Neuropsychotherapy: conceptual, empirical and neuroethical issues

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S173–S182 DOI 10.1007/s00406-009-0058-5

Neuropsychotherapy: conceptual, empirical and neuroethical issues Henrik Walter • Mathias Berger • Knut Schnell

Ó Springer-Verlag 2009

Abstract In this article we suggest a working definition for the concept of ‘‘neuropsychotherapy’’ encompassing three areas: the identification of mediators and targets of psychotherapeutic effects, the determination of new therapeutic routes using neurotechnology, and the design of psychotherapeutic interventions based on neuroscientific knowledge. We review neuroimaging studies of the psychotherapy of depression and discuss some of the methodological limitations inherent in functional Magnetic Resonance Imaging (fMRI) and common fallacies perpetrated in interpreting fMRI studies. Finally, we discuss some neuroethical issues related to this new and active field of research. In sum, we argue that neuroscience harbors great potential and add-on value for improving psychotherapeutic practice and research if applied properly. Keywords Neurobiology Psychotherapy fMRI Depression Neuroethics

Introduction One way to find out how medical experts think about the mind and the brain is to consider real cases. Consider a case witnessed by one of the authors of this article 20 years ago.

H. Walter (&) K. Schnell Department of Psychiatry and Psychotherapy, Division of Medical Psychology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany e-mail: [email protected] M. Berger Department of Psychiatry and Psychotherapy, University Medical Center, Hauptstraße 5, 79100 Freiburg, Germany

One night a young man was admitted to the hospital after signs of a paraplegia that occurred during sexual intercourse. A careful neurological examination revealed no known pattern of peripheral or central paralysis. Rather, the patient showed paralysis and numbness in both legs symmetrically following a ‘‘folk psychological’’ body schema, i.e., head, trunk, two arms, and two legs attached to the trunk. The symptoms strongly suggested that he had not a neurological but a psychiatric problem—a hysterical paralysis, classified today as a form of a dissociative disorder. Despite this clinical diagnosis, various examinations such as a cranial computer tomography (CCT) and a lumbar puncture were performed for forensic reasons, all with negative results. Just to be on the safer side, the patient was taken to the neurological ward for further observation. On the next day, he was investigated further with evoked potentials, including transcranial magnetic stimulation (TMS). TMS quantifies the time between a magnetic stimulation of the brain and the resulting muscle twitch in the leg. When TMS results reached the ward, a great uneasiness spread through the team: the results were pathological. Could it be that the patient had a ‘‘real’’ problem? The senior resident, an experienced TMS expert, came to the rescue. He repeated the TMS examination using a higher threshold to excite the brain. This time the results were normal. What a great relief: no ‘‘real’’ problem had been missed. The presented case reveals a kind of thinking still prevalent today: either a patient has a ‘‘real’’ neurological problem, implying that pathological findings can be discerned using one or another objective technique, or the patient has ‘‘just’’ a psychological problem, implying that no pathological findings will emerge. However, this thinking is seriously flawed: if a patient has an obvious psychological problem, there must be some neural mechanisms in the brain accounting for it. One explanation why

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Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S173–S182

neurologists tend to make the categorical difference between ‘‘organic’’ and ‘‘psychological’’ problems is the lack of techniques to detect a neurophysiological signature of the psychological mechanisms involved—at least 20 years ago. However, considering the clinical appearance of hysterical paralyzes, there surely must be some mechanism in the brain—most likely a pre-existing psychological body schema must be inhibited so that motor paralysis and/or sensory problems emerge, which clearly are different from feigned symptoms. Indeed, several neuroimaging studies have found evidence for specific mechanisms involved in conversion disorder [11, 63], demonstrating that paralysis in conversion disorder is brought about by different mechanisms than in feigned paralysis. However, no one has (yet) discovered the neurological basis of the folk psychological body schema that we all have in our mind, and consequently in our brain. Even today, the fact that neuroscientists are able to find a correlate or—as we prefer to say—a neural signature of psychological mechanisms still provokes astonishment and surprise. Frequently, newspaper headlines utilize such reactions by reintroducing a historic dualism, regarding the mind as an entity working independently from the brain and only occasionally leaving a trace in brain processes. According to a recent survey completed by nearly 200 Belgian health care workers, more than one-third regarded the mind and the brain as separate entities [15]. However, in science it is largely uncontroversial today that every kind of psychotherapy that changes thoughts, cognition, emotions, or behavior of patients has to exert its effects through changes in the brain. Brain processes cause behavior, and experiences affect the brain by altering gene expression, which changes the strength of synaptic connections that are the material basis for our beliefs, attitudes, memories, personality, and dispositions to react to external circumstances [29]. One metaphor to think of the brain is to regard it as the eye of the needle through which every psychotherapeutic intervention has to contrive. The emergence of cognitive neuroscience and neuroimaging methods has probably been one major cause for the attempt to connect neurobiology and psychotherapy, which has also been called ‘‘neuropsychotherapy’’ [24]. In this article, we want to suggest a working definition for neuropsychotherapy, review neuroimaging findings in the field of the psychotherapy of depression, and discuss the potential and also some limitations of this approach. Finally, we want to draw attention to some neuroethical issues.

by the renowned psychotherapy researcher Klaus Grawe [24] to denote the attempt to explain ‘‘how psychotherapy works by primary reference to neuroscientific evidence.’’ He also used it to characterize a helpful attitude for therapists: ‘‘Neuropsychotherapists’’ should be aware of neurobiological foundations of psychology while practicing psychotherapy. However, we would like to suggest a more systematic working definition of neuropsychotherapy in order to capture an increasingly popular field of research (see Table 1). We suggest to understand neuropsychotherapy as a field of applied research, trying to (i) identify neural mediators and functional targets of psychotherapeutic effects, (ii) determine new therapeutic routes using neurotechnology, and (iii) design psychotherapeutic interventions on the basis of neuroscientific knowledge. To illustrate our concept, we have provided some examples for each of the three aspects. Identifying neural mediators and functional targets of psychotherapeutic effects A typical example is the study of basic learning mechanisms such as fear conditioning and extinction in the context of psychotherapy. From animal studies, it has become clear that the extinction of conditioned fear responses is not due to a simple fading of neural responses but due to active inhibition of amygdala responses by the orbitofrontal cortex [38]. Here the amygdala response represents a target for psychotherapeutic interventions, which are mediated by activating the inhibitory functions of the orbitofrontal cortex. Neuroimaging studies in humans [51] actually provide a consistent explanation why ‘‘extinction’’ is really a kind of ‘‘un-learning’’ and why anxiety disorders tend to relapse even after successful therapy. Moreover, regarding personality disorders, the observation that subjects with psychopathy do not improve their inhibitory behavioral selfregulation after aversive behavioral experiences can be linked to an impairment of neural circuits mediating aversive operant conditioning mechanisms [7, 8]. Another example is the recent work on the neural basis of emotion regulation [5, 49, 50, 68]. Dysfunctional emotion regulation is central to many mental disorders. Accordingly, learning to control and regulate one’s emotions is a core

Table 1 Neuropsychotherapy as a research field (i)

Identify neural mediators and targets of psychotherapeutic interventions

What is neuropsychotherapy?

(ii)

Determine new therapeutic routes using neurotechnology

Although the idea of neuropsychotherapy can be traced back already to Freud [19], the term itself was introduced

(iii)

Design psychotherapeutic interventions on the basis of neuroscientific knowledge

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strategy of most psychotherapeutic approaches. Explicit emotion regulation is a process guided either by attention deployment or by the intentional use of various cognitive reappraisal strategies, such as detachment or reinterpretation [25]. To identify the pertinent mediating neural mechanisms of psychotherapeutic effects, neuroimaging in humans is indispensable, since explicit emotion regulation cannot be investigated in animals. Such research may not only provide clues to the mechanisms of emotion regulation but also reveal findings not apparent by using behavioral methods. For example, we could recently show that neural effects of emotion regulation extend beyond the time in which regulation is actively used. In healthy subjects, detachment has a sustained regulation effect on amygdala activation after 15 min when the formerly regulated stimuli are presented for a second time without any explicit regulation [68]. Moreover, this sustained regulation effect is smaller in subjects that show a paradoxical rebound of amygdala activation directly after the termination of intentional emotion regulation (Fig. 1). The sustained regulation effect is not present in patients with depression (Erk et al. data presented af the Society for Neuroscience Meeting, 2009), possibly explaining some of the emotional dysregulation. Apart from such basic research applications, another quickly growing field is the use of neuroimaging as a research tool in order to investigate the effects of

psychotherapy, i.e., changes in brain structure or function induced by psychotherapy [36]. Neuroimaging studies can be used to understand how psychotherapy changes the brain and may deliver some knowledge as to where specific psychotherapeutic interventions interfere in the brain’s functional systems. Methodologically, brain processes are mediators of psychotherapeutic effects. We will illustrate this aspect of neuropsychotherapy using the example of neuroimaging of the psychotherapy of depression. Last but not least, knowledge about the pathophysiology of the disorder might help patients to cope with their symptoms, offer some relief, and strengthen motivation to work on disease-related problems they encounter in their everyday life after being enabled to understand their underpinnings.

Fig. 1 Mechanisms of emotion regulation: a network comprising the right DLPFC and right inferior parietal cortex is active during emotion regulation using cognitive strategies. Activity in the amygdala is significantly reduced via MPFC (medial prefrontal cortex) during regulation as well as 10 min after regulation when showing the same pictures without cognitive regulation. However, an analysis of

Determining new therapeutic routes using neurotechnology One prominent and much discussed neurobiological application in psychotherapy is the use of psychotropic drugs to improve psychotherapeutic interventions. An early example is the now-illegal use of ecstasy in private psychiatric practice in Switzerland in the 1980s as a psycholytic drug [59]. More recently, the discovery that the neuropeptide oxytocin increases trust [34], mentalizing capacities [17], and attachment [10] has suggested its use in psychotherapeutic contexts. D-cycloserine is a drug that already has

the time course of the BOLD-signal shows that there is a paradoxical rebound immediately after terminating cognitive emotion regulation (increase in amygdala signal, depicted in grey). The extent of this immediate rebound effect reduces the effectiveness of emotion regulation after 10 min (adapted from Walter et al. 2009)

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been shown to improve psychotherapy by accelerating learning processes. This drug influences N-methyl-Daspartate (NMDA) receptors involved in learning and extinction and has been successfully combined with cognitive behavioral therapy in social anxiety disorder [26]. A clearly marked example of choosing direct routes to functional targets is the use of neurofeedback, i.e., the use of brain signals as a feedback for patients to alter their dysfunctional psychopathological states. For example, functional Magnetic Resonance Imaging (fMRI) has been used to influence the perception of pain by controlling the rostral anterior cingulate cortex (ACC), a region putatively involved in pain perception and regulation [14]. Neurofeedback with fMRI is championed for many applications [13] and could indeed be used during psychotherapy of obsessive-compulsive symptoms or for treating drug resistant hallucinations. Likewise, the use of quantitative electroencephalography in the controlled treatment of personality disorder and TMS in the treatment of conversion disorder [57] represent recently evolving, promising techniques of neuropsychotherapy.

mechanisms are well studied and it can be treated well by psychotherapy [28, 35]. Moreover, it has been studied with neuroimaging for more than a decade [16, 20]. Grawe used it as his prime example for neuropsychotherapy, and Aaron Beck, the pioneer of cognitive behavioral therapy (CBT) for depression, recently has called for a unified approach linking psychological and biological investigations in the study of depression [6]. Moreover, neuroimaging research on the underpinnings of depression has been inspired by the ongoing debate about different efficacies of antidepressant medication (ADM) compared to psychotherapy [16]. In the past decade, evidence has accumulated that ADM and CBT are effective through different neurofunctional mediators, i.e., causal pathways, since the two methods show differential efficacies in severe versus mild depression [33] as well as in relapse rates [16]. As a rather consistent finding, it has been reported that the amygdala of depressive patients shows increased resting metabolism [18] and increased [60] or sustained [62] activation to the presentation or anticipation of aversive stimuli [1]. In contrast, the resting metabolism of the prefrontal cortex (PFC) was found to be reduced [3, 43]. fMRI experiments demonstrated both an increase of amygdalar reactivity in an emotion-processing task and a decrease of dorsolateral prefrontal cortex (DLPFC) activation in a cognitive task [62], while both regions showed decreased functional connectivity in depressed patients. Based on these and similar findings, a concept linking increased bottom-up emotional reactivity and decreased top-down regulation of emotion emerged and is now frequently referred to as the cortico-limbic dysregulation model [40]. Investigations in healthy subjects demonstrate that these structures are actually involved during emotion regulation by means of a bottom-up/top-down interaction [4, 46, 49, 50, 64]. The model offers a layout to render a neurofunctional ‘‘mode’’ or dysfunctional network of depression as postulated by Beck [6]. The true pathophysiological significance of such a neurofunctional mode, i.e., a dysfunction of a distinct neural network, has to be proven experimentally. The first attempts were designed to identify the changes induced by pharmacotherapy. Anand et al. [2] demonstrated an increase of functional cingulo-limbic connectivity and a simultaneous decrease of limbic reactivity to aversive versus neutral pictures in a group of 12 patients under sertraline treatment over 6 weeks, with 10 out of 12 patients showing a good response. The demonstration of treatment-dependent changes in functional connectivity is crucial, because the concept of a ‘‘network disorder’’ implies a pathologic functional connectivity. The concept of depression as a network disorder is supported by longitudinal studies in depressed patients treated with fluoxetine or placebo. After therapy, increased

Designing psychotherapeutic techniques on the basis of neuroscientific knowledge This is probably the most ambitious and innovative part of neuropsychotherapy. One promising application for such ideas is the treatment of PTSD. Eye movement desensitization and reprocessing in the therapy of posttraumatic stress disorder (PTSD) [52] represents an example inspired by neurobiological knowledge. Furthermore, neuroscience provides new ideas how to design psychotherapeutic interventions with respect to traumatic memories [69] as exemplified by studying the phenomenon of reconsolidation, originally described in mice [47]. The term ‘‘reconsolidation’’ refers to the fact that memory traces are labilized and thus can be changed when they are restored. Recent evidence has shown that the context during reconsolidation has to be similar to the context of initial consolidation in order for reconsolidation to be possible [47]. Paying close attention to such neuroscientific findings may help to teach psychotherapists how to best evoke painful memories when planning to modify them to be less traumatically restored. In the following section, we will discuss one of the most popular aspects of neuropsychotherapy, namely, the use of neuroimaging in the course of psychotherapy, and we will use depression as a prime example.

Imaging neural effects of psychotherapy in depression Depression is a reasonable example for neuropsychotherapy: it is a major psychiatric disease; its neurobiological

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activity in DLPFC, ACC, premotor, parietal, posterior insular, and posterior cingulate cortices were observed, but decreased activity in the subgenual cingulate, parahippocampus, and thalamus [44]. Only fluoxetine responders showed additional subcortical and limbic changes. The isolated increase in cortical structures in the placebo condition was interpreted as a cortical top-down mechanism representing the placebo effect. Notably, changes in PFC observed under pharmacotherapy were inconsistent between these studies. The first two studies on the effects of psychotherapy in depression were carried out in 2001 [9, 39]. Brody et al. compared changes of resting-state PET glucose metabolic rates in 14 depressed patients receiving interpersonal therapy (IPT), 10 paroxetine-treated depressed patients, and 16 healthy controls in a nonrandomized pre-post design over 12 weeks. In the IPT group, metabolic decreases in right PFC, left ACC, left insula, and temporal cortex were observed. However, direct comparison of IPT and pharmacotherapy only rendered a difference in the metabolic increase in the right insula. In the second study, Martin et al. assigned 28 MD patients to either venlafaxine treatment (n = 15) or IPT (n = 13) and examined both groups with a SPECT scan before and during treatment, i.e., after six IPT sessions or 75 mg of venlafaxine over 6 weeks [39]. There was a greater clinical improvement in the venlafaxine group, possibly related to dosage of IPT and ADM. Over time, the ADM group showed increased right posterior temporal and right basal ganglia activation, while the IPT group showed an increase of activation in right basal ganglia combined with an increase in the right posterior cingulate. After all, these studies did not demonstrate a specific psychotherapy effect on PFC function in comparison to ADM. In a more recent PET study, Goldapple et al. [23] explored changes of resting-state brain metabolism in 14 outpatients receiving a varying number (15–20) of cognitive therapy sessions according to the Beck CT program. After a mean period of 26 weeks of therapy, there was an increase in glucose metabolism in the hippocampus and parahippocampal gyrus and dorsal ACC. Remarkably, and in line with the observation of Brody et al., they found activity decreases in several PFC regions, contradicting the hypothesis of increased PFC activation through modification of cognitive schemas. The contradiction was underlined by an ADM-dependent increase of metabolism in dorsolateral, ventrolateral, and medial prefrontal areas (left greater than right); parietal cortex; and dorsal anterior cingulate cortex in an earlier study of paroxetine effects during a 6-week treatment [31]. In a direct comparison of both methods in a later study, i.e., CBT and venlafaxine treatment, a decreased glucose metabolism bilaterally in the orbitofrontal cortex and left medial prefrontal cortex in

response to both treatment modalities was described along with increased metabolism in the right occipital-temporal cortex [32]. In sum, the reported observations suggest that psychotherapy is not a simple decrease of bottom-up and increase of top-down regulation, as suggested by initial models. It can be speculated that changes in PFC activation through psychotherapy and pharmacological treatment can only be understood by the differentiation of tonic, i.e., resting-state activation and event-related responses in the PFC [16]. A recently reported fMRI study by Fu et al. supports this suggestion. The study found a relative initial increase of reactivity in the right amygdala and hippocampus to the presentation of sad faces and a decrease in ACC activation during baseline conditions in a group of 16 patients with acute major depression compared to healthy controls [21]. The differences vanished after 16 CBT sessions [22]. This means that during therapy, stimulus-dependent reactivity decreased in the amygdala and increased in the ACC in comparison to healthy controls. However, there is still a lack of event-related fMRI studies and a great demand to understand alterations of context and stimulus-dependent neural mechanisms, since psychotherapy mostly addresses modification of dysfunctional context-related responses [6]. At this moment, the reported findings of changes in metabolic or functional activity under psychotherapy are still inconsistent, especially regarding PFC metabolism, possibly due to methodological differences between studies. In addition to pre-post designs, some authors have investigated the suitability of neuroimaging to predict therapy response [61]. Mayberg et al. found rostral anterior cingulate metabolism uniquely to differentiate treatment responders from nonresponders to ADM. Hypometabolism characterized nonresponders when compared with controls, in contrast to responders that were hypermetabolic previous to treatment [42]. The same direction of predictive signals was found in an fMRI study. Patients with greater initial relative anterior cingulate activation in response to negative versus neutral stimuli showed the most robust treatment response to venlafaxine [12]. The direction of predictive signals in the subgenual cingulate cortex has been found to be inversely arranged: Decreased sustained activation of this area predicted a response to CBT [61]. Moreover, the extent of functional connectivity of the subgenual cingulate with dorsolateral and orbitofrontal cortices also predicted a later response to pharmacological treatment [58]. In contrast to pre-post changes of brain function, the predictive analysis of anterior cingulate cortex consistently underlines the functional involvement of this region in the pathophysiology of depression and the predictive character of this region for the remission of symptoms [41]. After all, with respect to our definition of

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neuropsychotherapy, the function of the ACC, according to its predictive value, is possibly mediating the effects of psychotherapy on functional limbic targets like the amygdala. Future clinical fMRI studies will test this idea with designs modeling typical cognitive reactions and stimulusdependent affective dysfunctions in depression.

not allowing any direct inference to the level of the individual subjects. Many analyses are based on the idea of strict modularity of psychological subprocesses, an assumption known to not adequately render principles of higher brain function. Although results of fMRI studies provide objective data in a certain sense, reliability is rather low and validity is a matter of proper experimental study design. Many popular presentations of fMRI studies are flawed, as they seem to suggest that a functional brain pattern is as unchangeable as a structural deficit, or even worse, is inborn—two suggestive conclusions that are a logical non sequitur. One simple way to conceive of fMRI studies is to think of them as psychological experiments with an additional dependent variable. As already pointed out, their proper interpretation therefore requires solid knowledge about the principles of brain function, experimental design, analyses methods, and MR technology. However, we should be aware that fMRI has some major advantages that have never before been available in the history of neuroscience and psychology. Brain activity can now be mapped (although only indirectly) to functional brain systems during psychological experiments across the whole brain, including deep brain structures like the amygdala or the ventral striatum, which are important in psychiatry and psychotherapy. This can be done noninvasively, repeatedly, and in a standardized way. Brain signals are more closely linked to the biological causes of mental processes than peripheral measures, behavioral tests, or subjective reports. There are good reasons to assume that they are more sensitive to biological factors or psychological interventions than those other measures. However, in getting actively involved in fMRI-research for psychotherapy, a neuropsychotherapist will face major problems that go well beyond the methodological issues in fMRI. The preceding review about imaging in psychotherapy of depression has already indicated that large issues are more likely to emerge from clinical psychotherapy research itself. In fact, it is much easier to establish statistical quality assurance measures for fMRI measures than to control for possible confounds in the design of a clinical psychotherapy intervention study. The approach to use physiological outcome measures and the problems of their interpretation will hopefully further enforce standardized, concisely defined, and reliable psychotherapeutic procedures and techniques in such studies. Moreover, the comparison of neurofunctional states and external dependent variables, like self-assessments, might render both unexpected confounds and therapy-relevant effects. We found such an effect in patients’ reports of subjectively experienced affective arousal. Especially in short interventions, self-reporting of affective states does not necessarily reflect the actual change of neurofunctional or physiological states. We observed a decrease of correlation

Neuroimaging for psychotherapy: methodological considerations The idea of neuropsychotherapy has certainly been promoted by the development of neuroimaging providing fascinating and seemingly easily interpretable visual impressions of blobs of ‘‘brain activation’’, in particular with fMRI. Criticism of ‘‘blobology’’ has been vigorous among both scientists and the public [37, 65]. In fact, fMRI is not an elaborate mind reader [53, 54], nor is it a worthless and uninformative ‘‘neophrenology’’ that is condemned to fail, as has been occasionally argued. Here we agree with Logothetis [37], in assuming that the extreme positions probably ‘‘result from a poor understanding of the actual capacities and limitations of this technology, as well as, frequently, a confusion between fMRI shortcomings and potential flaws in modeling the organizational principles of the faculties under investigation’’ [37]. Although we cannot discuss these issues in detail [37, 65], we want to make explicit some of the limitations that fMRI faces. The physiological basis of almost all fMRI studies is to measure a signal based on cerebral vascular autoregulation, i.e., on the fact that there is increased blood flow in regions where neurons become active, resulting in a shift of the relation between oxygenated and deoxygenated blood. This blood-oxygen-level-dependent (BOLD) signal is measured with techniques based on quantum mechanics. The blood oxygenation is correlated with neuronal activity (‘‘neurovascular coupling’’) in a complicated and not yet completely understood way, which can be approximated by a linear relation. In fact, fMRI measures only the reaction of the vascular system induced by mass action of neurons but cannot measure neuronal activation itself. Therefore, it cannot distinguish between neuronal excitation and inhibition. Also, the BOLD signal is delayed in time, peaking only about 4–6 s after neural activation, and is smeared over time and thus cannot signal precise timing. Furthermore, fMRI signals are susceptible to artifacts (for example, small movements, blood flow in adjacent larger vessels, braintissue boundaries), are altered in diseased brains and are limited in spatial resolution. Moreover, most software packages are based on linear models, whereas the real brain physiology is highly nonlinear. Important, at this moment nearly all results of neuropsychotherapy are group results

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between arousal ratings and the amygdala activation of DBT responders in the course of therapy (see Fig. 2), although self-reports about experienced stimulus-dependent arousal were stable over time [55]. This observation suggests that changes in limbic areas are probably not always directly accessible as higher-order representations, which can be expressed in verbal reports. This assumption is relevant for therapy processes, as the patient’s verbal report to the therapist might actually not adequately reflect the changes of affective processing already induced by the therapy in the patient’s brain. This knowledge should remind therapists to explicitly focus on other channels of the patient’s affective expressions and that they should be longanimous when facing persisting complaints from the patient, for change might already be happening. The next step will be to link clinical parameters and neurofunctional modes. In contrast to the uniform definitions of depression, a reliable clinical and functional definition of diagnostic subgroups will be helpful in selecting appropriate interventions for distinct subtypes of depression. For example, neuroimaging might be helpful to understand the difference between episodic and chronic depression. Today, deep brain stimulation has been introduced as an end-of-the-line method to treat chronic depression by targeting specific neural structures like the

ventromedial prefrontal cortex or the ventral striatum. On the other hand, CBASP (Cognitive Behavioral Analyses System of Psychotherapy), specifically developed to treat chronic depression [45, 56] which targets interpersonal features with special interventions, has been proven to be as effective as medication for chronic depression [30]. Actually, if early-childhood trauma is present, CBASP can be more effective than medication [48]. Accordingly, it is very well conceivable that neuroimaging might help to indicate what type of treatment might be adequate for which type of patient by addressing dysfunctions of distinct functional subsystems of the brain. For example, one can use a battery of imaging tasks, including unspecific neurofunctional probes tagging functional systems assumed to be affected in most psychiatric patients, for example, amygdala activation [1]. In addition, this battery should include systems involved in functions possibly specifically impaired in chronic depression, like the theory-of-mind system [66, 67] or a design that renders interpersonal interaction directly (Schnell et al., in preparation). Such a functional system mapping could one day serve similar purposes in psychiatry as neuropsychological test batteries serve in neurology today. However, at the moment it is an open question whether neurobiological markers will achieve one day a differentiation between groups of depressive patients that is useful in clinical practice.

Neuroethical issues In this final section, we want to discuss some possible neuroethical issues arising when using neuroimaging in neuropsychotherapy. Neuroethics is the discipline concerned with ethical problems arising from monitoring or influencing the brain [27]. Here, we want to discuss three issues: (i) the allegedly ‘‘harmful objectivation’’ of the patient, (ii) the danger of premature application, and, perhaps somewhat surprising, (iii) the possible success of neuropsychotherapy. The issue of ‘‘harmful objectivation’’

Fig. 2 Temporal change of beta estimates (a proxy for the effect on brain signals) for the correlation between subjective ratings of arousal intensity and BOLD response in the left amygdala found in four individual responders during dialectical behavior therapy (DBT) [55]. Beta estimates are given in arbitrary units for five measurements. As beta estimates are centerd, negative values do not indicate negative correlations but a relative decrease of statistical connectedness of BOLD signals and ratings

Where neuroscience and psychotherapy meet in practice— for example, at conferences or in interdisciplinary discussions—a worry that is repeatedly brought forward by the psychotherapist camp is that a neuroscientific approach to psychotherapy would result in a cold, objective, and implicitly ‘‘bad’’ attitude toward the patient, focusing on explaining rather than understanding. And indeed, when neuroscientists are talking about psychotherapy, they often feed such worries, reflecting their lack of experience in working with patients. However, this does not imply that a deeper understanding of neurobiology in psychotherapists

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themselves makes them less empathetic. In contrast, we believe that correct explanations will increase the potential of psychotherapists to empathize with their patients and will not lead to an unhelpful reductionist attitude in the process of psychotherapy. However, for scientists on the other side, reductionism is a methodological virtue. Explanatory reduction is exactly the job scientists are supposed to do: They try to isolate variables, decrease variance, aim for complexity reduction, try to operationalize their questions, and try to be as objective as possible to deliver reproducible, interpretable results and not only just so stories. This scientific agenda is also a virtue for psychotherapy researchers. If one does not mix up scientific studies with the practice of psychotherapy, we do not consider more knowledge about the brain a deep ethical problem.

choice for this genetically determined disorder is not to repair the defective gene but something much easier, less invasive, and more effective: to keep a strict diet.

The danger of premature application This is a more important field of ethical concern. Usually, new technologies like neuroimaging tend to deliver new data quite rapidly that are not easy to interpret, although, in the case of neuroimaging, these technologies seem to have a straightforward translational aspect as they are intuitively telling. Based on the wrong understanding that ‘‘what you see is what you get,’’ lay people as well as professionals tend to prematurely translate scientific results into concrete actions. In doing so, three typically wrong inferences are drawn quickly. The first fallacy is premature generalization from one particular experiment or group to depressive patients in general. However, you cannot always generalize from one study on depression to every patient presenting with a depression; there are many varieties of this disorder. The second fallacy is to think that group differences can smoothly be translated to individuals. But judging the relevance of quantitative aspects of individuals’ brain signals does require either a standardized reference group to which individual measurements can be put into relation or very robust findings in single subjects allowing inferences to be drawn on the individual level. Both conditions are rarely met in neuroimaging studies. The third fallacy is to think that the measurement of a parameter gives direct access to causation and treatment options: If a characteristic measure for a disorder, group, or mechanisms is obtained, it is often inferred that changing this measure or parameter is the best way for effective treatment or change. However, this is not necessarily true, as many brain parameters might be only surrogate markers instead of factors causally contributing to a disorder. Furthermore, even if neuroimaging does discern causal factors, this does not imply that they should be targets of intervention. Sometimes indirect approaches are much more successful, as the case of phenylketonuria shows. The treatment of

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The possible success of neuropsychotherapy Despite all limitations, neuroimaging clearly has at least the potential to provide us with reliable surrogate markers or even indicators of causal factors of mental disorders and to extract clinically relevant parameters, at least in some instances, which can be used for diagnosis, prognosis or prediction of change within psychotherapy, also for individual subjects. Actually, to achieve this is the research agenda of medicine in general. Surely, achieving this would improve psychological medicine and help to treat patients better and more effectively. However, such success might bring with it further neuroethical problems—problems that are similar to those that have been discussed in other areas of biomedicine, for example, genetic medicine: How should we handle accurate, predictive knowledge in cases where therapeutic options are limited? How can we protect the privacy of reliable data about mental states? How can we prevent abuse of accurate information about mental dysfunction by institutions or the state? What should be done if new technologies are effective but costs are too high to make them available to everyone? We think that these issues are relevant and important. Actually, the fact that neurotechnologies are, at least at the moment, less powerful than media in general suggests, provides us with the opportunity to think in advance about these issues before they become practical problems on a large scale.

Conclusion We believe that neuroscience is already being integrated into psychotherapy and that this inevitable process cannot and should not be reversed. Established knowledge about brain function has already become part of psychotherapeutic education at some places and this development should be strengthened. We have suggested a working definition of neuropsychotherapy that includes the identification of mediators and functional targets, determination of new therapeutic routes to such targets, and finally even the design of psychotherapeutic techniques. We have shown that neuroimaging studies are increasingly used to study effects and mechanisms of psychotherapy. In order to prevent disappointment and to improve science, we think that the best way to promote neuropsychotherapy is to openly discuss not only its merits but also its limitations, because only when we regularly face our limits we may one day transcend them.


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Acknowledgments This work was partly supported by a BMBF grant to H.W. (01GP0804).

18. Drevets WC (1999) Prefrontal cortical-amygdalar metabolism in major depression. Ann N Y Acad Sci 877:614–637 19. Freud S (1895) Project for a scientific psychology. In: Srachey J (ed) Standard edition of the complete psychological works of Sigmund Freud. Hogarth Press, London, pp 294–397 20. Frewen PA, Dozois DJ, Lanius RA (2008) Neuroimaging studies of psychological interventions for mood and anxiety disorders: empirical and methodological review. Clin Psychol Rev 28:228– 246 21. Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET (2004) Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatr 61:877–889 22. Fu CH, Williams SC, Cleare AJ, Scott J, Mitterschiffthaler MT, Walsh ND, Donaldson C, Suckling J, Andrew C, Steiner H, Murray RM (2008) Neural responses to sad facial expressions in major depression following cognitive behavioral therapy. Biol Psychiatr 64:505–512 23. Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H (2004) Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatr 61:34–41 24. Grawe K (2004) Neuropsychotherapie. Hogrefe, Go¨ttingen 25. Gross JJ (2002) Emotion regulation: affective, cognitive, and social consequences. Psychophysiology 39:281–291 26. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW (2006) Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatr 63:298–304 27. Illes J, Bird SJ (2006) Neuroethics: a modern context for ethics in neuroscience. Trends Neurosci 29:511–517 28. Jauch-Chara K, Hohagen F (2009) Neurobiological correlates of psychotherapy of depression [Neurobiologische Korrelate der Psychotherapie bei Depression]. Zeitschrift fu¨r Psychiatrie, Psychologie und Psychotherapie 57:105–112 29. Kandel ER (1998) A new intellectual framework for psychiatry. Am J Psychiatr 155:457–469 30. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J (2000) A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 342:1462–1470 31. Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ (2001) Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatr 158:899–905 32. Kennedy SH, Konarski JZ, Segal ZV, Lau MA, Bieling PJ, McIntyre RS, Mayberg HS (2007) Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatr 164:778– 788 33. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5:e45 34. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435:673–676 35. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902 36. Linden DE (2006) How psychotherapy changes the brain—the contribution of functional neuroimaging. Mol Psychiatr 11:528– 538

Conflicts of interest statement The authors declare no conflicts of interest.

References 1. Abler B, Erk S, Herwig U, Walter H (2007) Anticipation of aversive stimuli activates extended amygdala in unipolar depression. J Psychiatr Res 41:511–522 2. Anand A, Li Y, Wang Y, Gardner K, Lowe MJ (2007) Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study. J Neuropsych Clin Neurosci 19:274–282 3. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida RM (1989) Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatr 46:243–250 4. Beauregard M (2009) Effect of mind on brain activity: evidence from neuroimaging studies of psychotherapy and placebo effect. Nord J Psychiatr 63:5–16 5. Beauregard M, Levesque J, Bourgouin P (2001) Neural correlates of conscious self-regulation of emotion. J Neurosci 21:RC165 6. Beck AT (2008) The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatr 165:969–977 7. Birbaumer N, Veit R, Lotze M, Erb M, Hermann C, Grodd W, Flor H (2005) Deficient fear conditioning in psychopathy: a functional magnetic resonance imaging study. Arch Gen Psychiatr 62:799–805 8. Blair J, Mitchel D, Blair K (2005) The psychopath: emotion and the brain. Blackwell, Oxford 9. Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Alborzian S, Phelps ME, Huang SC, Wu HM, Ho ML, Ho MK, Au SC, Maidment K, Baxter LR Jr (2001) Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings. Arch Gen Psychiatr 58:631–640 10. Buchheim A, Heinrichs M, George C, Pokorny D, Koops E, Hennigssen P, O’Connor MF, Gu¨ndel H (2009) Oxytocin enhances the experience of attachment security. Psychoneuroendocrinology (in press) 11. Cojan Y, Waber L, Carruzzo A, Vuilleumier P (2009) Motor inhibition in hysterical conversion paralysis. Neuroimage 47:1026–1037 12. Davidson RJ, Irwin W, Anderle MJ, Kalin NH (2003) The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatr 160:64–75 13. DeCharms RC (2008) Applications of real-time fMRI. Nat Rev Neurosci 9:720–729 14. de Charms RC, Maeda F, Glover GH, Ludlow D, Pauly JM, Soneji D, Gabrieli JD, Mackey SC (2005) Control over brain activation and pain learned by using real-time functional MRI. Proc Natl Acad Sci USA 102:18626–18631 15. Demertzi A, Liew C, Ledoux D, Bruno MA, Sharpe M, Laureys S, Zeman A (2009) Dualism persists in the science of mind. Ann N Y Acad Sci 1157:1–9 16. DeRubeis RJ, Siegle GJ, Hollon SD (2008) Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat Rev Neurosci 9:788–796 17. Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC (2007) Oxytocin improves ‘‘mind-reading’’ in humans. Biol Psychiatr 61:731–733

123

S182 37. Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453:869–878 38. Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5:844–852 39. Martin SD, Martin E, Rai SS, Richardson MA, Royall R (2001) Brain blood flow changes in depressed patients treated with interpersonal psychotherapy or venlafaxine hydrochloride: preliminary findings. Arch Gen Psychiatr 58:641–648 40. Mayberg HS (2003) Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 65:193–207 41. Mayberg HS (2003) Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin N Am 13:805–815 42. Mayberg HS, Brannan SK, Mahurin RK, Jerabek PA, Brickman JS, Tekell JL, Silva JA, McGinnis S, Glass TG, Martin CC, Fox PT (1997) Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8:1057–1061 43. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatr 156:675–682 44. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA (2002) The functional neuroanatomy of the placebo effect. Am J Psychiatr 159:728–737 45. McCullough JP (2003) Treatment for chronic depression: cognitive behavioral analysis system of psychotherapy (CBASP). Guilford 46. McRae K, Hughes B, Chopra S, Gabrieli JD, Gross JJ, Ochsner KN (2009) The neural bases of distraction and reappraisal. J Cogn Neurosci. doi:10.1162/jocn.2009.21243 47. Nader K, Hardt O (2009) A single standard for memory: the case for reconsolidation. Nat Rev Neurosci 10:224–234 48. Nemeroff CB, Heim CM, Thase ME, Klein DN, Rush AJ, Schatzberg AF, Ninan PT, McCullough JP Jr, Weiss PM, Dunner DL, Rothbaum BO, Kornstein S, Keitner G, Keller MB (2003) Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 100:14293–14296 49. Ochsner KN, Gross JJ (2005) The cognitive control of emotion. Trends Cogn Sci 9:242–249 50. Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, Gross JJ (2004) For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 23:483–499 51. Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004) Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43:897–905 52. Raboni MR, Tufik S, Suchecki D (2006) Treatment of PTSD by eye movement desensitization reprocessing (EMDR) improves sleep quality, quality of life, and perception of stress. Ann N Y Acad Sci 1071:508–513 53. Schleim S, Walter H (2007) Mind reading with the brain scanner? [Gedankenlesen mit dem Hirnscanner?] Nervenheilkunde 26:505–510 54. Schleim S, Walter H (2008) Mind reading: a challenge for neuroethics [Gedankenlesen—Eine Herausforderung fu¨r die Neuroethik]. In: Vogelsang F, Hoppe C (eds) Without the brain,

123


55.

56.

57.

58.

59. 60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

nothing works. Impulses for a neuroethics [Ohne Hirn ist alles nichts. Impulse fu¨r eine Neuroethik]. Neukirchener Verlag, Neukirchen-Vluyn, pp 150–168 Schnell K, Herpertz SC (2007) Effects of dialectic-behavioraltherapy on the neural correlates of affective hyperarousal in borderline personality disorder. J Psychiatr Res 41:837–847 Schoepf D, Konradt B, Walter H (2007) Specific psychotherapy of chronic depression with the Cognitive Behavioral System of Psychotherapy [Spezifische Psychotherapie der chronischen Depression mit dem Cognitive Behavioral Analysis System of Psychotherapy]. Nervenheilkunde 26:790–802 Schonfeldt-Lecuona C, Connemann BJ, Spitzer M, Herwig U (2003) Transcranial magnetic stimulation in the reversal of motor conversion disorder. Psychother Psychosom 72:286–288 Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S (2004) Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22:409–418 Sessa B (2007) Is there a case for MDMA-assisted psychotherapy in the UK? J Psychopharmacol 21:220–224 Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA (2001) Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatr 50:651–658 Siegle GJ, Carter CS, Thase ME (2006) Use of fMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am J Psychiatr 163:735–738 Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME (2007) Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatr 61:198–209 Spence SA, Crimlisk HL, Cope H, Ron MA, Grasby PM (2000) Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet 355:1243– 1244 Staudinger MR, Erk S, Abler B, Walter H (2009) Cognitive reappraisal modulates expected value and prediction error encoding in the ventral striatum. Neuroimage 47:713–721 Walter H (2009) What can we measure? Neuroimaging—an introduction into basic principles, common fallacies and their possible relevance for penal law and our idea of man. [Was ko¨nnen wir messen? Neuroimaging—eine Einfu¨hrung in methodische Grundlagen, ha¨ufige Fehlschlu¨sse und ihre mo¨gliche Bedeutung fu¨r Strafrecht und Menschenbild.] In: Schleim S, Spranger T, Walter H (eds) From Neuroethics to Neurolaw. The beginning of a new debate. [Von der Neuroethik zum Neurorecht. Der Beginn einer neuen Debatte.] Vandenhoeck & Ruprecht, Go¨ttingen, pp 67–103 Walter H, Abler B, Ciaramidaro A, Erk S (2005) Motivating forces of human actions. Neuroimaging reward and social interaction. Brain Res Bull 67:368–381 Walter H, Adenzato M, Ciaramidaro A, Enrici I, Pia L, Bara BG (2004) Understanding intentions in social interaction: the role of the anterior paracingulate cortex. J Cogn Neurosci 16:1854–1863 Walter H, von Kalckreuth A, Schardt D, Stephan A, Erk S (2009) The temporal dynamics of emotion regulation. PLoS ONE 4(8):e6726 Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56:19–32