How Psychotherapy Changes the Brain - The Contribution of Functional Neuroimaging

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FEATURE REVIEW

How psychotherapy changes the brain the contributionof functional neuroimagingDEJ Linden1,2

1School of Psychology, University of Wales Bangor, Bangor, UK and 2North West Wales NHS Trust, Bangor, UK

A thorough investigation of the neural effects of psychotherapy is needed in order to provide aneurobiological foundation for widely used treatment protocols. This paper reviews functionalneuroimaging studies on psychotherapy effects and their methodological background,including the development of symptom provocation techniques. Studies of cognitivebehavioural therapy (CBT) effects in obsessive-compulsive disorder (OCD) were consistentin showing decreased metabolism in the right caudate nucleus. Cognitive behavioural therapyin phobia resulted in decreased activity in limbic and paralimbic areas. Interestingly, similareffects were observed after successful intervention with selective serotonin reuptakeinhibitors (SSRI) in both diseases, indicating commonalities in the biological mechanisms of

psycho- and pharmacotherapy. These findings are discussed in the context of currentneurobiological models of anxiety disorders. Findings in depression, where both decreasesand increases in prefrontal metabolism after treatment and considerable differences betweenpharmacological and psychological interventions were reported, seem still too heterogeneousto allow for an integrative account, but point to important differences between the mechanismsthrough which these interventions attain their clinical effects. Further studies with largerpatient numbers, use of standardised imaging protocols across studies, and ideallyintegration with molecular imaging are needed to clarify the remaining contradictions. Thiseffort is worthwhile because functional imaging can then be potentially used to monitortreatment effects and aid in the choice of the optimal therapy. Finally, recent advances in thefunctional imaging of hypnosis and the application of neurofeedback are evaluated for theirpotential use in the development of psychotherapy protocols that use the direct modulation ofbrain activity as a way of improving symptoms.Molecular Psychiatry(2006)11, 528538. doi:10.1038/sj.mp.4001816; published online 7 March 2006

Keywords: psychotherapy; anxiety disorders; depression; functional magnetic resonanceimaging; positron emission tomography; selective serotonin reuptake inhibitors

Introduction

It has long been recognised by clinicians thatpsychological interventions can profoundly alterpatients sets of beliefs, ways of thinking, affectivestates and patterns of behaviour. Yet the putativemechanisms and underlying changes in the brainhave only recently attracted the attention theydeserve.1 This enterprise is important for two mainreasons. First, psychotherapy needs to be based on asound understanding of the biological processesinvolved. There is no reason why this generalstandard of contemporary medicine, which is, forexample, needed in order to detect and fight potentialside effects, should not apply here as well. Second, a

better understanding of these biological mechanismsmight aid in the improvement of therapeutic inter-

ventions or even in the utilisation of these verymechanisms, as in the case of neurofeedback.

One reason for the sluggish development of re-search into the neural side of psychotherapy might bethat here plastic changes in the human brain have to

be detected with noninvasive techniques, whileconventionally plasticity research has been con-ducted at the cellular level. Yet the tools of non-invasive functional brain imaging can now reliably

detect training- and learning-related changes in brainactivation patterns in healthy volunteers,2 and thereis no reason why this should not be possible in thoseaffected by mental disorders as well. Potentially,functional imaging can detect psychotherapy-relatedchanges at the level of brain areas and circuits, andthus contribute to an elucidation at least of the mostglobal neural mechanisms (Figure 1a). Such anapproach would not only benefit basic research intothe mechanisms of action of psychotherapy, but alsoaid our understanding of differences and commonal-ities between psycho- and pharmacotherapy, providea further tool for the evaluation of therapy effects and,might ultimately help clinicians to select optimal

Received 30 August 2005; revised 24 January 2006; accepted 30January 2006; published online 7 March 2006

Correspondence: Dr DEJ Linden, School of Psychology, Universityof Wales Bangor, Brigantia Building, Penrallt Road, Bangor LL572AS, UK.E-mail: [email protected]

Molecular Psychiatry (2006) 11, 528538&2006 Nature Publishing Group All rights reserved 1359-4184/06$30.00

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treatment for individual patients on the basis ofbaseline functional activation patterns3,4 (Figure 1b).

Most functional imaging studies into psychother-

apy effects have been conducted with nuclearmedicine methods like positron emission tomography(PET) or single photon emission computed tomogra-phy (SPECT), and assessed changes in brain metabo-lism or blood flow between a pre- and post-treatmentscan. The use of functional magnetic resonanceimaging (fMRI), which does not expose the patientto radiation, would potentially confer the advantageof more measurement points, including measures of

brain activation during treatment or at follow-up. YetfMRI has traditionally been used to probe the brainactivation patterns during perceptual or cognitivetasks, rather than to measure baseline brain metabo-lism. The use of fMRI for the detection of psychother-

apy-related changes thus presupposed twomethodological developments, the measurement ofthe neural correlates of psychopathology5 and tech-niques for symptom provocation in the MRI environ-ment.6

In this article, I shall first review functional imagingstudies that used symptom provocation techniques tomimic psychopathological states in a laboratorysetting. This avenue of research has been particularlysuccessful in obsessive-compulsive disorder (OCD)and simple phobias, and is also being pursued forsocial phobia, depression, and post-traumatic stressdisorder (PTSD). I shall go on to review the reports oftreatment trials that monitored the effects of psy-chotherapy with one of the functional imagingtechniques, sometimes comparing it with a groupreceiving standard pharmacotherapy. Subheadings forthe review of these studies will be according todisease (phobia, OCD, depression), rather than ima-ging modality. The selection of the material reviewed

in this section was based on a Pubmed search for theconjunctions of the term psychotherapy with func-tional imaging, functional magnetic resonance,positron emission, and single photon emission,on the reference sections of the retrieved originalreports, and on a textbook to which the authorcontributed.7 Studies on patients under the age of 18or on single cases were not included, nor were studiesemploying other biological markers or looking atpsychological interventions for substance abusedisorders. A search of The Cochrane Database ofSystematic Reviews (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clsysrev_arti-cles_fs.html, accessed on 14 December 2005) did not

yield existing systematic reviews of this topic. In thefinal sections, I shall discuss potential molecularmechanisms of psychological interventions, reviewfindings on neurobiological effects of specific psy-chological interventions and suggest topics for furtherresearch.

Symptom provocation and functional imaging

Symptom reduction is one of the main aims ofpsychotherapy in general, and can be regarded asthe benchmark against which the success of beha-

vioural and cognitive therapies is to be measured.Elucidation of the neural correlates of symptomreduction is therefore a primary goal of any investiga-tion into the biological mechanisms of psychotherapy.The reliable induction of the symptoms in question inthe imaging environment has been an important toolfor this enterprise. Such a symptom provocation willpermit the comparison of brain responses to triggerscenarios (e.g. for social phobia or PTSD) or stimuli(e.g. for simple phobias) before and after treatment,and thus the assessment of therapy effects on neuralactivation. It furthermore has the benefit of allowingthe comparison of response patterns to trigger stimuliin patients and healthy controls,810 elucidating

Figure 1 Three possibilities of integrating psychotherapyand functional neuroimaging with potential clinical im-plications. (a) Baseline imaging measures (with any of thetechnique discussed in the review) are obtained (1) before a

course of psychotherapy (2), after which patients areclassified as responders or nonresponders based on symp-tom improvement or other clinical outcome measures (3)and re-examined with the imaging protocol (4). Thistechnique allows for the assessment of psychotherapy-related changes in brain activation and their specificity forsuccessful outcome. With some modifications, this ap-proach has been used in all studies cited in Tables 13.(b) Baseline imaging measures are obtained (1) before acourse of either psycho- or pharmacotherapy (2), afterwhich patients are classified as responders or nonrespon-ders (3). This outcome information is entered into ananalysis of the pretreatment imaging data (4) with the aimof deriving activation patterns that are predictive oftreatment response (5). (c) Imaging identifies abnormalactivity in a particular brain area or network in a patient (1).This abnormal brain activity is targeted by psychotherapy(based on information derived from studies of type (a),neurofeedback, or a combination of both (2). Patients arethen classified as responders and nonresponders (3). Theoutcome data can then be compared with standardtreatment protocols. Post-treatment imaging (4) will beinformative but not mandatory.

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commonalities and differences in the processing ofaversive material.

A paradigm for the provocation of OCD symptomsduring PET scanning was developed by Rauch et al.11

They demonstrated increased regional cerebral bloodflow (rCBF) in the right caudate, left anteriorcingulate cortex (ACC) and bilateral orbitofrontalcortex (OFC) when patients were exposed to indivi-dually tailored provocative stimuli compared toneutral stimuli. Orbitofrontalstriatalthalamic acti-vation was also reported by McGuire et al.,12 whoadditionally found activity in the left hippocampusand posterior cingulate gyrus to correlate with theintensity of OCD symptoms. They suggested that theformer network might reflect urges to performcompulsive movements, while the latter might bemore related to the accompanying anxiety. Breiter etal.8 used a similar approach with fMRI, showingincreased blood oxygenation level-dependent (BOLD)signal in the right caudate, bilateral OFC, prefrontal

cortex (PFC) and temporal lobes. Thus, the conver-ging evidence from these studies points to increasedneural activity in the right caudate and bilateral OFCduring the experience of symptoms of OCD. Addi-tionally, the insula seems to be activated whencontamination fear is prominent.10 OFC and insulawere activated during the provocation of phobicsymptoms as well,13 as was the left amygdala.14

Symptom provocation studies of PTSD were basedeither on the presentation of trauma-related visual oracoustic stimuli or on script-driven imagery. Thelatter technique induces traumatic imageries and thusmimics flashbacks of the aversive events (as evi-denced by both subjective ratings and psychophysio-

logical parameters) by reading accounts of theirindividual traumatic experiences to patients duringfunctional imaging.15 Increased activation of the rightamygdala was found across provocation techniquesand imaging modalities,1517 while medial prefrontalareas were consistently reported to be less active inPTSD patients than controls when traumatic eventshad to be recalled.18,19 In regions of the medialtemporal cortex commonly associated with memoryretrieval and visual association areas involved inmental imagery both higher and lower activation have

been reported for PTSD patients, possibly reflectingthe heterogeneity of patient samples across studies.

Both autobiographical scripts and visual materialhave been used to induce sadness in patients withdepression and healthy volunteers. Beauregardet al.20

found higher activation in ACC and left medial PFCin patients than controls. Mayberg et al.21 foundactivity in the subgenual cingulate cortex to be high

both when sadness was induced in healthy indivi-duals and when dysphoric symptoms were present inpatients with MDD. One consistent finding seems to

be that the amygdala (particularly on the left) showshigher and/or longer responses to sadness-inducingstimuli in depressed patients than controls.22,23 Anormalisation of this induced amygdala hyperactivityhas been observed after treatment with antidepres-

sants,22 but functional imaging studies of psychother-apy effects in depression have so far exclusivelyrelied on resting state metabolic patterns. The same istrue for most studies on OCD, while studies on phobiahave utilised the symptom provocation techniquesdescribed above to assess the physiological effects ofpsychotherapy.

Functional imaging studies of psychotherapyeffects

Obsessive-compulsive disorderIncreased activity in the right caudate was thecommon finding of symptom provocation studies inOCD across imaging modalities.8,11 Correspondingly,all studies of the effects of cognitive behaviouraltherapy (CBT) in OCD on resting state glucosemetabolism or blood flow (Table 1) so far reported adecrease in right caudate activity in treatmentresponders.2426 This decrease of caudate activity

correlated with clinical improvement in one of thestudies, and showed no difference between CBT andtreatment with the selective serotonin reuptakeinhibitor (SSRI) fluoxetine.24

Two studies24,25 reported a correlation betweencaudate, OFC and thalamus activity before treatment,which would conform to current pathophysiologicalmodels of OCD.27,28 This correlation disappeared aftertreatment with either CBT24,25 or fluoxetine,24 againpointing to common or converging mechanisms

between psycho- and pharmacotherapy. The confir-mation of such converging effects would not only beclinically relevant but also help elucidate themechanisms of psychotherapy at the cellular andneurotransmitter level.

The only fMRI study of CBT effects in OCD29

assessed both effects on symptom provocation andon activation during a cognitive task (the Stroop task).Unfortunately, in this study, data from the CBT andthe SSRI group had to be pooled because of otherwiseinsufficient power, which made a comparison be-tween pharmaco- and psychotherapy impossible.

PhobiasSimple phobias are particularly suited to the inves-tigation of treatment effects with fMRI becausesymptom provocation is relatively straightforward

(Table 2). Whereas in most studies of OCD, PTSDand depression, the inducing triggers had to betailored individually, the symptoms of spider phobiacould be mimicked by standardised images14 or filmsequences30 of spiders, contrasted with innocuousanimals or natural objects. This use of identicalstimulus material across participants removes asource of variance that is especially undesirable instudies with small sample sizes.

Paquette et al.30 used this symptom provocationtechnique in order to assess the effect of symptomreduction by CBT directly. Before the intervention,patients showed increased activity of right dorsolat-eral PFC and parahippocampal gyrus to the aversive


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Table 1 Psychotherapy effects in OCD

Authors Trial size/interventions andprepost interval

Functional imaging technique Post-treatment decre

Baxteret al.24 N= 9 CBT,N= 9 fluoxetine,N= 4 healthy controlsa, all 1072 weeks

FDG (fluoro-deoxyglucose)-PET,resting state, normalised data,no PVCb

Responders: right caucorrelation between caudate and thalamu

Schwartzet al.25 N= 9 CBT, 1072 weeks FDG-PET, resting state,normalised data, no PVC

Responders: caudatecorrelation between

caudate and thalamuNakataniet al.26 N=22 CBT

(some also received clomipramine),duration based on clinical improvement

Xenon-enhanced CT(measures rCBF),resting state

Right head of caudat

Nakaoet al.29 N= 6 CBT,N= 4 fluvoxamine,12 weeks

fMRI during Stroop task andsymptom provocation

Bilateral OFC, DLPFACC (symptom prov

aControl groups are only listed where a second measurement after an interval comparable to the treatment period was obtainedpretreatment effects (as, e.g., in Nakatani et al.26).bPVC: partial volume correction.cFor some parts of the PET data analysis, data were pooled with those from Baxter et al.24.dBecause of the small N, data for the CBT and fluvoxamine groups were not analysed separately.

Table 2 Psychotherapy effects in phobias and panic disorder

Authors Trial size/interventions andprepost interval

Functional imaging technique Post-treatment decreases

Furmarket al.34 Patients with social phobia,N= 6: CBT,N= 6: citalopram,N= 6: waiting list, all 9 weeks

PET with oxygen15-labeled water,symptom provocation,normalised data, no PVC

Both treatment groups:bilateral amygdala, hippocampus,parahippocampal gyrus,further paralimbic areas

Paquetteet al.30 Patients with spider phobia,N= 12: CBT, 5 weeks

fMRI, symptom provocation Right dorsolateral PFC,parahippocampal gyrus

Straubeet al.

31

Patients with spider phobia,N= 14: CBT, 2 sessions,N= 14: waiting list

fMRI, symptom provocation Bilateral insula, thalamus,ACC in treatment but notwaiting list group

Praskoet al.75 Patients with panic disorder,N= 6: CBT,N= 6: different antidepressants,

both groups 3 months

FDG-PET, resting state,normalised data

Both treatment groups:mainly right frontal andtemporal regions,with partial overlapacross groups

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sequences. This difference disappeared after fourintensive exposure sessions in a group setting.Instead, patients showed a higher activity in visualassociation areas for aversive than neutral sequences,similar to the pattern observed in the healthycontrols. Thus, CBT seems to have led to a restitutionof normal cortical processing of the spider sequencesin these patients. A recent study by Straube et al.31

employed a similar design, but added a waiting listpatient group. Patients showed higher activation inthe ACC and insula bilaterally when pretreatmentfMRI was compared to healthy controls. This hyper-activation remained at the second measurement in thewaiting list group, but disappeared in the grouptreated with CBT. Thus, again, CBT of spider phobiawas accompanied by a normalisation of brain activityin specific areas. This reduction of ACC and insulaactivity might reflect (or underlie) the attenuation ofthe affective response to spiders after successfultreatment.31

Yet these studies30,31

probably do not present thefull pattern of pathological activation in simplephobias. For example, no hyperactivity was observed

before treatment in the amygdala in the study byPaquetteet al.,30 and neither study reported reductionof amygdala activity after treatment. This is at oddswith most studies of affective stimulus processingand aversive conditioning, and indeed with currentmodels of the pathophysiological network of simplephobias, and might be explained by habituationeffects in the block design.14

Several studies of patients with social phobia havealso shown hyperactivity of the amygdala, even witha weak form of symptom provocation, presentation of

human faces.32,33 After successful treatment, eitherwith CBT or citalopram, activation of amygdala andhippocampus was reduced in the symptom provoca-tion study by Furmark et al.,34 who utilised a publicspeaking task. Again, it is interesting to observe thatthe pharmacological and psychological interventionseem to have modulated the same brain areas, in thiscase parts of the limbic system. In the studies on OCD(see preceding section), CBT and SSRI had similareffects on metabolic patterns as well, presumablyleading to a reduction of the activity of fronto-striato-thalamic circuits.

Depression

While symptom provocation and resting state studiesproduced fairly consistent signatures of pathologicalmetabolism for OCD (right caudate hyperactivity) andphobias (limbic and paralimbic hyperactivity), thesituation is more complicated for major depressivedisorder (MDD). Most studies of resting state bloodflow or metabolism reported an anterior prefrontalhypoperfusion that normalised after the remission ofsymptoms of depression.35,36 Conversely, the inter-vention study by Brody et al.37 started from an initialprefrontal hypermetabolism that normalised in boththe IPT- and the SSRI-treated group (Table 3). T

able

3

Psychotherapyeffectsinm

ajordepressivedisorder(MDD)

Authors

Trialsize/interv

entions

andprepostin

terval

Functionalimaging

technique

Post-treatmentd

ecreases

Post-treatmentincre

ases

Brodyetal.37

N=14:IPT,

N=10:paroxeti

ne,

N=16:healthy

controls,

all12weeks

FDG-PET,restingstate,

globalnorm

aliseddata,

imagefusionwithMRI

Bothtreatmentg

roups:

bilateralPFC;IP

T:

leftventralACC;

paroxetine:leftmiddleACC

Bothtreatmentgrou

ps:

lefttemporallobe

Martinetal.39

N=13:IPT,

N=15:

venlafaxine,all

6weeks

HMPAO-SP

ECT,restingstate,

normalised

data,noPVC

None

IPT:Rightbasalgan

glia,posteriorCC;

Venlafaxine:rightbasalganglia,

posteriortemporalcortexa

Goldappleetal.38

N=14:CBT,

2677weeks

(standarddevia

tion),

N=13:paroxeti

ne,

6weeks(sampl

efrom

differentstudy)

FDG-PET,restingstate,

normalised

data,noPVC

CBT:bilateralPF

C;

Paroxetine:righthippocampus

CBT:bilateralhippo

campus,

dorsalCC;Paroxetine:

leftdorsolateralPFC

aTheposteriortemporalcortexactiv

ationwaseliminatedwithonepatie

ntsexclusion.


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Decreases in lateral prefrontal metabolism were alsoobserved after successful treatment with CBT.38

In this study by Goldapple et al.,38 the group thatunderwent pharmacological treatment differed fromthe CBT group in that it showed an increasedmetabolism in left dorsolateral PFC after the trial.Although this finding does not directly contradictthat of Brody et al.,37 because in that study thedecrease of PFC metabolism in the SSRI group wasmore ventral and lateral, it indicates that mechanismsof pharmaco- and psychotherapy might be moredivergent in MDD than in the disorders discussedabove. Yet one region of convergence of the twoapproaches seems to be in the right basal ganglia,where another recent study39 found increased activityafter successful treatment with either IPT or venlafax-ine, a combined serotonin and norephinephrinereuptake inhibitor.

The functional imaging studies of therapy effects inMDD thus yielded partly heterogeneous results across

studies and also across treatment approaches. Theheterogeneity across studies might be an effect of themany different symptoms that can contribute to adiagnosis of MDD according to the DSM IV,40 the useof resting state (rather than symptom provocation)paradigms and the absence of well-characterised andreplicable abnormalities prior to treatment.41 It is alsoimportant to consider that all of the PET or SPECTstudies on treatment effects in depression reportednormalised, rather than absolute or quantitativeregional blood flow or glucose metabolism (Table 3)(the same applies to studies on phobia and OCD,Tables 1 and 2). The normalisation approach yieldsratios of activity for each region of interest (ROI)

compared to the global mean of the whole brain or theipsilateral hemisphere. Thus, changes in global brainmetabolism or blood flow between pre- and post-treatment scan can influence the outcome in a ROI.An absolute increase in rCBF or regional glucosemetabolism might still result in a lower ratio to globalactivity, if the latter increases more, and would thus

be reported as post-treatment decrease of normalisedactivity. Fully quantitative studies42 would be a wayto resolve this issue, but are considerably moredifficult and invasive.

Another important feature of the methodologyemployed in the reviewed studies is the absence of

corrections for differences in tissue volume. De-creased regional blood flow or glucose metabolism,as measured by PET or SPECT, does not necessarilyreflect reduced neural activity, but might be an effectof locally reduced grey matter volume. This partialvolume effect is due to the low spatial resolution ofthese techniques. It has been shown to explain, atleast partly, reduced blood flow and metabolism insubgenual cingulate cortex in patients with depres-sion.43 In this data set, full correction for corticalvolume differences even resulted in a reversal of theeffect, with patients showing higher metabolic activ-ity than controls.44 Thus, any local hypometabolismin a patient group can be an effect of cortical volume

loss in that area, although volume loss in areasoutside the limbiccorticostriatopallidothalamicloop has rarely been reported in MDD.45

Whether loss of brain tissue might have thusexplained some of the metabolic decreases aftertreatment cannot be determined based on the presentstate of the literature. While some studies on childrensuffering from OCD found grey matter decreases aftertreatment with the SSRI paroxetine,46,47 volumetricmeasures were stable in a group of adult patients withunipolar depression over a 3-month period of treat-ment with antidepressants.43 It would certainly behelpful if future functional imaging studies alsoincluded high-resolution MRI before and after treat-ment to determine potential structural changes andenable partial volume correction.

At present, the available evidence suggests that anymodel that relies on global frontal hypometabolism toexplain symptoms of depression and its reversal toaccount for treatment effects would be oversimplify-

ing the complex nature of cortico-cortical andsubcortical interactions in affective disorders. Thedifference between the neural correlates of clinicalimprovement after pharmacological and psychologi-cal interventions37,38 is a case in point. Thesedifferences were particularly pronounced in the study

by Goldapple et al.,38 where opposite changes wereobserved in PFC (decrease after CBT, increase afterparoxetine) and limbic areas (increase after CBT,decrease after paroxetine). The authors interpretedthe specific CBT-related changes in brain activation ascorrelates of the learned reduction of ruminations andmaladaptive associative memories (frontal decreases)and increased attention to emotional stimuli (limbic

increases). The differences between CBT and pharma-cotherapy were explained in the framework of top-down versus bottom-up effects, with CBT operatingmore through the former and pharmacotherapy morethrough the latter (e.g. limbic and subcortical areas).

The theoretical framework proposed by Goldappleet al.38 to account for the observed differences in theneural effects of psycho- and pharmacotherapy isattractive because it recognises that any therapeuticimprovement of a complex disorder like depression islikely to be mediated through altered interactions

between several brain areas rather than unidirectionalchanges in a single region. It also allows for predic-

tions about changes in specific networks based on thecontent and behavioural targets of a particularpsychological intervention. However, it will ulti-mately have to be tested in prospective trialscomparing pharmaco- and psychotherapy effects indepression, ideally with the inclusion of molecularmarkers of their respective effects at the synapticlevel.

Molecular mechanisms of psychotherapy

What, then, can we infer from the functional imagingliterature on the molecular mechanisms that underlieor modulate responses to psychotherapy? In the


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absence of molecular imaging studies (e.g. PET withneurotransmitter receptor ligands) of psychotherapyeffects, these inferences will have to be indirect. Wecan evaluate the extant functional imaging studies ofpsychotherapeutic interventions as to their compat-ibility with and impact on current neurobiologicaland neurochemical models of psychological disor-ders, and we can adduce parallels from pharmacolo-gical or alternative interventions, where molecularimaging studies have indeed been performed.

With the development of specific radiotracers of theserotonin transporter (SERT) for SPECT and PET,48,49

in vivo molecular imaging studies of the effects ofSSRIs have become feasible. The main consistentfinding across these studies has been that radiotracer

binding to SERT decreases with SSRI treatment,reflecting the expected blockade of binding sites bythe SSRI. Blockade of SERT by SSRI has beendocumented for midbrain, striatum, amygdala andfurther subcortical areas. It has been shown to occur

in healthy individuals50

and in patients with depres-sion,5052 social phobia53 and OCD.50,54 SERT occu-pancy was around 80% at therapeutic doses of theSSRIs fluoxetine, citalopram, sertraline and parox-etine and the serotonin and norephinephrine reup-take inhibitor velafaxine.50

How can these findings be related to the changesobserved in the functional imaging studies discussedin this paper? The molecular imaging studies indi-cated SSRI binding to SERT in areas, where thefunctional imaging studies showed reduced bloodflow34 or glucose metabolism24 in SSRI responders,for example, the amygdala for social phobia53 and thestriatum for OCD.50 SERT-mediated reuptake of

serotonin into the presynaptic cell, which is partlyblocked by administering an SSRI, is an ATP-dependent and thus metabolically very demandingprocess. The reduced metabolic activity in these areasafter treatment with an SSRI might thus reflect thedecreased activity of SERT. Reduced striatal glucosemetabolism in OCD and reduced limbic blood flow insocial phobia were also observed after CBT.24,34

The similarity of the functional imaging findingsindicates a convergence of the neural pathways thatmediate pharmacotherapy and psychotherapy effects,at least for phobia and OCD. This convergence and thecommonalities in the clinical effects might suggest

that psychotherapy effects in anxiety disorders canalso be mediated through the serotonin system.55

However, this claim is at present not supported bybiochemical or molecular imaging evidence forchanges in the serotonin system after psychologicalinterventions. Future studies of psychotherapy inanxiety disorders should therefore assess potentialchanges in neurotransmitter metabolites to determinewhich system is likely to be involved. Concurrently,molecular imaging will be needed to determine thelevel at which these changes take place. This wouldhave to involve radiotracers that probe the presynap-tic (e.g. transporter proteins), postsynaptic (e.g.receptors) and postreceptor (e.g. proteins involved

in signal transduction) levels of synaptic transmis-sion.49 Functional imaging studies as discussed inthis paper cannot resolve the molecular pathwaysmediating the therapy effects, but may play animportant role in defining the target areas to beprobed with the molecular techniques.

The molecular underpinnings of psychotherapyeffects in depression likewise still wait to be ex-plored. Molecular imaging studies of nonpharmaco-logical interventions have only been performed fortotal sleep deprivation.56 The therapeutic success ofsleep deprivation was associated with lower bindingof a dopamine D2 receptor ligand and thus higherdopamine release, and with reduction in cingulateperfusion. Reduced ACC glucose metabolism was alsoobserved in patients with MDD who responded toIPT.37 This might implicate the dopamine system inthe therapeutic effects of IPT, but the other mono-amine neurotransmitters have been shown to influ-ence the activity of the cingulate as well.37,57 The

reduced activity in lateral PFC, as evidenced byreduced glucose metabolism, after both IPT37 andCBT38 has been suggested to be an effect of increasedsynaptic serotonin, either through GABAergic inhibi-tory interneurons or direct suppression of glutama-tergic activity.37 Yet, multiple neuromodulatorsystems could be responsible. Direct molecularimaging of psychotherapy effects in depression willtherefore be paramount. Again, functional imaginghas identified key nodes in the pathophysiologicalnetwork of depression, such as the cingulate, basalganglia, lateral PFC and hippocampus, that will beworthwhile targets for these molecular studies.

Intervention-specific effects

The functional imaging studies of psychologicalinterventions in mental disorders, which were re-viewed in the previous sections, elucidated some ofthe neural correlates of symptom reduction andgeneral clinical improvement. In most studies thatcompared pharmacological and psychological inter-ventions (with the exception of Goldapple et al.,38)the effects on cerebral metabolism were rather similar.Thus, they are informative on the dysfunctionalcircuits generating the symptoms of a specific diseaseand potentially useful for treatment evaluation, but

reveal little about any specific neural mechanismsthrough which psychotherapy might operate. In orderto clarify the neural mechanisms of a psychologicalintervention, it will probably not suffice to compare itto standard pharmacotherapy in a classic controlledtrial setting. Rather, investigators will have to changethe parameters of the treatment protocol, varying thedesired mental states that they aim to induce, andapply it across different patient groups. While thiswill be very challenging even with the most standar-dised CBT protocols, the results obtained withhypnosis, targeting specific mental states, and withneurofeedback, explicity targeting specific brainareas, are encouraging.


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Functional imaging of hypnosisPositron emission tomography images were acquiredduring hypnosis while participants were exposed tonociceptive stimuli. Hypnotic suggestions selectivelytargeted the intensity and the affective component ofthe pain.58 In the latter case, the painful experiencewas reported as being less aversive, and ACC (but notsomatosensory cortex) activity was reduced.59 Con-versely, when the intensity of pain was modulated byhypnosis, activity in the somatosensory cortex con-tralateral to the stimulated hand was attenuated.60

Similar results were obtained during hypnosis-in-duced depersonalisation.61

These studies revealed the neural correlates ofdifferent aspects of hypnotic analgesia. They showedACC or somatosensory cortex to be suppressed,depending on the content of the hypnotic suggestions.Yet by what mechanism are these areas suppressed?Studies of hypnotic induction and suggestion indi-cate that activation of medial PFC and left dorsolat-

eral PFC62

might be nonspecific features of hypnosisthrough which the effects on specific symptoms aremediated.

Neurofeedback with functional magnetic resonanceimagingWhile hypnosis, in this respect similar to some CBTprotocols, aims to induce certain mental states (andthe accompanying physiological reaction), the newtechnique of neurofeedback directly targets theactivity of a specific brain area. This technique,originally developed with EEG slow cortical poten-tials at low spatial resolution for binary communica-tion with paralysed patients,63 has recently been

expanded for fMRI, using techniques for real-timeimage analysis. Weiskopfet al.64 used such a braincomputer interface to train a volunteer to modulatethe BOLD signal in his own ACC. The point about thisapproach is that participants are not supposed tomodulate activity of a certain brain region by engagingin a specific task (e.g. increase activity in the fusiformface area by mental imagery of faces), but learn toevoke a mental state that reliably corresponds to acertain activation level in that region. For this reason,noneloquent regions of the brain are ideally targetedto demonstrate the feasibility of the fMRI-basedneurofeedback technique.

The initial approach of deCharms et al.65

combinedthe induction of a specific mental state (imagining ahand movement) with neurofeedback training, whichallowed their volunteers to enhance activity inprimary motor cortex without actually performing amovement. Such a self-regulation of cortical activity

by neurofeedback might play a therapeutic role in itsown right, and first reports on pain reduction bymodulation of ACC activity66 are encouraging. Thestudies reviewed here might help define target areasfor the transfer of this technique to symptom reduc-tion in psychiatric disorders. However, any lastingtherapeutic effect in psychiatric patients wouldprobably require a modulation of functional connec-

tivity patterns67 rather than solitary brain regions andthus presuppose further methodological develop-ments.

Similar considerations apply to the assessment oftherapy effect with the symptom provocation-basedfunctional imaging. While this technique provides animportant instrument for the detection of neuralchanges during psychotherapy, any stable changesin neural networks or rewiring should becomemanifest in changes in functional connectivity pat-terns that can be detected in asymptomatic states aswell.

In sum, studies of hypnosis have revealed theability to selectively suppress ACC or somatosensorycortex during nociceptive processing, depending onthe aspect of pain that was to be influenced. Theregulation of the activity of a particular brain areamight also be achieved directly by neurofeedback.Combined with the evidence from symptom provoca-tion techniques, this technique may eventually result

in the development of neuroimaging-based psy-chotherapies (Figure 1c). Beyond the interestingclinical possibilities, these prospects also presentnew ethical challenges and will surely have an impacton the mind-brain debate in the years to come.

General discussion and conclusions

Functional neuroimaging is a promising tool for theinvestigation of the brain changes induced by psy-chotherapy. So far, only few studies have used it toassess the effects of CBT in OCD and phobia, and ofCBT and IPT in depression. In OCD, psychologicalintervention led to decreased metabolism in the

caudate and a decreased correlation of right OFCwith ipsilateral caudate and thalamus. The hyper-activity of the caudate in OCD and its activitydecrease after intervention conform to its putativerole in the pathophysiology of this disorder. Dysfunc-tional striato-thalamic pathways have been impli-cated in inefficient thalamic gating, leading tohyperactivity in orbitofrontal and other corticalareas.68 Such a scenario would be compatible withthe functional neuroimaging findings, especially ifincreased caudate activity led to disinhibition of thethalamus by means of the direct pathway, whichwould indeed increase the correlation between

caudate, thalamus and OFC activity. Finer resolutionof functional imaging studies (e.g. in order to look forevidence of suppression of activity at the level of theglobus pallidus internus) would be required to furtherdisentangle the differential contribution of the basalganglia to the pathophysiology of OCD. The promi-nent reduction of caudate activity after treatmentmight be explained in the context of the high level ofstriatal plasticity that has been shown in numerousstudies of implicit and associative learning in humanand animal models.69,70

In phobia, the most consistent effect of successfulCBT on brain activation was a decrease in limbic andparalimbic areas. It is plausible that decreasing


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amygdala activation, in particular, should accompanythe reduction of phobic symptoms because bothmechanical lesions and chemical suppression of theamygdala have consistently resulted in a reduction of

both subjective and psychophysiological measures offear.71 However, based on these functional imagingfindings alone, we cannot determine whether thedecrease in amygdala activity after treatment was thecause or rather the effect of symptom reduction.Altered neural processes in other brain areas (whichmight have been interindividually more variable andtherefore not detected in group analysis) could haveresulted in the originally offensive stimuli beingperceived as less aversive with the consequence ofreduced firing of amygdala neurons. More detailedinvestigations of network changes during the treat-ment of anxiety disorders, involving measures offunctional67 or effective72 connectivity, will be re-quired in order for such questions to be addressed.

Interestingly, in both OCD and phobia, similar

effects were obtained in the CBT and SSRI-treatedgroups. These findings, albeit preliminary, point to acommon final pathway for the neural changes under-lying the clinical effects of a biochemical and apsychological intervention. It is remarkable that thedifference in the effects between drugs with similarpharmacological effects (fluoxetine and citalopram)across different disease groups (OCD: decrease ofcaudate activity and OFC-caudate-thalamus correla-tion;24 phobia: decrease of limbic and paralimbicactivity34) was much more pronounced that than

between drug and psychotherapy within the samedisease group. Thus, the brain changes induced byand underlying the effects of therapy seem to be more

dependent on the original dysfunctional area orneural network than on the nature of the intervention.This view is supported by evidence from an FDG-PETstudy by Saxena et al .,73 which reported majordifferences between OCD and depression in thepretreatment metabolic patterns that predicted aclinical response to paroxetine.

Studies of depression yielded a less consistentpattern than those of OCD and phobia, with reports of

both decreases and increases in prefrontal metabolismafter successful treatment, and considerable differ-ences between pharmacological and psychologicalinterventions in some studies. Some of these incon-

sistencies might be attributable to a lack of replicablebaseline abnormalities of regional cerebral metabo-lism in depression. In general, the small number offunctional imaging studies on psychotherapy effects(24 per disease group) and enrolled patients (notmore than 30 in any of the studies, considerably lessin some) warrant replication with larger patientsamples before the clinical utility can finally beassessed.

Of the reviewed studies, five assessed changes inglucose metabolism, three measured blood flow andthree measured changes in task-induced blood oxy-genation (the BOLD signal of fMRI). While all thesephysiological parameters are considered indirectly to

reflect neuronal activity, they are governed bydifferent regulatory system and are thus prone toinfluences from different confounding variables, forexample, changes in neurovascular coupling inelderly patients in the case of fMRI.74 Thus, it would

be desirable for future functional imaging studies oftherapy effects to follow standardised protocols, or atleast include a standardised component to whichindividual research groups could add their ownparadigms.

For PET or SPECT studies, future protocols shouldinclude the comparison of baseline activity with acontrol group, the acquisition of MR images for partialvolume correction, and, ideally, quantification ofglucose metabolism or blood flow. For BOLD fMRI,which is by its very nature a relative measure, controltasks of basic sensory stimulation (that are notexpected to lead to different activation patterns inrelation to treatment) might be useful in order tocorroborate the specificity of the effects of interest.

Wherever possible, research should also aim atintegrating functional imaging with molecular tech-niques such as radioligand imaging or biochemicalanalysis of metabolites in order to elucidate themolecular mechanisms of psychotherapy and itscommonalities and differences with pharmacotherapy.

The experience with functional imaging studies ofpsychotherapy so far has been that in some disorders(e.g. OCD) findings were rather consistent while forothers (e.g. depression) they differed across studiesand treatment modalities. Findings in OCD arecompatible with a model of initial hyperactivity in astriatothalamicorbitofrontal network, which is nor-malised in a similar way after treatment with either

psycho- or pharmacotherapy. Conversely, in depres-sion, psycho- and pharmacotherapy seem to operatethrough different pathways, one more top-down, theother more bottom-up. We will have to hope that asmore evidence from functional and metabolic imaging

becomes available, more detailed models of the neuralpathways of psychotherapy effects can be con-structed.

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How Psychotherapy Changes the Brain - The Contribution of Functional Neuroimaging