by schizophrenics (Cohen and Servan-Schreiber, 1992), evidenced by studies using ...... [27] Goldberg, David; Benjamin, Sidney; Creed, Francis (1987)Psychiatry In ... [30] Goldstein, M; Deutch, A.Y. (1992) Dopaminergic mechanisms in the ...
A Partial Model Of Cognitive Dysfunction In Schizophrenia
Alastair Reid
MSc Dissertation Centre for Cognitive Science University of Edinburgh September, 1993 NIVER
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Contents 1 Introduction
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2 Schizophrenia In Brief 2.1 Symptomatology of schizophrenia : : : : : : 2.2 Predisposing, precipitating and genetic factors 2.3 Prognostic indicators : : : : : : : : : : : : : 2.4 Type 1 and Type 2 schizophrenics : : : : : :
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3 The Pathogenesis Of Schizophrenia 3.1 The dopamine hypothesis of schizophrenia : 3.1.1 Mechanism of action of neuroleptics 3.1.2 Dopamine in the CNS : : : : : : : 3.1.3 Other neurotransmitters : : : : : : 3.1.4 Role of dopamine in conditioning : 3.2 More recent dopamine hypotheses : : : : : 3.2.1 The new dopamine hypothesis : : : 3.2.2 Grace : : : : : : : : : : : : : : : 3.2.3 Deutch : : : : : : : : : : : : : : : 3.2.4 Csernansky et al : : : : : : : : : : 3.2.5 Bachneff : : : : : : : : : : : : : :
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4 Other Brain Abnormalities in Schizophrenia 4.1 Metachromatic Leukodysrophy (MLD) : 4.2 The hypofrontality hypothesis : : : : : : 5 Aspects of Cognitive Dysfunction 5.1 Linguistic Dysfunction : : : 5.2 Specific Tests : : : : : : : :
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6 The Neuropsychology of Schizophrenia: Gray et al’s Model
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7 The Prefrontal Cortex And Schizophrenia
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8 Working Memory And The Prefrontal Cortex 8.1 Working memory : : : : : : : : : : : : : : : : 8.2 The functions of the PFC : : : : : : : : : : : : 8.2.1 Neurophysiology : : : : : : : : : : : : 8.2.2 ‘Higher’ functions—a model : : : : : : 8.3 Localising working memory to the PFC : : : : 8.4 Defects in working memory and schizophrenia :
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9 Connectionist Modelling And Schizophrenia 9.1 Cohen and Servan-Schreiber : : : : : : 9.2 Hoffman : : : : : : : : : : : : : : : :
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10 Modelling The Prefrontal Cortex 10.1 Structure : : : : : : : : : : 10.1.1 Afferents : : : : : : 10.1.2 Efferents : : : : : : 10.1.3 Dopamine : : : : : 10.1.4 Interneurons : : : : 10.2 Cortical computation : : : : 10.2.1 Modelling neurons : 10.2.2 Loop dynamics : : :
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11 Discussion
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12 Acknowledgements
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1 Introduction The aim of this thesis is to attempt to synthesise a model of schizophrenia that relates the cognitive dysfunction to anatomic and physiological disturbances occurring in schizophrenics, and then to consider ways in which a neural network implementation of this model may be constructed. Neural networks may be seen as tools for the task of reconciling cognitive science with neuroscience, a task that many workers have viewed as worthwhile (see Changeux and Dehaene, 1989). Such a reconciliation does imply a particular philosophical stance, namely that it is possible to account for cognitive processes in terms of neuroscience. I will not dwell on this philosophical issue but will assume that such a reconciliation is both valid and desirable. My approach is from both the cognitive and biological levels, with the intention of synthesising facts from both levels into an integrated model. Schizophrenia provides a massive and challenging arena in which to construct models by virtue of the complexity of its cognitive and biological features. Dysfunction is seen to occur at both levels and therefore makes it suited to neural network modelling. Its great complexity, however, leads me to propose only a partial model. Another reason for modelling schizophrenia is that there is still much to be learnt about the biological disturbances that cause it. Within the medical and neuroscientific communities there is not a consensus of opinion on any aspect of the disease, from aetiology and pathogenesis to diagnosis and treatment. More recently, with advances in neuroscientific techniques, there have been a number of new proposals regarding the biological bases for the illness. The starting point for this thesis was Gray et al’s (1991) detailed account of the ‘neuropsychology of schizophrenia’. This is one of the first attempts at reconciling the biological features of schizophrenia with behaviour and although it focuses on behavioural rather than cognitive details it has really provided the background for my project. Gray et al led me in two directions; both towards the new hypotheses regarding dopamine and involvement of the prefrontal cortex in schizophrenia, and towards a consideration of the cognitive defects that occur in schizophrenia. Both areas are ‘active research fields’ and so it has been necessary to delve into a fair degree of detail in some places. The fact that there is not a concrete understanding of the biological mechanisms involved makes the project of computer modelling that much more relevant in that it provides a framework within which to test hypotheses. This is only true if the model has an adequate degree of biological plausibility.Neural networks provide a greater degree of biological plausibility than standard computational systems and are inherently dynamic models—a necessary feature for any potential model of a ‘process’ as complex as schizophrenia. Having discussed some aspects of the neuroscience and cognitive features of schizophrenia, I have proceeded via Gray et al’s model to show how a primary lesion in the prefrontal cortex may give rise to the observed symptoms of schizophrenia. I will suggest that the prefrontal cortex plays a coordinating role in an hypothesis-generating loop that accounts for the generation of appropriate responses in novel situations. It is proposed that a dysfunction of this loop gives rise to the positive symptoms of schizophrenia, while a direct failure of the prefrontal cortex is responsible for the negative symptoms. Finally, some consideration is given to the features that a neural network model may be expected to have and how these may be generated. I do not propose an explicit network architecture as time and space preclude this, but it is hoped that the outlines presented in this thesis provide a detailed foundation on which future modelling may be built. One final comment regarding schizophrenia is that in addition to being an appropriate subject for modelling and a direct benficiary from such modelling, it is also a very socially relevant subject. Schizophrenia is diagnosed in approximately one per cent of adults throughout the world and as well as being extremely debilitating is essentially incurable. Any advances in our understanding of this disease must be a good thing.
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2 Schizophrenia In Brief 2.1
Symptomatology of schizophrenia
Schizophrenia is classically divided into acute and chronic forms which essentially correlate with the type of symptoms displayed. The symptoms are divided into positive and negative (tables 1 and 2)(Goldberg 1987 et al). A predominance of the former would traditionally constitute the diagnosis of acute illness and a predominance of negative symptoms would imply chronic illness. In addition to the positive symptoms described there is a general motor over-activity seen in ‘acute’ schizophrenics. They are restless, often making repeated hand movements and pacing up and down, sometimes violent.
2.2
Predisposing, precipitating and genetic factors
Predisposing factors for schizophrenia include a pre-morbid schizoid (or anti-social or sociopathic) personality—shy, withdrawn, few friends or social contacts, eccentric behaviour; birth trauma, and month of birth—there is an increased incidence in those born in January, February and March in the Northern Hemisphere and a reciprocal peak in those born in June, July and August in the Southern Hemisphere. The incidence of schizophrenia has peaks at the 25-30yrs age range and a smaller one in the over-65’s. Precipitating factors include stressful life events in the three weeks preceding the onset of symptoms. Such events may be either desirable or undesirable and so can be seen as general environmental stressors. There is a fourfold increase in the chance of relapse if a patient returns to an environment where he/she receives a high level of negative ‘expressed emotion’, yet under-stimulation tends to exacerbate negative symptoms. Genetic factors have repeatedly been shown. The incidence of schizophrenia in the general population is roughly 1 per cent but for a person with an affected sibling or parent the incidence is 12 per cent, and for a child with two schizophrenic parents the incidence is 25 per cent. Monozygotic twin studies also support a role for genetic transmission, with a 50-60 per cent concordance between twins reared apart (i.e. different environments). This concordance rate is far too low for a simple autosomal inheritance model to be developed and implies an interaction between environment and genes. However the fact that genes do play a role in the evolution of the illness implies that there must be some physical abnormality underlying at least predisposition to schizophrenia.
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Prognostic indicators
The following are considered indicators of a poor prognosis i.e. a gradual worsening of negative symptoms: 1. 3. 5. 7.
Family history of schizophrenia 2. Schizoid personality Stressful home environment 4. Poor previous work record Gradual onset, no obvious precipitating event 6. Pronounced negative symptoms Absence of prominent affective or catatonic symptoms
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Positive Symptoms Reduced Contact With Reality: Disorders of thought possession (thought insertion/broadcasting/withdrawal). The conviction that one’s thoughts are not one’s own or are known to others, or are caused by others. Passivity phenomena: the belief that movements, feelings, impulses are generated or controlled by other people or forces. Hallucinations:
Thought echo: The experience of one’s own thoughts as being spoken aloud from the outside world. Auditory hallucination: Characteristically the patient hears him/herself referred to in the third person.
Disturbed Thinking:
Knight’s move/Derailment: A loosening of associations in speech causing disjointed nonsensical speech—essentially semantic errors. Neologisms: frequent use of invented words.
Delusions:
Primary delusions: Persistently held abnormal or bizarre beliefs held outside the context of normal societal values. Delusional perception(very characteristic of schizophrenia): Delusions occurring secondary to some other morbid process such as hearing voices. The perceptions are normal but are given delusional significance. This contrasts with secondary delusions, which occur in a variety of psychiatric conditions, and are an attempt by the patient to reconcile his/her strange experiences with the real world e.g. ascribing the cause of hallucinations to computers.
Emotional Disturbance:
Incongruous affect: Inappropriate outbursts of laughter or anger, sometimes in response to internal morbid experiences. Table 1:
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Negative Symptoms Poverty of Speech: The patient speaks little and shows reduced complexity of speech. Slowness of Thought and Movement Emotional Flatness:
An absence of normal modulation of mood with a lack of facial expressiveness and emotional responsiveness.
Loss of Volition:
Poor motivation to work, or to care for oneself in severe cases. This leads to a general underactivity and social withdrawal. This is worsened if living in an under-stimulating environment. Table 2:
2.4
Type 1 and Type 2 schizophrenics
The distinction between positive and negative symptoms is a very important one which has strong implications for any explanatory theory regarding the aetiology and/or pathology of schizophrenia. First it is important to state that ‘acute’ and ‘chronic’ are terms which have mainly temporal meaning in that the former is applied (as elsewhere in medicine) to a disease state of short duration, usually with a rapid onset and progression, and the latter to a more persistent and insidious condition progressing more slowly and lingering longer. Often the acute state may become a chronic state. In schizophrenia, which is diagnosed purely from symptoms, we have two distinct symptom sets which overlap. Thus patients may present initially with either negative or positive symptoms or a mixture of both which may or may not progress to the opposite symptomatology. However it is true that acute episodes of schizophrenia are comprised of predominantly positive symptoms and that chronic schizophrenics generally display a preponderance of negative symptoms, and because there are no ‘objective’ tests for schizophrenia the terms ‘acute’ and ‘chronic’ lack a physical definition and become aligned with ‘mainly positive symptoms’ and ‘mainly negative symptoms’. They are thus more loosely associated with their traditional temporal values and have no aetiological significance whatsoever. This makes them rather vague and useless terms. However most researchers into schizophrenia, at the neuroscience and the medical levels, continue to use them, causing some confusion. Crow (1980) introduced a new dichotomy: Type 1 vs. Type 2 schizophrenia (table 3) to help characterise the two potentially distinct disease-states. Most explanatory theories find it hard to reconcile the two symptom sets and so it may seem reasonable to say that there are two separate disease processes at work, although I shall argue otherwise. The three lines of evidence Crow used are: 1. that amphetamine-like drugs exacerbate positive schizophrenic symptoms but have little effect on negative symptoms; 2. that there are cognitive changes that resemble organic states (cf. dementia) associated with negative symptoms; and 3. that there are structural changes in the brains of patients with long-standing negative symptoms. More recent work seeks to reconcile the positive and negative symptom sets as arising from a single
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Type 1 Positive symptoms
Type 2 Negative symptoms
Associated with ‘acute’ schizophrenia
Associated with ‘chronic’ schizophrenia
Good response to typical neuroleptics
Poor response to typical neuroleptics
Reversible disease-state
Irreversible disease-state
No intellectual deficit
Sometimes intellectual deficit
Postulated aetiology: due to increased dopamine receptors
Postulated aetiology: due to cell loss and structural changes in the brain
Table 3: pathological mechanism—I shall discuss some such theories in the following sections but one outcome of the new theories is that the acute vs. chronic dichotomy has become even more meaningless. I propose to stick to Crow’s terms using Type 1 and Type 2 as names for the two disease-states.
3 The Pathogenesis Of Schizophrenia 3.1
The dopamine hypothesis of schizophrenia
The basic Dopamine Hypothesis of schizophrenia rests on several pieces of evidence: 1. Possibly the most important fact is that all anti-psychotic drugs (neuroleptics) act by blocking central dopamine D2 receptors. 2. Long-term use of typical neuroleptics (i.e. haloperidol and related drugs) can cause a Parkinsonian type of state with a shuffling gait and repetitive and pointless motor actions (tardive dyskinesia— Parkinson’s Disease arises from underactivity of the nigrostriatal DA pathway. 3. There is an increase in the number of post-synaptic D 2 receptors in the neostriatum, in particular the Nucleus Accumbens (NAcc.) and Ventral Pallidum (VP), in the brains of schizophrenics at post-mortem. The mesolimbic dopaminergic pathway has traditionally been implicated because of the involvement of NAcc. 4. Dopamine agonists such as amphetamine, L-DOPA and phencyclidine (PCP), and possibly cocaine also, can induce acute psychotic states indistinguishable from Type 1 schizophrenia in normal individuals. PCP can also induce negative symptoms. 5. The above drugs exacerbate the positive symptoms of schizophrenia, though amphetamines have little effect on negative symptoms. The hypothesis is that there is overactivity in the mesolimbic DA system of schizophrenics. This rather basic hypothesis fails to account for much of the symptomatology of schizophrenia and various other anomalies such as the two week time lag between administration of neuroleptics (and 7
concomitant anti-psychotic action) and measurable changes in DA concentration, or the lack of change in DA concentrations in the brains of chronically treated schizophrenics, or the enlargement of lateral ventricles that has consistently been observed. These objections to the basic hypothesis are not new but more recent work has provided more detailed information regarding the neurochemistry and neurophysiology of the brain and with it new theories pertaining to schizophrenicpathology. I will review some of the more recent findings regarding neurochemical changes in schizophrenia before moving on to extensions of the basic dopamine hypothesis. 3.1.1
Mechanism of action of neuroleptics
Neurolpetics are now categorised into typical and atypical, haloperidol being an exemplar of the former and clozapine an exemplar of the latter. There are some significant differences between the two classes: not all patients respond to haloperidol but virtually all do to clozapine; haloperidol is much more likely to cause extrapyramidal side-effects (e.g. tardive dyskinesia); clozapine has some action against negative symptoms whereas haloperidol has none. The main mode of action of neuroleptics is to cause a prolonged depolarisation blockade of D2 receptors in the striatum. The two main DA projections in the mid-brain are from the zona compacta of the substantia nigra (A.9) to the dorsal striatum (nigrostriatal path) and from the ventral tegmental area (VTA or A.10) to NAcc and the PFC (mesolimbic path). The locus of activity for anti-psychotic effects of both class of neuroleptic appears to be the shell region of the NAcc. (Deutch at al, 1992). Meshul et al (1992) also found that haloperidol acts on accumbal and striatal DA terminals while clozapine has an effect only on accumbal DA. Another study (See et al, 1992), examining chronic use of haloperidol has shown that the basal levels of DA in the extra-cellular fluid (ECF) of both the striatum and NAcc. are normal but there is an increase in dopaminergic metabolites (DOPAC) in striatal ECF but not NAcc. ECF. This implies that chronic use of haloperidol increases turnover of DA in the nigrostriatal path but not the mesolimbic. This has been borne out by Moghaddan and Bunney (1993). Buschbaum et al (1992b) were investigating the striatal metabolic rate in relation to response to haloperidol and showed that schizophrenics with an initially low rate (as measured by PET scans showing glucose uptake—an indication of terminal rather than cell body activity) responded to haloperidol much better than those with an initially normal rate. The responders also showed an increase in striatal metabolic rate to roughly normal, while non-responders showed no change in metabolic rate. Accordingly Essig and Kilpatrick (1991) have shown an increase in DA synthesis/metabolism in the striatum as an acute response to neuroleptics. Buschbaum et al (1992a) also found that there was diminished metabolism in the basal ganglia of never-medicated schizophrenics.Interestingly, amphetamine has been shown to reduce striatal metabolic rate (cited in Buschbaum et al, 1992b) The conclusions that may be drawn from the foregoing are: first, that the involvement of DA in the pathogenesis of schizophrenia is not a simple case of ‘hyperdopaminergia’ which is treated by giving DA-reducing drugs; second, that if the shell of the NAcc. is a locus for the anti-psychotic (i.e. anti-positive symptoms) action of neuroleptics, then it is probably implicated in the generation of such symptoms; and finally that a reduction in striatal metabolism appears to be related to psychosis in schizophrenia. 3.1.2
Dopamine in the CNS
The action of DA within the CNS is complex and has not been clearly defined; most work has been done on the role of DA within the striatum. It is important to mention the fact that mesocortical DA neurons have the following features which contrast with mesolimbic and nigrostriatal DA neurons: reduced sensitivity to agonists and antagonists, lack of tolerance, and resistance to depolarisation-
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induced inactivation caused by chronic neuroleptic treatment (Bachneff, 1991). This provides more evidence for the striatum having a role in the genesis of positive schizophrenic symptoms. The main origin of the DA system in the CNS is in the A.9 and A.10 areas previously mentioned, where there is a co-localisation with either cholecystokinin (CCK) and/or neurotensin (NT) (i.e. these are found in neurons with DA). Afferents to the A.10 area (VTA) are of three main types: dopaminergic, forming a short negative feedback loop; GABA’ergic, forming a long negative feedback loop; and excitatory amino acids (EAA’s) from various regions, in particular the PFC. The latter inputs act on NMDA receptors and provide the primary depolarising stimulus for generation of burst-firing. PCP and related drugs act here by increasing the firing rate and amount of burst activity in the A.10 DA neurons (French et al, 1993). 1 DA is considered to be an inhibitory neurotransmitter, attenuating both inhibitory and excitatory post-synaptic potentials (IPSP’s and EPSP’s) (Pennartz et al, 1992). There are at least two types of DA receptor—D1 and D2. In the striatum there is evidence that stimulation of D1 receptors potentiates the functioning of D2 receptors and also that there are discrete populations of D 1 receptors and D2 receptors with very few both present on the same striatal cell. There are also DA autoreceptors which respond to the ECF DA that exists at low levels at dopaminergic terminals, these are thought to be D2 receptors since D1 autoreceptors are 1000 times less sensitive and the ECF level of DA would not be high enough to activate them. The highest levels of D1 receptors found in the brain as a whole are found in the caudate-putamen and NAcc., which suggests a role in the modulation of motor activity, probably post-synaptic (Fremau et al, 1991). The role of ECF DA is crucial to Grace’s recent DA hypothesis (cf. section 3.2.2). 3.1.3
Other neurotransmitters
There are several major neurotransmitter systems within the CNS—DA, noradrenaline, acetylcholine; and there are also a large number of other neurotransmitters that interact with these systems and increasingly seem to play a vital role in modulating the major systems, the neuropeptides are particularly important here, as are GABA’ergic neurons. The neuropeptides include CCK and NT both of which are co-localised with DA neurons in the VTA. CCK also acts to distinguish various sub-populations of GABA interneuron (also known as local circuit neurons or LCN’s) in the PFC. GABA neurons are considered to be exclusively inhibitory and constitute the majority of interneurons within the brain. The EAA’s, in particular glutamate, are very important in the control of parts of the DA system. A faintly philosophical point is in order here. In general neurotransmitters add another layer to the functional complexity of the brain. There are at least three intersecting dimensions to be investigated, those of neuroanatomy, neurophysiology, and now neuropharmacology. It is impossible to describe specific functions in terms of only one or two of these factors, and conversely it is unlikely that any of the elements within these dimensions has a precise function at the behavioural level. Consequently it makes little sense to ascribe ‘whole organism’ functions to specific neurotransmitter systems. However, each system has certain distinctive physical characteristics and its own tree of distribution and so at some level it does make sense to talk of the functional specialisation of parts of a system. For example, in investigating the mesolimbic DA system we find that it may be a substrate for behavioural conditioning. 1
For a very comprehensive review of the factors controlling VTA DA activity see Kalivas, 1993.
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3.1.4
Role of dopamine in conditioning
Having described very sketchily some of the physical characteristics of the DA system it is now useful to consider some of the functional aspects. There is an expanding body of data implicating DA and the NAcc. as the ‘prime movers’ in the process of conditioning. The PFC is also involved, according to Deutch (1993), through distinct DA innervations that “can be functionally dissociated on the basis of responsiveness to stress”. The stress sensitive region of the PFC projects to the NAcc. shell region, which is also responsive to stress. Mild footshock (or stress) in rats is seen as conditioned fear, and increases DA metabolism in the PFC, but not the NAcc. (Deutch, 1993). More prolonged stressing causes activation of the A.10 DA system, which innervates both NAcc. and the PFC. If DA and the NAcc. are involved in conditioning we would expect neuroleptic drugs to cause a reduction in the extent of conditioning. This is very definitely the case, for example Jones and Robbins (1992) found that with a 90 per cent reduction in DA at the NAcc. there was a reduction in spontaneous motor activity of rats and attenuation of the conditioned locomotor response to food. Young et al (1993) also found reduced conditioning proportional to the dose of neuroleptic given and the opposite effect when amphetamine was given.The latter workers also noted an increase in conditioning when a neuroleptic was injected directly into the principal sulcus (PS) of the PFC. This would imply an inhibitory role for DA in the PFC (as in the striatum and elsewhere). Feldon and Weiner (1992) and Young et al (1993) have looked at the effects of neuroleptics and amphetamines on latent inhibition—an effect whereby pre-exposure to a particular conditioning stimulus on its own delays subsequent learning of the appropriate response to that stimulus. This is a measurable effect in rats and is found to be lost when amphetamines are injected into the NAcc. of rats, when normal subjects are given amphetamines, in Type 1 schizophrenics, and in untreated male rats raised in an under-stimulating environment. All the above losses are reversed by neuroleptics. So we have a link between schizophrenia, conditioning and the mesolimbic and mesocortical DA systems. It would appear that a stressful event causes release of DA in the NAcc. and PFC from ascending VTA afferents. This assists in classical conditioning and causes a loss of latent inhibition. Loss of latent inhibition can be seen as an inability to ignore irrelevant stimuli, or a failure of selective attention and from the above appears to be related to some sort of hyperdopaminergic state within the mesolimbic DA system. It is now time to look at some recent theories of the dysfunction of the DA system in schizophrenia, in particular that of Grace.
3.2 3.2.1
More recent dopamine hypotheses The new dopamine hypothesis
Grace (1991, 1993) has introduced a novel and potent hypothesis to account for the various conflicting results that arise from the basic dopamine hypothesis. Grace and others (Deutch ,1992; Csernansky et al, 1991) have suggested that the major defect in schizophrenia is in the cortical regulation of subcortical DA systems thus reconciling defects in the PFC with dopaminergic abnormalities. I will call the idea that a dysfunction in the regulation of the subcortical DA system is responsible for the generation of at least the positive symptoms in schizophrenia the new dopamine hypothesis. 3.2.2
Grace
In his 1991 paper Grace introduces a two tier concept to account for the dynamics of DA release in the striatum. This system is composed of a tonic and a phasic component to DA release. The tonic release of DA occurs in response to glutamate (GLU) from PFC afferents acting pre-synaptically on NMDA 10
receptors and is spike-independent. DA released in this manner is thought to underlie the basal ECF DA in subcortical structures. Changes in this background level should trigger homeostatic mechanisms to restore the correct balance and so by regulating this background level corticostriatal afferents will modulate the sensitivity of the tonic DA receptors. This in turn will bring about homeostatic changes that will alter the responsivity of the whole DA system and thus modulate the amplitude of the phasic DA response. The phasic response is a transient DA release produced by the burst firing of DA neurons. It is a brief but large amplitude pulse that activates post-synaptic receptors and is rapidly removed from the synaptic cleft by the fast high-capacity re-uptake systems before any homeostatic mechanisms are initiated. The way in which the tonic DA modulates phasic DA must be via autoreceptors which, as mentioned previously, would be D2 receptors. A decrease in the activation of these autoreceptors would potentiate impulse-dependent phasic DA release. If the decrease in tonic DA is maintained then the ultimate outcome would be: 1. an increase in DA synthesis (as a homeostatic response); 2. an increase in the number of D2 receptors; and 3. sprouting of DA axons. These changes would maintain a stable level of tonic DA but would cause an up-regulation of the phasic DA response. Now the release of tonic DA is postulated to be triggered by GLU from the PFC, and it is noted (Grace, 1993; Youngren et al, 1993) that in the NAcc. the prefrontal cortical GLU neurons synapse on the same dendritic spines as the dopaminergic VTA afferents, and also the glutamatergic afferents from the hippocampus, in the NAcc. It has also been shown that DA inhibits GLU release from GLU terminals in the dorsal striatum (though no data exists for the NAcc. as yet) (Gray, 1991 pg.6). If there was a sustained reduction in the excitatory prefrontal input then this could produce the scenario envisaged above—an up-regulated phasic DA system that responds to environmental stressors with increased frequency and amplitude of burst firing. Grace considers the dynamic range of the phasic DA system to be extended at both ends in the schizophrenic, with positive symptoms being generated by a low tonic-high phasic combination. This ties in with the various observations regarding amphetamines, PCP and neuroleptics. He claims, however that negative symptoms “are best correlated with tonic DA levels, with severely depressed tonic DA leading to the emergence of negative symptoms”. I find this hard to reconcile with the foregoing theory unless it is taken to mean an absolute reduction in the level of DA in the NAcc, in other words a hypodopaminergic state, but how this arises is unclear. It is also unclear precisely how the positive symptoms arise from a hyperdopaminergic state. These criticisms notwithstanding, Grace’s mechanism does provide a potential common path for the generation of psychoses in the limbic striatum. It is also worth noting that although the major factor in reducing tonic DA is very likely to be a reduced GLU input the origin of this input is not clear. I will make the case for the primary lesion to reside in the PFC, however the hippocampus, temporal cortex and amygdala also provide glutamatergic inputs to the NAcc.
3.2.3
Deutch
Deutch (1993) also believes that the main defect lies in the PFC. He cites evidence for distinct parallel cortico-striato-thalamic circuits (see also Groenewegen et al, 1990) and claims that these are functionally different. He describes a ‘mild stressor’ circuit and a ‘prolonged stressor’ circuit (see figure 1) both of which are affected in schizophrenia—the former is more associated with the limbic system and the latter with the dorsal striatum. His main thesis is that there is a functional deafferentation of the PFC which results in an increase in subcortical DA tone, in keeping with Grace’s hypothesis. He believes that there is a reduction in dopaminergic terminals in the PFC which would reduce inhibitory effects on the glutamatergic pyramidal cells, which in turn would cause an increase in subcortical DA 11
PFC Infralimbic
PFC Anterior Cingulate
NAcc. Shell
NAcc. Core
VP dorsolat.
VP ventromed.
Subthalamic Nucleus
Lat Hypothalamus
SN (A.9)
VTA (A.10)
Figure 1: Parallel Cortico-striato-thalamic Circuits if subcortical DA is released in a simple fashion—against Grace’s hypothesis. Deutch assumes an increase in GLU in the NAcc. which has been demonstrated under stress but not in schizophrenics; he also cannot account for the increase in D2 receptors in schizophrenia since an increase in GLU in the NAcc. would, if anything, cause a decrease in D2 receptors. 3.2.4
Csernansky et al
Csernansky et al (1991) postulate that an increase in and disorganisation of ‘activity’ triggers a series of changes in subcortical DA transmission. They postulate the following train of events: increased activity in the limbic circuit (which is activated by hippocampal excitation and inhibits ongoing behaviour) causes an increase in GLU to the NAcc.; this is intended to reduce DA release from this site (contra Grace’s theory)—the reasoning here is that although GLU acting directly on the NAcc. causes an increase in the release of DA, glutamatergic projections to the VTA are relayed via GABA neurons thus inhibiting release of DA from the VTA neurons i.e. reducing the level of DA at NAcc.; there is a consequent up-regulation of post-synaptic D2 receptors; and the final outcome is that environmental stimuli acting in the normal way to release DA cause an excessive DA effect due to the hypersensitive D2 receptors. This theory accords with Grace’s somewhat but there are several points that seem unacceptable. First, there is no evidence to suggest that the excitatory pre-synaptic action of GLU on the NAcc. terminals is out-weighed by the reduction in DA release by the GLU-GABA relay to the VTA. Second, there are also direct excitatory inputs to the VTA acting on NMDA receptors as well as the GABA mediated inputs (Kalivas, 1993), thus there is a direct burst-firing action from the GLU inputs—in fact one study (Kalivas and Duffy, 1991) concludes that somatodendritic (i.e. in the NAcc in this case) and axonal (i.e. VTA-initiated) release of DA are both affected by the same factors, the former being less influenced by axon-potential generation than the latter. Finally, this theory does not explain the reduced levels of GLU in the CSF of schizophrenics. The proposition that the primary 12
deficit is in the neuronal cytoarchitecture of the limbic system (more specifically in the hippocampus and amygdala), which is the proffered explanation for the increased activity, does remain a possibility. If the disorganisation led to a reduction in activity then we could apply Grace’s theory directly to the result. This is a re-iteration of the problem of deciding where the primary deficit lies (if there is just one deficit) in the face of the fact that several neuronal structures seem to be affected in schizophrenia. 3.2.5
Bachneff
Turning to Bachneff (1991) we have another slant on the familiar theme. Bachneff has reviewed a large number of PET and MRI studies up to 1990. He concludes that although there is convincing evidence of brain atrophy in schizophrenia there is little concord on where the ‘primary’ lesion lies and also that the relation between this atrophy and schizophrenic symptoms remains unknown. He finds that the MRI and PET evidence does implicate DA and the cerebral structures containing the DA systems. In reviewing neuropathology data in conjunction with the MRI and PET data he then states that the absence of gliosis in the affected cortical areas suggests that the nature of the disorder in schizophrenia is not an on-going degenerative process but rather a genetic or neurodevelopmental problem—in agreement with other data including monozygotic twin studies. He also states that observed hippocampal and para-hippocampal atrophy may be an incidental finding and secondary to the action of stress-induced glucocorticoids, to which these structures are particularly vulnerable. This point is strengthened when we bear in mind the growing acceptance of the involvement of stress mechanisms in schizophrenia. His ultimate conclusion is that there is a dysfunction involving the interneurons (or LCN’s) of the PFC and temperolimbic areas. I will return to consider the details of his hypothesis when discussing the other brain abnormalities that occur in schizophrenia, having focused mainly on dopaminergic aspects so far.
4 Other Brain Abnormalities in Schizophrenia So far I have focused mainly on the dysfunction of dopaminergic mechanisms in schizophrenia so now I would like to like to look at some other brain abnormalities in schizophrenia, in particular those relating to the hypofrontality hypothesis.
4.1
Metachromatic Leukodysrophy (MLD)
MLD is a rare disease which is often indistinguishable from Type 1 schizophrenia in its initial stages (Hyde et al, 1992). It is a demyelinating disease which typically has an onset in early adult-hood characterised by auditory hallucinations, bizarre delusions and other psychotic symptoms but which then progresses to sensorimotor loss and dementia—at which point the psychotic symptoms are lost. The demyelination results in a loss of periventricular and callosal white matter, in other words there is a loss of subfrontal white matter which would suggest a loss of cortico-cortical and cortico-subcortical connections. This loss of subfrontal white matter is noted in genetically predisposed juveniles long before the psychosis develops, which may be explained by requiring further normal developmental changes in cortical and/or subcortical architecture to occur before this loss is reflected as a functional deficit, or merely be due to progression of the demyelination past a critical deficit threshold. In either case it suggests that there is a threshold limit to the number of connections required for normal functioning, and below that threshold psychotic behaviour is generated. It is interesting to compare MLD with prefrontal leukotomy. The latter is acute, completely excommunicates the frontal lobe and does not usually produce psychotic behaviour, in contrast with 13
the former. The fact that excessive demyelination in MLD or total excommunication by leukotomy do not produce psychosis implies that there is another threshold limit on the number of connections below which psychotic behaviour ceases and more basic functions are affected i.e psychosis requires a minimum degree of normal functioning. Hyde et al conclude that: “psychosis can result from and perhaps depends on dysfunctional connectivity between certain extrafrontal and subcortical structures...” which agrees entirely with the new dopamine hypothesis and implicates a loss of frontal connections, including prefrontal connections. Hoffman and Dobscha (1989) make good use of this MLD data in their network simulations of the positive symptoms of schizophrenia (see section 9.2
4.2
The hypofrontality hypothesis
The idea that the frontal cortex is involved in the pathogenesis of schizophrenia has been around since Kraeplin first described the symptoms of the illness in 1914. With the advent of PET, CT, rCBF (regional Cerebral Blood Flow) and now MRI scanners it has been possible to study the anatomy and certain functional parameters of the neocortex in vivo. The large variation in the protocols of the various scanning studies of schizophrenics brains means that results often appear to conflict with each other (for a review of studies up to 1990 see Bachneff, 1991 and Andreasen et al, 1992) —however there are some fairly consistent findings amidst the confliction. One of these is that there is an underactivity in the frontal cortex, especially when performing frontal lobe tests, in particular the WCST which has been localised to the dorsolateral region (or Principal Sulcus (PS)) of the PFC [7/94]. This underactivity is the basis of the hypofrontality thesis, and there is clearly an interaction between this and the new dopamine hypothesis—namely that underactivity in the PFC would lead to a reduction in afferent activity to the NAcc. thus causing an up-regulation of accumbal D2 receptors and hyperdopaminergic effects. Other recent studies also provide support for the hypofrontality hypothesis (Buschbaum et al, 1992; Andreasen et al, 1992; Wolkin et al, 1992; Nakagawa et al, 1991). All of these studies ruled out neuroleptic effects as the cause of the hypofrontality. Ebmeier et al show hypofrontality, especially of the PFC, in acute actively psychotic unmedicated patients—an important study since this is a very rare sample population. It also indicates that hypofrontality is not solely associated with negative symtpoms, although there is significant support for a positive correlation between hypofrontality and negative symptoms. There is also a large amount of evidence relating reduced performance on various tests of cognitive function by schizophrenics and underactivity of the frontal lobes, especially the PFC. In the next section I will discuss some of the tests used to assess cognitive function and show that schizophrenics perform poorly on these. Liddle (1992) has shown that the anterior cingulate is most activated during the suppression of competing responses during the stroop test, linking the limbic cortex with contextual effects in a manner that would fit with Gray et al’s model. Others have found that willed action in normals causes an increase in rCBF that is specific to the PFC—willed action is simulated by asking subjects to make a deliberate choice. This ties directly with the reduced PFC function and perseveration noted in schizophrenics. It also attributes to the PFC the role of intentionality,
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5 Aspects of Cognitive Dysfunction The cognitive abilities of schizophrenics have not been investigated to any extent until very recently. Presumably changes in attitude stemming from the advances of cognitive psychology and cognitive science have broadened this avenue of study. There are three main areas of cognitive dysfunction that have been studied at the moment —although these areas are mainly determined by what researchers have looked at so far; also there is probably some overlap between them. The fields are: 1. linguistic dysfunction; 2. performance of specific tests of cognitive function and; 3. working memory deficits. Most of the work has been carried out on Type 2 schizophrenics, since it is generally believed that Type 1’s have little or no intellectual impairment—indeed there is overall far less data on all aspects of Type 1 schizophrenia. This is because: a. they are a very difficult population to manipulate as far as psychological testing goes; b. the diagnosis of schizophrenia in the USA (DSMIII-R criteria) cannot be made until symptoms of the illness have been present for six months, by which time most patients will have either be in remission or on neuroleptics which confound test/scanning results; c. there is virtually no post-mortem data from purely Type 1 patients since Type 1 schizophrenia is not fatal of its own accord and patients either enter permanent remission or exhibit Type 2 symptoms; d. PET, NMR, and MRI brain scanners are all relatively new, and again the cooperation of acutely psychotic patients is hard to achieve.
5.1
Linguistic Dysfunction
The inter-relation between language and thinking has meant that language has always been a prime tool for investigating cognitive function and dysfunction. In the case of schizophrenia the linguistic changes are generally deemed to reflect various disorders of thinking rather than specific disorders of language production/comprehension. This is borne out by interviews with patients with a good degree of insight into their illness who are able to describe post facto the strange mental events they experienced during an episode of acute psychosis. From their comments it is clear that the disease processes affect perception and responses to perceptions as a whole, this contrasts with stroke patients who are often aware of linguistic mistakes they are making without being able to do anything about them. Early studies focused on semantic deficits, in particular lexical ambiguities, since these stem directly from many of the positive symptoms described. In general there is a poor use of context by schizophrenics (Cohen and Servan-Schreiber, 1992), evidenced by studies using cloze analysis (guessing the missing words from a transcript of speech), speech reconstruction, cohesion analysis, and lexical ambiguities (in particular dominant vs. subordinate meanings of homonyms. Most of the subjects in the studies are described as ‘chronic’. Hoffman et al (1980) attempted to introduce a system for categorising schizophrenic speech deficits at a semantic/pragmatic level. He developed a set of criteria which he claimed were diagnostic for schizophrenia, his intention being that these would form some sort of objective measure for diagnosing schizophrenia. However other workers were unable to replicate his accuracy of diagnosis using the criteria. Beveridge and Brown (1985) found the criteria ultimately to be rather subjective—the clinician in general having to invent the missing parts (either syntactic or semantic) of a phrase in order to provide the appropriate data for Hoffman’s criteria to operate on. Beveridge and Brown noted that one of the main flaws in Hoffman’s program was the fact that formal semantics (then as now) is still a rather fledgling discipline with a lack universally accepted theories, thus making it unsuitable to base objective diagnostic criteria upon. More recent studies have revealed some empirical facts regarding schizophrenic speech; for 15
example King at al (1990) and Thomas et al (1990). These two studies in fact comprise a longitudinal three year study investigating the deterioration in language of schizophrenics. Using 16 variables grouped into the four categories of complexity, fluency, integrity and co-ordination it was found that there was a deterioration in all the syntactic variables (which comprised 14 of the 16 variables and were strictly rule-based) but a marginal improvement in the two semantic variables for Type 2 patients, although the number of semantic errors (subjectively adjudged) was still greater than in controls. Type 1 patients showed few syntactic errors although more than controls, and interestingly did not produce a significant number of semantic errors. The clinical condition of the patients was measured separately and half of the subjects were deemed to be ‘well’ or ‘improved’, while the other half were ‘unchanged’ or ‘deteriorated’; the decline in language ability was markedly worse in the patients who had ‘deteriorated’. Analysis was restricted to intra-sentence errors however, and it is very likely that Type 1 patients would show severe changes at a discourse level of analysis. None of the patients in these studies had spent long periods of time in hospital, and a matched group of manics who were maintained on similar medication for the same period showed no deterioration in language whatsoever. Thus two possible confounding factors—institutionalisation (i.e. an implicitly under-stimulating environment) and medication, were ruled out. These results do suggest that there is an underlying deterioration in some aspects of cerebral function separate from symptomatic states. There is evidence also that there is a relationship between low complexity of speech and early onset of illness the latter being indicative of poor prognosis. This is the start of the construction of empirical links between cognitive function and schizophrenic disease-states.
5.2
Specific Tests
Kolb and Wishaw (1983) conducted a battery of neuropsychological tests on a sample of schizophrenics who were tested within one week of admission for a first episode. The patients had been medicated with neuroleptics for at least 24 hours before testing, which suggests that they exhibited a Type 1 condition although this is not explicitly stated. Tests included the Chicago Word Fluency Test, the Wisconsin Card Sorting Test (WCST) and the Rey Complex Figure. The first of these requires the patient to write as many words as possible in five minutes beginning with the letter ‘s’, then as many four-letter words as possible in four minutes beginning with the letter ‘c’. The Rey Complex Figure requires the subject to copy the Rey Figure (a strange line drawing) and then to reproduce as much of it as possible (without prior warning) 45 minutes later; this is essentially a form of delayed response task. The WCST is described below. These tests had been used over the previous 30 years on neurological patients both pre- and post-operatively, thus a a degree of anatomical specificity could be claimed for them. Kolb and Wishaw found decreased performance by schizophrenics in most of the frontal lobe and all of the temporal lobe tests, but normal performance on parietal lobe tests, and more controversially a decrease of 15 points on the Wechsler Adult Intelligence Scale.The two frontal lobe tests performed normally were Digit Span and Block Span (repeating a sequence of taps on different blocks). A one year follow-up study found a dramatic improvement on all tests except the long-term recall of the Rey Figure—also these patients were on maintenance doses of neuroleptic thus ruling out medication as a confounding variable. They conclude that the frontal lobe deficits apparent in schizophrenics are bilateral. Other workers have produced similar results using the Raven’s Progrssive Matrix test, Chicago Word Fluency Test and Design Fluency Test. The first of these seems to be functionally located to the posterior lobe and is performed normally by schizophrenics. The latter two are both frontal lobe tests, the first being located to the left hemisphere and the second to the right hemisphere. 16
Both of these are executed less well by schizophrenics, as found by Kolb and Wishaw also. Stroop The Stroop Test is an old test designed to show the interference between two modalities of visual sensation. The test uses words written in ink of one colour but spelling a different colour e.g. the word RED written in green ink. The task is to respond to the spelt colour; control stimuli are either words written in black spelling colours or a row of XXXXX’s in a certain colour. It is noted that normals have a harder time selectively attending to colours than to words. There have been only five studies (according to Cohen and Servan-Schreiber (1992)) applying this test to schizophrenics, one of which did not measure reaction times, and another of which used only 4 patients as a sample—all tests used ‘chronic’ patients, which are more likely to be Type 2’s but not necessarily. However the results of these tests show that schizophrenics perform significantly worse on this task than normals—they exhibited an overall slowing of response but most marked when required to respond to colours. This corresponds with the thesis that the major cognitive deficit in schizophrenia is a lack of selective attention, thus the schizophrenic has great difficulty in ‘switching off’ or not responding to the inappropriate modality. The thesis that lack of selective attention or over-attention has been advanced in slightly different forms by several researchers and I will cover it more fully when discussing Gray’s Model (cf. section 6.). Wisconsin Card Sorting Test The WCST has become a major tool in investigating frontal lobe function and dysfunction. In investigating putative links between schizophrenia and prefrontal cortex dysfunction the WCST clearly has an important role to play. The test uses a deck of 128 cards each of which has a certain number (one to four) of the same shape in a certain colour. There are four different shapes and four different colours. This means that there are three dimensions for each card to vary in, and four graduations within each dimension. The test is run by laying four master cards face-up, which must between them represent each of the 12 variables. The testor then silently chooses a rule by which the cards must be sorted and the testee must attempt to match the remaining cards, one by one, with the appropriate master card and so deduce the rule. There can only be three rules (corresponding to the three dimensions of variation) and the testor silently changes the rule after 10 consecutive cards are correctly sorted. It has long been known that ‘frontal’ patients (i.e. patients with frontal lobotomies/leucotomies) perform poorly on this test. There is now conclusive evidence that Type 2 schizophrenics also perform poorly on this test (Sullivan et al, 1993; Braff et al, 1991; Franke et al, 1992; Berman and Weinberger, 1990). Using principal components analysis Sullivan et al show that perseveration is a deficit in performing the WCST that is statistically significant for schizophrenia. Perseveration is said to occur when the testee does not change the rule that they are using but perseveres with a previously successful rule when the testor changes the rule. In other words the testee is unable to generate a new rule or hypothesis. This may be perceived as responding to an inappropriate stimulus (the old rule) when there has been a signal from the environment to change behaviour, or a lack of selective attention. Perseveration is seen also in other contexts where decision-making must occur, again there is an over-attention to old information e.g. on performance of the Design Fluency Test some patients repeatedly drew the same design even when explicitly told that this was incorrect and that each drawing should be different (Kolb and Wishaw). One of the very important features of the WCST is that using radionuclide scanning of normals performance of it has been localised to the dorsolateral PFC. This is very interesting since it completes a circle relating schizophrenia to dysfunction of the PFC and the ‘hypofrontality’ hypothesis. Thus schizophrenics perform poorly on the WCST, the WCST is functionally located to the PFC of normals and presumably of schizophrenics also, and the PFC is 17
hypothesised to be hypofunctional in schizophrenia. There is a good body of data on hypofrontality which I will introduce in more detail in later sections, however it must be stressed that this is a key concept in the theory of schizophrenia I am presenting.
6 The Neuropsychology of Schizophrenia: Gray et al’s Model So far I have looked at the cognitive and biological aspects of schizophrenia separately, however my aim is to produce some sort of integrated model that goes some way to reconciling these two aspects. One model already existing is that of Gray et al (1991) who have attempted to provide a synthesis of the neuropathological, neuropharmacological, neuroanatomic and cognitive features of schizophrenia using Gray’s septohippocampal system (Gray, 1982) at the core. The basic psychological deficit in schizophrenics is discussed and various views are listed (pg.3), the overall picture being that of a failure of selective attention, automatic processing, placement of current ‘input’ in context—all synonymous with the idea of a “weakening of the influence of spatial and temporal [my italics] regularities on perception.” (pg.2) .This is placed in the context of Broadbent’s theory of pigeon-holing which works by: “(1) integrating information from the present context and past experience of similar contexts and (2) biasing both the interpretation of current sensory input and the preparation of responses to that input in relation to the expected probabilities of events as derived from that integration” From this it is argued that there is “a weakening of the influence of the regularities of past experience on current perception” (pg.3) in schizophrenics which is in fact the core abnormality responsible for generating the positive symptoms (Gray’s model only deals with positive symptoms i.e only with Type 1 schizophrenia). Another telling quote is from Helmsley: “schizophrenics are less able to make use of the redundancy and patterning of sensory input to reduce information processing demands” (pg.3). All of this amounts to some sort of information processing defect that gives rise to both the positive symptoms of schizophrenia and the cognitive deficits discussed earlier. Unfortunatley Gray et al only really consider the former. At the level of conditioning Gray et al consider three phenomena: Latent inhibition (previously described), the Kamin blocking effect, and partial reinforcement extinction effect (PREE) (see pp7-8). All of these demonstrate an impingement of prior knowledge in a particular context on subsequent learning within that context; and in accord with my earlier discussion on conditioning, all of these effects are removed by amphetamines and the amphetamine effect is itself removed by neuroleptics, implying that dopaminergic mechanisms are involved. There also appears to be evidence that neuroleptics have an opposite effect to amphetamines on the behaviour of normal animals. Gray et al also have evidence that damage to the hippocampus causes a disruption of these effects, but also that destruction of serotonergic afferents (from the median raphe) to the hippocampus causes a loss of latent inhibition. This ties in with the hallucinogenic properties of LSD, which blocks serotonin autoreceptors and reduces firing. As mentioned previously, the core element of this model is the septohippocampal system (SHS)(Gray, 1982). The information processing functions attributed to this model are illustrated schematically in figure 2 The ‘plans’ in figure 2 are generated in the PFC, the ‘predictions’ arrive via the cingulate cortex and anteroventral thalamus, and the stored regularities residing in the neocortex are accessed via the 18
Stored Regularities
The World
Generator Of Predictions
Comparator
Plans
Figure 2: The septohippocampal system as comparator entorhinal cortex. The interaction between this whole system and the motor system is considered to be via subicular projections. The motor system is intended to be implemented within the basal ganglia. Thus motor programs are selected, initiated and terminated by inputs to the striatum while outputs are patterns of cell firing that represent specific motor programs. There are two loops which have different control functions: the caudate motor system and the accumbens motor system (figure 3) Each of these is seen as three interacting reverberatory loops (from Swerdlow and Koob (1987)) utilising DA, GLU and GABA. In each structure within the loop a particular subset of cells will be firing, which precise subset dependent on the nature of the motor act to be performed. The overall control of these loops must be cortical and it is the PFC that has this overall coordinating task. The final output from these loops is via arrays of GABA’ergic Spiny I cells which comprise about 96 per cent of the entire striatal neuronal population. There are many convergent inputs to these neurons, I have mentioned prefrontal, hippocampal and DA neurons from the VTA or SN, but there are also inputs from the thalamus. The Spiny I neurons are linked with each other by lateral inhibitory connections, so that different input patterns can trigger precise output patterns. One view on the functional significance of the inputs is that they are divided into those that are responding to environmental stressors (reinforcers associated with particular cues), and those which are firing as part of the movements which the animal is making which affect the occurence of this reinforcement. Striatal cells are seen as responding initially only to the appropriate conjunction of cue plus movement, but then eventually become activated by the cue alone. This would account for conditioning behaviour. The subset of cells active in a particular action-reaction (cue-reinforcer) state include cells from all parts of the loops, involving the cortex as well. Presumably the development of this system such that distinct susbsets of neurons representing a combination of motor commands and conditioning and/or reinforcing inputs has been through a complex process of synaptic modifications. The caudate motor system defines what a motor program step is by selecting which inputs should fire which Spiny I cells; the accumbens system has two functions, to switch between steps in the motor program and to monitor the smooth-running of the program in terms of approaching a goal—the latter requiring interaction with the SHS. This interaction with the SHS is via the subiculo-accumbens pathway. Input from the amygdala to the NAcc. is thought to be responsible for selection and initiation of the next step in the 19
GLU+ MOTOR CORTEX
GLU+ VENTRAL THALAMUS
I
GABA-
LIMBIC CORTEX
I
GLU+
GLU+ CAUDATE PUTAMEN
GLU+
II
GLU+
GABA-
DORSOMED. GABATHALAMUS
DORSAL PALLIDUM
NUCLEUS ACCUMBENS
II GABA-
VENTRAL PALLIDUM
DA-
DA-
III
III S. N. (A. 9)
V. T. A. (A. 10) GABA-
GABA-
Figure 3: The caudate and accumbens motor systems program. One more hypothesis of function is that the neurons in NAcc. respond to novel stimuli. This has already been considered in the context of stress responses, amphetamines and increased DA, where there is evidence for a positive association between these features. Another aspect of this is that after repeated exposure to the same novel stimulus it ceases to be novel and so the ‘novel-behaviour’ response should also cease. In terms of DA this means a modulation of the hyperdopaminergic response. It may seem that this will occur automatically as part of Grace’s homeostatic mechanism—however it is not clear what time span we are considering since the equilibriation Grace predicts has a time course of days to weeks whereas habituation to a novel stimulus should have a time course of minutes and should also depend on the ‘stressfulness’ of the stimulus i.e more rapid habituation for less stressful stimuli. The two stress circuits of Deutch may be implicated here—he sees the caudate as being part of the mild stress circuit and the NAcc. as part of the major/prolonged stress circuit which involves the basal ganglia as a whole in novelty responses. In the present model the SHS is given the function of comparing inputs with previous memory stores and ‘deciding’ whether a stimulus is novel or not through it’s function of comparing the actual outcome of a motor step with the expected outcome—and transmitting this to the NAcc. via the subiculum. As mentioned earlier the PFC is incorporated to coordinate the caudate, accumbens, and SHS via various connections. Now to relate this complex model to schizophrenia. It is hypothesised that there is some sort of defect in the subiculo-accumbens pathway that disrupts the transmission of information from the SHS to the NAcc. This information is that telling whether the actual outcome of a motor step matches with that expected, in other words that which dictates whether to respond as though to a novel stimulus or not. Clearly it is thought that there is an under-transmission or hypofunctioning of that pathway since there is a reduction in the influence of the SHS on accumbal motor activities. This pathway is excitatory (probably glutamatergic) so that a reduction will have the effect of reducing tonic DA and thus increasing phasic DA as Grace suggests. Gray et al cite evidence that damage to the hippocampus 20
and also disconnection of the subiculo-accumbens pathway “impairs the normal tendency to to learn to ignore the novel event of non-reward embedded in a partial reinforcement schedule.”.However if this leads to up-regulation of DA activity in the NAcc. then the resultant loss of context effect can be attributed to dysfunction of the DA system arising from loss of control from a distant source not necessarily the hippocampus, e.g the PFC as a contender. The same studies also showed that disconnection of the subiculum did not impair the capacity for motor programs to be interrupted—the other proposed function of the subiculo-accumbens pathway. This model, then, is fairly complex and is pitched at a very behavioural level. Its two most successful aspects are that it introduces the concept of reverberatory loops into the motor control system and it provides a plausible explanation for one of the major deficits in schizophrenia—the failure of context. With regard to the first of these, some dysfunction of these loops is considered to be behind the generation of the positive symptoms of schizophrenia. More specifically, the failure to relate particular stimuli to a context and consequently to respond as though all stimuli are novel. Stimuli in this sense include internal sensations and actions such as thoughts and speech 2 . This failure is attributed to an inability of the motor system in the midbrain to interact with the SHS comparator, however this linkage (the subiculo-accumbens pathway) should also prevent switching between steps in the program e.g. perseverative behaviour and repeated motor actions (stereotypies). The model highlights the role of the SHS as comparator i.e. as having the function of comparing present sensory input (or stimuli) with stored regularities (memories) and deciding how novel that input is. This may be seen as a process of removing redundant data from the input to determine the degree of novelty and thus assist in choosing appropriate responses. This ties in with other conceptions of the hippocampus as being a mediator for the laying down of ‘sensational’ memory traces (knowledge of events, people and places) during which redundant information needs to be removed to prevent repeated traces of the same thing. There are several criticisms to be made regarding the application of this model to schizophrenia however. First, the neuronal changes observed in the temperolimbic system in schizophrenia are very generalised and affect many structures as mentioned earlier. There is no direct evidence that there is a specific lesion of the subiculo-accumbens pathway, and there is no reason to believe that the combined effects of neuronal loss through the majority of the temperolimbic system has a net effect of producing this one specific lesion. Secondly, the direct connections between the PFC and the NAcc. have largely been ignored. Evidence for hypofunctioning of the PFC has not been considered, thus the possible effects of a dysfunctioning PFC have not been incorporated into the model. Thirdly,the stereotypical motor behaviour is attributed to dysfunction of the caudate motor system, however the caudate motor system is composed of the nigrostriatal DA pathway amongst other things, and while this is implicated in the pathogenesis of Parkinson’s Disease it is definitely not implicated in schizophrenia. Stereotypical behaviour dose arise in schizophrenia in the form of perseveration but this occurs at the cognitive level rather than the behavioural level i.e. inability to choose new actions or to respond to new stimuli rather than repeated motor actions—to illustrate, schizophrenics are often agitated and show a general motor over-activity, they may pace up and down and fidget a lot and on testing (e.g. WCST) they are slow to change rules when necessary; motor stereotypies are similar but involve repetition of a specific action without being agitated or over-aroused e.g. lip-smacking, hand-rubbing. In fact the latter occur with prolonged use of neuroleptics. Gray et al correctly ascribe 2 These assumptions lie more in the realms of philosophy and I will not consider them here, but there are many, e.g. Searle, who would not agree that thoughts, speech and kicking a football are all governed by the same neural circuitry.
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the generation of motor stereotypies to dysfunction in the caudate motor system, however it is incorrect to associate this with schizophrenia. Fourthly, there is no accounting for the intermittent nature of Type 1 schizophrenia and the fact that the balance between positive and negative symptoms varies from patient to patient as does the course of the illness (although there is a progressive trend toward a severe Type 2 state (defect state)). It is suggested that the various sub-types of positive symptoms may be accounted for by subtle variations in the pathological resonances that occur in the reverberatory motor loops.
7 The Prefrontal Cortex And Schizophrenia There is now increasing evidence e.g. Breier et al (1992), to support the idea of atrophy of the PFC white matter in schizophrenia, which would clearly lead to hypofunctionality. However there is also evidence that there are similar changes in temperolimbic structures, as well as loss of periventricular white matter (which leads to enlarged ventricles, one of the earliest scanning findings), so the issue is not clear cut. It is still plausible that limbic abnormalities may arise secondarily to PFC dysfunction. Several new studies have looked at developmental aspects that could lead to loss of white matter. Akebarian et al (1993) found changes in the white matter of the principal sulcus of the PFC that were consistent with a neurodevelopmental disturbance that compromised the normal developmental pattern of cell death. Akebarian et al found similar changes across a broad distribution of neurons in the temporal lobes of ‘chronic’ schizophrenics. It is not clear whether these changes could arise secondarily to some cortical dysfunction, and if so which area was the site of the primary dysfunction. Others have looked at the entorhinal cortex, which carries a broad sweep of projections from the PFC to most of the limbic system, in patients who had had prefrontal lobotomies or leukotomies. These were ‘chronic’ patients with no history of neuroleptic medication. Changes in the entorhinal cortex “consistent with disturbed development” were found, but again it was thought possible that these may have arisen subsequent to changes in the PFC. These changes amounted to a reduction in entorhinal efferents i.e. a reduction in excitatory input to targets such as NAcc. and the amygdala. At the functional level they cite Damasio’s model which states that regeneration of past experience is through time-locking the constituent pieces of experience. The time-locking function is considered to occur in the PFC but the entorhinal cortex conveys the information, thus a disruption in this pathway could cause problems in accessing memories. This ties directly with Gray et al’s model, although the site of the lesion is different. Frith and Done also claim that schizophrenia results from disruption of the projections from entorhinal and cingulate cortices to the SHS. Gray et al point out that the post-mortem changes in the schizophrenic hippocampal formation 3 and parahippocampal gyrus are compatible with either reduced input from PFC to entorhinal cortex, or impaired output from subiculum to NAcc., or both. This definitely counts in favour of the hypothesis that the primary deficit is in the PFC. To return to biological evidence for developmental errors, Pettegrew et al (1991) have discovered membrane alterations in the principal sulcus of the PFC in unmedicated first-episode schizophrenics. The main findings are a reduction in ATP use, implying hypofunction, and a change in the ratio of phosphomonoesters (PME) to phosphodiesters (PDE) to match that found in ageing brains. A similar change also occurs transiently and to a lesser degree in normal adolescents, and interestingly one of the ‘normal’ adolescent subjects who demonstrated an abnormally large change in the PME/PDE ratio went on to develop schizophrenic symptoms while the study was in progress. These findings agree with the loss of PFC white matter seen in other studies and may be explained by the idea of excessive 3
The hippocampal formation includes the CA1, CA3, subiculum (main output), dentate gyrus and entorhinal cortex (main input)
22
synaptic pruning. There is evidence for programmed neuronal cell loss, loss of callosal axons and synaptic elimination in the PFC of normal adolescents. If this process were taken to excess then we would expect to find the membrane changes described above, and it would also account for the loss of white matter and hypofunctioning of the PFC, the changes in callosal white matter noted elsewhere and account for the early adulthood onset of schizophrenia.
8 Working Memory And The Prefrontal Cortex 8.1
Working memory
The idea of working memory has arisen as an off-shoot from the long-term—short-term memory systems. Working memory is basically a mnemonic process whereby propositions or items of information are briefly held ‘on-line’ to be operated on via a trial-by-trial process. According to Daneman and Carpenter working memory is the capacity to simultaneously store and process information. The tripartite model (Baddeley 1992) is proposed to have the following components: a phonological loop, a visuospatial sketchpad and a central executive. The phonolgical loop has probably been the most investigated, often using neurological patients with specific memory defects. The loop is composed of two elements: a speech-based store which holds a memory trace for approximately two seconds without updating, and an articulatory control process which updates the store by a recycling process akin to subvocal rehearsal. The store is thought to be speech-based because of the phonolgical similarity effect where memory span for similar sounding items is less than for dissimilar sounding items. There is obligatory access to this store by incoming irrelevant speech, and subvocal rehearsal is prevented by actual vocalisation (articulatory suppression). The phonological loop is thought to be particularly important in learning novel vocabulary, and does not appear to be required for ordinary comprehension. The visuospatial sketchpad is less well defined but is similar to the phonological loop in that it has a brief store and update loop that refreshes by rehearsal. The sketchpad can be functionally further subdivided into a pattern-based or object identity function and a spatial function. Storage can be disrupted by irrelevant visually presented ideas and by concurrent spatial processing. The central executive has been largely ignored until recently. Its role within Baddeley’s model is complex and diverse but one of its most important functions is to coordinate the information from the two other subsystems. Baddeley cites Norman and Shallice’s model of attentional control as a contender for the central executive. The idea behind this is that actions are controlled by “pre-existing schemata” in an undemanding situation, but if the situation is novel or threatening then a Supervisory Attentional System (SAS) takes control. It is proposed that the SAS is located in the frontal lobes to account for deficits in frontal lobe patients—impaired planning ability and problems with attention i.e. perseveration and/or over-attention (the former probably being a special case of the latter). As mentioned elsewhere these are the self-same problems seen in schizophrenics. One measure of central executive function is random sequence generation, which is performed more poorly as the speed of generation increases. Frontal patients also show reduced ability on this task, however there are no studies explicitly testing the performance of schizophrenics on it.
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Effects on sensory discrimination Able to learn new simple habits Over-reaction to all stimuli but accompanied by an entrenched responsiveness to old familiar stimuli that are part of well-established tasks. Slow to learn tasks requiring discrimination, and if the two ‘discriminada’ are presented at different times then learning is almost non-existent. Effects on motility Hyperactivity dependent on environment i.e. a more stimulating environment produces a disproportionate increase in activity Lesions to area 8 (prearcuate) cause an overall reduction in eye movement and reduced performance in visual search tasks. Effects on instinct/emotive behaviour Comprehensive ablation (as with lobotomy/leukotomy) causes impoverishment of emotional life and social isolation Dorsolateral lesion causes increased aggression and reduced emotional expression Table 4: Summary of the effects of PFC ablation (in monkeys).
8.2 8.2.1
The functions of the PFC Neurophysiology
The functions of the PFC, to the extent that they are known, have been deduced largely from frontal patients and experimentation with Macaque monkeys. The effects of ablation studies are summarised in table 4. The PFC is divided anatomically into different regions, many of which are functionally distinct also. The ventral and medial parts are thought to be related to affective/motivational functions and ‘inhibition control’; the dorsolateral region is related to ‘cognitive’ functions. These two regions have different phylogeny and ontogeny and separate connections with other cerebral structures, underlining their different functions. The PFC matures slowly and is later in completing synaptogenesis than other areas of the brain. This correlates with observations that if PFC lesioning occurs before two years of age then none of the above effects occur, and also the degree of degeneration of prefrontostriatal fibres observed after ablation of the PFC depends on the age at which ablation takes place. Fuster (1989) describes the PFC as a type of sensory association cortex. It receives input from the thalamus and virtually all areas of the cortex with convergence at the single cell level of one, two, or many modalities thus coping with stimuli of diverse origins and qualities. It also has control functions in that it selects which sensory inputs should have access to higher cerebral structures, it is involved in motor control functions by connections with the striatum and NAcc. and eye movements appear to be controlled by the prearcuate area (area 8). This leads to the idea that it is involved in sensory-motor integration. The principal sulcus (dorsolateral PFC) is deemed to be particularly important for the guidance
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of behaviour by representational information. Ablation of the principal sulcus causes loss of spatial delayed response ability as measured by delayed response tasks (DRT). An example of a DRT would be requiring someone to look at a screen with several differently coloured dots on it and then to switch the screen off and ask them to point at the green dot, for example. The spatial location of that dot has been stored somewhere in the principal sulcus (we hypothesise) and is available for a short period for the person to act on, thus the behaviour is guided by the representation of the stimulus rather than the stimulus itself. Without a sulcus animals (monkeys) are unable to use stored information to ‘inform’ a correct choice, although associative memory is preserved. The principal sulcus seems to be specific for spatial information only, with object identity (pattern-based) information being encoded in the inferior ventrolateral convexity (Wilson et al, 1993). So there is sensory-motor integration over time at least in the principal sulcus. At the level of neurophysiology we find a special slow surface-negative potential recorded from the principal sulcus during the time interval separating sensory cue from delayed response. GoldmanRakic (1990) found that in the monkey principal sulcus during a DRT different neurons coded different target locations. Many neurons showed phasic or tonic responses that were time-locked to more than one phase of the task, and others registered directional activity. This suggests that there are distinct neuronal sub-populations that encode for ‘input’, ‘hold’ and ‘output’ functions. Goldman-Rakic also found that excitatory (or inhibitory) delay period activity terminated abruptly when post-saccadic activity in another group commenced, implying some sort of communication between functional groups. Further, tonic excitatory delay period activity was noted to be coupled with phasic presaccadic activity, and tonic inhibitory delay period activity in the same neurons (in another trial) was coupled with phasic post-saccadic activity in the opposite direction. The conclusion that the authors draw from this is that same neuron may participate in the selection and initiation of motor action in one direction while at the same time inhibiting inappropriate responses. Fuster (1990) notes that there are also cells which respond to temporally separate but mutually contingent stimuli and motor responses and also that topographic patterns of organisation are not apparent—emphasising the temporal binding properties of the PFC. He describes the role of the PFC in terms of a Perception-Action cycle in which there is a motor and a sensory hierarchy, each of which progresses from primary area to premotor area and then to the PFC at the top—the other ends of the hierarchies are connected by external forces i.e. the environment. 8.2.2
‘Higher’ functions—a model
The PFC is implicated in the ‘higher’ functions such as reasoning and planning; in the context of Gray et al’s model it is a generator of predictions. From a ‘metaphysiological’ point of view it has the function of imposing meaning on an organism’s activities, or alternatively it provides context or assigns relevance to activities. This is evidenced when, for example, sufferers of chronic pain undergo prefrontal leukotomy—the result of this is that the patient still suffers the sensations previously causing pain only now it does not hurt. The PFC is not required for survival, removal of it results in various effects as described above but ‘everyday’ activity is maintained, thus basic stimulus:response matching (or automatic processing) must occur at a lower level. In Gray et al’s schema this process is largely mediated by the SHS in conjunction with the motor systems and long-term memories. So how does it provide meaning, context or relevance. I would suggest the schema in table 5 This is a rough sketch lacking in implementational detail but it does fit with the facts outlined above. The precise interface between PFC and thalamus/cortical inputs dictating the switch from automatic to controlled (or subconscious to conscious) processing is especially in need of further 25
1. The PFC receives filtered input from the rest of the cortex, not necessarily direct sensations, we could possibly call them propositions. The input is gated by reciprocal thalamic inputs reflecting the mood and bodily state of the organism. The PFC is only ‘on-line’ in novel situations or where planning is required. 2. This input pattern is stored temporarily i.e. an internal representation is formed. We now have a situation looking for a response. 3. A response is found by a best-fit or hypothesis-testing process. This is seen to occur at the level of loops. The PFC coordinates this activity by receiving both sensory input and the conditioned response which it puts ‘on hold’ (familiar situations e.g do not switch on the prefrontal cortex and so the conditioned response is not kept ‘on hold’ but ‘unthinkingly’ enacted). This allows for a period of hypothesis-testing. It is assumed that stimulus response pairs are accessed by the SHS, and so the conditioned response is also sent to the striatum where motor programs are encoded. At this point circular activity occurs within the subloops II and III of the accumbens and caudate motor loops of Gray’s model. The activity within these loops is coordinated by the PFC, this coordination may amount to phase-locking of the activity within these loops. Resonance within these loops allows for the generation of a new motor program by changing the network dynamics within the spinyI arrays. The new motor program is then released to the motor cortex (and elsewhere) where it can be put into practice. The hippocampus will eventually begin to encode a new stimulus-response pair. I have adopted here Gray et al’s assumption that motor programs do not necessarily have to be physically acted out but may be directed within, in the same way that sensory input to the cortex may come from within as well as externally. An immediate consequence of this is that the starting point for generating a new response will always be from the previously learnt stimulus-response pair, thus the effects of past-experience provide the initial conditions for the change in striatal network activity. 4. The duration of hypothesis-testing depends on the physical situation of the organism and is relayed by thalamic inputs e.g. if there is imminent danger then the above process is truncated, and may be totally absent leaving conditioned responses to be acted out unchecked (automatic processing). 5. It is suggested that there is background activity in the above-mentioned circuits, giving rise to a stream of consciousness type of activity.
Table 5:
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delineation. The origins of schizophrenic symptoms can be described in terms of the above ‘hypothesisgenerating’ model. Positive symptoms occur from a dysfunction of the loops originating in the PFC. If their activity becomes out of phase then the interaction between the two loops may be lost. This would result in the failure of the accumbens system to switch between steps in a motor program (as required in Gray et al’s model) and the generation of bizarre and inappropriate internal and external activity in response to stimuli. Overactivity of the dopamine system, as described above, leads to the PFC remaining ‘on-line’ for prolonged periods, although the actual level of activity within the PFC is reduced. Negative symptoms arise from a failure to generate any new motor programs or hypotheses. This may be due to extreme hpofunctioning of the PFC or due to a kindling effect on the SHS secondary to positive symptoms. The latter would cause the kindled circuits to remain active for a long time and preclude the relaying of newer responses to the PFC.
8.3
Localising working memory to the PFC
It seems clear from the description of the functions of the PFC and the proposed structure of working memory that there is a great deal of overlap between the two, leading to the idea that at least some aspects of working memory can be localised to the PFC. In addition there are immediate comparisons between the central executive (assuming the Norman and Shallice model) noted above and aspects of Gray et al’s model. Here is a brief summary of the relevant functions of the three items: SAS This coordinates the action of the visuospatial and phonological loops. The former is localised in the PFC, the spatial part being specific to the principal sulcus. The SAS is also responsible for planning and selection of attention. SHS This is intended to match expected outcomes with actual outcomes in terms of motor responses. It is localised to the hippocampus and related structures. The hippocampus is generally considered to be a mediator in the laying down of long-term memory association stores. PFC Responsible for sensory-motor integration over time. Defects in the PFC cause failures of selective attention (viz. perseveration and over-attention) and planning. The PFC interacts with the SHS via afferents coursing through the anterior cingulate cortex to the entorhinal cortex and then to the subiculum and there is also an excitatory reciprocal connection from the hippocampus back to the PFC . Goldman-Rakic (1992) claims that the prefrontal terminals in the presubicular area can act to gate hippocampal output, she also considers the PFC and hippocampus as part of a common circuit which share common cognitive domains but serve different sub-functions in the overall cognitive operation. The connections between the SHS and the PFC are important in that these allow the PFC to receive the conditioned response as the starting point for the generation of a new response, as outlined above. From this we might state that much of the function of working memory is carried out in the PFC but that connections with the SHS are required for full functioning. The phonological loop, however, seems to be less related to the regions of the PFC we have so far considered. If we consider the function of the phonological loop to be involved in the acquisition of language (a large subject which I will not discuss) then we may imagine a loop with Wernicke’s area and the PFC, and another with Broca’s area and the PFC. Subvocal rehearsal is seen as reverberation in the Broca-PFC loop in response to reverberation in the Wernicke-PFC loop, the latter only occurring when the input is novel or not understood. Integration occurs in the PFC where both loops intersect.
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8.4
Defects in working memory and schizophrenia
I have shown that the PFC is a likely candidate for the primary lesion in schizophrenia and that the PFC is also the site for many aspects of working memory, in order to complete the triangle it is worth considering whether there are direct links between schizophreniaand dysfunction of working memory. There are virtually no direct studies of working memory in schizophrenia, largely because a precise formulation of the functions of working memory is lacking. However if the DRT is considered to be a specific measure of working memory function then the following study is relevant. Park and Holzman (1992) have specifically investigated the relation between working memory and schizophrenia using a spatial DRT. They found that schizophrenics (in-patient and medicated) had impaired performance on a visual and haptic (touch-sensation) DRT but normal digit-span and sensory control task performances. The latter of these does not use representational information and the digit-span taps verbal working memory. With respect to working memory as a whole, Baddeley (1992) concludes that “working memory measures appear to correlate very highly with performance on a range of reasoning tasks that have traditionally been used for measuring intelligence” and it was noted earlier that Kolb and Wishaw found a decrease in score on the Wechsler I.Q. test. There appears to be a dearth of data on the performance of schizophrenics on memory tests, however the general picture is that long-term memory stores are not disrupted but there is impairment in the retrieval of this information. This ties with Gray et al’s model in which either the access to long-term memories is deficient or the ability to use the memories in the process of comparing expected outcomes with actual outcomes is deficient—both of these functions are proposed to be mediated by Gray’s septohippocampal system. One study that loosely tackles this issue (Schwartz et al, 1992) has focused on three aspects of memory: 1. memory for temporal order, 2. procedural learning and 3. the relation between implicit and explicit memory 4 . They found that (in ‘chronic’ and medicated schizophrenics) there was an impairment in memory for temporal order and also an impairment of explicit memory, though normal implicit memory priming effects were maintained. The tests of explicit memory used newly acquired data and so the results indicate either poor generation of memory stores or poor access, they do not address pre-existing memories which are presumed to be intact. This implies a disorder of both the PFC and the hippocampal formation, both of which are known to be dysfunctional in schizophreniaand both of which are implicated in working memory. From a more general point of view working memory, or at least the central executive part of it, can be considered to be involved in the task of ‘directing attention’ and planning actions. Both of these processes are faulty in schizophrenia and so, at the level of cognition, there is clearly a defect in working memory in schizophrenics. Since the similarity between the sites of lesion in schizophrenia and those implicated in working memory—primarily the PFC and hippocampal formation—is so great I would suggest that schizophrenia could be formulated alternatively as a specific failure of working memory.
9 Connectionist Modelling And Schizophrenia Connectionist modelling of schizophrenia is a relatively new pursuit and owing to the complexity of this subject for modelling the two models described below take quite different approaches. To my knowledge these models comprise the extent of the literature on the subject. 4
Implicit memory is procedural, explicit memory is declarative or episodic and is related to the acquisition of time-eventplace information—thus the hippocampal formation is implicated in its functioning
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RESPONSE "red"
red
green
INK COLOUR
"green"
Word Reading
Colour Naming
red
green
WORD
TASK DEMAND
Figure 4: Stroop Network of Cohen, Dunbar and McClelland
9.1
Cohen and Servan-Schreiber
Cohen and Servan-Schreiber (1992) have elected to focus on the dysfunction of selective attention and language in schizophrenia. They model three tasks: the Stroop task, a continuous performance task (CPT), and a lexical disambiguation task. The first of these I have already described, the second requires a subject to respond to a target stimulus that occurs amid a stream of similar stimuli, and the third requires selection of the contextually correct meaning of a potentially ambiguous word. All three of these tasks are intended to capture context effects and accordingly schizophrenics perform poorly on them. Their aim in modelling these three tasks is to show that a disturbance in the internal representation of contextual information can account for schizophrenic deficits in selective attention and language, and in addition that a change in one parameter of the model can cause a switch from normal to schizophrenic behaviour. This parameter is deemed to represent the neuromodulatory effect of dopamine (DA). The models used are very simple and have no ‘anatomic correctness’ but are purely functional i.e. they model a cognitive process only. I will look at one of their models, that dealing with the Stroop effect, in slightly more detail. This model has the basic architecture as shown in figure 4 The model has two paths, one for colour-naming and one for word-naming, and reaction time is considered to be the number of cycles that it takes for an output unit to accumulate a specified amount of activation i.e. to have chosen a word (or colour). The model also has two ‘task demand’ units which are intended to represent intentionality or selective attention, so that stimulation of these units should over-ride any conditioned responses. The model was trained in the usual way but was given more training on word-naming than on colour-naming in order to mimic human adults who are assumed to have more experience generating a verbal response to written words than to colours. The result of this is that the word-naming path is activated preferentially or from a behavioural viewpoint this stimulus:response pair has been conditioned more strongly than the colour-naming one, which has the net effect that when one of
29
the colur units and one of the word units are stimulated the output will register the word ‘colour’ rather than the colour ‘colour’. When the ‘task demand’ unit for colour-naming is activated however, then the colour-naming task takes precedence and the response is the colour ‘colour’, thus intentions are able to over-ride conditioned responses. Cohen and Servan-Schreiber see the task demands as providing “the context necessary to disambiguate the stimulus and choose the appropriate response”. From the discussion in the previous section this task is clearly localised to the PFC in adults. A pattern of activation in the task demand module can then be seen as an internal representation of context. Simulations involved running 1000 trials on each task to generate a significant level of results. Noise was introduced to simulate the variability of humans at performing the task; without noise the tasks were performed perfectly. Results obtained from the model are identical to human results. At this point the parameters are left fixed. The next stage is to change the model in some way so as to simulate changes in the schizophrenic brain and at the same time simulating their performance on the Stroop task. Cohen and ServanSchreiber focus on the DA changes found in schizophrenics; they assume that “dopamine can modulate the response properties of post-synaptic cells such that both inhibitory and excitatory responses to other afferent inputs are potentiated [my italics]. Some investigators have described this effect as an increase in the “signal-to-noise ratio” of the cells’ behaviour...”. They also assume that there is a decrease in dopaminergic activity in the PFC, in accordance with the hypofrontality hypothesis. Finally they choose the parameter of gain to represent the neuromodulatory effect of DA in their models. The activation function they use is a logarithmic function producing a sigmoidal activation curve (net input plotted against activation), and the steepest slope of this curve has an activation coordinate corresponding to baseline firing. Also, a constant negative bias is included. These features are designed to correlate with data from physiological experiments on real biological systems. The negative bias represents the fact that small increments in excitatory drive produce changes in firing frequency of proportionately greater magnitude than the same increments in inhibitory drive. To simulate the effects of a reduction in PFC DA activity the gain parameter is reduced in the task demand units only. A value of 0.6 was found to be the most effective. Simulations were run again and two effects were noted: 1. an overall increase in the response time for both tasks (i.e. increase in number of cycles required for output activation to be reached), and 2. a disproportionate increase in response-time in the colour-naming task. These results mimic performance of schizophrenics. An explanation for these results is that both tasks rely on context to some extent, but the colour-naming one is more context-dependent and so is affected more so than the other by a failure to apply contextual regulation. This example of attempting to model cognitive processes in a biologically plausible way demonstrates quite effectively some of the advantages and pitfalls of the paradigm. The main advantage is, as Cohen and Servan-Schreiber put it, “to make it possible to examine the effects of biological variables on behaviour without having to reproduce the entire brain.” Thus we can set a model to represent a cognitive task and because the model is biologically plausible we assume that there will be some correspondence between the parameters of the model and the biological variables thought to underlie the task. It is the ability to alter one (or more) parameters of a complex system mimicking a cognitive task and observe the effects on the system as a whole that is the power of this modelling paradigm. The nature of the correspondence between biological variable and model parameter is a moot point however. According to Smolensky this correspondence is at the sub-symbolic level. Thus if a model is biologically plausible enough then we can make inferences from the model to the biological system at a sub-symbolic level. The degree of biological plausibilty determines the level of processing at which 30
inferences may be made e.g. if a model incorporates representations of ionic fluxes then by changing the relevant parameters we may be able to make inferences regarding the role of these fluxes on the operation of the modelled system as a whole. This is precisely where the Cohen and Servan-Schreiber model fails. The main problem is that there is a mis-match between the level of biological plausibilty of their model and some of the deductions which they wish to draw from it. To be more specific, they claim that the effect of internal representation of context on the activity of the net can be seen as directing attention to the more appropriate processing pathway. This claim seems valid to me since it lies at the sub-symbolic level i.e. the pattern of activation across the task demand units may be fairly said to portray the internal representation of context 5 . Rightly, no claim is made relating the numerical manipulations that occur in the network to produce this pattern of activity with neuronal processes in the brain. However, Cohen and Servan-Schreiber do make claims relating the information processing properties of the network to dopamine activity. In my view these claims are less valid because the model does not have adequate biological plausibility, in particular the back-propagation algorithm is not found to operate in biological neuronal networks, and the assumptions made regarding the information-processing properties of dopamine are essentially wrong. It is true that the mechanism of action of dopamine and its role in cognitive processes is still not totally understood, however there is very strong evidence supporting dopamine having inhibitory activity at synapses (Lewis, 1992;Goldman-Rakic, 1992;Bachneff, 1991; Grace, 1991) and virtually all other studies. Cohen and Servan-Schreiber cite many references showing this inhibitory action in the striatum, but choose to ignore them and follow one or possibly two studies in support of a potentiating action in the striatum. Having made this assumption it is further stretched to account for dopamine activity in the PFC, which has been studied less than in the striatum but all studies so far indicate an inhibitory action. Cohen and Servan-Schreiber cite many of these studies but persist in contrasting them with the “potentiating effects of dopamine that are known [my italics] to occur (at least within the striatum).”. They mention the electron microscope studies (Goldman-Rakic, 1992) that show that DA synapses are symmetric and therefore extremely likely to be inhibitory and also that many dopamine terminals synapse on GABA interneurons which are inhibitory thus giving dopamine a disinhibitory role. If the direct dopamine inhibition and the indirect disinhibition are operational on the same pyramidal cell (as Lewis and others have suggested) then clearly dopamine can have a modulatory effect. There is no evidence that this effect amounts to potentiation as Cohen and Servan-Schreiber claim. The strength of their claims, as shown by the following quote, is understandable in that if dopamine has an attenuating effect (as most studies show) rather than potentiating then the correlation between gain and dopamine is the reverse of what is claimed and the results of all the simulations are in fact ‘upside-down’ and do not correlate at all with schizophrenic performance. They say: “The success of our models at the behavioural level may be taken as a prediction concerning the validity of the biological assumptions upon which they are based. That is, our models predict that dopamine should have the same gain-like effect in prefrontal cortex that has been observed for cells in the striatum. In this respect, the models provide theoretical guidance for further studies at the physiological level.” which contrasts with their admission that “we have concerned ourselves...less with the specific details of the neurophysiological mechanisms from which [the potentiating effects of DA] arise”. An omission which they make at their peril, I would suggest. 5 This is interesting as it shows how a pattern of activation in the PFC may provide the framework in which an object can be correctly ascribed meaning or relevance i.e. semantic processing
31
From this it becomes clear that in using this modelling paradigm one must be very careful in choosing the correct level of correspondence between the structure of the model and established biological facts in order to draw inferences and make predictions.
9.2
Hoffman
Hoffman has chosen a very different approach to modelling schizophrenia (Hoffman and Dobscha, 1989; Hoffman and McGlashan, 1993). He has focused on the generation of the positive symptoms of schizophrenia. His motivation was from data related earlier describing hypofrontality, synaptic pruning and a dysfunction of the latter process accounting for the former finding in schizophrenia. He does not dwell overly on the role of DA in schizophrenia—side-stepping the associated controversy, but instead looks at the system, either PDP or neuronal system, as a whole. Using a standard Hopfield recurrent net he demonstrates the presence of what he describes as parasitic foci arising from the pruning of connections according to an ‘axonal pruning rule’. This rule is seen as an implementation of neural Darwinism, where neurons compete with each other to be connected to other neurons. The rule takes a given coefficient and multiplies it by the physical distance between two connected units, if the result is greater than the synaptic strength (weight) on that connection then that connection is pruned away. Thus longer connections are more likely to be lost than shorter ones (see Hoffman and Dobscha, 1989). The network is used to store random patterns (memories) before the pruning process; these memories can be considered as a gestalt consisting of a collection of features. Overpruned networks showed the following features: 1. amalgamation of memory fragments, 2. bizarre output unrelated to input, 3. autonomous functioning of certain subpopulations of neurons within the network, 4. following from 3. certain ‘modules’ produced a particular pattern of output regardless of information from other parts of the network. The output from these modules was fixed and did not represent any of the pre-existing memories. This form of ‘network pathology’ is referred to by Hoffman and co-workers as a parasitic focus. It is possible to conceive of this behaviour giving rise to the positive symptoms of schizophrenia if it were to arise in a biological network. What is envisaged is that foci generate abnormal but coherent patterns of firing (in contrast to epileptic foci which produce completely meaningless activity) which, depending upon the anatomic location of the focus , generates auditory hallucinations, thought disorders and delusional perceptions (see Hoffman and McGlashan, 1993: pp 125-7 for more details on mechanisms of symptom generation). This idea ties with my suggestion for the generation of positive symptoms being a dysfunction of loops, although whether parasitic foci actually exist is a moot point. The idea that an underactivity in the PFC arising from synaptic loss can generate positive symptoms by causing a dysfunction of loop processing (which is implicit in a recurrent neural networK) is common to both proposed mechanisms. Hoffman and McGlashan also point out an interesting secondary action of parasitic foci, namely that repeated hippocampal stimulation is likely to occur in view of its role in coordinating the storage of long-term memories. This would mean that the same pattern (hallucination, delusion or other idee fixe) is repeatedly presented. This may have a ‘kindling’ effect, whereby repetitive electrical stimulation of the hippocampus causes kindled circuits to remain hyper-responsive for months, and also produces a generalised loss of synapses. Pantelis (1991) mentions a similar effect at the amygdalar bodies. This could account for the fact that schizophrenic relapses usually result in the same symptoms occurring and are more likely in the immediate aftermath of an ‘acute’ episode. Also a prolonged loss of synapses would result in axonal degeneration and show as a loss of white matter and reduced volume—features that are found in schizophrenics. These changes would presumably be permanent and could partly account for the ‘defect’ state (very pronounced negative symptoms) where there is a 32
I DA/ACh
II PV
III MD Thalamus
IV CRF
V
NA ACh DA
VI
CCK
NEOCORTEX AND HIPPOCAMPUS
THALAMUS
STRIATUM
Figure 5: Layers of the prefrontal cortex, from Lewis et al, 1992. DA = Dopamine; ACh = Acetylcholine; MD Thalamus = Mediodorsal nucleus of the thalamus; CCK = Cholecystokinin; CRF = Corticotropin releasing factor; PV = Parvoalbumin; NA = Noradrenaline. clear loss of declarative memory function. Hoffman and McGlashan conclude that their model does not account for the effects of neuroleptics in reducing positive symptoms. In my account of the generation of positive symptoms this can be accounted for. If we see the overactivity in some loops, containing both the PFC and the striatum and NAcc., as causing re-entrant sounds, thoughts, beliefs and ideas, then it may be postulated that dysfunction is generated at one site in the loop, but by damping overactivity at another site then the activity of the loop as a whole is damped.
10 Modelling The Prefrontal Cortex 10.1 Structure Having discussed the potential role of the PFC in schizophrenia and at some models that have attempted in different ways to incorporate aspects of PFC function, I would now like to look more closely at the structure of the PFC. Fuster (1989) describes it as “homotypical isocortex, clearly laminated, with a well-developed internal granular layer (layer IV) that differentiates it from the rest of the frontal cortex”. Like the rest of the neocortex it is divided into six layers or laminae with layer I being the most superficial and layer VI the deepest (see figure 5) Layer IV contains a few small pyramidal cells but mostly granule cells—‘stellates’—these have short dendrites which extend to form a spherical dendritic field, and short axons which form nets around the neighbouring pyramids. The axonal plexus in layer IV is mainly of terminal afferents—most of which are from the mediodorsal (MD) thalamus.
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10.1.1
Afferents
The PFC receives afferent connections from many structures, in particular the following: cortical association regions, mediodorsal (MD) nucleus of the thalamus, VTA (source of dopaminergic projections), hippocampus, amygdala, hypothalamus and the pons. The thalamic afferents synapse mainly in layer IV and the cortical afferents in layer III. The thalamic input is topographically mapped but there are separate projections to the orbital/medial regions and the dorsolateral region. Interestingly the projections to the dorsolateral PFC come from a region of the thalamus which receives afferents mainly from the PFC itself, Kuroda et al (1993) found that there is an excitatory monosynaptic loop from prelimbic PFC projections (layer VI) to the MD thalamus and back to layer III of the PFC. 10.1.2
Efferents
The PFC has direct reciprocal connections with all of its afferent connections, and in addition projects to the striatum and NAcc. with no direct feedback. This projection is implicated in the proposed ‘hypothesis-testing’ loop controlled by the PFC and including the striatum, NAcc. and SHS. The dorsolateral PFC projects mainly to the hippocampus and parahippocampal gyrus—again emphasising the separate functions of parts of the PFC. The efferents to the limbic system, which include most of the dorsolateral projections, pass through the anterior cingulate cortex which is most activated during the Stroop task and which has the highest dopaminergic activity of all the PFC. 10.1.3
Dopamine
Dopaminergic activity is highest in the anterior cingulate region and lowest in the dorsolateral area. It is also distributed across layers in a bilaminar fashion being highest in superficial layers (I, II, III) and deep layers (V, VI), with very little activity in layer IV. There is a thin layer of D2 receptors in the superficial part of layer V, but only D 1 receptors are found in all other layers. 10.1.4
Interneurons
The interneurons within the PFC are mostly GABA’ergic (as with the rest of the cortex). They can be subdivided according to co-localisation of other proteins (see figure 5) and are found mainly in layers II, III and especially IV. They occur in highest numbers in the PFC and are developmentally late in arriving. It is thought that GABA interneurons form one of the targets for DA terminals and it has been noted that GABA and DA are mutually antagonistic. Bachneff (1991) suggests that this has the net effect of counter-balancing stress-induced DA activity and preventing over-reaction. Now we need to put all this together. Several workers (Changeux and Dehaene, 1993; GoldmanRakic, 1992) have suggested the importance of synaptic triads in modulating synaptic actions, both in the cortex and in the striatum. Goldman-Rakic has shown with electron-microscope studies that there are triads involving a symmetric (presumed inhibitory) DA synapse and an unidentified asymmetric synapse both occurring on the dendritic spines of cortical pyramidal neurons in layer I. Another potential triad arrangement is shown in figure 6 Now a pyramidal neuron in layer III could receive this type of modulation. It would also receive excitatory input form other cortical afferents and maybe hippocampal afferents also. For my proposed model it is necessary that the layer III ‘input’ neurons can communicate with the layer V ‘output’ neurons to the striatum, (although the layer III neurons are implicated in the initiation of actual motor actions). This clearly implies a role for layer IV which has a very large number of interneurons, but also receives the thalamic afferents, allowing for a direct impingement of mood and bodily state 34
DA
-
_
-
GABA
The Synaptic Triad
GLU
+
Figure 6: on the processing function of the PFC. This connection also needs to occur across time also. If the major defect in schizophrenia is a reduction of GABA interneurons (as noted by Benes et al) due to an over-pruning of excitatory synapses, then clearly a dysfunction in the connections between ‘input’ and ‘output’ layers will occur. If the GABA neuron deficit occurs across the whole of the PFC then the modulatory effects that these have on pyramidal neurons in other layers will be disrupted also, and in layers where these modulatory effects occur in conjunction with DA then the result would appear as a dysfunction in the DA system. This will appear as a net over-activity of DA here causing increased inhibition of pyramidal cells, thus reducing GLU output to subcortical structures and setting the scene for a reduction in tonic DA in the NAcc. and causing an up-regulation of the phasic system. This does imply that DA has an inhibitory action throughout. It also shows how DA is implicated in the modulation of PFC processes but that is not the sole modulator, the key being the triadic arrangement of synapses.
10.2 Cortical computation The remaining task is to reconcile the foregoing with a modelling paradigm. It seems to me that there are four levels at which equivalences or mappings must be made: cellular, microcircuit, macrocircuit and cognitive. The biology to model equivalences are summarised in table 6. Each of the first three levels presents a modelling challenge. I will make some comments regarding modelling neurons and the dynamics of reverberatory loop systems. Clearly it is desirable for each level to be modelled in order that it may be incorporated into the next to give an integrated biologically plausible model. Such a model still requires a large amount of approximation to account for the multitude of parameters that it does not encompass. However, by stipulating a direct equivalence at each level of processing it is hoped that the quintessential properties of the schizophrenic brain/mental processes will be captured. With such a model there should be an adequate number of parameters which may be varied, and changes in behaviour at different levels will hopefully provide an insight into the processes at work in schizophrenic and normal brains.
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Biology Cellular
Model Biologically plausible neurons incorporating dendritic computations and synaptic triad modulation
Microcircuit
Architecture to reflect interneuron circuits and demonstrate the physiological function of the PFC
Macrocircuit (loop)
The model must show the dynamics of a reverberatory loop system incorporating the PFC as modelled above
Cognition
There must be an interpretation of the performance of the system as a whole which mimics chosen cognitive processes.
Table 6: Features of a model of schizophrenia 10.2.1
Modelling neurons
In order to generate deeper biological inferences from computer network models I have been advocating a high (or higher) degree of biological plausibilty in the structure of the network itself. Directly relevant to this issue is the fact that the standard McCulloch and Pitts ‘neuron’ is a massive simplification of a real neuron. The main problem is that the dendritic tree of the neuron has been ignored until recently. The next approach is that of compartmentalisation which entails dividing the neuron into a varying number of compartments and describing equations (Hodgkin-Huxley type) governing activity for each separate compartment. The level of modelling depends on the number of compartments that are used, but modelling to the level of ionic channel activity has been achieved. Unfortunately such high levels of detail require very large computational resources to model just a single neuron, a network of such highly detailed neurons is at the moment not feasible. Shepherd et al (1991) have recently compared active spines against active dendrites using a relatively simple four compartment model. They conclude that localising active membrane properties to apical dendrites rather than spines provides as rich a computational structure as active spines and also provides for more potent inhibitory actions on this activity, making it more open to modulation. They suggest that impulse firing is therefore contingent on the summation of all dendritic activity gated by global inhibition. A single dendritic tree can compute any threshold function. From this they propose a canonical pyramidal neuron with a generic computational structure that can be elaborated and adapted for families of related functions in different parts of the cortex. Thus the synaptic triad arrangement on dendritic spines mentioned above forms part of a massive input to the ‘threshold computation’. The inhibitory actions of GABA interneurons take an increasingly important role in governing pyramidal cell behaviour according to this account. Thus a more biologically plausible network architecture may be achieved by using such canonical neurons, with many synapses, particularly inhibitory and excitatory pairs, and with lateral inhibitory connections and complex threshold functions. The nature of the threshold function is a goal for future research however. In a slightly different vein Pellionisz (1989) has suggested that in order to reduce the complexity of the geometry of dendritic trees while preserving the intrinsic structure they be modelled with fractal geometry rather than the standard Euclidean form. The main idea behind this stems from the observation that the branching of dendritic trees shows a high degree of ‘self-similarity’. This is where 36
C
CHAIN MODEL
COMPARATOR MODEL
Figure 7: Chain and comparator connections between oscillators more distant parts of the tree have a pattern which is a scaled-down version of the whole tree i.e. there is a qualitative similarity between the whole neuron and its parts. Such structures may be built by recursive use of a ‘code’ and it is suggested that in the case of neurons repeated access to genetic coding provides just such recursion. There is a link with chaos theory in that the geometry of a strange attractor is also of fractal form, however the computational relevance of a fractal neuron is not clear. 10.2.2
Loop dynamics
In earlier sections I have considered the potential role of the PFC in controlling an hypothesisgenerating loop which accounts for the ability to select appropriate actions in novel situations and failure of this loop as generating the positive symptoms of schizophrenia. It is now necessary to consider how such activity may be represented in a network. Kammen et al (1989) have shown that in order for a subset of active oscillating units in an array of oscillatory units to be able to be phase-locked a comparator network is preferable to a chain architecture (see figure 7). In the model suggested above the comparator function will need to be performed by a representation of the PFC. Such a phase-locking function is in keeping with the temporal binding that is known to occur at the cellular level in the PFC. If the model is to incorporate representations of other biological structures these will need to be simplified since the intention is not to produce a replica of the brain. These may be seen as modules with ‘network’ type activity; it is assumed that this activity is oscillatory i.e. microcircuit activity. Within each module controlled by the PFC there is an active pattern which is a subset of a large number of patterns, the nature of which is governed by an attractor or attractors within the module. The role of the PFC is to coordinate these attractors, and at a global level it is loosely suggested that the PFC functions as an attractor attractor, where each point in the PFC attractor defines a stable subset of phase-locked attractors within the modules. The idea of a more global attractor has been looked at by Basar et al (1989). They use EEG -waves as a measure of preparatory activity, which implies some measure of PFC function, and assume that “phase-locked repeatable activity prior to a cognitive target is a general working strategy of the brain”. Measuring the activity of subjects performing a visual delayed response task involving temporal prediction shows an ordering of this otherwise disordered activity. The ordering arises as the subject learns to predict the timing of the stimulus signal. If the signal is presented randomly then prediction performance decreases and also no ordering of activity appears. They propose that the transition from chaotic to repeatable, coherent and ordered states implies a bifurcation, that is a transition from a strange attractor to another type of attractor producing obviously ordered behaviour.
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In terms of PFC function it indicates that the PFC does demonstrate attractor behaviour, and that a bifurcation occurs when the PFC is required to perform some temporal-binding function i.e. the background chaotic activity becomes ordered. Relating this to schizophrenia, a dysfunction of the PFC may alter the nature of the attractor thus inducing a disruption in the coordination of the other attractors controlled by the PFC. This uncoordination may be seen as a disruption of phase-locking and thus give rise to out of phase attractors and consequently out of phase loop activity. This would correspond to the generation of parasitic foci that Hoffman has proposed to account for the positive symptoms of schizophrenia. Negative symptoms can be seen as a direct failure of planning and motivational activity from the PFC dysfunction. If the PFC is totally absent, as with lobotomised patients, then this attractor activity must be absent though motor actions continue to be performed. It is assumed that in the absence of PFC coordination then standard conditioned stimulus-response pairs dictate activity of the organism, thus bifurcation from strange attractor to ‘other’ attractor is triggered by novel situations where conditioned responses are inappropriate (as determined by the SHS). Hippocampal and dopaminergic inputs must play a part here. Clearly the above is very conjectural. However it does suggest an approach in tackling the complex dynamics of schizophrenia. The level of microcircuit is notably missing from the above also. This is where the ‘real work’ needs to be done and is beyond the scope of this thesis. In mentioning potential biologically plausible building blocks (the canonical pyramidal neuron) and outlining the dynamics that a model may be expected to display my intention has been to provide a framework within which to build a specific neural network architecture.
11 Discussion In this thesis I have attempted to build a case for the prefrontal cortex being the location of the primary lesion in schizophrenia and as such a key aspect in models of schizophrenia. I have considered four levels of description at which there is a correlation or equivalence between a neural network model and the biological and cognitive processes occurring in humans. Implicit in these levels is the fact that there is a transition from one to the other, thus cognitive science is seen to be reconcilable with neuroscience. The nature of these transitions may be thought of as a scaling processes or change in dimensionality. At a cellular level excessive synaptic pruning in the prefrontal cortex has been shown to generate a dysregulation of the subcortical dopamine systems. Dopamine has an important neuromodulatory role in the prefrontal cortex and the striatum. Its action appears to arise through the arrangement of synaptic triads which comprise inhibitory dopamine terminals and excitatory terminals synapsing on the same dendritic spines. Dopamine activity is closely tied with processes of conditioning. Network modelling at this level may require the use of more biologically plausible neurons such as Shepherd et al’s canonical pyramidal neurons which incorporate complex dendritic computations into the standard McCulloch and Pitts neuron. This would an extra degree of biological plausibilty to a network, allowing for deeper inferences to be drawn from simulations. At the microcircuit level the activity of GABA’ergic interneurons is proposed to account for the physiological functions of the prefrontal cortex, in which ‘temporal-locking’ of cells is seen to occur during delayed response tasks. This constitutes an integration of sensory and motor function.It is proposed that interneurons in cortical layer IV provide a major communication network whereby cortical inputs and outputs in layer III can be connected with striatal outputs in layer V. Layer IV also receives major thalamic inputs, thus allowing for the interaction of mood and bodily functions with
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‘higher’ processes. In schizophrenia the number of interneurons is reduced leading to impairment of the physiological functioning of the prefrontal cortex. In a network model this level of description corresponds to the actual architecture of the network. I have not provided an explicit architecture but in discussing the physiological arrangement I hope to have indicated the features that such an architecture will require. At a macrocircuit or loop level, I have attempted to account for the processing functions of the prefrontal cortex. It is generally considered to play a major role in planning responses. I have suggested that the prefrontal cortex coordinates a hypothesis-generating loop which provides predictions for Gray et al’s septohippocampal system. This loop is only ‘on-line’ when required to over-ride conditioned responses or to direct behaviour in novel situations, and I have suggested that background activity may form a type of ‘stream of consciousness’. Hypofunction of this loop is considered to generate the negative symptoms of schizophrenia while positive symptoms arise from a discoordination of the components of the loop. Modelling this dynamic system involves a significant degree of complexity. I have considered each component of the loop to be an oscillatory subsystem which has its own set of attractors. A comparator configuration for such a network has been shown to be the most appropriate in producing phase-locked activity and so the prefrontal cortex is seen to take this role. In order for looping to occur, however, there must be some variation from the uniform comparator model shown in figure 7. The prefrontal cortex is now seen to coordinate the attractors of the subsystems and the idea that it acts as an ‘attractor attractor’ has been raised. When not ‘on-line’ the prefrontal cortex attractor seems to be a strange attractor, giving rise to chaotic ‘subconscious’ activity. However when it is ‘on-line’ a bifurcation occurs and an ‘ordered’ attractor is seen. Hippocampal, thalamic and dopaminergic inputs are responsible for the control of the bifurcation. In schizophrenia it is suggested that a change in the nature of this attractor due to alterations in the anatomical and physiological substrate is responsible for the disordered behaviour witnessed. Finally, specific cognitive tasks have been considered. Testing of cognitive function demonstrates impaired performance by schizophrenics on tests of frontal lobe function. In particular the Wisconsin Card Sorting Test appears as especially useful in that it has shown to be localised to the dorsolateral prefrontal cortex in normal subjects and schizophrenics show distinctive perseverative errors in performing it. Also delayed response tasks are directly related to prefrontal cortex processing and are performed poorly by schizophrenics. The latter is considered to be a function of working memory and the connections have been made between the prefrontal cortex, working memory and schizophrenia. I have suggested that the cognitive deficits of schizophrenia may be seen as impairment of working memory. The aim of modelling must be to replicate the performance of normal subjects on appropriate tasks, and then to attempt to generate schizophrenic performance by lesioning the model in appropriate ways. Clearly each of these levels of modelling provides a challenge, however each is seen as necessary in order to make a model biologically plausible enough for valid inferences to be derived. It is my intention that the foregoing provides a sound framework within which to build a more specific model architecture for future modelling of schizophrenia.
12 Acknowledgements I would like to thank my supervisor David Willshaw for his kind support. This work was made possible by a studentship competition award from the ESRC.
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