Neuroimaging and the Functional Neuroanatomy of Psychotherapy

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Psychological Medicine, 2005, 35, 1385–1398. f 2005 Cambridge University Press doi:10.1017/S0033291705005064 Printed in the United Kingdom

REVIEW ARTICLE

Neuroimaging and the functional neuroanatomy of psychotherapy

JOSHUA L. ROFFMAN*, CARL D. MARCI, DEBRA M. GLICK, DARIN D. DOUGHERTY AND SCOTT L. RAUCH Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

ABSTRACT Background. Studies measuring the effects of psychotherapy on brain function are under-rep- resented relative to analogous studies of medications, possibly reflecting historical biases. However, psychological constructs relevant to several modalities of psychotherapy have demonstrable neurobiological correlates, as indicated by functional neuroimaging studies in healthy subjects. This review examines initial attempts to measure directly the effects of psychotherapy on brain function in patients with depression or anxiety disorders. Method. Fourteen published, peer-reviewed functional neuroimaging investigations of psychotherapy were identified through a MEDLINE search and critically reviewed. Studies were compared for consistency of findings both within specific diagnostic categories, and between specific modalities of psychotherapy. Results were also compared to predicted neural models of psychotherapeutic interventions. Results. Behavioral therapy for anxiety disorders was consistently associated with attenuation of brain-imaging abnormalities in regions linked to the pathophysiology of anxiety, and with activation in regions related to positive reappraisal of anxiogenic stimuli. In studies of major depressive disorder, cognitive behavioral therapy and interpersonal therapy were associated with markedly similar changes in cortical–subcortical circuitry, but in unexpected directions. For any given psychiatric disorder, there was only partial overlap between the brain-imaging changes associated with pharmacotherapy and those associated with psychotherapy. Conclusions. Despite methodological limitations, initial neuroimaging studies have revealed convergent and mechanistically sensible effects of psychotherapy on brain function across a range of psychiatric disorders. Further research in this area may take advantage of emerging neuroimaging techniques to explore a broader range of psychotherapies, with the ultimate goal of improving clinical decision-making and treatment.

INTRODUCTION more effort towards understanding the neural mechanisms of medication than of psycho- Functional neuroimaging studies provide a therapy (Fig. 1). This disparity has persisted means to observe and characterize changes in brain function related to psychiatric interven- despite the similar costs and clinical efficacy of medication and psychotherapy for common tions. Since the introduction of this research psychiatric disorders (Antonuccio et al. 1995; tool, investigators have devoted considerably Goldman et al. 1998; Satcher, 1999). Historical bias toward medications as being a clearly * Address for correspondence: Joshua L. Roffman, M.D., defined ‘biological’ intervention, compared with Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. the more complex psychosocial intervention of (Email: jroff[email protected]) psychotherapy (Westen et al. 2004), has likely 1385 1386 J. L. Roffman et al.

15 Number of studies 10

0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Year

FIG. 1. Imaging/medication (%) and imaging/psychotherapy (&) studies by year. Method: An Ovid MEDLINE search was completed using key words related to neuroimaging (e.g. PET, fMRI, SPECT), and medication (e.g. psychotropic) to find studies including both neuroimaging and medication between the years 1966 and 2003. Based on the abstracts generated from this search, we selected studies based on four criteria: included studies were published in English between 1990 and 2003, used human subjects, and investigated psychiatric (e.g. depression) rather than neurological (e.g. Parkinson’s Disease) disorders. A similar search was conducted using key words related to neuroimaging and psychotherapy (e.g. psychotherapy, intrapersonal therapy, cognitive behavioral therapy, and psychodynamic therapy). contributed to this imbalance. However, as first discuss how future research efforts may refine suggested well before the era of functional neuro- our physiological understanding of how psycho- imaging, the changes in affect, behavior, and therapy works, and why this knowledge may be cognition that are mediated by psychotherapies clinically useful. undoubtedly have biological underpinnings (Freud, 1895). In recent years, the number of studies using neuroimaging to explicitly evaluate neural correlates of psychotherapy has PUTATIVE NEURONAL MECHANISMS steadily increased. These studies answer the call OF PSYCHOTHERAPY for more biologically rigorous approaches to Many potentially unhealthy cognitive and psychotherapy research (Kandel, 1998). emotional patterns targeted by psychotherapy In this review, we will address how neuro- appear to have measurable biological analogs imaging research is beginning to reveal the (Beutel et al. 2003). One salient example in- relationship between psychotherapy and brain volves repression, or the unconscious ‘forget- function. We shall first give examples of how ting’ of threatening ideas or experiences. In a psychological constructs relevant to psycho- recent investigation by Anderson and associates therapy, such as extinction, cognitive restruc- (2004), healthy subjects were instructed either to turing, and repression, have been associated remember or ‘forget’ target words. In a recall with discrete brain activity. While long con- task, presentation of ‘forget’ words was asso- sidered the ‘building blocks’ of psychotherapy ciated not only with poor recall of those words, on a theoretical level, these constructs appear to but also with increased activation of the pre- have parallel meaning on the level of neuro- frontal cortex (PFC) and decreased hippo- anatomy. Second, we will evaluate the emerging campal activation. These results replicated a literature on psychotherapy-related changes in previous study conducted by Bunge and col- brain activity profiles, drawing some preliminary leagues (2001), who also found that the an- comparisons among different psychotherapies, terior cingulate gyrus directs attention away and between psychotherapeutic and psycho- from unwanted memories. Thus, active ‘for- pharmacological approaches. Finally, we will getting’ modulated by the PFC and anterior The functional neuroanatomy of psychotherapy 1387 cingulate may have relevance to the psycho- studies implicates the ventral PFC and amyg- dynamic concept of repression. dala in this process (Milad et al. in press). The process of psychotherapy may also Targeted lesions or specific pharmacological engage dedicated neural circuitries that are par- inhibition of the amygdala interfere with fear ticularly responsive to a discrete mode of treat- conditioning in rodents (see Maren & Quirk, ment. We find examples of this in studies related 2004 for a review), while functional neuro- to psychodynamic, cognitive, and behavioral imaging studies in humans have consistently therapy; such studies have used healthy subjects associated amygdalar activation with con- to investigate analogs of specific therapy pro- ditioned fear responses (Buchel et al. 1999; cesses. When a psychodynamically oriented Fischer et al. 2000; Charney, 2003; Cheng et al. therapist ‘takes a history’, this elicits episodic 2003). Analogous studies in rats (Lebron et al. memories from the patient in a focused way. 2004) and humans (Gottfried & Dolan, 2004; However, when the same therapist observes the Phelps et al. 2004) suggest that the ventral PFC patient ‘free associate’, episodic recall occurs in mediates the retention and recall of extinction a less organized, more random way. Andreasen for conditioned fear responses by keeping and co-workers (1995) observed that while the amygdala in check. One might, therefore, random memories engaged assocation cortex in expect extinction-based behavioral therapies in frontal, parietal, and temporal regions, focused humans to work either by potentiating ventral memories selectively activated verbal areas PFC activity or attenuating the amygdala (or (including Broca’s area and the left frontal both). operculum). Thus, the less ‘censored’ process of Collectively, the growing number of studies free association may engage wider networks related to the psychotherapy process point to a of association cortex, facilitating exploration of plausible neuronal substrate for psychother- latent aspects of the patient’s symptomatology apeutic interventions. In this setting, we have or personality. also seen emerge a critical mass of studies that In cognitive behavioral therapy (CBT) for directly evaluate the neurobiological effects of depression, patients are sometimes asked to psychotherapy in patients with mood and anxi- revisit bad or painful memories and explicitly ety disorders. re-evaluate their negativity toward the memory. Using a related paradigm in healthy subjects, Ochsner and colleagues (2002) observed a relationship among reappraisal of negative stim- THE PROBLEM OF VARIABLE uli, improvement in mood, and brain activity METHODOLOGY patterns. Subjects rated their mood before and Before examining the literature on psycho- after being asked to ‘re-interpret’ highly nega- therapy and neuroimaging in detail, we must tive scenes in a more positive light. Reappraisal recognize that heterogeneities across these was associated with both improved mood and studies often limit our ability to compare them increased activity in dorsolateral and dorsome- directly (Table 1). There exist many specific dial PFC, but decreased activity in the amygdala differences in rationale, technique, and efficacy and orbitofrontal cortex. These findings suggest of the various psychotherapeutic modalities in a model of cognitive therapy: while limbic and use today. Several of these modalities, includ- ventral prefrontal structures generate negative ing BT, CBT, and interpersonal therapy (IPT) affect in response to a certain stimulus, dorsal lend themselves well to controlled experi- prefrontal circuitry may be engaged through mental design by using manual-based treatment reappraisal techniques to dampen this outflow in a time-limited setting. However, even among from more ventral structures (see also Ochsner manualized treatment programs, adherence to & Feldman Barrett, 2001; Scherer et al. 2001). a given framework is often far from absolute As a final example, we turn to behavioral (Ablon & Jones, 2002). In several of the therapy (BT). BT for anxiety disorders often reviewed studies, although the therapeutic relies on desensitization or extinction of learned modality is called one thing (e.g. CBT), the responses to anxiety-provoking stimuli. Con- description of the psychotherapeutic process verging evidence from animal and human more closely resembles another (e.g. BT). Table 1. Studies examining the functional neuroanatomy of psychotherapy 1388

Study Therapy type Subjects Comparisons Imaging Post-treatment ﬁndings Comments

Baxter et al. BT, 10 weeks 9 patients with 9 patients with OCD, FDG-PET, 1. Decreased metabolism in R caudate in both 1. Multiple co-morbidities (1992) OCD taking fluoxetine resting groups 2. Uncoupling of cortico-striato-thalamic 2. Unclear if uncoupling circuit in combined subject pool occurred as effect of BT Schwartz CBT, 10 weeks 9 patients with None FDG-PET, 1. Decreased metabolism in R caudate 1. Some patients also et al. (1996) OCD, plus resting 2. Uncoupling of cortico-striato-thalamic received group CBT earlier cohort circuit Nakatani BT, varying 31 patients with 31 healthy controls Xe-CT, resting 1. Decreased CBF in R caudate 1. 21 patients also took et al. (2003) duration treatment- clomipramine refractory OCD 2. Lack of standardized treatment 3. Poor sensitivity to basal ganglia Furmark Group CBT, 8 6 treatment-naive 6 waitlist patients and 6 PET, while 1. In CBT and citalopram groups, decreased 1. Small numbers in each et al. (2002) weeks patients with citalopram patients observed reading limbic metabolism group social phobia script 2. In CBT group, decreased periaqueductal gray metabolism al. et Roffman L. J. 3. In citalopram group, decreased thalamic metabolism Paquette et al. Group CBT, four 12 patients with 13 healthy controls fMRI, while 1. Decreased activation in parahippocampal 1. Extent of post-CBT (2003) 3-hour sessions spider phobia viewing spiders gyrus and dorsolateral prefrontal cortex anxiety testing unclear Goldapple CBT, 15–20 17 patients with Post-hoc comparison to FDG-PET, 1. In CBT group, decreased metabolism in 1. 3 patients dropped out et al. (2004) sessions MDD 13 patients given resting/avoiding multiple frontal regions, increased in limbic 2. No imaging control paroxetine ‘ruminating’ regions group 2. In paroxetine group, changes in opposite direction Martin et al. IPT, 6 weeks 13 patients with 15 patients with MDD SPECT, resting 1. In each group, increased CBF in right basal 1. Semi-random design (2001) MDD given venlafaxine ganglia 2. Short duration of 2. In IPT group, increased CBF in R posterior treatment cingulate Brody et al. IPT, 12 weeks 14 patients with 10 patients with MDD FDG-PET, 1. In both MDD groups, decreased 1. Non-randomized with (2001a) MDD given paroxetine and resting metabolism in prefrontal cortex, increased in baseline differences 16 healthy controls inferior temporal cortex and insula between groups Brody et al. IPT, 12 weeks 14 patients with 25 patients with MDD FDG-PET, 1. Correlation of symptom cluster 1. Paroxetine and IPT (2001b) MDD given paroxetine resting improvement with reduced frontal lobe groups apparently metabolism combined 2. Positive correlation for cognitive symptoms 2. No correction for multiple comparisons Penades et al. Group ‘neuro- 8 patients with None SPECT, during 1. Weakly increased CBF in frontal lobe, 1. No control intervention (2002) psychological schizophrenia, Tower of correlated with improvement in test score rehab,’ 12 weeks on olanzapine London task 2. Non-specific imaging measure The functional neuroanatomy of psychotherapy 1389

Methodological inconsistencies created by the use of single versus multiple therapists, differing numbers of sessions, and varying milieus (e.g. individual versus group therapy) should also be considered when comparing studies. The neuroimaging modalities that have been employed in psychotherapy research also vary. on patient preference hypotheses imaging with neuropsych measures group 1. Group assignment based 2. Multiple co-morbidities 1. No specific regional 2. No attempt to correlate 1. Single case, no follow-up 1. Small numbers in each These techniques provide indices of brain activity by measuring glucose metabolism or cerebral , obsessive–compulsive disorder; blood flow (CBF). Although the relationship between glucose metabolism or CBF and neuronal activity remains controversial (Giove et al. 2003), it is commonplace to use the term ‘brain activity’ essentially interchangeably with ‘metabolic activity’ or ‘hemodynamic activity’. Among the studies reviewed below, the prin- cipal imaging techniques applied include functional magnetic resonance imaging (fMRI), 18fluorodeoxyglucose positron emission tomography (FDG-PET), and 99mtechnetium hexa- correlation metabolism positively correlated with treatment response during treatment phase in 3 of 5 patients frontal lobe in R inferior frontal cortexoccipital and cortex bilateral methylpropyleneamineoxime single photon emis- 2. Fluoxetine patients exhibited a negative 1. For BT patients, L orbitofrontal cortex 1. Global increases in CBF most apparent 1. Increased CBF in anterior cingulate, L 1. In cognitive therapy group, increased CBF sion computed tomography (99mTc-HMPAO SPECT). These imaging modalities differ with respect to mechanism, image resolution, and patient-related limitations (see Dougherty et al. 2004 for a detailed review). Moreover, there are resting (at baseline only) presumably resting being read scripts working memory and vigilance tasks several methods for examining regional brain FDG-PET, fMRI, during

ﬂuorodeoxyglucose positron emission tomography; Xe-CT, xenon-enhanced computed tomography; activity, including voxel-based techniques (such technetium hexamethylpropyleneamineoxime single photon emission computed tomography; R, right; 18 m

99 as SPM) and region-of-interest (ROI)-based approaches. ROI-based methods enable fewer multiple comparisons and respect anatomical boundaries. Alternatively, voxelwise methods can be more data driven (and hence less biased), and may ultimately provide a better measure given fluoxetine schizophrenia given occupational therapy, 6 healthy controls 9 patients with OCD None SPECT, while None SPECT, 6 patients with of functional connectivity (Dougherty et al. 2004). Several additional design considerations should be taken into account when comparing these investigations. In most imaging studies of treatment effects, subjects are scanned before OCD PTSD traumatic brain injury schizophrenia, on antipsychotics 5 patients with 6 patients with and after a trial of psychotherapy (or a comparison intervention), and in some cases, activation differences over time are compared with a group of healthy or waitlist control subjects. Some functional neuroimaging studies examine brain activity while the subject is rest- therapy,’ 6–36 sessions remediation therapy,’ 12 weeks BT, 8–12 weeks 18 patients with EMDR, 3 sessions 1 patient with ‘Cognitive rehab ‘Cognitive ing in the scanner, others while the subject is engaged in a cognitive or affective task related . . .

. to the psychiatric condition (e.g. exposure to an et al et al

et al anxiety-provoking stimulus). Recognizing these et al design concerns, we now turn to the studies BT, Behavioral therapy; CBT, cognitive behavioral therapy; IPT, interpersonal therapy; EMDR, eye movement desensitization and reprocessing; OCD (1998) (1999) (1999) (2002) MDD, major depressive disorder; PTSD, post-traumatic stress disorder; FDG-PET, Levin Brody Wykes Laatsch L, left. CBF, cerebral blood ﬂow; fMRI, functional magnetic resonance imaging; SPECT, themselves. 1390 J. L. Roﬀman et al.

BEHAVIORAL THERAPY AND exhibited active psychiatric co-morbidities [al- OBSESSIVE COMPULSIVE DISORDER though two subjects had a prior history of major (OCD) depressive disorder (MDD).] Furthermore, all patients were off psychotropic medications The first neuroimaging studies of psycho- for at least 2 weeks. Consistent with the earlier therapy, conducted by Baxter and colleagues study, response to BT was associated with re- (Baxter et al. 1992; Schwartz et al. 1996), in- duction of metabolic activity in the caudate cluded patients receiving BT for OCD. At the nucleus, especially on the right side. Among time these studies were published, a prevailing patients who responded to treatment, the initial neurocircuitry model of OCD was better estab- cortico-striato-thalamic correlation described lished than for other psychiatric conditions, earlier again disappeared with treatment. thus making it an attractive focus for brain- However, in this case uncoupling was demon- imaging studies. OCD involves abnormally strated specifically in patients who responded to regulated cortico-striato-thalamic circuitry; psychotherapy. provocation of OCD symptoms has been asso- Analogous findings were recently reported in ciated with increases in CBF in the orbitofrontal a larger study (n=62) by Nakatani and associ- cortex, anterior cingulate cortex, striatum, and ates (2003). Using xenon-enhanced computed thalamus (McGuire et al. 1994; Rauch et al. tomography (Xe-CT), the investigators noted 1994). a significant reduction in the right caudate Baxter and associates (1992) used PET to in- following BT for OCD. However, several vestigate resting cerebral glucose metabolism in methodological limitations may have influenced patients with OCD. Patients received 10 weeks this result, including concomitant use of clomi- of either fluoxetine (n=9) or BT (n=9), the lat- pramine in 21 subjects, lack of standardized ter focused on exposure and response preven- treatment, high drop-out rate, and relative tion. Comparisons between these groups, as well insensitivity of Xe-CT to CBF changes in the as with a control group, were made at baseline basal ganglia. and after the course of treatment. Among both groups of OCD patients, the investigators found a reduction in glucose metabolism in the right COGNITIVE BEHAVIORAL THERAPY caudate nucleus following treatment; moreover, AND PHOBIAS patients who responded more completely to Two recent neuroimaging studies examined treatment exhibited a more profound reduction CBT in phobic patients, combining exposure- than non-responders. Further, among patients based treatment (akin to BT) with cognitive who responded favorably to treatment, Baxter strategies. The cognitive components focused on and associates observed an uncoupling of changing negative misattributions related to hyperactivity in the right caudate, orbitofrontal fear-inducing stimuli. Of particular interest was cortex, and thalamus. However, because medi- the effect of treatment on activity in the amyg- cation and psychotherapy treatment groups dala and other limbic structures. Recall that were combined, it remained unclear whether this while the amygdala is believed to play a central uncoupling occurred specifically in patients who role in the fear response, ‘top-down’ modu- received only BT. Psychiatric co-morbidities in lation by the ventral PFC has been postulated to many OCD subjects posed a second prominent mediate the process of long-term extinction limitation. Despite these concerns, the results (Milad et al. in press). were intriguing in that they not only showed a Furmark and colleagues (2002) used PET to significant change in brain function following examine group CBT versus citalopram for psychotherapy treatment, but also that the treatment of social phobia. Unlike previous in- change occurred in the region consistent with vestigations where patients were imaged while the known pathophysiology of OCD. simply resting in the scanner, here subjects were In a follow-up FDG-PET study, Schwartz asked to read a speech about a personal experi- and colleagues (1996) examined a second cohort ence in front of an audience of 6–8 nearby ob- of nine patients with OCD. Unlike their servers. Subjects were also observed at a close previous study (1992), none of the subjects distance by a video camera. Prior to treatment, The functional neuroanatomy of psychotherapy 1391 subjects exhibited prominent activation in lim- changes might reflect the restructuring of con- bic structures, including the amygdala, hippo- scious cognitive defenses; with the completion campus, and adjacent temporal cortex. Patients of successful psychotherapy, less demand was in the CBT arm received eight weekly group placed on the dorsolateral PFC to plan a reac- therapy sessions that specifically targeted anxi- tion to the perceived threat. This notion is con- ety associated with public speaking. In contrast sistent with Ochsner et al.’s recent (2004) ob- to waitlist control subjects who did not change servation that the dorsal PFC may play a role over time, patients in both treatment arms in up-regulating negative affect and limbic out- demonstrated a significant reduction of activity flow under conditions where an aversive stimu- in these limbic and paralimbic regions. Of note, lus must assume personal salience. Following while no change in activity was observed in therapy, a shift of activity to the ventral PFC ventral PFC in the CBT group, patients receiv- could prompt down-regulation of limbic ac- ing citalopram exhibited activity reductions in tivity, and consequently dampen the fear reac- this region after treatment. Additional differ- tion. This pattern is again consistent with the ences were also evident between treatment findings of Ochsner et al. (2004), who correlated groups. Patients receiving cognitive therapy right ventral PFC activity with down-regulation showed decreased CBF in the periaqueductal of negative affect and limbic outflow when sub- gray area, which has been associated with de- jects were asked to de-emphasize personal con- fense behaviors (Behbehani, 1995). Subjects nections to aversive stimuli. taking citalopram exhibited thalamic reductions Taken together, these studies are consistent in CBF, potentially reflecting reductions in sen- with the model of BT-related desensitization to sory input to the amygdala (Charney & Deutch, aversive stimuli described earlier in our review. 1996). These results imply that CBT and citalo- Modulation of limbic activation following fear pram therapy for social phobia might dampen provocation may involve either reductions of limbic response by different mechanisms, even if CBF in limbic and adjoining paralimbic regions, the ventral prefrontal components of these me- or enhancement of CBF in ventral PFC, or chanisms remain unclear. It should be noted, perhaps both (as suggested by Paquette et al. however, that this study included subjects with 2003). The contributions of the cognitive parts slightly varying diagnoses (e.g. specific and of CBT to hemodynamic changes in these generalized social phobias). studies remain unclear – however, it should be Another provocation study by Paquette and noted that in both cases, the description of the colleagues (2003) related similar findings, in this therapy process clearly points more towards case by exposing non-medicated, spider-phobic behavioral approaches (e.g. extinction-based patients to pictures of spiders during fMRI processes). scans. Compared to non-phobic control subjects, patients initially exhibited significant activation in the parahippocampal gyrus and right COGNITIVE BEHAVIORAL THERAPY dorsolateral PFC#. After successful group CBT AND DEPRESSION sessions using exposure therapy, patients dem- MDD has often been associated with alterations onstrated significantly less activation in both the in prefrontal brain activity in untreated patients parahippocampal gyrus and right dorsolateral (Drevets, 1998), with dorsal areas (including the PFC, and increased activation in the right ven- dorsolateral PFC) exhibiting decreased activity, tral PFC. Paquette and associates linked the and ventral frontal regions demonstrating in- abatement of the parahippocampal gyrus re- creased activity (Dougherty & Rauch, 1997, sponse to a dampening of contextual memory Mayberg, 1997; Drevets, 2000; Rauch, 2003). A (believed to be mediated by this structure). They single functional neuroimaging study of CBT in further suggested that the dorsolateral PFC medication-free, depressed patients has been reported by Goldapple and colleagues (2004). # It is worth noting that the lack of activation of the amygdala, Neuroimaging was conducted with FDG-PET while surprising, has been replicated in several other studies of spider before and after the psychotherapy trial, with phobia (Fredrikson et al. 1995; Rauch et al. 1995; Johanson et al. 1998), possibly reflecting the interaction of specific phobias and spe- patients being instructed to ‘avoid ruminating cific patterns of limbic hyperactivity. on any one topic’ during scanning. A post-hoc 1392 J. L. Roffman et al. comparison was made to a second group of pa- (2002), who posit that ventral frontal and limbic tients who had been given paroxetine. hyperactivity exacerbate negative affect. To Surprisingly, in the CBT group, metabolism in reconcile these differences, we invoke the notion multiple frontal regions including the dorso- that brain activation represents an interaction lateral PFC decreased after therapy. Given the between treatment protocol and underlying association of depression with reduced dorso- brain state (Seminowicz et al. 2004). In this case, lateral PFC activity at baseline, and the model while both investigations involved cognitive re- of CBT elaborated earlier in this review, this structuring, Goldapple et al. examined patients finding is somewhat counterintuitive. The with depression, and Ochsner et al. looked at authors related the reduction in prefrontal healthy controls. Bearing this same interaction metabolism to treatment-related diminution of in mind, we may consider whether psy- ‘active rethinking and reappraisal of emotional chotherapies other than CBT induce similar ideas’. This interpretation is somewhat akin to changes in brain activity among patients with that offered by Paquette and colleagues (2003) depression. for reduced dorsal prefrontal demand in suc- cessfully treated spider phobia. At the same time, however, it contradicts the notion that IPT AND DEPRESSION CBT enhances patients’ abilities to reappraise IPT, like CBT, is a manualized, time-limited affect-generating stimuli (e.g. Ochsner et al. therapy that lends itself well to controlled trials. 2002). Notably, among patients who received However, in contrast to CBT, IPT emphasizes paroxetine in the Goldapple investigation, PFC improving interpersonal relationships, often metabolism increased with medication therapy, drawing directly on the relationship between even though efficacy was comparable to CBT, patients and their therapists. Several recent stud- again implying that medication and CBT may ies have examined changes in CBF associated work through different mechanisms. with the treatment of depression with IPT. In In addition to changes in the PFC, Gold- each case, neuroimaging comparisons were apple and associates also described changes in made to a second group of depressed patients limbic and paralimbic activity after treatment. receiving pharmacotherapy. However, once again a differential pattern In a 6-week study of 28 patients with MDD, emerged for subjects receiving CBT and parox- Martin and associates (2001) compared the ef- etine. Subjects in the CBT group exhibited fects of IPT and venlafaxine (37.5 mg daily) on significant increases in activity in the hippo- regional CBF using 99mTc-HMPAO SPECT. campus, parahippocampal gyrus, and dorsal Subjects had been drug-naive or drug-free for cingulate gyrus. In the paroxetine group, sub- the 6 months preceding the study. After baseline jects exhibited less activity in hippocampal and scans, subjects in the IPT group received 6 parahippocampal regions, as well as decreased weeks of psychotherapy by the same therapist, activity in the posterior cingulate and ventral while those in the venlafaxine group were seen subgenual cingulate. Based on these results, and for 15 minutes every 2 weeks. Both groups im- on known functional and anatomic relation- proved clinically, and in both groups Martin ships between implicated brain regions (Friston, and co-workers observed an increase in blood 1994; Horwitz et al. 1999), Goldapple and flow in the right basal ganglia. However, sub- colleagues proposed a modality-specific model jects in the IPT group also exhibited an increase of treatment response in depression. Anti- in right posterior cingulate activity. Consistent depressant medications appear to have exerted with Goldapple and colleagues (2004), Martin ‘bottom-up’ effects by disengaging ventral et al. underscored the importance of limbic and frontal and limbic regions. In contrast, CBT ef- paralimbic recruitment in psychotherapy-medi- fected ‘top-down’ changes by reducing cortical ated changes; however, it should be noted that processing in favor of ventral and limbic regions Martin and colleagues described changes only in mediating attention to personally relevant one specific paralimbic region. emotional and environmental stimuli. Again, Bearing this single finding in mind, it is im- this result (and interpretation) oppose the emo- portant to note several methodological limitation regulation model of Ochsner and colleagues tions of this study. Martin and colleagues The functional neuroanatomy of psychotherapy 1393 employed a semi-randomized design, in which changes in dorsolateral PFC metabolism. This subjects with a strong preference for IPT or finding is especially germane in light of the venlafaxine could choose that treatment; four negative correlation between activity in the subjects pre-selected venlafaxine, while one dorsolateral PFC and improvement on global chose IPT. Of note, striatal perfusion appeared depression scores after CBT. This distinction greater at baseline among subjects in the IPT suggests that while CBT may specifically dam- group, potentially reflecting this design limi- pen ‘over-thinking’ and rumination aspects of tation. Additional problems included a lack of dorsolateral PFC function in depression, IPT comparison to healthy control subjects, failure potentially improves general cognitive abilities to exclude co-morbid anxiety disorders, and the mediated by this region. Again these findings relatively poor resolution of subcortical struc- must be interpreted cautiously pending repli- tures by SPECT. Finally, it is important to note cation, and in consideration of design limita- that patients in the venlafaxine group demon- tions: no effort was made to separate patients strated a more robust response to treatment. It receiving IPT or paroxetine for correlations may be argued, though that both treatments with hemodynamic changes, and no correction were sub-optimal, given the relatively low dose for multiple comparisons was implemented de- of venlafaxine and the brief duration of IPT. spite a total of six symptom clusters being as- A longer, 12-week study of similar design was sessed in each of 12 ROIs. conducted by Brody and co-workers (2001a), who used PET to examine 24 patients who received IPT or paroxetine. While this study in- WHERE DO WE STAND? THEMES AND cluded a control group of healthy subjects, all LIMITATIONS patients were allowed to self-select into the drug Several themes emerge when considering these or therapy groups. Of note, subjects in the par- studies in aggregate. First, psychotherapy-re- oxetine cohort were less ill at baseline, and lated changes in brain activation appear strik- exhibited greater improvement over time than ingly similar within patients who share the same those in the IPT group. However, these design psychiatric diagnosis. For example, despite their limitations aside, Brody et al. found a decrease methodological limitations and heterogeneities in dorsal and ventral prefrontal cortical metab- (e.g. patients receiving concomitant pharma- olism with IPT treatment directly analogous to cotherapy or multiple types of psychothera- that described by Goldapple et al. (2004). In peutic interventions), each of the reports addition, the authors described an increase in examining psychotherapeutic interventions for metabolism in limbic and paralimbic regions OCD yielded comparable results. In each case, (in this case, the right insula and left inferior BT resulted in decreased metabolism in the temporal lobe) in both treatment groups com- caudate nucleus, a finding consistent with the pared to controls. Unlike Goldapple, though, well-established pathophysiology of the dis- Brody and associates reported a decrease in order (Saxena et al. 1998). Moreover, both PFC activation with paroxetine. fluoxetine and psychotherapy for OCD appear In a follow-up study using a larger cohort of to uncouple dysfunctional cortico-striato- 39 patients receiving either paroxetine or IPT thalamic circuitry. In two studies examining for MDD, Brody and colleagues (2001b)at- patients with phobias, a reduction in limbic or tempted to correlate treatment-related changes paralimbic activity was observed following in brain activity with improvement in specific treatment, again consistent with the hypothe- mood symptom clusters. In all subjects, reduc- sized pathophysiology. Among studies of de- tions of ventral and dorsal frontal lobe metab- pression, following successful psychotherapy olism were associated with improvements in the with CBT or IPT, patients surprisingly – but anxiety/somatization and psychomotor retar- consistently – exhibited decreased activity in dation symptom clusters of the Hamilton dorsal frontal regions and increased activity in Depression Rating Scale, and in the tension/ ventral frontal and subcortical regions (notably anxiety and fatigue clusters of the Profile of including limbic and paralimbic structures). Mood States. Interestingly, improvement in It is particularly intriguing that in MDD, cognitive disturbance positively correlated with both CBT and IPT have been associated with a 1394 J. L. Roffman et al. similar pattern of CBF alterations. Given the psychotherapy and pharmacotherapy achieved different theoretical approaches of these two similar efficacy, they were associated with over- treatments, how might we account for this lapping – but not identical – changes in brain- common pattern? As suggested above, when imaging profiles. Moreover, patients who re- considering the interacting effects of psychiatric ceived pharmacotherapy exhibited less reliable condition and therapeutic approach on brain patterns of brain activation than those who were activity, perhaps underlying pathophysiology treated with psychotherapy, even when the same is the predominant factor. Another possibility, medication (paroxetine) was used in different as suggested by Caspar (2003), is that while studies (Brody et al. 2001a; Goldapple et al. neuroimaging technologies allow us to visualize 2004). This discrepancy has also been observed a ‘final common pathway’ of sorts, the more among studies examining exclusively psycho- relevant changes in brain physiology attribu- pharmacological interventions (e.g. Brody et al. table to psychotherapy may involve more 1999; Kennedy et al. 2001). Seminowicz and microscopic phenomena. It is conceivable, al- colleagues (2004) have attempted to explain though presently difficult to confirm, that CBT these differential effects through a path-model- and IPT exert differing effects on cellular or even ing meta-analysis of studies involving medi- molecular levels. A third possible explanation is cation and CBT to treat depression. Their suggested by the work of Ablon & Jones (2002). analysis, which includes subjects from the Studying patients with MDD, these authors Goldapple et al. (2004) study, assumes that used a standardized measure (the Psychotherapy treatment response is dependent not just on Q-sort) to compare psychotherapy process specific interventions but rather on the interac- variables in transcripts of CBT versus IPT ses- tion of pre-treatment brain state, brain respon- sions. These process variables were related to siveness, and treatment choice. They suggest the contributions of the patient, therapist, and that among responders to CBT, fronto-frontal the patient–therapist interaction. Ablon & Jones processing abnormalities appear to predomi- observed that successful IPT and CBT sessions nate, while those who ultimately respond to both conformed strongly to the same set of medications exhibit altered fronto-limbic dys- process variables, implying that despite thera- regulation. However, the predictive validity of pists’ differing theoretical orientations, the work this model has yet to be tested prospectively. of therapy remained quite similar. It is tempting The use of such general descriptors ‘limbic’ and to speculate that the similarity of CBF changes ‘frontal’ should also be viewed with caution, seen after IPT and CBT reflects a neural corre- given the considerable structural and functional late of this phenomenon. heterogeneity of these regions. Regardless of what mechanism might best A third theme is that each study used two explain the observed similarities of CBT and rounds of neuroimaging – one before treatment, IPT for depression, these findings point to the and the other afterward – and the majority in- need for adherence measures when attempting volved patients resting passively during scans. A to ascribe treatment effects to any particular potential confound of this approach is that psychotherapeutic approach. This notion be- while changes in brain activation over time may comes critical when attempting to match specific reflect correlates of symptom improvement, psychotherapeutic interventions with specific they do not necessarily imply a mechanism of changes in brain activation profiles. For ex- treatment action, on either neuroanatomical or ample, in both studies of CBT for phobic dis- cellular/molecular levels. This is problematic orders (Furmark et al. 2002; Paquette et al. even among those studies where subjects were 2003), it appeared that behavioral interventions actively participating in cognitive or behavioral predominated over cognitive ones – thus, it is tasks related to their underlying disorder. For not surprising that the CBF correlates of symp- example, in the Furmark et al. (2002) study, the tom improvement so closely matched those lack of ventral PFC activation following the predicted by animal and healthy human analog completed course of treatment was surprising models of behavioral therapy. given its proposed role in modulating limbic A second recurring theme of this review, outflow; however, it is possible that such in- especially among studies of MDD, is that while creased activity occurred during the treatment, The functional neuroanatomy of psychotherapy 1395 and was missed because the second scan oc- neuroimaging to predict treatment outcome. curred after the completion of therapy. (Of note, This work is akin to recent studies that have neuroimaging studies involving drug interven- used electroencephalography (EEG) within 48 h tions suffer from a similar limitation, since it is of starting treatment to predict whether patients difficult to differentiate brain activity changes will ultimately respond to antidepressants (e.g. that occur while an individual is actively taking Cook et al. 2002). Brody and associates (1998) a medication from those that occur as a conse- reported differential responses to behavioral quence of taking the medication.) Thus, while therapy and fluoxetine for OCD based on pre- this review strongly suggests that significant, treatment PET scans. Among patients who re- and in many cases, unique changes in the brain ceived BT, Brody observed a positive corre- are associated with psychotherapy, little can be lation between treatment response and baseline concluded about the precise neurobiology and metabolism in the left orbitofrontal cortex; mechanisms involved in these changes. however, the inverse pattern was seen among patients in the fluoxetine group. This finding involves a region implicated not only in the patho- FUTURE STUDIES OF PSYCHOTHERAPY physiology of OCD (McGuire et al. 1994; AND BRAIN FUNCTION Rauch et al. 1994), but also in desensitization of A logical next step in addressing the problem of anxiety-provoking stimuli as described earlier mechanism would involve, at the least, ad- (Gottfried & Dolan, 2004; Phelps et al. 2004). ditional functional scans interpolated during Brody and colleagues thus propose that patients the course of therapy, and at best, real-time imag- with increased orbitofrontal cortex activity at ing during psychotherapy sessions themselves. baseline may be predisposed to benefit from ex- Technical and logistical limitations of fMRI, tinction-based therapy for OCD. However, as PET, and SPECT preclude the naturalistic use patients in the Brody et al. study were allowed to of these imaging tools in this manner. However, select their own treatment group, this interpret- novel neuroimaging technologies hold some ation must be viewed with caution. While ad- promise for these applications. One such tool, ditional prospective studies in this area are near-infrared spectroscopy (NIRS), permits needed, the ability to construct individualized measurement of cortical CBF less invasively treatment plans using biological markers (such than fMRI, and is both more portable and less as neuroimaging) could ultimately allow pa- expensive. Safe and practical for repeated meas- tients and clinicians to move away from the ures, NIRS has been employed to measure current ‘trial-and-error’ approach, minimizing CBF in patients with a variety of neuro- frustration as well as lost time and expense. psychiatric conditions (for a review see Strang- Thus far neuroimaging studies of psycho- man et al. 2002) and in research involving basic therapy have focused on manual-driven, time- auditory and cognitive processing (Sato et al. limited treatments. However, much is to be 1999). A second optical technique currently in gained by subjecting other commonly used development, two-photon microscopy, can po- therapeutic techniques to investigation with tentially image deeper brain activity in vivo even functional neuroimaging methods. For ex- on the cellular level (Miller, 2003); it has been ample, a single case report illustrates the nor- suggested that in the future this technique may malization of serotonin receptor binding, as find its way into psychotherapy research as determined by SPECT, in a patient with bor- well (Zabarenko, 2004). Just as psychophysio- derline personality disorder following 1 year of logical recording methods have been used to psychodynamic psychotherapy (Viinamaki et al. permit simultaneous measurements from both 1998). Still, at present there are no published patient and therapist (e.g. Marci et al. 2004), the reports of brain activation changes associated use of next-generation, non-invasive optical with either psychodynamic psychotherapy or techniques could also permit simultaneous dialectical behavioral therapy, two empirically measurements in clinical settings, providing a supported treatments widely in use. Another powerful assay of patient–therapist interactions. case report describes increased CBF in the an- On the more immediate horizon, investi- terior cingulate gyrus and frontal lobe following gators have already begun to use functional eye movement desensitization and reprocessing 1396 J. L. Roffman et al.

(EMDR), a novel (although not yet empirically Seminar at MGH for their contributions to this validated) treatment for post-traumatic stress manuscript. disorder (Levin et al. 1999). Several studies have demonstrated increased frontal lobe metabolism DECLARATION OF INTEREST following cognitive rehabilitation therapies for schizophrenia (Penades et al. 2002; Wykes et al. None. 2002) and traumatic brain injury (Laatsch et al. 1999; Strangman et al. in press). Finally, with a REFERENCES renewed focus on psychotherapy as an alterna- Ablon, J. S. & Jones, E. E. (2002). Validity of controlled trials of tive treatment to medications in child and ado- psychotherapy: findings from the NIMH Treatment of Depression lescent patients, extension of neuroimaging Collaborative Research Program. American Journal of Psychiatry studies to include this population is warranted. 159, 775–783. Anderson, M. C., Ochsner, K. N., Kuhl, B., Cooper, J., Robertson, E., This work could also elucidate the unique effects Gabrieli, S. W., Glover, G. H. & Gabrieli, J. D. (2004). Neural of age-appropriate treatments on the developing systems underlying the suppression of unwanted memories. Science 303, 232–235. brain. Child imaging will presumably rely on Andreasen, N. C., O’Leary, D. S., Cizadlo, T., Arndt, S., Rezai, K., imaging methods that avoid ionizing radiation; Watkins, G. L., Ponto, L. L. & Hichwa, R. D. (1995). the safety of repeated measures in children is Remembering the past: two facets of episodic memory explored with positron emission tomography. American Journal of Psy- another important consideration. chiatry 152, 1576–1585. Antonuccio, D. O., Danton, W. G. & DeNelsky, G. Y. (1995). Psychotherapy versus medication for depression: challenging the CONCLUSION conventional wisdom with data. Professional Psychology: Research and Practice 26, 574–585. While functional neuroimaging techniques have Baxter, L. R., Schwartz, J. M., Bergman, K. S., Szuba, M. P., Guze, revolutionized biological psychiatry research B. H., Mazziotta, J. C., Alazraki, A., Selin, C. E., Ferng, H. K., Munford, P. & Phelps, M. E. (1992). Caudate glucose metabolic over the past decade, the potential of neu- rate changes with both drug and behavior therapy for obsessive- roscientific tools to explore and refine psycho- compulsive disorder. Archives of General Psychiatry 49, 681–689. social interventions remains largely untapped. Behbehani, N. M. (1995). Functional characteristics of the midbrain periaqueductal gray. Progress in Neurobiology 46, 575–605. With efforts to understand basic psychological Beutel, M. E., Stern, E. & Silbersweig, D. A. (2003). The emerging constructs in neurological terms well underway, dialogue between psychoanalysis and neuroscience: neuroimaging perspectives. Journal of the American Psychoanalytic Association initial forays into the neuroimaging of psycho- 51, 773–801. therapy have suggested plausible and apparently Brody, A. L., Saxena, S., Mandelkern, M. A., Fairbanks, L. A., Ho, convergent mechanisms by which therapy M. L. & Baxter, L. R. (2001b). Brain metabolic changes associated with symptom factor improvement in major depressive disorder. changes the brain. The specific implications of Biological Psychiatry 50, 171–178. this research on clinical practice remain uncer- Brody, A. L., Saxena, S., Schwartz, J. M., Stoessel, P. W., tain, but it is likely that additional work in this Maidment, K., Phelps, M. E. & Baxter, L. R. (1998). FDG-PET predictors of response to behavioral therapy and pharmacother- area will further demystify and validate apy in obsessive compulsive disorder. Psychiatry Research 84, 1–6. psychotherapy in the eyes of patients and clin- Brody, A. L., Saxena, S., Silverman, D. H., Alborzian, S., Fairbanks, L. A., Phelps., M. E., Huang, S. C., Wu, H. M., Maidment, K. & icians alike (Gabbard, 2000; Beutel et al. 2003). Baxter Jr., L. R. (1999). Brain metabolic changes in major de- Functional neuroimaging also offers the prom- pressive disorder from pre- to post-treatment with paroxetine. ise to improve clinical outcomes in two ways: Psychiatry Research 91, 127–139. Brody, A. L., Saxena, S., Stoessel, P., Gillies, L. A., Fairbanks, L. A., first, by helping to inform treatment selection, Alborzian, S., Phelps, M. E., Huang, S.-C., Wu, H.-M., Ho, M. L., and second, by providing an enhanced vocabu- Ho, M. K., Au, S. C., Maidment, K. & Lewis, R (2001a). Regional lary for discussing psychological and thera- brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary find- peutic concepts central to psychotherapy. The ings. Archives of General Psychiatry 58, 631–640. added perspective of functional brain imaging, Buchel, C., Dolan, R. J., Armony, J. L. & Friston, K. J. (1999). Amygdala-hippocampal involvement in human averse trace con- when used to its full potential, may thus ditioning revealed through event-related functional magnetic res- strengthen the credibility and utility of a time- onance imaging. Journal of Neuroscience 19, 10869–10876. honored mainstay in psychiatric treatment. Bunge, S. A., Ochsner, K. N., Desmond, J. E., Glover, G. H. & Gabrieli, J. D. (2001). Prefrontal regions involved in keeping in- formation out of mind. Brain 124, 2074–2086. Caspar, F. (2003). Psychotherapy research and neurobiology: chal- ACKNOWLEDGMENTS lenge, chance, or enrichment? Psychotherapy Research 13, 1–23. Charney, D. S. (2003). Neuroanatomical circuits modulating fear The authors are grateful to the Psychotherapy and anxiety behaviors. Acta Psychiatrica Scandinavica Supplemen- Research Group and the Psychiatry Writing tum 417, 38–50. The functional neuroanatomy of psychotherapy 1397

Charney, D. S. & Deutch, A. (1996). Functional neuroanatomy of Laatsch, L., Pavel, D., Jobe, T., Lin, Q. & Quintana, J.-C. anxiety and fear: implications for the pathophysiology and treat- (1999). Incorporation of SPECT imaging in a longitudinal ment of anxiety disorders. Critical Reviews in Neurobiology 10, cognitive rehabilitee therapy programme. Brain Injury 13, 555– 419–446. 570. Cheng, D. T., Knight, D. C., Smith, C. N., Stein, E. A. & Helmstetter, Lebron, K., Milad, M. R. & Quirk, G. J. (2004). Delayed recall of F. J. (2003). Functional MRI of human amgydala activity during fear extinction in rats with lesions of the ventral medial prefrontal Pavlovian fear conditioning: stimulus processing versus response cortex. Learning and Memory 11, 544–548. expression. Behavioral Neuroscience 117, 3–10. Levin, P., Lazrove, S. & van der Kolk, B. (1999). What psychological Cook, I. A., Leuchter, A. F., Morgan, M., Witte, E., Stubberman, testing and neuroimaging tell us about the treatment of posttrau- W. F., Abrams, M., Rosenberg, S. & Uijtdehaage, S. H. (2002). matic stress disorder by eye movement desensitization and re- Early changes in prefrontal cortical activity characterize clinical processing. Journal of Anxiety Disorders 13, 159–172. responders to antidepressants. Neuropsychopharmacology 27, Marci, C. D., Moran, E. K. & Orr, S. P. (2004). Physiologic evidence 120–131. for the interpersonal role of laughter during psychotherapy. Dougherty, D. D. & Rauch, S. L. (1997). Neuroimaging and clinical Journal of Nervous and Mental Disorders 192, 689–695. models of depression. Harvard Review of Psychiatry 5, 138–159. Maren, S. & Quirk, G. J. (2004). Neuronal signaling of fear memory. Dougherty, D. D., Rauch, S. L. & Rosenbaum, J. F. (2004). Essentials Nature Reviews Neuroscience 5, 844–852. of neuroimaging for clinical practice. American Psychiatric Martin, S. D., Martin, R. M. N., Rai, S. S., Richardson, M. A., Association: Washington. Royall, R. & Eng, I. E. E. (2001). Brain blood flow changes in de- Drevets, W. C. (1998). Functional neuroimaging studies of depressed patients treated with interpersonal psychotherapy or ven- pression: the anatomy of melancholia. Annual Review of Medicine lafaxine hydrochloride: preliminary findings. Archives of General 49, 341–361. Psychiatry 58: 641–648. Drevets, W. C. (2000). Functional anatomical abnormalities in limbic Mayberg, H. S. (1997). Limbic-cortical dysregulation: a proposed and prefrontal cortical structures in major depression. Progress in model of depression. Journal of Neuropsychiatry and Clinical Brain Research 126, 413–431. Neuroscience 9, 471–481. Fischer, H., Andersson, J. L., Furmark, T., Fredrikson, M. (2000). McGuire, P. K., Bench, C. J., Frith, C. D., Marks, I. M., Frackowiak, Fear conditioning and brain activity: a positron emission tom- R. S. J. & Dolan, R. J. (1994). Functional anatomy of obsessive- ography study in humans. Behavioral Neuroscience 114, 671–680. compulsive phenomena. British Journal of Psychiatry 164, 459– Fredrikson, M., Wik, G., Annas, P., Ericson, K. & Stone-Elander, S. 468. (1995). Functional neuroanatomy of visually elicited simple pho- Milad, M. R., Rauch, S. L., Pittman, R. K. & Quirk, G. J. (in press). bic fear: additional data and theoretical analysis. Psycho- Fear extinction in rats: implications for human brain imaging and physiology 32, 43–48. anxiety disorders. Biological Psychiatry. Freud, S. (1895). Project for a scientific psychology. Standard Edition Miller, G. (2003). Spying on the brain, one neuron at a time. Science 1, 295–397. 300, 78–79. Friston, K. (1994). Functional and effective connectivity in neuroi- Nakatani, E., Nakgawa, A., Ohara, Y., Goto, S., Uozumi, N., Iwakiri, maging: a synthesis. Human Brain Mapping 2, 58–78. M., Yamamoto, Y., Motomura, K., Iikura, Y. & Yagagami, T. Furmark, T., Tillfors, M., Marteinsdottir, I., Fischer, H., Pissiota, A., (2003). Effects of behavior therapy on regional cerebral blood flow Langstrom, B. & Fredrikson, M (2002). Common changes in cer- in obsessive-compulsive disorder. Psychiatry Research 124, 113– ebral blood flow in patients with social phobia treated with cit- 120. alopram or cognitive-behavioral therapy. Archives of General Ochsner, K. N., Bunge, S. A., Gross, J. J. & Gabrieli, J. D. Psychiatry 59, 425–433. (2002). Rethinking feelings: an FMRI study of the cognitive Gabbard, G. O. (2000). A neurobiologically informed perspective of regulation of emotion. Journal of Cognitive Neuroscience 14, psychotherapy. British Journal of Psychiatry 177, 117–122. 1215–1229. Giove F., Mangia, S., Bianciardi, M., Garreffa, G., DiSalle, F., Ochsner, K. N. & Feldman Barrett, L. (2001). A multi-process Morrone, R. & Maraviglia, B. (2003). The physiology and metab- perspective on the neuroscience of emotion. In Emotion: olism of neuronal activation: in vivo studies by NMR and other Current Issues and Future Directions (ed. R. J. Davidson, methods. Magnetic Resonance Imaging 21, 1283–1293. H. Goldsmith and K. R. Scherer). Oxford University Press: Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., New York. Kennedy, S. & Mayberg, H. (2004). Modulation of cortical-limbic Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, pathways in major depression. Archives in General Psychiatry 61, S., Gabrieli, J. D. & Gross, J. J. (2004). For better or worse: 34–41. neural systems supporting the cognitive down- and up-regulation Goldman, W., McCulloch, J., Cuffel, B., Zarin, D. A., Suarez, A. & of negative emotion. Neuroimage 23, 483–499. Burns, B. J. (1998). Outpatient utilization patterns of integrated Paquette, V., Levesque, J., Mensour, B., Leroux, J.-M., and split psychotherapy and psychopharmacology for depression. Beaudoin, G., Bourgouin, P. & Beauregard, M. (2003). ‘Change the Psychiatric Services 49, 477–482. mind and you change the brain’: effects of cognitive-behavioral Gottfried, J. A. & Dolan, R. J. (2004). Human orbitofrontal cortex therapy on the neural correlates of spider phobia. Neuroimage 18, mediates extinction learning while accessing conditioned re- 401–409. presentations of value. Nature Neuroscience 7, 1144–1152. Penades, R., Boget, T., Lomena, F., Mateos, J. J., Catalan, R., Horwitz, B., Tagamets, M. A. & McIntosh, A. R. (1999). Neural Gasto, C. & Salamero, M (2002). Could the hypofrontality modeling, functional brain imaging, and cognition. Trends in pattern in schizophrenia be modified through neuropsycholo- Cognitive Sciences 3, 91–98. gical rehabilitation? Acta Psychiatrica Scandinavica 105, 202– Johanson, A., Gustafson, L., Passant, U., Risberg, J., Smith, G., 208. Warkentin, S. & Tucker, D. (1998). Brain function in spider pho- Phelps, E. A., Delgado, M. R., Nearing, K. I. & LeDoux, J. E. (2004). bia. Psychiatry Research: Neuroimaging 84, 101–111. Extinction learning in humans: role of the amygdala and vmPFC. Kandel, E. R. (1998). A new intellectual framework for psychiatry. Neuron 43, 897–905. American Journal of Psychiatry 155, 457–469. Rauch, S. L. (2003). Neuroimaging and neurocircuitry models per- Kennedy, S. H., Evans, K. R., Kruger, S., Mayberg, H. S., taining to the neurosurgical treatment of psychiatric disorders. Meyer, J. H., McCann, S., Arifuzzman, A. I., Houle, S. & Neurosurgery Clinics of North America 14, 213–223. Vaccarino, F. J. (2001). Changes in regional brain glucose metab- Rauch, S. L., Jenike, M. J., Alpert, N. A., Baer., L., Breiter, H. C. R., olism measured with positron emission tomography after parox- Savage, C. R. & Fischman, A. J. (1994). Regional cerebral blood etine treatment of major depression. American Journal of Psy- flow measured during symptom provocation in obsessive- chiatry 158, 899–905. compulsive disorder using oxygen 15-labelled carbon dioxide and 1398 J. L. Roffman et al.

positron emission tomography. Archives of General Psychiatry 51, circuitry in major depression: a path modeling metanalysis. 62–70. Neuroimage 22, 409–418. Rauch, S. L., Savage, C. R., Alpert, N. M., Miguel, E. C., Baer, L., Strangman, G., Boas, D. A. & Sutton, J. P. (2002). Non-invasive Breiter, H. C., Fischman, A. J., Manzo, P. A., Moretti, C. & neuroimaging using near-infrared light. Biological Psychiatry 52, Jenike, M. A. (1995). A positron emission tomographic study of 679–693. simple phobic symptom provocation. Archives of General Psy- Strangman, G., O’Neil-Pirozzi, T. M., Burke, D., Cristina, D., chiatry 52, 20–28. Goldstein, R., Rauch, S. L., Savage, C. R., Glenn, M. B. (in press). Satcher, D. (1999). Mental health: a report of the surgeon general. Functional neuroimaging and cognitive rehabilitation for people United States Public Health Service. with traumatic brain injury. American Journal of Physical Medicine Sato, H., Takeuchi, T. & Sakai, K. L. (1999). Temporal cortex acti- and Rehabilitation. vation during speech recognition: an optical topography study. Viinamaki, H., Kuikka, J. & Tiihonen, J. (1998). Change in mono- Cognition 73, B55–B66. amine transporter density related to clinical recovery: a case- Saxena S., Brody, A. L., Schwartz, J. M. & Baxter, L. R. (1998). control study. Nordic Journal of Psychiatry 52, 39–44. Neuroimaging and frontal-subcortical circuitry in obsessive- Westen, D., Novotny, C. M. & Thompson-Brenner, H. (2004). The compulsive disorder. British Journal of Psychiatry 173 (Suppl. 35), empirical status of empirically supported psychotherapies: as- 26–37. sumptions, findings, and reporting in controlled clinical trials. Scherer, K. R., Schorr, A. & Johnstone, T. (2001). Appraisal Processes Psychological Bulletin 130, 631–663. in Emotion. Oxford University Press: New York. Wykes, T., Brammer, M., Mellers, J., Bray, P., Reeder, C., Williams, Schwartz, J. M., Stoessel, P. W., Baxter, L. R., Martin, K. M. & S. & Corner, J (2002). Effects on the brain of a psychological Phelps, M. E. (1996). Systematic changes in cerebral glucose treatment: cognitive remediation therapy: functional magnetic metabolic rate after successful behavior modification treatment of resonance imaging in schizophrenia. British Journal of Psychiatry obsessive-compulsive disorder. Archives of General Psychiatry 53, 181, 144–152. 109–113. Zabarenko, L. M. (2004). Psychoanalysis, neuroscience, and cog- Seminowicz, D. A., Mayberg, H. S., McIntosh, A. R., Goldapple, K., nitive psychology: some samples from recent research. Psycho- Kennedy, S., Segal, Z. & Rafi-Tari, S. (2004). Limbic-frontal analytic Psychology 21, 488–491.