Chapter 6.2., results are reported from a subset of patients participating in the rTMS trial, who completed fMRI measurements

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before and after the treatment. rTMS may have effects locally, on the site of stimulation, which in this case consists of the left or bilateral temporo-parietal junction. However, rTMS may also affect distal brain regions because they are functionally connected. The goal of this study was to first identify patterns of functional connectivity associated with AVH, and then to assess the potential of rTMS to induce changes in the connectivity of the stimulated brain area. Subjects underwent an fMRI scan during the resting state before and after rTMS treatment. Changes in functional connectivity have previously been established in schizophrenia during task performance. The resting state on the other hand is characterized by default mode neural activity that is not evoked by a particular task, and is hypothesized to relate to self-referenced processing. Functional connectivity in this state could be affected by ongoing AVH activity, and rTMS may interfere with these processes. Finally, the third part of this thesis provides a summary and discussion of the empirical findings described in this thesis. Critical reflections on the methods and suggestions for future research are postulated.

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62

PART II: EMPIRICAL STUDIES

63

64

Chapter 4: Cognitive Basis of AVH

65

66

4.1. Semantic expectations can induce false perceptions in hallucinationprone subjects

Ans Vercammen & André Aleman

Department of Neuroscience, University Medical Center Groningen, The Netherlands & BCN NeuroImaging Center, University of Groningen, The Netherlands

Schiz.Bull. 2008 Jun 17. [Epub ahead of print]

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ABSTRACT

BACKGROUND. Recently, it has been proposed that exaggerated top-down processing may generate spontaneous perceptual output, and that this may constitute a cognitive predisposition towards hallucinations. In this experiment we investigated whether hallucination-proneness would be associated with increased auditory-verbal perceptual expectations, and at which processing level this occurs. METHODS. From 351 undergraduate students screened for hallucinationproneness, using the Launay-Slade Hallucination Scale, 42 subjects were recruited for participation. Two word recognition tasks were administered, in which top-down influences on perception were manipulated through sentence context (“semantic task”) or auditory imagery (“phonological task”). RESULTS. Results revealed that LSHS scores were correlated with the number of semantically primed errors. Subjects with higher levels of hallucination proneness were more likely to report hearing a word that fit the sentence context, when it was not actually presented. This effect remained significant after controlling for general performance on the task. In contrast, hallucination proneness was not associated with phonologically primed errors. CONCLUSIONS. We conclude that aberrant top-down processing, particularly in the form of strong semantic expectations, may contribute to the experience of auditory-verbal hallucinations.

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INTRODUCTION

Auditory-verbal hallucinations (AVH) constitute a characteristic symptom in the schizophrenia spectrum. Up to 70% of patients report this experience at one point during the course of their illness.(Slade & Bentall, 1988) Although generally linked with psychiatric and neurological disorders, it is now acknowledged that during their lifetime, 5 to 15% of the general population may have the experience of hearing voices without an objective basis.(Tien, 1991; Johns et al., 2004) These experiences may, to an important degree, resemble the hallucinations observed in schizophrenia.(Barrett & Caylor, 1998) Indeed, a growing number of studies consider psychosis to be on a continuum with normal functioning.(Johns & van, 2001) A frequently applied questionnaire to measure these sub-clinical schizotypal characteristics is the LaunaySlade Hallucination Scale (LSHS; Launay & Slade, 1981) Scores on the LSHS can be employed to identify hallucination proneness in subjects from a non-psychiatric population. The study of such subjects has the advantage that results are not confounded by the contribution of variables such as hospitalization, medication effects, illness duration, and cognitive deficits. Within the theoretical framework of the continuum hypothesis, the study of a sub-clinical sample can lead the way towards a putative cognitive mechanism underlying hallucination genesis in schizophrenia. Despite decades of psychological investigation, the cognitive mechanism responsible for the transformation of self-generated mental events into speech perceptions or hallucinations, remains unclear.(Aleman & Laroi, 2008) Recent theoretical accounts propose the possibility that AVH are due, not to pathologically enhanced mental imagery, but to an increased impact of such top-down influences on perception.(Aleman et al., 2003; Behrendt, 1998; Grossberg, 2000) Perception is not a passive process, but a reconstructive effort.(Kveraga et al., 2007) In bottom-up processing, information flows from the senses upward into the perceptual system in the brain. Top-down processing occurs concurrently, and has the capacity to reshape this incoming information. In top-down processing, internal models of the (acoustic) environment, i.e. prior knowledge of the properties and dependencies of the objects in this environment, are employed to interpret sensory information and generate

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expectations. In the case of hallucinations, there may be a distorted balance between these bottom-up and top-down processing pathways, in such a way that a relatively higher priority is assigned to top-down factors in determining the final percept. (Behrendt, 1998; Grossberg, 2000) Indeed, it has been proposed that excessive topdown processing, e.g. in the form of serial linguistic expectations, may lead to the generation of spontaneous perceptual experiences. (Hoffman et al., 1999) A form of top-down processing has been studied using the verbal transformation effect, which refers to the tendency to perceive illusory transformations of repeatedly presented words. For instance, subjects may report hearing ‘dress’ or ‘stress’ upon looped presentation of the word ‘tress’. The number of such reported transformations were found to be positively correlated with the disposition towards hallucinations in healthy subjects.(Bullen et al., 1987) Another study in schizophrenia patients with and without hallucinations, indicated that explicit suggestion may play a crucial role in the verbal transformation effect observed in hallucinating subjects.(Haddock et al., 1995) We designed two tasks in order to investigate, at a more automatic level of processing, whether increased influence from top-down factors in auditory-verbal perception would be related to hallucinatory predisposition in healthy individuals. Secondly, we sought to test at which level of processing this occurs, namely at the level of semantic processing, or the level of phonological processing. This question is important, as patients with schizophrenia (and healthy subjects with hallucinations alike) tend to hear meaningful messages and not random auditory stimuli. Thus, it could be hypothesized that semantic expectations play a role in priming hallucinatory perceptual experiences. The stimuli employed in both tasks are auditory-verbal, and thus bear upon the phenomenological experience of hallucinations, in contrast to previous research where preliminary evidence for increased top-down influences was observed using tone stimuli.(Aleman et al., 2003)

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METHODS

Subjects An abbreviated version of the LSHS (Laroi & Van der Linden, 2005b), using only those items tapping into hallucinatory experiences (items 4, 8, 9, 16), was used to screen 351 undergraduate students from the faculties of Behavioral and Social Sciences, Mathematics and Natural Sciences and Spatial Sciences at the University of Groningen. The items were selected based on a published factor-analysis (Laroi et al., 2004). A total of 42 subjects (17 females), of which half scored in the upper and half in the lower quartile of the abbreviated LSHS, were invited for participation in the actual experiment. This sampling procedure reasonably ensured sufficient variability in hallucination scores in our final sample. Subjects were included only if they reported no current or past psychiatric disorder, and if their native language was Dutch. Ultimately, 3 subjects did not complete the semantic task and 2 failed to complete the phonological task. Furthermore, Cook’s D test was used to identify any observations that were exerting a disproportionate effect, which would posit a threat to a valid and reliable analysis. Based on this test, two subjects were disqualified as outliers. A final subject was excluded due to an abnormal audiogram (see procedure).

Materials and Procedure All participants received oral and written information on the procedures of the experiment, and informed consent was obtained. Participants then filled out the full LSHS-R questionnaire (Laroi & Van der Linden, 2005b). Next, standard audiograms were obtained for each participant, using a descending method with 5 dB steps, within the speech frequency range, in order to ensure adequate auditory perception. Subjects were seated in front of a computer screen and given headphones for sound presentation. Each participant completed both tasks, and task order was counterbalanced across participants. Semantic task. Stimuli consisted of short sentences of 5 to 7 words (for examples, see table 1). A pilot study was conducted to test the stimulus materials in an unrelated sample of 28 individuals. Respondents were presented with a number of sentences up

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to the penultimate word, and were asked to fill in the first thing that came to mind. Sentences, on which at least 75% of respondents filled in the same word, were regarded as highly predictable. Fifty such predictable sentences were selected for the experiment. Subsequently, fifty unpredictable sentences were constructed from the same sentences, by filling in a final word that none of the respondents had reported, within grammatical and semantic constraints. For each of these 100 sentences the final word was masked by white noise, at a sound level where the stimulus was 1

difficult, but not impossible to detect . Finally, 50 sentences were created from the same stimuli, by omitting the last word and only presenting a burst of white noise. This was done at the same sound level as the stimuli masked by noise. In this fashion, a total of 150 stimuli were used in the experiment, whereby in a third of cases the predictable word was presented, in a third the unpredictable word was presented, and in a third only white noise appeared. The sequence of stimuli was randomized. Subjects were asked to press the appropriate response button to indicate whether or not they heard a word, and subsequently to identify this word out loud. Subjects were encouraged to identify the word only if they were positively convinced, and otherwise to state that they were uncertain of its identity a total number of 150 trials were presented.

1

The sound-to-noise level of the embedded words was determined with a small pilot experiment in an unrelated sample of subjects. The same sentences (for the semantic task) and words (for the phonological task) used for the actual experiment were presented with the target word embedded in noise. Subjects were asked to try and identify the target word. Four different sound-to-noise levels were tested. Because we were primarily interested in error rates, we wanted to make sure subjects would make enough errors. Therefore, we selected the sound-tonoise level on which approximately 70% of trials were correctly identified. In addition, all sound stimuli were normalized to the same dB level, such that all “noise+word” and “noise alone” stimuli were matched on sound level.

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SENTENCE

PREDICTABLE

UNPREDICTABLE

The thief reported to the

police

owner

The sailor sells his

boat

chair

She sunbathes for hours on the

beach

roof

The accused listened to the plea of his

attorney

mother

Before bedtime she always tells a

story

lie

He takes the elevator up to the second

floor

meeting

She tossed her dirty clothes in the

hamper

bushes

The unfortunate carpenter hit his

thumb

toe

The magician pulled a rabbit out of his

hat

coat

…

…

…

Table 1 lists examples of stimuli used in the semantic task. Sentences were presented up to the penultimate word, after which a burst of white noise appeared. In a third of the trials only noise was presented. In the rest of the trials a word was embedded in the noise, at a sound level such that it was difficult to identify. In half of the trials the word was very predictable given the sentence context. In the other half of the trials, the word was unpredictable, but fit within grammatical and semantic constraints. Phonological task. A trial began with the presentation of a spoken prime word. The words were selected from a published list (Hermans & de Houwer, 1994), and consisted of adjectives, with similar levels of frequency and familiarity in the Dutch language. After hearing the prime word, a delay period of 2 seconds followed, wherein subjects were asked to form an auditory mental image of the word. The last phase of the trial consisted of a burst of white noise. On half of the trials only white noise was presented. In the other trials a target word was embedded in the noise. On half of these trials the target word was identical to the ‘imaged’ prime. On the other trials the word was different. Subjects responded in the same fashion as in the semantic task. A total of 216 trials were presented, divided in 2 blocks.

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Statistical analyses As our primary analysis concerned the question whether hallucination proneness would be associated with a greater number of top-down errors, we first performed a correlation analysis between LSHS score and the rates of each error type. Subjects could make two kinds of ‘positive’ errors, or instances on which a stimulus was erroneously perceived, namely, ‘top down errors’ and ‘confabulations’. ‘Top-down errors’ were scored in the phonological task, when the subject’s response was the prime word, but the target word was different, or only noise was presented. In the semantic task a top-down error was scored when the subject’s response was the predictable word, but the target was unpredictable or only noise was presented. ‘Confabulations’ were scored when the subject’s response was erroneous, but unrelated to the prime in the phonological task or to the sentence context in the semantic task. We calculated partial correlations between LSHS score and the error rates while controlling for general task performance (the controlling variable was the percentage of correct button presses, which indexes the ability to simply detect the presented stimuli in the acoustic noise). Further, ‘misses’ were scored when the subject failed to identify a stimulus, and we calculated the number of ‘unsure’ response. Correlations were calculated between these error rates and the LSHS score. Secondly, in order to verify that the experimental manipulation was successful, repeated measures analyses with LSHS score as the between subjects variable were conducted on the RT and accuracy data acquired from the button press responses. Within subject variables were Stimulus Type: ‘same’, ‘different’ or ‘noise only’ in the phonological task and ‘predictable’, ‘unpredictable’ or ‘noise only’ in the semantic task.

RESULTS

A single peak distribution, which was positively skewed [skewness=.848 (.393); kurtosis=-.088 (.768)], was observed in the full LSHS-R scores (see figure 1). Therefore, we treated LSHS score as a continuous variable, which matches well with the conception of hallucination proneness as a continuum within the population.

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Figure 1 shows the histogram representing the frequencies of full LSHS scores in our sample of first year undergraduate students. Mean=19.44 (12.03). With regard to the correlation analyses, we observed a positive and significant correlation between LSHS score and the number top-down errors in the semantic task [r=.342; p Bilat.; p Plac.; p=.06

5.44 (.53)

4.66 (.50)

4.77 (.83)

14.89 (5.04) 30.22 (8.48) 62.11 (15.62)

13.00 (4.12) 29.45 (7.83) 59.56 (14.45)

16.65 (4.64) 34.44 (10.41) 67.11 (16.70)

p-value

n.s. n.s. n.s. n.s.

n.s. n.s. n.s.

Table 1 represents the clinical and demographical characteristics of the three patient 2 groups and the healthy control group. T-tests and X tests were conducted to assess group differences for continuous and discrete variables, respectively. AVH Assessment All patients filled out the Auditory Hallucination Rating Scale (Hoffman et al., 2003). This scale assesses AVH on 7 characteristics: frequency, reality, loudness, number of voices, length, attention dedicated to the hallucinations, and hallucination-

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induced arousal. A general score is obtained as well, by summing the items, to give a measure of general AVH severity. In addition, each patient was interviewed with the semi-structured Positive and Negative Syndrome Scale (PANSS; Kay, Fiszbein, & Opler, 1987). Assessments were made once, a maximum of two days before the start of the rTMS treatment, and again, a maximum of two days following the final rTMS session, by two trained raters who were blind to the treatment condition.

rTMS procedure and outcome measures Institutional review board approval (University Medical Center Groningen) was obtained for the procedure as described below. The study had a double blind parallel design, in which subjects were allocated to one of three treatment conditions in a pseudo-random fashion, in order to ascertain equal group sizes. Conditions consisted of rTMS application to the left TPJ (n=9), the bilateral TPJ (n=9) or sham stimulation (n=9). Only the TMS administrator was aware of the intervention type. A Magstim Rapid System (Magstim Company Ltd, Whitland, Wales) with a 70 mm figure-of-eight coil was used. For each of the participants in the active rTMS conditions, the resting motor threshold (MT) was assessed on the first day of the trial, according to the procedure described by Schutter et al. (2006). Treatment stimulation sites were determined using the 10-20 International System. Subjects were fitted with standard issue EEG caps (Easycap GmbH, Germany), with the electrodes and electrode holders removed. In the left condition, the coil was fixed on the point halfway between the T3 and P3 electrode position (Hoffman et al., 2003). In the bilateral condition, stimulation was administered to the same location for half the duration of the session, and during the second half of the session, stimulation was switched to the right hemisphere, halfway between the T4 and P4 electrode position. Stimulation was performed at 90% of the individual MT. The placebo condition consisted of sham stimulation performed on the same location as the left rTMS condition, with the use of a Magstim sham coil, which does not deliver a measurable magnetic field, but does produce the same clearly audible clicking sound, at the same frequency of 1 Hz. Patients received a total of 12 rTMS sessions, each lasting 20 minutes, consisting in total of 14400 pulses.

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Treatment was conducted over the course of 6 working days. There was always a minimum 5 hour delay in between subsequent sessions.

fMRI data acquisition Images were acquired on a 3T Phillips Intera scanner (Best, The Netherlands), with a standard SENSE head coil. Scanning was conducted in a dimly lit room. An anatomical scan was obtained first, comprising a 3-D T1-weighted image, covering the whole head. The following parameters were used: TR=25 ms; echo time=4.6 ms; flip 2

angle=30 ;̊ field-of-view=256 mm ; slice thickness=1 mm; 160 transverse slices; no gap. For the resting state scan, subjects were instructed to close their eyes, try to “clear their mind”, but not to fall asleep. Functional images were collected using a field-echo EPI sequence with the following parameters: TR=2300 ms; echo time=28 ms; flip angle=85

2

;̊ field-of-view= 220 mm . A total of 200 whole brain volumes were

acquired, consisting of transverse 39 slices, with 3 mm slice thickness and no gap. Scan duration was 469 ms.

fMRI data preprocessing Data were processed in Matlab (MathWorks, Natick, MA), using the Statistical Parametric Mapping package

(SPM5; Wellcome Department for Imaging

Neuroscience, London, UK; http://www.fil.ion.ucl.ac.uk/spm). For each subject, EPI images were corrected for differences in slice timing and then spatially realigned to the first image in the series. The functional images were coregistered to the T1weighted anatomical image. Images were normalized into standardized Montreal Neurological Institute (MNI) space, and spatially smoothed with a 10 mm Gaussian kernel.

Region-of-interest connectivity analysis ROIs were defined a priori, based on a literature review of activation studies of AVH (Allen et al., 2008) and encompassed the temporo-parietal junction (TPJ), inferior frontal gyrus (IFG; consisting of Broca’s area and the right hemisphere homotope area), anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC),

150

amygdala, and insula. ROIs were selected bilaterally, from the volumes-of-interest defined in the BrainMap database (Fox & Lancaster, 1994; Nielsen & Hansen, 2002). MNI coordinates are presented in table 2. The Marsbar toolbox implemented in SPM5 was used to extract time courses for each of the individual ROIs, averaged over all voxels within the ROI. Left TPJ and right TPJ, corresponding to the approximate site of rTMS stimulation, were selected as seed regions. Pearson correlation coefficients were subsequently calculated between time courses of the seed regions and each of the remaining ROIs. Fischer’s transformations were applied to the correlations in order to obtain Z-scores and improve normality of the data.

Region of Interest Left Temporo-Parietal Junction Left Anterior Cingulate Gyrus Left Broca’s Area Left Dorso-Lateral Prefrontal Cortex Left Amygdala Left Insula Right TemporoParietal Junction Right Anterior Cingulate Gyrus Right Homotope of Broca’s Area Right Dorso-Lateral Prefrontal Cortex Right Amygdala Right Insula

X coordinate

Y coordinate

Z coordinate

Volume (mm)

-50.7

-31.4

22.7

25440

-7.2

20.6

35.5

16408

-40.9 -36.3

11.7 31.3

13.9 23.7

29128 42544

-23.8 -36.2 50.6

-4.6 7.7 -31.4

-17.5 4.14 22.7

1488 12832 25320

6.7

20.4

35.7

17740

40.9

11.7

13.9

29120

36.2

31.2

23.6

42264

23.8 36.2

-4.6 7.7

-17.5 4.14

1480 12824

Table 2 lists the Regions-of-Interests with their respective MNI coordinates (see also http://neuro.imm.dtu.dk/services/jerne/ninf/voi.html).

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Data analysis First, group differences between hallucinating patients and healthy controls were assessed by means of Mann-Whitney U tests on the Z-value indices of connectivity between the seed regions and each of the predefined ROIs, at baseline, before rTMS. Then, within the group of hallucinating subjects, non-parametric correlations (Kendall’s τ) were computed between the measures of hallucination severity and Zvalues. FDR-correction was applied at p=.05, using the procedure described by Benjamini and Hochberg (1995), to correct for multiple comparisons. Due to the small sample size, non-parametric tests were used to test individual changes in symptomatology and functional connectivity after rTMS treatment. Wilcoxon’s matched pairs tests were conducted within each of treatment groups (left rTMS, bilateral rTMS and placebo).

RESULTS

Effects of symptomatology Analysis of group differences revealed a widespread decrease of functional connectivity with the TPJ in the patients, compared to controls. However, the only effect surviving FDR correction was a significantly decreased connectivity between left TPJ and the right homotope of Broca’s area in patients compared to controls (Z=2.88; p=.004); see figure 1.

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Figure 1 shows the group difference in functional connectivity between healthy controls and patients with AVH. Connectivity is expressed as the Z-value corresponding to the Pearson correlation coefficient of the averaged time courses extracted from the two ROIs: the left temporo-parietal junction and the right hemisphere homotope of Broca’s area. Correlational analyses within the group of hallucinators revealed a negative association between the P3 hallucination item of the PANSS and functional connectivity between the left TPJ and the left and right anterior cingulate (τ=-.51; p 10 days), with higher intensities (100-110% of the motor threshold) and more pulses per session appeared to have stronger effects. For the treatment of auditory hallucinations, such a detailed and systematic evaluation has not yet been performed. It is however conceivable that these parameters may play an important role in this instance as well. Given the relatively clean side-effect profile of 1 Hz rTMS (Machii, Cohen, Ramos-Estebanez, & Pascual-Leone, 2006) stimulation at supra-threshold intensities could be advocated. The duration of the treatment could also be extended, both in terms of session duration and in total number of sessions, especially since there appears to be a gradual build-up of the effect over the course of subsequent sessions. Interestingly, in their meta-analysis of rTMS trials of AVH treatment, Aleman et al. (2007) did observe that those studies which failed to find a positive effect were on average quite short in duration, or did not use continuous stimulation. Our own study protocol was characterized by a two day delay halfway in the treatment (i.e. a weekend hiatus). In addition, due to technical restrictions, the bilateral stimulation condition had a short time lag halfway in the session, as at this point the coil had to be switched from the left tot the right hemisphere. This may have

188

contributed to our finding of a modest clinical effect especially in the bilateral group. Another parameter that could be varied, is the frequency of stimulation. The presumed inhibitory effects of 1 Hz rTMS are thought to counteract pathological overactivity in the speech cortex. Interestingly, a recent case study reported beneficial effects of 20 Hz rTMS (Dollfus et al., 2008). A larger follow-up open study (MontagneLarmurier, Etard, Razafimandimby, Morello, & Dollfus, 2009) in 11 patients revealed a significant reduction in global severity and frequency of AVH between baseline and post-treatment day 12. Subjects were treated for 2 days with 20 Hz rTMS. The target area was identified by fMRI as the highest activation cluster along the posterior part of the left superior temporal sulcus from the BOLD signal of each subject during a language task. When subjects were re-assessed 6 months after rTMS treatment, complete cessation of AVH was maintained in 2 patients. The authors explain their observations by referring to the potential of high frequency rTMS to induce inhibitory effects. In addition, they compare the findings with the effects observed in patients with tinnitus, in whom the effect of high frequency rTMS over the left temporoparietal region was found to be equivalent to that of low frequency rTMS .However, the lack of a placebo group in this study precludes strong conclusions. In sum, it is evident that clinical rTMS trials will benefit from a detailed investigation of the specific effects of the different parameter settings.

1.4.3.4. Duration of rTMS effects Another issue of particular clinical and practical relevance in rTMS treatment studies is the durability of the rTMS-induced changes. In our study we do not report on symptom scores past the one week post-treatment follow up assessment, and the effect on brain response was measured at just one time point post treatment. Previous trials have observed clinical improvements lasting about 15 weeks in half of the subjects (Hoffman et al., 2005). In further research it would be informative to continue to assess patients during maintenance treatment, after the first effective rTMS treatment phase. Fitzgerald, Benitez, Daskalakis, De Castella & Kulkarni (2006) observed that a repeat course of rTMS led to marked improvements in AVH severity. Another case study confirmed this finding (Thirthalli et al., 2008), tentatively

189

suggesting that the protocol has potential in terms of long term maintenance treatment of AVH. Evidently, further research is necessary to verify these results in larger samples.

1.4.3.5. Potential working mechanisms of rTMS Finally, a general issue that pertains to all clinical applications of rTMS concerns the fact that the working mechanism of rTMS is still poorly understood. Its effects have been likened to long term potentiation and depression (Pascual-Leone et al., 2002). The general consensus is that frequencies of 1 Hz or less have inhibitory influences on the underlying cortex, whereas frequencies of 5 Hz or more have excitatory effects. However, patterns of neuronal response may be more complex, as a recent study showed that short TMS pulse trains led to an initial period of excitation, followed by prolonged suppression of the neural response (Allen, Pasley, Duong, & Freeman, 2007). Furthermore, alternative protocols, such as theta-burst stimulation (Franca, Koch, Mochizuki, Huang, & Rothwell, 2006; Nyffeler et al., 2006; Stefan, Gentner, Zeller, Dang, & Classen, 2008) and enhanced inhibitory effects due to priming with high frequency stimuli (Iyer, Schleper, & Wassermann, 2003) illustrate that the assumption of cortical inhibition or excitation at certain frequencies is probably too simple. Also, the effect of rTMS appears to be highly dependent on the state of the stimulated cortex (Siebner et al., 2004; Silvanto, Muggleton, & Walsh, 2008; Silvanto, Muggleton, Cowey, & Walsh, 2007). Pasley et al. (2009) for instance, observed that higher pre-TMS activity predicted larger post-TMS responses in the visual cortex. They further remark that this feature could actually be used to a certain advantage in the treatment of clinical disorders. It is conceivable that one could manipulate the activity of the stimulated cortex in real time during the treatment, e.g. by having the subject perform a particular task. Beyond the synaptic effects, TMS might have consequences on other neuronal processes, such as genetic and protein regulation, and circuit-level patterns, such as oscillatory activity in functional networks. Furthermore, TMS might have non-neuronal effects, such as changes in blood flow, which are still poorly understood.

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Complex interactions between local responses and propagations of rTMS induced alterations across the brain are likely to have repercussions in terms of clinical effects. The future for TMS research and its clinical utility lies in the further clarification of its neurophysiological and molecular effects on the neural architecture, in order to enable the optimization of treatment parameters.

2.

Final remarks

2.1.

Contributions of this thesis to AVH research

The work described in the present thesis was designed to contribute to the rich research tradition on AVH, and comprised investigations into the cognitive and neuropsycho-biological profile of the hallucinating patient. Firstly, we showed that the predisposition to experience AVH is associated with changes in the perception and evaluation of external speech stimuli. Particularly, it appears that the speech perception of hallucinating individuals is influenced to a larger extent by internal factors, such as expectations based on the current context, and processes of mental imagery. Secondly, in this thesis we reported results form structural and functional neuroimaging studies, implicating regional variations in anatomy and hemodynamic response in the inner speech processing network in relation to AVH. In another study, we also observed evidence of alterations in functional connectivity in this network, as a function of AVH severity. These studies demonstrate that alterations in certain cognitive and neural processes covary with the propensity to hallucinate, and may point towards potential targets for cognitive/behavioral therapy. In order to devise a more biologically oriented treatment for AVH, our understanding of the anatomical and functional neural architecture underlying AVH should be developed further. We reported on one such attempt. The effect of 1 Hz rTMS to the left or bilateral speech perception cortex on symptom severity was assessed in patients with medication resistant AVH. Moderate changes in AVH severity were observed after a 6 day treatment, particularly in the group receiving stimulation of the left hemisphere, although the bilateral group appeared to benefit from rTMS as well, by showing

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reduced emotional responsivity to their AVH. These results are in line with previous clinical trials, and highlight the critical contribution of speech perception areas in AVH. A subsample of patients also underwent resting state fMRI scans before and after treatment, allowing the assessment of alterations in functional connectivity in response to rTMS. This analysis did not reveal changes in the connections previously identified as correlated with AVH severity. Some trends towards alterations in other connections were observed, but clearly the functional consequences of rTMS at the neuronal level deserve further investigation.

2.2.

Towards a comprehensive neurocognitive model ?

In sum, over recent years significant progress has been made in AVH research. Taken together, the available data appear to suggest that AVH result from alterations in the processing of externally presented and internally generated ‘speech’ stimuli and the skills involved in discriminating real from imagined events. Evidence furthermore suggests that perceptual discrimination may be more influenced by contextual factors. A bias towards externalized attributions appears to be present as well. Subjects prone to hallucinations may make overconfident and/or hasty decision about the (source of their) perceptions. The link between these aberrant cognitive processes and alterations in their respective neural substrates has been assessed as well. Both in this thesis, and in the literature in general, particularly the network of inner speech processing regions has received a lot of attention. Abnormalities in the production, monitoring and perception of internally generated speech percepts have been observed. However, perhaps due to their inherently subjective character, and the fact that much of the research on AVH relies (at least to some extent) on patient reports in the characterization of the symptom, AVH remain a rather elusive phenomenon, and a comprehensive and empirically validated account of AVH has yet to be defined in detail. Specifically, we would like to suggest that any comprehensive theory of AVH should explain the following aspects, and ideally provide a framework to empirically verify them.

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(1) It seems evident that in the case of AVH, an internal event is not recognized as self-generated and thus misattributed to an external source. Inner speech seems a likely candidate to be the raw material of AVH. However, as was Pierre (2009) remarked, the intuitive appeal of the inner speech account notwithstanding, a clear and consistent definition of ‘inner speech’ is lacking. A further exploration of the phenomenology of inner speech, and how it relates to verbal thought, auditory imagery, verbal memory, and AVH will be vital in accounting for the phenomenology and etiology of AVH. (2) The suggestion that AVH result from a defective judgment system, and attributional biases, does not imply that these assessments are produced at a conscious level, fitting with the observation that AVH are most often not under the subject’s conscious control. But, just what makes certain internally generated events more susceptible to this misattribution? Efforts should be made to identify internal and/or external contextual variables (e.g. psychosocial stress, suggestibility, emotional states, cognitive deficits, …) that may predispose this misattribution. (3) Given the observation that AVH tend to occur in healthy subjects as well, and the fact that many psychiatric patients present with experiences intermediate between normal images and hallucinations, a theory of AVH should take into account the conception of a continuum between normal perception and hallucinations. The actual form in which hallucinatory experiences present in otherwise healthy individuals and patients with schizophrenia no doubt differ to some extent. For instance, hallucinations in healthy subjects tend to have a more positive message, and are often experienced as helpful or guiding (Sommer et al., 2008a). The underlying processes however must overlap to a certain degree. In any case, given the doubtful pathognomonic status of hallucinations, it seems reasonable to regard them as objects of research in their own right, free from psychiatric classification. The question as to what distinguishes schizophrenic thinking and neural processes from healthy neuro-cognition will thus require elegant and inventive experimental designs that accommodate the possibility of a continuous, rather than dichotomous relationship between “symptoms” and “normal” neurocognitive processes.

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(4) AVH are not random discharges of a faulty neural system. They often have a very personal relevance. Presumably the content of an AVH reflects the current situational context, activations of episodic memory, personality characteristics etc. Further research into life events precipitating hallucinations, personality structure, stress levels, and the potential reinforcing consequences of AVH are likely to contribute to a better understanding of psychological determinants the phenomenon. A theory of AVH should explain how these processes interact with the putative neurocognitive and/or perceptual deficits observed in hallucinating subjects. (5) AVH have a distinct emotional component in terms of their precipitating context (stressful life events, social isolation,…), their actual content (abusive and derogatory comments) and in terms of the subject’s response (feelings of anxiety and depression). Thus, a particular affective state may influence the occurrence of AVH at different levels. It has been suggested that stress and anxiety may negatively influence self-monitoring systems, resulting in misattributions of internally generated events, and at the same time influence top-down factors, such as perceptual expectations (Aleman & Laroi, 2008). Research paradigms could benefit from the manipulation of the emotional content of presented stimuli, as the cognitive and neural deficits or changes observed in association with AVH may be amplified in response to affectively salient stimuli compared to neutral stimuli. Finally, the importance of the scientific community’s interest in the origin and mechanism of AVH is emphasized by the fact that, especially in the case of medication resistance, AVH represent a significant source of subjective burden (Falloon & Talbot, 1981). In order to devise new and more efficient treatments, it will be necessary to continue to develop a comprehensive and empirically validated account of AVH, and to better our understanding of the phenomenon at different levels of psychological and biological causation and determination.

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NEDERLANDSE SAMENVATTING

195

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Focus van het proefschrift Hallucinaties zijn een bijzonder menselijk fenomeen. Beschrijvingen van hallucinatieachtige fenomenen en ‘visioenen’ duiken regelmatig op in de literatuur, maar het was pas in de 19

de

eeuw dat de eerste systematische wetenschappelijke

studies werden gerapporteerd. Het is in deze periode dat het concept ‘hallucinatie’ werd geïntroduceerd als een generische, overkoepelende term voor een reeks van ervaringen die betrekking konden hebben op verschillende zintuigen. De Franse psychiater Esquirol heeft hierin een zeer belangrijke rol gespeeld en stelde dat hallucinaties bestaan uit ‘een sterke overtuiging van een sensorische ervaring, terwijl er geen extern object is dat het zintuig op de daarbij passende manier beïnvloedt’. Vandaag wordt door het merendeel van de onderzoekers geaccepteerd dat hallucinaties ontstaan door het foutief toewijzen van intern gegenereerde informatie aan een externe bron, hoewel de precieze onderliggende cognitief-emotionele processen nog steeds niet helemaal duidelijk zijn. Hallucinaties zijn bekend in een groot aantal lichamelijke en psychische aandoeningen, maar zijn in het bijzonder karakteristiek voor schizofrenie. Echter, een interessant aspect van hallucinaties is dat ze niet noodzakelijk pathognomonisch zijn. Ze komen ook vrij frequent voor bij gezonde individuen, onder bijzondere omstandigheden zoals rouw, sensorische deprivatie en andere stressvolle situaties. Steeds meer onderzoekers onderschrijven dan ook de idee van een continuüm tussen psychotische symptomen en ‘normale’ perceptuele en cognitieve processen. Het onderwerp van het huidige proefschrift betreft één specifieke vorm van hallucinaties, met name auditief-verbale hallucinaties of ‘stemmen’ bij patiënten met schizofrenie. Schizofrenie is een psychotische stoornis, gekenmerkt door positieve symptomen (hallucinaties, wanen,…), negatieve symptomen (vlak affect, verlies van initiatief,…), en cognitieve stoornissen (taal- en geheugenproblemen,…). Hallucinaties komen met name zeer frequent voor bij deze groep patiënten. Uit onderzoek blijkt dat 50 tot 70% van alle patiënten in de loop van de stoornis ermee te maken krijgt (Andreasen & Flaum, 1990). Bij auditief-verbale hallucinaties (AVH) hoort de persoon vaak zijn eigen gedachten luidop uitgesproken, of hoort hij een stroom van commentaar op zijn gedachten en acties, of een groep van stemmen die in de derde

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persoon over hem converseren. Soms richten de stemmen zich rechtstreeks tot de stemmenhoorder en geven ze hem ook opdrachten en instructies (Nayani & David, 1996). Het onderzoek gerapporteerd in dit proefschrift had als doel de cognitieve en neurale basis van hallucinaties verder te verduidelijken. Een aantal verschillende methoden werd toegepast om specifieke hypotheses te toetsen, die betrekking hebben op de neurocognitieve processen die mogelijk gerelateerd zijn aan AVH. De studies

focusten

op

verschillende

verklarkingsniveaus:

het

gedrag,

m.n.

cognitief/perceptuele processen, structurele veranderingen in het brein en functionele correlaten in het brein. Eerst werden bevindingen van twee gedragsstudies gerapporteerd, waarin werd nagegaan of er aantoonbare wijzigingen zijn in de manier waarop mensen met (de neiging tot) hallucinaties auditief-verbale stimuli verwerken onder ambigue omstandigheden. Meer specifiek werd de hypothese getest dat hallucinaties gepaard gaan met een toegenomen invloed van zogenaamde top-down processen, zoals verwachtingen en mentale verbeelding, op de perceptie. Niet alleen de verwerking van externe spraakstimuli, maar ook interne spraak is mogelijk abnormaal bij individuen die stemmen horen. Daarom werd vervolgens de focus gelegd op het neurale netwerk dat betrokken is bij interne spraak. Met behulp van (f)MRI werd onderzocht of AVH gelinkt konden worden aan de structurele en functionele

kenmerken

van

dit

netwerk.

Deze

cognitieve

studies

en

beeldvormingsonderzoeken bieden inzicht in correlaties tussen kenmerken van AVH en cognitief-perceptuele processen en hun neurale basis. Het is echter niet mogelijk om op basis van deze bevindingen causale verbanden te leggen. Daarom werd in het laatste deel van het proefschrift gebruik gemaakt van repetitieve Transcraniele Magnetische Stimulatie (rTMS), een techniek die het mogelijk maakt om tijdelijk direct in te grijpen op hersenactiviteit in een specifiek gebeid. Het effect dat geobserveerd wordt in het gedrag kent dan een oorzakelijk verband met het beïnvloede hersengebied. In één studie werd onderzocht of toepassing van 1 Hz rTMS op ofwel de linker ofwel de bilaterale temporo-parietale regio klinisch observeerbare effecten had, m.n. een vermindering van AVH. Tenslotte werd nagegaan of AVH

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gerelateerd konden worden aan veranderingen in functionele connectiviteit van deze regio, en of 1 Hz rTMS deze functionele connecties kon beïnvloeden.

De cognitieve basis van auditief-verbale hallucinaties Één van de eerste cognitieve theorieën over AVH stelde dat ze het gevolg waren van een té levendige (auditieve) verbeelding. Ondanks de intuïtief aantrekkelijke logica van dit idee, is het waarschijnlijk een té simpele voorstelling. Recent werd geopperd dat het eerder zou gaan om een verstoorde balans tussen zogenaamde ‘bottom-up’ en ‘top-down’ processen. De onderliggende idee is dat perceptie steeds een reconstructie is, waarbij de waarnemer zich niet enkel baseert op wat er via de zintuigen binnen komt, maar ook op (geleerde) kennis van de wereld, perceptuele verwachtingen en contextfactoren. Hallucinaties treden mogelijk op wanneer deze top-down factoren de overhand krijgen (Behrendt, 1998; Grossberg, 2000). In Hoofdstuk 4.1. werd deze hypothese onderzocht in een groep gezonde proefpersonen die gescreend waren op de neiging tot hallucinaties. Het voordeel van een dergelijke onderzoekspopulatie is dat de bevindingen niet beïnvloed worden door storende factoren die bij patiënten vaak wel een rol spelen, zoals het gebruik van medicatie, ziekenhuisopnames, cognitieve problemen, etc. Aangezien er een groeiende consensus bestaat dat psychotische belevingen zoals hallucinaties op een continuüm liggen met normale perceptuele en cognitieve processen, kan dergelijk onderzoek toch inzichten opleveren die geëxtrapoleerd kunnen worden naar het fenomeen zoals het zich voordoet bij patiënten. De Launay-Slade Hallucination Scale (LSHS; Launay & Slade, 1981), een vragenlijst die de neiging tot hallucinaties meet, werd afgenomen van 351 eerstejaarsstudenten. Tweeënveertig proefpersonen met uiteenlopende scores op de LSHS werden uitgenodigd voor deelname aan het eigenlijke experiment. Alle proefpersonen voerden twee taken uit: een semantische taak en een fonologische taak. In de eerste taak werden zinnen auditief aangeboden, waarbij het laatste woord verborgen was in witte ruis, en waarbij dit woord sterk of zwak voorspelbaar was uit de voorgaande zin. In de tweede taak moesten proefpersonen steeds een gegeven woord in gedachten houden. Vervolgens werd ofwel hetzelfde, ofwel een ander, ofwel geen woord aangeboden in witte ruis. Bij

199

beide taken moesten proefpersonen aangeven welk woord ze dachten te horen in de ruis. Uit de resultaten bleek dat de score op de LSHS positief correleerde met de neiging tot top-down fouten in de semantische taak, dat wil zeggen, proefpersonen met een hogere score waren meer geneigd om het verwachte woord te horen in de ruis, wanneer dit niet werkelijk aangeboden werd. Hieruit werd geconcludeerd dat de neiging tot hallucinaties gerelateerd is aan een versterkte invloed van verwachtingen op de perceptie en dat dit voornamelijk voortvloeit uit semantische context, aangezien in de fonologische taak geen verband werd gevonden. In hoofdstuk 4.2. werd gekeken of dergelijke processen ook aan de orde zijn bij hallucinerende patiënten met schizofrenie. Een spraakperceptie taak werd ontworpen waarin top-down invloeden een belangrijke rol speelden. Voor de analyse van de data werd gebruik gemaakt van Signaal Detectie Theorie. Deze analyse biedt de mogelijkheid om een onderscheid te maken tussen perceptuele efficiëntie en responsbias. Het eerste proces beschrijft de precisie van het perceptuele systeem, terwijl de responsbias doelt op de individuele criterium dat een persoon hanteert om te beslissen of een waarneming een werkelijke stimulus was. Het eerste is eerder een bottom-up proces, terwijl de bias gezien kan worden als een top-down proces. Drie groepen proefpersonen, met name schizofreniepatiënten met en zonder hallucinaties, en gezonde controles voerden de taak uit, waarbij ze moesten beslissen of een auditief aangeboden woord gelijk was aan een eerder aangeboden woord dat verborgen was in witte ruis. De meest interessante bevinding was dat hallucinerende patiënten in vergelijking met niet hallucinerende patiënten een verhoogde perceptuele efficiëntie vertoonden. De groep hallucinerende patiënten had ook een positieve responsbias, ofwel een algemene neiging om op basis van weinig informatie snel over te gaan op de positieve identificatie van een stimulus. Hieruit werd geconcludeerd dat hallucinaties gepaard lijken te gaan met een toegenomen focus op auditief-verbale stimuli, in combinatie met een vrij liberaal criterium in het beslissingsproces of een stimulus écht is of niet. Patiënten met stemmen zijn blijkbaar eerder geneigd om valse positieven toe te staan, wat leidt tot een verhoogde kans op het detecteren van werkelijke stimuli, maar tevens af en toe zal leiden tot een foutieve waarneming, ofwel een hallucinatie.

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Beide studies impliceren dat top-down processen een rol spelen in de cognitieve basis van hallucinaties. Gezonde proefpersonen met de neiging tot hallucinaties en hallucinerende patiënten met schizofrenie lijken onder ambigue omstandigheden eerder geneigd te zijn om de aanwezigheid van een specifieke stimulus te aanvaarden op basis van (geïnduceerde) verwachtingen. Verder onderzoek zal moeten uitwijzen of dit een effect is dat enkel optreedt in de auditieve modaliteit, dan wel dat het gaat om een meer algemene cognitieve predispositie. Verder is het op basis van dergelijk onderzoek niet duidelijk wat de richting van het verband is, en dus of deze cognitief-perceptuele processen de oorzaak zijn van AVH. Een andere mogelijkheid is dat de (al dan niet frequente) ervaring van hallucinaties aanleiding geeft tot een verhoogde sensitiviteit voor auditief-verbale stimuli door de emotionele en persoonlijke relevantie van de AVH ervaring. Dit zou dan weer kunnen leiden tot een perceptueel systeem dat bijzonder gefocust is op spraakstimuli.

De neurale basis van hallucinaties In de laatste jaren zijn er een aantal studies verschenen die een verband hebben aangetoond tussen AVH en veranderingen in de structuur en functie van (voornamelijk frontale en temporale) hersengebieden die betrokken zijn bij de verwerking en monitoring van interne spraak (Shergill et al., 2003). In hoofdstuk 5.1. werd Voxel-Based-Morphometry (VBM), een geautomatiseerde techniek om het volume van hersengebieden te beoordelen, gebruikt om na te gaan of de ernst van AVH gelinkt kan worden aan lokale structurele veranderingen in het neurale netwerk van hersengebieden die instaan voor interne spraak. Ten tweede werden structurele covariatie-patronen onderzocht in temporale en frontale hersengebieden. Structurele covariatie verwijst naar correlaties tussen regionale hersenvolumes, die het gevolg zijn van gezamenlijke beïnvloeding door interne of externe factoren, dan wel ervaringsgerelateerde plasticiteit (Mechelli, Friston, Frackowiak, & Price, 2005). Structurele hersenscans van 24 patiënten met schizofrenie en AVH werden beoordeeld. Uit de resultaten bleek dat de ernst van de AVH gerelateerd was aan een toegenomen volume van de grijze massa in de linker inferieur frontale gyrus (IFG). Uit

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functioneel MRI onderzoek is eerder gebleken dat dit gebied, wat betrokken is bij spraakproductie, ook geactiveerd wordt tijdens AVH (McGuire, Shah, & Murray, 1993). Bovendien kan een toegenomen aanspraak op een bepaald gebied leiden tot een volumetoename in dit gebied (Maguire, Woollett, & Spiers, 2006). Deze bevinding lijkt er dus op te wijzen dat ernstigere hallucinaties dit gebied sterker belasten. Analyse van de structurele covariaties van dit gebied toonde vervolgens aan dat de correlaties tussen het volume van de IFG en het volume van een aantal andere regio’s in het interne spraak-netwerk beïnvloed werd door de ernst van de AVH. Deze gebieden betroffen met name de contralaterale homologe IFG, de middelste en superieure delen van de temporale gyrus, de hippocampus en insula van de linker hemisfeer. Eerder onderzoek toonde aan dat er abnormale verbindingen zijn tussen linker frontale en temporale regio’s bij patiënten met schizofrenie, zowel op het gebied van structuur als functie (Mitelman, Buchsbaum, Brickman, & Shihabuddin, 2005; Lawrie et al., 2002; Ford, Mathalon, Whitfield, Faustman, & Roth, 2002). Abnormale patronen van structurele covariatie werden eveneens geobserveerd bij patiënten met schizofrenie (Mechelli et al., 2007). Deze studie vormt een uitbreiding van deze bevindingen in de zin dat structurele veranderingen gelinkt konden worden aan de ernst van een specifieke symptoom, met name AVH. Het blijkt dus dat interne spraak een proces is dat waarschijnlijk betrokken is bij het ontstaan van AVH. Er zijn echter een aantal specifieke aspecten die interne spraak onderscheiden van hallucinaties: het auditieve karakter en het feit dat de persoon een hallucinatie ervaart als een ‘echte stem’, anders dan de eigen stem. Een punt van kritiek op de interne spraak-theorie is dan ook dat het de fenomenologische complexiteit niet volledig zou kunnen vatten. In hoofdstuk 5.2. werd een onderzoek gerapporteerd dat erop gericht was na te gaan of er een relatie was tussen deze karakteristieke perceptuele kenmerken van AVH en activiteit in het netwerk van interne spraak-gebieden. tweeëntwintig patiënten met schizofrenie en frequente hallucinaties ondergingen een fMRI scan, terwijl ze een taak uitvoerden die sterk beroep doet op interne spraak. Tweelettergrepige woorden werden visueel aangeboden en proefpersonen moesten beslissen of de klemtoon ligt op de eerste of tweede lettergreep. Dit vergt het ophalen van de gepaste fonologische code en dus

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het intern ‘uitspreken’ van het woord. Eerder is aangetoond dat deze taak beroep doet op zowel spraakproductie als spraakperceptie gebieden (Aleman et al., 2005). In eerste instantie werd de activiteit beoordeeld in een reeks van a priori gedefinieerde hersengebieden, welke geselecteerd werden op basis van literatuuronderzoek, en die het verondersteld interne spraak-netwerk vormen. Ten tweede werd een index berekend die de lateralisatie van de hersenactiviteit weergeeft. Uit het onderzoek bleek dat de luidheid van de AVH gerelateerd was aan afgenomen taakgerelateerde activiteit in gebieden betrokken bij de productie, perceptie en monitoring van interne spraak. Eerder onderzoek toonde reeds aan dat AVH en spraakverwerking mogelijk beroep doen op dezelfde neurale bronnen (Plaze et al., 2006). Uit dit onderzoek blijkt dat dit ook geldt voor interne spraak. Het gevoel van ‘echtheid’ van de AVH was echter niet op een lineaire manier gerelateerd aan activiteit in het deze gebieden. Wel was er een associatie met verminderde lateralisatie van de interne spraak-activiteit. Het is reeds langer bekend dat patiënten met schizofrenie verminderde taallateralisatie vertonen (Bleich-Cohen, Hendler, Kotler, & Strous, 2009; Li et al., 2007; Zhang et al., 2008; Sommer, Ramsey, & Kahn, 2001). Deze studie lijkt er dus op te wijzen dat een toegenomen bijdrage van rechts hemisferische gebieden bij interne spraak gelinkt is aan de ervaring van een ‘echte’ stem. Hoewel de linker hemisfeer lang werd gezien als de taal-hemisfeer, is gebleken dat de rechter hemisfeer ook een beperkte capaciteit heeft voor taalproductie. Bovendien is de perceptie van nietlinguistische aspecten van taal (prosodische kenmerken, niet-letterlijke taal, etc.) een functie die ondersteund wordt door de rechter temporale regio’s. Het is dus mogelijk dat hallucinaties hun oorsprong vinden in spontane activiteit in gebieden die betrokken zijn bij interne spraak, en dat de abnormale co-activatie van gebieden in de rechter hemisfeer deze interne spraak als het ware verrijken waardoor het uiteindelijke percept moeilijker te onderscheiden is van een externe stem. De studies gerapporteerd in hoofdstukken 5.1. en 5.2. ondersteunen een populair idee in de literatuur, namelijk dat interne spraak een proces is dat in belangrijke mate bijdraagt tot het ontstaan van AVH. Een aantal zaken vereisen echter nog verdere opheldering. Toekomstig onderzoek zal moeten uitmaken waarom patiënten met schizofrenie ook gewone interne spraak hebben. Men kan zich de vraag stellen

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waarom interne spraak in bepaalde situaties herkend wordt als een externe stem, en op andere momenten niet foutief wordt toegewezen aan een externe bron. Mogelijk spelen emotionele processen hierin een belangrijke rol. Vooral wanneer interne spraak een negatieve ondertoon heeft, zou deze door de persoon niet erkend kunnen worden als zelf-gegenereerd. In ieder geval lijkt het er dus op dat secundaire attributie-processen betrokken zijn bij het toekennen van een specifieke identiteit en betekenis aan de foutief geïnterpreteerde interne spraak.

Interventies met repetitieve Transcraniele Magnetische Stimulatie (rTMS) Uit het bovengaande blijkt dat er aanzienlijke evidentie bestaat dat (interne) spraakverwerkingsprocessen abnormaal verlopen bij stemmenhoorders. Het is dus ook niet verrassend dat de posterieure superieure temporale regio, een essentieel gebied voor de perceptie van spraakstimuli, werd geïdentificeerd als een cruciaal onderdeel van het neurale netwerk dat (over)geactiveerd is bij AVH (Allen, Aleman, & McGuire, 2007). Dit gebied werd dan ook voorgesteld als een gepaste kandidaat-regio voor de toepassing van rTMS (Hoffman et al., 2003). Wanneer rTMS toegepast wordt met een frequentie van 1 Hz, heeft het een inhiberende invloed op de onderliggende hersencortex (Pascual-Leone, Davey, Rothwell, Wassermann, & Puri, 2002). De techniek biedt dus een non-invasieve manier om direct in te grijpen op neurale processen, met als doel de vermindering van symptomatologie. De eerste studie die de toepassing van 1 Hz rTMs beoordeelde op het voorkomen van AVH had bemoedigende resultaten in drie patiënten met medicatie-resistente AVH (Hoffman et al., 1999). Twee van de drie patiënten rapporteerden bijna volledige afname van hun AVH gedurende ten minste twee weken. Een vervolgonderzoek in een uitgebreidere groep patiënten bevestigde deze eerste resultaten. Behandeling met rTMS bleek efficiënter dan placebo en leek vooral effect te hebben op de frequentie van AVH en in de aandacht die ze opeisen (Hoffman et al., 2000). Ondanks het feit dat niet alle daaropvolgende studies dergelijke positieve resultaten boekten, bleek uit twee recente meta-analyses dat 1 Hz rTMS ter hoogte van de linker superieure temporale gyrus/inferieure parietale regio effectief is in de behandeling van AVH. Hoofdstuk 6.1. beschrijft een studie waarin werd onderzocht of de toepassing van

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rTMS op de bilaterale temporo-parietale junctie (TPJ) de effectiviteit van de behandeling zou kunnen verhogen. Uit recente neuroimaging onderzoeken is namelijk gebleken dat niet alleen de linker hemisfeer, maar ook de rechter hemisfeer geactiveerd wordt bij AVH (Lennox, Park, Medley, Morris, & Jones, 2000; Shergill, Brammer, Williams, Murray, & McGuire, 2000; Sommer et al., 2008). Bovendien zijn er aanwijzingen dat de lateralisatie van taalactiviteit verminderd is bij patiënten met hallucinaties (Sommer, Ramsey, Aleman, Bouma, & Kahn, 2001; Sommer et al., 2001). Doordat de rechter temporale cortex een belangrijke rol speelt in de verwerking van emotionele prosodie en non-linguistische aspecten van taalverwerking, werd verondersteld dat rTMS toepassing in deze hemisfeer zou kunnen leiden tot een meer complete behandeling. Er werd met name verwacht dat ook de meer emotionele aspecten beïnvloed zouden worden. Zesendertig patiënten werden behandeld met ofwel rTMS van de linker TPJ, de bilaterale TPJ of placebo-stimulatie. De ernst van hun symptomen werd gemeten aan de hand van zelf-rapporteringsschalen, waaronder de Auditory Hallucination Rating Scale (Hoffman et al., 2003) en de Positive and Negative Affect Scale (PANAS). Verder werd elke patiënt vóór en ná behandeling beoordeeld aan de hand van de Positive en Negative Syndrome Scale (PANSS), door twee interviewers die blind waren t.o.v. de conditie waaraan de patiënt was toegewezen. Uit de zelf-gerapporteerde resultaten bleek dat alle drie de groepen enigszins verbetering vertoonden in termen van hallucinatie-frequentie, vooral in de vergelijking van de situatie 1 week na het einde van de behandeling ten opzichte van de baseline. De klinische beoordelingen lieten echter alleen in de actieve rTMS groepen een vermindering in de ernst van de AVH zien. De placebo groep bleef stabiel. Over het algemeen genomen leek de linker groep de beste respons te laten zien en kon er dus geen evidentie gevonden worden voor de hypothese dat bilaterale rTMS efficiënter zou zijn dan unilaterale rTMS. Wel bleek de bilaterale groep een verminderde emotionele respons te hebben op hun AVH ná behandeling met rTMS, wat de hypotheses ondersteunt dat de rechter hemisfeer mogelijk bijdraagt aan de emotionele saliëntie van de AVH. Gezien de kleine groepsgroottes, het optreden van opvallende placebo-effecten bij een aantal patiënten en het feit dat de geobserveerde verbetering gemiddeld genomen slechts matig was, moeten de conclusies van het

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onderzoek voorzichtig geïnterpreteerd worden. Verder onderzoek, bij voorkeur in grote groepen patiënten in een multi-center trial, is nodig om uit te maken hoe men de parameters kan wijzigen om een optimaal effect te bewerkstelligen. Een eerste interessante ontwikkeling is individueel aangepaste behandeling gebaseerd op structurele of functionele MRI beelden, waarbij het magnetische veld wordt gericht op de gebieden die specifiek bij dat individu betrokken zijn bij de AVH. Ten tweede zijn er aanwijzingen uit onderzoek naar de behandeling van depressie met rTMS, dat méér stimuli per dag aanleiding geven tot sterkere effecten (Gershon, Dannon, & Grunhaus, 2003). De meeste klinische trials bestonden uit een relatief klein aantal sessies en beperkten de stimulatie-intensiteit tot 90% van de motorische drempelwaarde. Aangezien 1 Hz rTMS een relatief veilige techniek is, zou een langdurigere en mogelijk ook intensere behandeling nieuwe perspectieven kunnen bieden. Het werkingsmechanisme dat aan de basis ligt van de geobserveerde verbetering in de symptomatologie blijft echter nog een groot vraagteken. Slechts een zeer klein aantal studies heeft aandacht besteed aan veranderingen in het neurale substraat ten gevolge van rTMS behandeling van AVH. Horacek et al. (2007) maakten gebruik van Positron Emission Tomografie (PET) en Low Resolution Braim Electromagnetic Tomography (LORETA) om het effect van rTMS op het hersenmetabolisme te meten tijdens rust, na een twee weken durende behandeling. Hieruit bleek dat rTMS leidt tot een lokaal verlaagd hersenmetabolisme in het gebied dat gestimuleerd wordt. Er werden echter ook secundaire effecten geobserveerd, met name een toename in metabolisme in de contralaterale cortex en meer frontale hersengebieden. Het lijkt er dus op dat rTMS naast plaatselijke inhiberende effecten, ook faciliterende effecten heeft via verbindingen over het corpus callosum, dat de twee hersenhelften verbindt. Een ander onderzoek bij 3 patiënten vond een toename en normalisatie van het patroon van hersenactiviteit tijdens een taaltaak na succesvolle behandeling met rTMS (Fitzgerald et al., 2007). In hoofdstuk 6.2. werd een studie gerapporteerd waarin werd onderzocht of rTMS behandeling invloed heeft op de functionele verbindingen van de gestimuleerde regio. Een subgroep van de patiënten die deelnamen aan de klinische trial (gerapporteerd in hoofdstuk 6.1.) ondergingen een rust-fMRI scan vóór en ná de behandeling. Deze zogenaamde ‘resting state fMRI scan’

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laat toe om hersenactiviteit te meten die niet wordt uitgelokt door een specifieke taak. Men veronderstelt dat deze intrinsieke hersenactiviteit bestaat uit processen zoals zelfreflectie, interne spraak, het ophalen van episodische geheugenfragmenten en mentale verbeelding (Gusnard & Raichle, 2001; Raichle et al., 2001; Greicius, Krasnow, Reiss, & Menon, 2003). Interessant is dat deze processen ook vaak worden genoemd als deficiënt bij patiënten die stemmen horen. Men zou dus kunnen verwachten dat AVH gerelateerd zijn aan ‘abnormale’ activatiepatronen tijdens deze rusttoestand. In de analyse van de rustscan werden de bilaterale temporo-parietale regio’s (TPJ) uitgekozen als zogenaamde ‘seed regions’. Vervolgens werden correlaties berekend tussen het activatiepatroon van deze regio’s en het activatiepatroon van een reeks ‘regions of interest’, die deel uitmaken van een netwerk dat betrokken is bij de verwerking en monitoring van interne spraak. Wanneer de patronen een gelijkaardige verloop kennen, wordt verondersteld dat ze functioneel met elkaar verbonden zijn. In eerste instantie werden verbindingen in dit netwerk vergeleken tussen een groep van 27 gezonde proefpersonen en een groep van 27 patiënten met AVH, vóór de behandeling met rTMS. Vervolgens werd ook binnen de groep van patiënten gekeken of de ernst van de AVH kon gelinkt worden aan bepaalde veranderingen in de verbindingen. Tenslotte werd onderzocht of de behandeling met 1 Hz rTMS invloed had op de verbindingen waarvan gebleken was dat ze een relatie vertoonden met de ernst van AVH. Uit de resultaten bleek dat activiteit in de linker TPJ, een belangrijk knooppunt in het neurale netwerk betrokken bij interne spraak en AVH, relatief verminderde synchronisatie vertoont met activiteit in gebieden die een functie hebben in aandacht en cognitieve controle, het verwerken van informatie die betrekking heeft op het ‘zelf’, en de herkenning dat een actie zelfgegenereerd is. Het potentieel van 1 Hz rTMS om deze abnormale patronen in functionele verbindingen te wijzigen, bleef echter onduidelijk. De verbindingen die in de correlationele analyses naar voren kwamen als gerelateerd aan de ernst van AVH bleken onveranderd na behandeling met rTMS, niettegenstaande er klinische verbetering werd geobserveerd. Daarom suggereerden we dat deze veranderingen in functionele verbindingen niet noodzakelijk direct gerelateerd zijn aan de hallucinerende status, maar eerder het neurale substraat vertegenwoordigen van de

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cognitieve predispositie voor hallucinaties. Verder onderzoek in grotere groepen, waarbij onderscheid gemaakt kan worden tussen patiënten die goed reageren op de behandeling en degenen die weinig of geen verbetering vertonen, zal nodig zijn om rTMS geïnduceerde effecten op functionele verbindingen beter te kunnen beoordelen.

Conclusies Er bestaat een lange onderzoekstraditie naar hallucinaties. Ontwikkelingen op het vlak van neurale beeldvorming hebben er voor gezorgd dat er in de laatste jaren een behoorlijke vooruitgang is geboekt in het onderzoek naar de (afwijkende) hersenprocessen die aan de basis liggen van AVH. Het onderzoek dat gerapporteerd werd in het huidige proefschrift had als doel bij te dragen aan het groeiende begrip van de cognitieve en neurale basis van AVH bij patiënten met schizofrenie. De resultaten wijzen erop dat hallucinaties resulteren uit stoornissen in de perceptie van spraak en in de vaardigheid om echte van ingebeelde gebeurtenissen te onderscheiden. Personen met een neiging tot hallucineren nemen mogelijk (te) snelle en overtuigde beslissingen over (de bron van) hun waarnemingen, op basis van beperkte informatie. Bovendien blijkt dat de waarneming bij deze individuen in sterkere

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beïnvloed

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door

contextfactoren

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verwachtingen en mentale verbeelding. Verder werd ook de link gelegd tussen cognitieve processen en veranderingen in het neurale substraat. In de literatuur heeft vooral het netwerk van spraakverwerkingsgebieden veel aandacht gekregen in de literatuur. Ook in dit proefschrift werd evidentie gerapporteerd dat AVH gerelateerd kunnen worden aan structurele en functionele wijzigingen in gebieden betrokken bij de productie, perceptie en het monitoren van interne spraak. Desalniettemin, mogelijk door hun inherente subjectieve karakter en het feit dat veel onderzoeken noodzakelijkerwijs gebaseerd zijn op rapporteringen van patiënten zelf, blijven hallucinaties een vrij ongrijpbaar fenomeen. Vele individuele studies hebben verschillende aspecten van de onderliggende werkingsmechanismen bloot gelegd, maar een alomvattend en volledige empirisch getoetst model blijft vooralsnog uit. Het belang van de wetenschappelijke interesse in de zoektocht naar

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de oorzaken en kenmerken van dit fenomeen wordt onderschreven door het feit dat vooral in het geval van medicatieresistentie - hallucinaties een belangrijke bron van subjectief lijden zijn. Om nieuwe en meer efficiënte behandelingen te ontwikkelen zal het nodig zijn om het begrip van hallucinaties verder uit te breiden op het niveau van sociale, psychologische en biologische determinanten en deze verschillende niveaus te koppelen in een integrale aanpak.

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Het dankwoord is misschien wel het meest gelezen hoofdstuk van eender welk proefschrift. Vandaar dat dit stuk met gepaste zorg en aandacht werd geschreven. Mocht ik onverhoopt toch nog iemand vergeten zijn, blame it on my head and not my heart, zoals ze zeggen.

Als eerste wil ik mijn promotor, Prof. André Aleman, bedanken. André, hoewel ik geen ervaring had met onderzoek naar psychiatrische stoornissen, toonde je wel meteen vertrouwen in mijn vaardigheden om dit project tot een goed einde te brengen. Jouw enthousiasme werkte bovendien erg aanstekelijk. Steeds stond ik versteld van jouw enorm uitgebreide kennis over ons vakgebied. Ik heb het ook erg gewaardeerd dat jij ons als PhD studenten maar wat graag op pad stuurde naar interessante congressen op exotische locaties ☺. Over het algemeen kijk ik terug op een geslaagde 4 jaar, ook al gaat een PhD traject gepaard met ups and downs. Ik zal vast niet zo snel zo’n imposant CV en zo’n lijvige publicatielijst als jij bij elkaar sprokkelen, maar jouw succes als (nog steeds jonge!) onderzoeker is een voorbeeld voor beginnende wetenschappers zoals mezelf. Bedankt daarvoor! Mijn co-promotor, Dr. Henderikus Knegtering, heeft zeker ook mijn dank verdiend. Beste Rikus, jij werd eigenlijk pas echt concreet betrokken in het laatste jaar van mijn promotietraject. Maar ik heb ontzettend veel gehad aan jouw suggesties. Jij las mijn manuscripten meteen door en voorzag ze van inzichtelijke commentaar, en dat gaf mij echt het gevoel dat je het werk belangrijk en interessant vond. Mijn oprechte dank voor je bijdrage en veel succes met je nieuwe baan bij Lentis. Ik denk dat iemand als jij zeer belangrijk is voor het bouwen van een brug tussen de klinische praktijk en de onderzoekswereld! En natuurlijk ook bedankt voor de gezellige sociale momenten tijdens congressen en bijeenkomsten! Graag wil ik de leesscommissie, Prof. R.J. Van den Bosch, Prof. G. Vingerhoets, Prof. W.H. Brouwer & Prof. D.J. Veltman bedanken voor de snelle beoordeling van het proefschrift. Guy, jou wil ik ook nog even apart bedanken, omdat jij degene was die me aan André voorstelde ☺. Ik bewonder ook jouw brede wetenschappelijke interesse, en mede daardoor heb een super leuke en interessante stage gehad in het

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UZ Gent, wat mij toch echt geïnspireerd heeft om verder te gaan in het neurowetenschappelijk onderzoek. Merci! Tijdens het onderzoek is een zeer aangename en vruchtbare samenwerking ontstaan met een hele groep mensen van het Universitair Centrum Psychiatrie (UCP): Hanneke Westenbroek, jou wil ik bedanken omdat je altijd tijd vrij wilde maken voor het recruteren van deelnemers en intake gesprekken met TMS-kandidaten. Samen met de gemotiveerde mensen van de verpleging op PSP2 (echt geweldig!) heb je er voor gezorgd hebt dat ‘mijn’ patiënten niets tekort kwamen en zich op hun gemak voelden tijdens hun verblijf. Binnen het UCP hebben ook Richard Bruggeman, Jack Jenner en Hans den Boer een niet te onderschatten rol gespeeld voor het TMS onderzoek. Jullie enthousiasme en vertrouwen hebben de studie echt een steun in de rug gegeven. Ook Cees Slooff, Lex Wunderink en Hans Klein (resp. GGZ Drenthe, Friesland en Groningen) wil ik van harte bedanken voor hun inzet bij het recruteren van TMS-kandidaten en hun verdere bijdrage aan de TMS studie en de publicatie die daaruit volgde. Marieke van der Werff, bedankt voor het coördineren van alle lopende studies. Dankzij jou verliep de recrutering en het inplannen van patiënten echt een stuk efficiënter! Graag wilde ik ook Leontien Wubbema, en de overige dames van het secretariaat van de psychosencluster bedanken voor de ondersteuning. Pieter-Jan Mulder, bedankt dat ik gebruik mocht maken van jouw PANSS-expertise. De cursus en de consensusbesprekingen waren erg nuttig en vaak ook heel gezellig! Verder heb ik ook veel gehad aan de SCAN-cursus, en daarvoor wilde ik Fokko Nienhuis graag even in de bloemetjes zetten. Mijn eerste stapjes in fMRI-land werden begeleid door een aantal mensen van het NIC, die door hun expertise en enthousiasme hebben geholpen om de verschillende fMRI projecten in goede banen te leiden. Anita en Judith, bedankt voor de technische en inhoudelijke ondersteuning bij het scannen, en natuurlijk ook voor de gezellige babbel wanneer de proefpersonen braaf hun taakjes aan het uitvoeren waren ☺. Remco, bedankt voor het meedenken over de paradigma’s en de analyses. Het is één ding om te weten hoe zo’n ingewikkeld apparaat als een MRI-scanner werkt, maar nog wat anders om het uit te leggen aan een psycholoog…knap hoor ☺

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Dan natuurlijk ook dank aan mijn kamer-genootjes: Marjolijn, Marte, Lisette en Edith. Ik geloof dat wij bekend staan als de groenten- en fruitkamer, maar als PhD student moet je ook letten op je gezondheid, of niet ☺? Die vitamientjes konden we vaak goed gebruiken! Want wat hebben we allemaal hard gewerkt! Fijn dat we altijd bij elkaar terecht konden met wetenschappelijke en niet-zo-wetenschappelijke vragen, of om gewoon - onder het genot van een illegaal gezette kop Senseo-koffie bij te kletsen over PhD-motivatie-dips, publicatie-frustraties, oude liefdes, nieuwe liefdes, heropgelaaide liefdes, kinderen en stief-kinderen, enzovoort. Marte en Marjolijn, jullie in het bijzonder bedankt omdat jullie de belangrijke taak van paranimf wilden uitoefenen! Ook de andere ‘Cognies’: Ramona, Gemma, Katharina en Johan, Hedwig en Esther, Marieke en Branislava, bedankt voor de fijne samenwerking, de gezellige congresbezoeken en de interessante discussies tijdens onze Cognies-meetings en Journal Clubs. Ruud, jij ook in het bijzonder bedankt voor je paddestoelen-kennis ☺. Lotte, wat grappig dat mijn buurvrouw ook mijn collega bleek te zijn (of was het nou vice versa?). Veel succes verder met je eigen aio-carrière, en ook aan Yffie wens ik veel succes en vooral ook nog veel plezier samen! Tinie, Hedwig en Evelien, bedankt voor de secretariële ondersteuning. Jullie waren (en zijn!) de ruggegraat van het NIC en BCN. En voor de mensen van het BCN office (Britta, en later Nynke, Janine, Diana, Rob, en later Gerry): dank voor het organiseren van de interessante lezingen en symposia, voor de ondersteuning bij de administratie, maar ook voor de minder wetenschappelijke bijeenkomsten. Ik heb in de afgelopen 4 jaar ook veel hulp gehad van mijn stagiaires: Evelien, Anke, Kim en Sarah. Ik vond het erg leuk om met jullie samen te werken, en hoop dat ik jullie een leuk (maar realistisch ☺) beeld hebben gekregen van het neurowetenschappelijk onderzoek. En verder hebben ook onze flow-manager, en student-assistenten van de cognies groep natuurlijk fantastisch werk verricht. Bedankt, Betty, Leonie en Annerieke! Dank natuurlijk ook aan de andere ‘bewoners’ van het NIC, die misschien niet rechtstreeks of inhoudelijk betrokken waren bij mijn onderzoek, maar die wel hebben gezorgd voor gezellige lunches, koffie-en thee-pauzes, lekkere verjaardagstaarten

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(van Granny’s uiteraard!) en in het algemeen een toffe werksfeer. De dolle dolma dames krijgen een apart bedankje: Jojanneke, Harma, Marleen, Marte, Marjolijn & Hiske (see you down under!). Under het motto ‘all work and no play make Jack a dull boy’, heb ik me in de afgelopen 4 jaar ook met extra-curriculaire activiteiten bezig gehouden. Meer nog, ik vermoed dat ik zelf ondertussen opgenomen zou zijn in de psychiatrie, als ik niet af en toe de promotie-stress van me af had kunnen zweten op het frisbee-veld. Mijn allerhartelijkste dank gaat dus uit naar de bende van Gronical Dizziness! Misschien moet ik in eerste instantie vooral Marleen bedanken, want die heeft niet alleen mezelf, maar ongeveer het halve NIC aan het frisbee-en gekregen ☺. Lieve GD’ers, ik heb met heel veel plezier samen met jullie gefrisbee’d, en ge-BBQ’d, gequizzed enz, en in het algemeen gewoon ongelofelijk veel lol gehad. Terwijl ik dit schrijf hebben we nog een fantastisch Europees Kampioenschap in het vooruitzicht, waar ik erg veel zin in heb! Hopelijk wordt het een mooie afsluiter van mijn Groningse frisbee-carrière. Ik zal jullie missen! Wat zou het eenzaam zijn in het hoge noorden, voor een bourgondische Belgische, zonder mede-Nederbelgen? Nen dikke merci dus, Koen, Katrien, Lieselotte Isabelle en Tim, voor de gemeenschappelijke verbazing over broodjes-kroket uit de muur, patatjes oorlog, gesloten bakkers op zondagochtend, ranzige pinda-saus, onbegrijpelijke bureaucratische rompslomp (‘sorry, maar daar ga ik niet over’ ????) en andere gekke Hollandse gewoontes. Martijn, op dag 1 van mijn aanstelling op het NIC stelde jij voor om mij Groningen te laten ontdekken bij wijze van een kroegentocht…En in Café de Minnaar sloeg de vonk over ☺. Hoewel het uiteindelijk niet is gelopen zoals we gedacht of gehoopt hadden, zal mijn tijd in Groningen onlosmakelijk met jou verbonden blijven. Bon, jij dacht altijd dat ik eerder klaar zou zijn met mijn PhD dan jij…en je kreeg nog gelijk ook ☺. Veel succes met je nieuwe plannen, en met de kleine Wouter, die vast veel te snel groot wordt! Door naar Groningen te verhuizen heb ik in de laatste jaren mijn Belgische vriendjes en vriendinnetjes veel te weinig gezien. Het zal er niet echt beter op worden, helaas. Maar gelukkig is er Skype en webcams, en e-mail en facebook ☺. Kim en

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Isabelle, veel geluk samen en nog eens gefeliciteerd. Tof dat jullie er op mijn promotie bij zullen zijn. Sarah, ook al zien we elkaar niet vaak, je bent voor altijd mijn zon aan een koor-tje ☺. Kelly, misschien zal het er nu niet meer van komen om bij elke verjaardag samen te gaan eten, maar dan maken we het wel dubbel goed als ik weer in het land ben! Lili*, ook met jou houd ik een band, wherever… En om met een cliché te eindigen: last, but definitely not least wil ik mijn familie bedanken! Jullie zijn mijn grootste fans, hoewel het voor velen onder jullie niet helemaal duidelijk was wat ik nu precies de hele tijd zat te doen daar in Groningen. Iets met hersenen, toch ☺? Mams en Paps, bedankt voor jullie vertrouwen, en dat jullie me altijd mijn eigen keuzes laten maken, ook al brengt dit me nu naar de andere kant van de wereld…Steven, je kan er niet met de moto komen, maar kom je me toch bezoeken down under? Bedankt ook aan de rest van de familie, Oma, Moe en Va, de tantes en nonkels, neven en nichten, voor de gezellige, Bourgondische bijeenkomsten wanneer ik thuis was. Want thuis is toch nog altijd een beetje ‘onder de kerkentoren’ ☺.

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CURRICULUM VITAE

Ans Vercammen werd op 10 februari 1982 geboren te Herentals, België. Ze voltooide haar Humaniora opleiding aan het St.-Jozefinstituut (Herentals), in de richting Grieks-Wiskunde. In 2000 is ze begonnen aan de kandidaats-opleiding Psychologie aan de Universiteit Gent. Tijdens de licentiaatsfase koos ze voor de richting ‘Experimentele en Theoretische Psychologie’. In het laatste jaar van deze opleiding liep ze stage in het Laboratorium voor Neuropsychologie in het Universitair Ziekenhuis Gent. Daar was ze betrokken bij een studie rond de visuele herkenning van gebruiksvoorwerpen en een onderzoek naar de mogelijkheid om taal-lateralisatie te meten met behulp van transcraniële Doppler ultrasonografie. Haar master-scriptie betrof een serie experimenten waarin met behulp van Event-Related Potentials de rol van het werkgeheugen in eenvoudige responsselectie-processen werd onderzocht. In 2005 begon ze als Ubbo-Emmius bursaal aan de Rijksuniversiteit te Groningen, onder begeleiding van Prof. André Aleman. Het onderzoek richtte zich op de cognitieve en neurale basis van auditieve hallucinaties (‘stemmen horen’) bij patiënten met schizofrenie. Dit promotie-onderzoek, uitgevoerd in het BCN NeuroImaging Center, in samenwerking met het Universitair Centrum Psychiatrie, heeft uiteindelijk geresulteerd in dit proefschrift. In November zal ze als Postdoc aan het werk gaan in het Prince of Wales Medical Research Institute in Sydney, Australië, waar ze onderzoek zal doen naar de effectiviteit van een oestrogenen-therapie in de behandeling van schizofrenie.

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LIST OF PUBLICATIONS

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Peer-reviewed journals • Vercammen, A., Aleman, A. (2008). Semantic expectations can induce false perceptions in hallucination prone individuals. Schizophrenia Bulletin, June 17 (Epub ahead of print). • Vercammen, A., de Haan, E.H., Aleman, A. (2008). Hearing a voice in the noise: auditory hallucinations and speech perception. Psychological Medicine, 38(8):1177-84. Epub dec 13, 2007. • Vingerhoets, G., Vandamme, K. & Vercammen, A. (2008). Conceptual and physical object qualities contribute differently to motor affordances. Brain and Cognition, November 27 (Epub ahead of print). • Modinos, G., Vercammen, A., Mechelli, A., Knegtering, H. & Aleman, A. Structural covariance in the hallucinating brain: a voxel based morphometry study. (accepted for publication by The Journal of Psychiatry and Neuroscience, march 2009). • Vercammen, A. Knegtering, H., Bruggeman, R., Westenbroek, J.M., Jenner, J.A., Slooff, C.J., Wunderink, L. & Aleman, A. (2009). Effects of bilateral repetitive transcranial magnetic stimulation on treatment resistant auditory-verbal hallucinations in schizophrenia: A randomized controlled trial.Schizophrenia Research, August 12 (Epub ahead of print). Dutch journals • Vercammen, A. & Aleman, A. (2008). Auditieve hallucinaties in schizofrenie. Tijdschrift voor Neuropsychiatry en Gedragsneurologie, 2, 48-51. Manuscripts under revision or under review • Vercammen, A., Knegtering, H., Bruggeman, R. & Aleman, A. Perceptual characteristics of auditory-verbal hallucinations are associated with activation of the inner speech processing network. (Manuscript under revision) • Vercammen, A., Knegtering, H., den Boer, J.A., Liemburg, E.J. & Aleman, A. Functional connectivity of the temporo-parietal junction in schizophrenia: Hallucinations and TMS effects. (Manuscript under review) • Hoekert, L.M., Vercammen, A., Kahn, R.S., Knegtering, H. & Aleman, A. Aberrant attribution of emotional salience to neutral vocal and facial expressions predict symptomatology in schizophrenia patients. (Manuscript under review). Conference abstracts • Vercammen, A., Knegtering, H., Bruggeman, R. & Aleman, A. (2009). Subjective loudness of auditory-verbal hallucinations interferes with processing in th brain areas implicated in inner speech. Abstract presented as a poster at the 9 World Congress of Biological Psychiatry, Paris, France. • Vercammen, A., J. A. Jenner, J. A. Den Boer, C. J. Slooff, H. C. Klein, R. Knegtering, R. Bruggeman, D. Wiersma, A. Aleman (2009). Auditory-verbal hallucinations and mental imagery compete for shared neural resources: an fMRI study. Abstract presented as a poster at the International Congress on Schizophrenia Research, San Diego, USA.

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• Aleman, A., Liemburg, E.J., Knegtering, H., Bruggeman, R., Jenner, J.A., Curcic-Blake, B., Vercammen, A. (2009). Perceived reality and loudness of auditoryverbal hallucinations is associated with reduced connectivity between thalamus and auditory cortex: an fMRI study in schizophrenia patients. Abstract/Oral presentation at the International Congress on Schizophrenia Research, San Diego, USA. • Liemburg, E.J., Vercammen, A., Knegtering, H., Bruggeman, R., Jenner, J.A., Curcic-Blake, B. & Aleman, A. (2009). Abstract/Oral presentation at the International Congress on Schizophrenia Research, San Diego, USA. • Vercammen, A. (2008). Auditory-verbal hallucinations in schizophrenia: Cognition, brain and treatment. Oral presentation at the Cognitive Neuropsychiatry Conference, Antwerp, Belgium. • Vercammen, A., Knegtering, H., Jenner, J.A., Slooff, C., Westenbroek, H., Bruggeman, R., Aleman, A. (2008). Efficacy of bilateral rTMS over temporo-parietal cortex in reducing auditory hallucinations in schizophrenia. Abstract presented as a poster at the annual meeting of the Cognitive Neuroscience Society, San Francisco, USA. • Vercammen, A., Knegtering, H., Jenner, J.A., Slooff, C., Westenbroek, H., Bruggeman, R. & Aleman, A. (2008). Efficacy of bilateral rTMS treatment over the temporo-parietal cortex in reducing medication-resistant auditory hallucinations in schizophrenia. Schizophrenia Research, 98 Supplement 1, February 2008, p27. Oral presentation at the Biennial Winter Workshop on Schizophrenia and Bipolar disorder, Montreux, Switzerland. • Vercammen, A. de Haan, E.h. & Aleman, A. (2007). Hearing a voice in the noise: Increased top-down influence on the perception of words in patients with auditory hallucinations. Schizophrenia Bulletin, 33, p564-547. Abstract presented as a poster at the International Congress on Schizophrenia Research, Colorado Springs, USA.

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