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REVIEW ARTICLE
Functional Neuroimaging
in Psychiatry
Evaluation of psychotherapy and development of new treatments
David E. J. Linden
SUMMARY
Introduction: Functional neuroimaging has already provided important insights into the cerebral
mechanisms of psychopathology. It is now increasingly being used in the investigation of the
cerebral effects of therapy as well. Changes in brain function and metabolism following drug
therapy and, increasingly, psychotherapy, have been documented. Methods: Selective literature
review. Results: The most widely replicated effects include the reduction of limbic and paralimbic
activity after behavioural therapy for phobia, and the normalisation of striatal hyperactivity in obsessive compulsive disorder. The pattern of results in depression is more patchy, with some results suggesting hyperactivity in the subgenual cingulate. This finding triggered a recent study of
deep brain stimulation to the subgenual cingulate. However, the clinical efficacy of this technique
in depression requires assessment in further studies. Discussion: The role of functional neuroimaging in the discovery of faulty cerebral feedback loops and the monitoring of treatment protocols appears promising, but studies to date are limited by methodological problems. New technical developments in imaging-based neurofeedback may result in the use of functional imaging
as a therapeutic tool.
Dtsch Arztebl 2006; 103(38): A 2472–8.
Key words: psychotherapy, functional magnetic resonance imaging, positron emission tomography,
neurofeedback, depression
F
unctional imaging has assumed a central role in neuroscience research in the past ten
years. Positron emission tomography (PET) and single photon emission computed
tomography (SPECT) enable the visualization of blood flow or glucose metabolism in the
resting state. Functional magnetic resonance imaging (fMRI) is used to measure brain activity in response to a stimulus or task. fMRI, in particular, allows insight into the physiology
and pathology of perception and cognition and has become an indispensable tool for psychological, neurological, and psychiatric research. Its clinical applications, however, remain
very limited at present. Its most important current use is for preoperative brain mapping.
In psychiatry, fMRI has led to an improved understanding of the cerebral correlates of
psychopathological phenomena (e1, e2), cognitive disorders, and genetic risk factors. Studies on
changes in brain activity during the treatment of mental illness may have particular clinical
relevance. Functional neuroimaging has been used to study the effects of treatment, not just with
medications of different kinds, but also with electroconvulsive therapy (e4), vagus nerve stimulation
(e5), and, last but not least, various types of psychotherapy (Table). This use of psychological
techniques (psychometry and psychotherapy) in combination with biological techniques (functional
neuroimaging) typifies the trend in modern psychiatry toward the integration of these two approaches
to mental illness, which were once widely held to be incompatible.
Possible clinical applications of functional neuroimaging in psychiatry include
> assessment of the effects of treatment,
> determination of differential indications for treatment,
> identification of target areas for neurophysiological treatment methods, either invasive
(deep brain stimulation) or noninvasive (transcranial magnetic stimulation), and
> development of neurobiologically inspired treatments such as neuropsychotherapy
and neurofeedback.
These clinical prospects will be discussed after a brief review of the research techniques
themselves and of the studies that have been performed with them to date to assess the
effect of psychotherapy.
School of Psychology, University of Wales Bangor und Mental Health and Learning Disability Directorate, North West Wales NHS
Trust (PD Dr. med. Dr. phil. Linden, D. Phil)
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TABLE
Changes in regional cerebral activity after psychotherapy in different types of mental illness
Mental illness
Increased activity
Decreased activity
Studies and
treatment methods
Obsessivecompulsive disorder
None
Caudate nucleus (RH)
(2, 3) (both CBT) (4) (BT)
Social phobia
None
Amygdala,
hippocampus,
parahippocampal gyrus
(bilateral)
(9) (CBT)
Arachnophobia
Visual association
cortex (bilateral)
Insular cortex,
thalamus,
dorsal AC (bilateral),
parahippocampal gyrus,
DLPFC (RH)
(7, 8) (both CBT)
Depression
Hippocampus, PCC,
dorsal ACC (bilateral),
basal ganglia (RH)
DLPFC, VLPFC, OFC,
dorsal ACC
(14) (CBT) (15, 25)
(both IPT)
ACC, anterior cingulate cortex; BT, behavior therapy; CBT, cognitive behavior therapy; DLPFC, dorsolateral prefrontal cortex;
IPT, interpersonal therapy; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; RH, right hemisphere; VLPFC, ventrolateral prefrontal cortex
Research techniques of functional neuroimaging in psychiatry
The classic method of demonstrating changes in brain function after psychotherapy or
pharmacotherapy involves measurement of the cerebral blood flow or glucose metabolism
at rest. This technique is based on the assumption that the intervention under study
achieves its beneficial clinical effect (symptom reduction) by changing baseline cerebral
activity. This assumption is most plausible when the condition in question can be shown to
be associated with abnormal cerebral activity before it is treated. In the absence of any reliable evidence of regional hyper- or hypoactivity at rest before treatment, there is a risk that
this method will yield false negative results.
In such cases, functional neuroimaging with symptom provocation may be a more sensitive way of detecting treatment-related changes. The classic application of this technique
is to the study of specific phobias, e.g., arachnophobia, in which clinical symptoms can be
induced with appropriate pictures or film clips. The success of symptom provocation is
gauged with questionnaires or psychophysiological methods. The goal is to demonstrate
abnormal brain activity with functional imaging correlated with the presence of symptoms,
e.g., activity in the limbic system of persons with arachnophobia while looking at pictures
of spiders, but not in the limbic system of normal controls exposed to the same pictures (1).
Effective treatment ought to be accompanied by a normalization of the abnormal activity in
parallel with an improvement of symptoms. The major limitation of this technique is that
clinically relevant conditions only rarely have such a narrowly circumscribed phenotype. In
syndromes with more complex phenotypes, such as depression, a restricted focus on a
single symptom in a provocation study might yield oversimplified or erroneous conclusions about disease-related changes in brain activity.
One advantage of functional neuroimaging with symptom provocation, in comparison to
measurements at rest, might be a higher retest reliability, because the signal is presumably
less dependent on uncontrollable factors. This question deserves systematic study, because
the elimination of confounding effects, such as that of different levels of cognitive activity
in the "resting states" before and after treatment, is a challenge facing all researchers that
use functional neuroimaging to measure the effect of treatment.
Other poorly controllable confounding factors include the global effects of medication
on brain metabolism-e.g., in studies in which patients are treated with both psychotherapy
and medication-and non-specific physiological variables such as the pattern of sleep, the
time since the last meal, and the consumption of caffeine and nicotine. These effects are
only partly compensated for by the normalization of regional effects on global brain metabolism that is routinely performed as part of the processing of PET and SPECT images.
The quantitative conclusions that can be drawn are, therefore, limited.
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Treatment effects in obsessive-compulsive disorder
Current pathophysiological models of obsessive-compulsive disorder postulate uncontrolled neuronal activity in the thalamus, orbitofrontal cortex (OFC), and anterior cingulate
cortex (ACC). Pathological activation of the corpus striatum (Figure 1) might play an
important causal role; this structure influences the "gating" function of the thalamus by way
of a cortico-striato-thalamocortical regulatory loop. In fact, most functional neuroimaging
studies at rest and with symptom provocation have revealed hyperactivity in the thalamus,
OFC, and ACC, as well as in the caudate nucleus (though less consistently).
Three PET studies on the effect of psychotherapy on obsessive-compulsive disorder
have been performed to date. All three showed a reduction of activity in the right
caudate nucleus (2, 3, 4). Moreover, patients with obsessive-compulsive disorder were
found to have an elevated correlation between striatal, thalamic, and OFC activity that
was no longer present after successful treatment. This was true both for patients treated
Figure 1:
Topographical anatomy of various
areas of the brain, as seen in a
T1-weighted magnetic resonance
image with three-dimensional reconstruction and a combination of axial
and coronal planes of section.
1 amygdala,
2 putamen ,
3 caudate nucleus (2 and 3 together
form the corpus striatum),
4 cingulate gyrus,
5 insular cortex,
6 parahippocampal gyrus.
The image was processed with
Brain Voyager software.
with cognitive behavioral therapy and for patients in the control group, who were treated
with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (2, 3). The convergence
of the biological effects of psychological and pharmacological intervention is
especially relevant to our understanding of the mechanisms of action of psychotherapy.
A newly published fMRI study with symptom provocation (5) provides further evidence
along the same lines, revealing lower activity in the thalamus, as well as in the frontal lobe and
cingulate cortex, after successful treatment. The behavioral therapy (BT) and SSRI groups
could not be separately analyzed in this study because of the small number of patients.
The clinically relevant question of possible differences between the cerebral mechanisms underlying obsessions and compulsions cannot yet be answered from the findings
of functional neuroimaging studies. All studies involving symptom provocation were limited, for obvious practical reasons, to the provocation of obsessive thoughts (6). The intervention studies discussed above did not reveal any difference between the effects of cognitive behavioral therapy (CBT) on these two symptom complexes.
Treatment effects in phobias
Specific phobias are especially well suited for study with fMRI, because the symptoms can
be provoked in a standardized manner. In contrast, symptom provocation in obsessivecompulsive disorder or post-traumatic stress disorder must be tailored to the symptoms and
history of the individual patient. Symptom provocation studies monitoring the effect of
treatment in phobias have yielded promising initial results.
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A study on the cerebral correlates of the successful behavioral therapy of arachnophobia
revealed hyperactivity in the parahippocampal gyrus and the dorsolateral prefrontal cortex
before the intervention, which normalized after only four exposure sessions (7). Another
arachnophobia study (8) showed that video clips of spiders provoked greater than normal
activation in the insula and anterior cingulate cortex, which normalized after successful CBT.
In patients with social phobia, reduced activity was found in the amygdala and neighboring areas both after psychotherapy and after treatment with the SSRI citalopram (9). A possible role for the amygdala in the maintenance of phobic reactions would have implications
for etiological research, as it would be most consistent with learning-theoretical models of
the anxiety disorders, e.g., an anxiety conditioning model. It is hoped that further interventional studies using functional neuroimaging for treatment monitoring, beyond the
small number that have been performed to date, will shed further light on this question.
Because standardized images are easiest to use in disorders with relatively homogeneous
symptoms, such as isolated arachnophobia, these disorders also lend themselves particularly well to multicenter studies. Multicenter functional imaging studies along similar lines
have already been carried out successfully on a nationwide level, e.g., in schizophrenia. We
hope that the current initiatives in support of psychotherapeutic research will give rise to
analogous projects employing standardized treatment and imaging protocols to study
anxiety and obsessive-compulsive disorders.
Functional neuroimaging and depression
Symptom provocation under experimental conditions is more difficult in depression than in
the disorders discussed above and can at best induce only some, but not all, components of
the depressive syndrome. The brain areas participating in the control of mood can be detected in normal subjects by the induction of sadness with pictures or short stories; in particular, activity in the subgenual area, i.e., the portion of the cingulate gyrus that lies under the
genu of the corpus callosum (10), and the amygdala is correlated with the degree of
sadness. The applicability of these findings to depression is debated; one study (10) paradoxically showed that the same stimulus that induced sadness in normal persons led to a remission of symptoms in patients with depression. It seems, however, that the cerebral networks for sadness and depression do indeed overlap, at least in part.
Aside from the problem of methodologically valid symptom provocation, the use of
functional neuroimaging to study the mechanisms of depression and its treatment is further
complicated by the lack of an unambiguous metabolic correlate of depression in the brain.
Most studies have shown prefrontal hypoactivity normalizing after remission (12). The
increase of prefrontal metabolism accompanying improvement of symptoms was
independent of whether the improvement followed pharmacotherapy with fluoxetine or
placebo treatment (13), e.g., inpatient hospitalization without any specific treatment of
depression. Another study (14), however, yielded a contradictory result: in patients whose
depressive symptoms responded well to cognitive behavioral therapy (CBT), the improvement was associated with a reduction of metabolism in the entire lateral prefrontal cortex.
A reduction of prefrontal glucose metabolism was also found after successful treatment
with interpersonal therapy (IPT) (15).
The authors propose the following model to explain this divergence between pharmacoand psychotherapy. Activity in the prefrontal cortex declines over the course of treatment
with CBT in parallel with negative thoughts. The simultaneously observed increase in the
activity of the hippocampus and dorsal cingulated gyrus correlates with increased attentiveness to emotional stimuli. The effects of pharmacotherapy with SSRI-increased prefrontal
activity and decreased activity in the hippocampus and other limbic areas, such as the ventral cingulate gyrus-are in the opposite direction to those of CBT because they reflect a
direct influence on synaptic transmission, rather than cognitive control (14).
This model is of interest because it is not limited to a change in the activity of a single
region of the brain. In a disorder as complex as the depressive syndrome, clinical improvement probably results from a modification of the interactions of multiple brain regions. In
any case, the differences between treatment types should be investigated in further prospective studies employing standardized imaging techniques.
Functional imaging in the more restricted sense, i.e., the measurement of blood flow,
blood oxygenation, or glucose metabolism with PET, SPECT, or fMRI, hardly permits
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any inferences to be drawn about molecular mechanisms. This might be achievable with
a combination of these techniques with molecular imaging methods, such as radioligand
PET or SPECT and magnetic resonance spectroscopy. With its high spatial resolution,
functional neuroimaging permits more precise identification of the target areas for
molecular imaging.
Functional neuroimaging and neurophysiological treatment
The reproducibility of the above-described changes in resting brain metabolism in depression is not merely of theoretical interest. Mayberg and colleagues recently published a
pilot study of deep brain stimulation (DBS) in the cingulate region in patients with intractable depression (16). They made explicit use of the findings of functional neuroimaging to
provide a rationale for this type of treatment and to choose the target site of stimulation.
In this study, DBS electrodes were implanted into the white matter underlying the subgenual cingulate cortex in six patients. The authors of the study, using PET, had previously
found this area to be hyperactive in patients with depression. Four patients were clinically improved six months after implantation. The small number of cases and the lack of a control
group make it difficult to generalize from these findings. Larger, controlled studies of cingulate DBS must certainly be awaited before the clinical utility of this method can be assessed.
Perspectives for functional neuroimaging in clinical psychotherapy
Functional neuroimaging may perhaps point the way toward less invasive treatment strategies, including what has been called "apparatus-based psychotherapy" (17). New technical
improvements enabling real-time analysis of fMRI data have led to the development of
neurofeedback techniques based on fMRI, which are analogous to earlier ones based on
electroencephalography (EEG). Just as in classic biofeedback, persons undergoing neurofeedback train themselves to regulate their own brain activity. Subjects in a pilot study
were able to manipulate the fMRI activity of their anterior cingulate cortex voluntarily
(Figure 2) (19).
This type of training can only be performed over the course of several sessions in an
MRI scanner and therefore requires a certain amount of discipline on the part of the
patient. Moreover, any clinical effects it might have, such as an improvement of depressive
symptoms after voluntary suppression of cingulate activity, remain to be demonstrated.
Initial clinical findings have been published for this form of training when used to treat
pain (20).
Figure 2: Sagittal and coronal sections of the brain. Color coding (red-orange) indicates the areas in which an experimental subject was able
to change the level of activity significantly after neurofeedback training. The borders of the dorsal and ventral anterior cingulate cortical areas
are drawn in yellow and violet, respectively. From Weiskopf N, Veit R, Erb M et al.: Physiological self-regulation of regional brain activity using
real-time functional magnetic resonance imaging (fMRI): methodology and exemplary data. Neuroimage 2003; 19: 577-586, reprinted with
the kind permission of Elsevier Science, Amsterdam.
Another approach to neurobiologically based psychotherapy is neuropsychotherapy. In
this approach, the scientific understanding of dysfunctional regulatory circuits in various
mental illnesses is exploited to develop psychotherapeutic techniques that can specifically
influence these circuits (21).
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Functional neuroimaging finds further application in psychiatry as a means of monitoring treatment effects and of studying the neurophysiological correlates of response and
non-response to treatment. The difficulty (and often impossibility) of predicting a patient's
responsiveness to a certain type of pharmacotherapy or psychotherapy on clinical grounds
alone is one of the greatest problems currently facing clinical psychiatry. In the future, functional neuroimaging may help us predict the likelihood that a particular form of treatment
will be successful before it is initiated (22). This information can be used in clinical decision-making, e.g., in the decision whether to apply pharmacotherapy or psychotherapy.
Some initial results of this type are already available. In a study of patients with obsessive-compulsive disorder, a relationship was found between glucose metabolism in the left
orbital frontal cortex and the success of either behavioral therapy or treatment with
fluoxetine (23). A high metabolic rate was correlated with good responses to behavioral
therapy, but poor responses to pharmacotherapy. It is clearly not possible to make any treatment recommendations on the basis of this small, non-randomized study. Nonetheless, the
concept underlying it seems promising, i.e., that differences between specific pathophysiological mechanisms can be used to identify subgroups within a clinical diagnostic category
that are more likely to respond to certain forms of treatment.
With the exception of a few case studies (22), functional neuroimaging studies involving
psychotherapy have been limited, so far, to manualized short-term therapies such as cognitive behavioral therapy and interpersonal therapy. A further extension of functional neuroimaging to the study of psychodynamic techniques would certainly be of great interest, particularly because concrete hypotheses on their neurobiological effects have already been
proposed on the basis of experimental studies of plasticity in animals (24).
In conclusion, the newer methods of functional neuroimaging, particularly functional
magnetic resonance imaging, have already made major contributions to basic research in
psychiatry. They now seem to have arrived at the threshold of clinical applicability. The
application of functional neuroimaging to psychotherapy would not imply that older,
psychological techniques have been discarded and replaced by newer, biological ones.
Rather, it would enable further refinement of the indications for, and use of, therapeutic
methods in the light of an improved neurobiological understanding of mental illness.
Conflict of Interest Statement
The authors declare that no conflict of interest exists according to the Guidelines of the International Committee of Medical
Journal Editors.
Manuscript received on 23 September 2005, final version accepted on 14 March 2006.
Translated from the original German by Ethan Taub, M. D.
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ADDITIONAL REFERENCES
This text is a
translation from
the original
German which
should be used
for referencing.
The German
version is
authoritative.
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e3. Hariri AR, Weinberger DR: Imaging Genomics. British Medical Bulletin 2003;65: 259–70.
e4. Frodl T, Meisenzahl EM, Möller HJ: Bedeutung der bildgebenden Verfahren in der Beurteilung der Elektrokonvulsivtherapie. Nervenarzt 2004; 75: 227–33.
e5. Zobel A, Joe A, Freymann N, et al.: Changes in regional cerebral blood flow by therapeutic
vagus nerve stimulation in depression: An exploratory approach. Psychiatry Res 2005; 139: 165–79.
Corresponding author
Priv.-Doz. Dr. med. Dr. phil. David E. J. Linden, D. Phil.
Brigantia Building
Road, Bangor LL57 2AS
Great Britain
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