Neuroimaging of psychotherapy for obsessive–compulsive disorder: A systematic review

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Neuroimaging of psychotherapy for Obsessive-Compulsive Disorder: a systematic review Anders Lillevik Thorsen, Odile A. van den Heuvel, Bjarne Hansen, Gerd Kvale

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Psychiatry Research: Neuroimaging

Received date: 1 July 2014 Revised date: 20 October 2014 Accepted date: 11 May 2015 Cite this article as: Anders Lillevik Thorsen, Odile A. van den Heuvel, Bjarne Hansen, Gerd Kvale, Neuroimaging of psychotherapy for ObsessiveCompulsive Disorder: a systematic review, Psychiatry Research: Neuroimaging, http://dx.doi.org/10.1016/j.pscychresns.2015.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Neuroimaging of psychotherapy for Obsessive-Compulsive Disorder: a systematic review Authors: Anders Lillevik Thorsen1a,b, Odile A. van den Heuvelc,d, Bjarne Hansena,e and Gerd Kvalea,e a

OCD-team, Haukeland University Hospital, Bergen, Norway

b

Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway

c

Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

d

Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam,

The Netherlands e

Department of Clinical Psychology, University of Bergen, Bergen, Norway

1

Corresponding Author. Tel.: +4790367617. E-mail address: [email protected]

Abstract The symptoms of obsessive-compulsive disorder (OCD) include intrusive thoughts, compulsive behavior, anxiety, and cognitive inflexibility, which are associated with dysfunction in dorsal and ventral corticostriato-thalamocortical (CSTC) circuits. Psychotherapy involving exposure and response prevention has been established as an effective treatment for the affective symptoms, but the impact on the underlying neural circuits is not clear. This systematic review used the Medline, Embase, and PsychINFO databases to investigate how successful therapy may affect neural substrates of OCD. Sixteen studies measuring neural changes after therapy were included in the review. The studies indicate that dysfunctions in neural function and structure are partly reversible and statedependent for affective symptoms, which may also apply to cognitive symptoms. This is supported by post-treatment decreases of symptoms and activity in the ventral circuits during symptom provocation, as well as mainly increased activity in dorsal circuits during cognitive processing. These effects appear to be common to both psychotherapy and medication approaches. Although neural findings were not consistent across all studies, these findings indicate that people with OCD may experience functional, symptomatic, and neural recovery after successful treatment.

Keywords: Frontal-striatal circuits, Functional imaging, Cognitive behavioral therapy, Exposure and response prevention, Orbitofrontal cortex, Caudate nucleus.

1. Introduction Obsessive-compulsive disorder (OCD) is characterized by obsessive thoughts and compulsive acts, which are associated with anxiety, reduced quality of life and functional impairment, as described in current nosologies (World Health Organization, 1993; American Psychiatric Association, 2013). Recommended treatments for OCD include cognitivebehavioral therapy (CBT) with exposure and response prevention and pharmacological treatment by selective serotonin reuptake inhibitors (SSRIs), with eventual adjuvant atypical antipsychotic medication in treatment-resistant cases (Abramowitz, 1997; Bloch et al., 2006; Gava et al., 2007). There is also burgeoning evidence for the effectiveness of other forms of cognitive therapy and psychotherapy (Fairfax, 2008; Calkins et al., 2013). Three decades of neuroimaging research in OCD have provided a better understanding of the underlying neural mechanisms. Future neuroimaging research in OCD might be valuable in addressing mediators of treatment outcome, which may lead to better personalized treatment (Lennox, 2009; Linden and Fallgatter, 2009). The neurobiology of OCD is associated with dysfunction within the parallel corticostriato-thalamocortical (CSTC) circuits. Early literature mainly focused on the role of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and striatum (Saxena and Rauch, 2000; Whiteside et al., 2004; Menzies et al., 2008). Recent research, however, also suggests the importance of the amygdala, cerebellum, anterior insula/operculum, hippocampus, parietal cortex, and dorsolateral prefrontal cortex, as well as the structural and functional connectivity of the implicated neural networks (Husted et al., 2006; Menzies et al., 2008; Rotge et al., 2008; Harrison et al., 2009; Milad and Rauch, 2012; Harrison et al., 2013; Piras et al., 2013; Anticevic et al., 2014).

A better understanding of OCD as a heterogeneous condition has emerged from the use of dimensional approaches (e.g,. Leckman et al., 1997; Mataix-Cols et al., 2005), which also allows for the exploration of common and symptom-specific neural substrates (MataixCols et al., 2004; van den Heuvel et al., 2009; Harrison et al., 2013; de Wit et al., 2014; Radua et al., 2014). The diversity in symptom profiles seems to be represented by the diversity of implicated neural circuits. Symptoms of anxiety, disgust, contamination fear and harm sensitivity (such as in checking) seem to be strongly related to the limbic circuit and the saliency network. Cognitive rigidity, impaired response inhibition, compulsivity and symmetry/ordering behaviors seem to be mainly related to an imbalance between a hyperactive ventral frontal-striatal circuit and impaired top-down cognitive control from dorsal frontal-striatal and fronto-parietal circuits. (Friedlander and Desrocher, 2006; MataixCols and van den Heuvel, 2006; Kwon et al., 2009). The direction of the altered frontalstriatal activation during cognitive tasks in OCD is dependent on the task level, co-morbidity, capacity to compensate, and level of limbic interference, as shown by two recent functional magnetic resonance imaging (fMRI) studies using the visuo-spatial n-back task (de Vries et al., 2014) and the stop-signal task (de Wit et al., 2012). Although a complete overview of the neural abnormalities in OCD is outside the scope of this review, it is important to consider how they generate hypotheses on potential brain changes during psychotherapy. One hypothesis is that efficacious psychotherapy can normalize function and structure in the areas activated during the experimental tasks, which would support the notion of state-dependent abnormalities in function and structure, rather than a trait perspective of OCD symptoms and cognitive deficits. Another hypothesis is that psychotherapy enhances the compensatory mechanisms while leaving the trait vulnerability untouched. In both cases, one might expect these functional changes to involve altered functional and structural connectivity within the implicated brain circuits.

The aim of this review is to examine the evidence for neural changes after psychotherapy in OCD. The reviewed studies are examined in the context of both research on neuroimaging and psychotherapy, in order to describe an integrated perspective on the treatment of OCD. 2. Methods Studies using neuroimaging methods to investigate psychotherapy effects for OCD were found using the Medline, Embase and PsycINFO databases, as well as manually searching the references of related publications. The search was designed to include as many methods of imaging as possible, and therefore included the terms “functional magnetic resonance imaging”, “positron emission tomography”, “radionuclide imaging”, “magnetic resonance spectroscopy”, “electroencephalogram”, magnetoencephalogram”, and “magnetic resonance imaging”. Different approaches to psychotherapy were also sought, using the terms “cognitive behavioral therapy”, “behavior therapy”, “cognitive therapy”, and “psychodynamic therapy”. Inclusion criteria for studies were as follows: psychotherapy had to be a form of treatment; neuroimaging had to be used both before and after treatment; and all participants had to be adults. 3. Results Of the 16 included studies in this review, 12 used functional imaging methods to investigate changes in brain activity. One studied applied electroencephalography (EEG), one used magnetic resonance imaging (MRI) to investigate gray matter volume before and after treatment, while two studies investigated neural metabolites. Table 1-4 summarizes the methodology and findings of each study, categorized by the method of neuroimaging. 3.1. Resting-state functional imaging

Table 1 about here Baxter et al. (1992) investigated changes in glucose metabolism in OCD after treatment using a sample of nine OCD participants receiving behavior therapy, nine receiving fluoxetine, and four healthy controls. On the basis of resting state FDG-PET (18Ffluorodeoxyglucose positron emission tomography), a common finding in both treatment groups was a significant decrease in glucose metabolic rate in the head of the right caudate nucleus. However, drug treatment also resulted in a reduction in metabolic rates in the right ACC and left thalamus, effects that were not evident in those receiving behavioral therapy. Treatment also affected intrahemispheric activity, as seen in a decrease in positive correlations between the right OFC, caudate nucleus and thalamus, as well as an increase in positively correlated activity between the left cingulate cortex and caudate nucleus. A limitation of the study is the small sample size, reducing statistical power, as well as the nonrandomization of participants. Schwartz et al. (1996) aimed to further investigate the effects of behavior therapy (BT) with resting state FDG-PET, by combining data from nine new OCD participants and nine BT-treated OCD participants from a previous study (Baxter et al., 1992). Schwartz and colleagues replicated previous findings of reduced metabolism in the right caudate after treatment. They also reported a decreased post-treatment correlation between activity in the right caudate nucleus, OFC and thalamus, as well as a decrease in left caudate activity when combining data from both studies. The small simple size and the lack of control subjects are major methodological concerns. Saxena et al. (2009) investigated whether intensive and short-term cognitive behavior therapy (CBT) could produce changes in glucose metabolism in 10 OCD participants, compared with 12 healthy controls. Imaging was performed using FDG-PET with participants

in a resting state. OCD participants showed a significant decrease in bilateral thalamic metabolism, along with an increase in right dorsal ACC metabolism, while controls showed a decrease in left dorsal ACC metabolism. Methodological limitations were the small sample size, the fact that six OCD participants were taking SSRIs, and the presence of major depression in one participant. Apostolova et al. (2010) measured glucose metabolism using FDG-PET in participants under resting conditions. Seven of the OCD participants were receiving paroxetine and nine were receiving CBT. Results showed an increase in right caudate activity after successful treatment, regardless of treatment modality. The study did not include a control group, and participants chose their own form of treatment. In addition, several participants had comorbid diagnoses. Nakatani et al. (2003) applied xenon-enhanced computed tomography (Xe-CT), under resting conditions, using a sample of 31 OCD participants receiving BT and 31 healthy controls. Due to drop-outs and technical issues, only 22 OCD participants remained for the pre-post treatment analyses. The authors reported a significant reduction in blood flow in the right head of the caudate in responders to treatment. However, a potential confounder was that 21 of the original 31 OCD participants underwent pharmacological treatment in addition to psychotherapy. Also, the second scan was not given after a fixed interval, but was instead performed after the researchers deemed the OCD participants to have achieved sufficient clinical improvement, an assessment that was not standardized. Furthermore, important methodological shortcomings of the study are the use of Xe-CT, lack of sophisticated software for determining brain regions, and the inclusion of OCD patients with comorbid disorders.

Yamanishi et al. (2009) investigated whether BT could affect regional cerebral blood flow using single photon emission computed tomography (SPECT) carried out under resting conditions in 45 individuals with a diagnosis of OCD who were resistant to treatment with SSRIs. For treatment responders, the authors found significantly decreased regional cerebral blood flow in the left middle frontal gyrus, right medial PFC and right OFC, and increased activation in the right ipsilateral fusiform gyrus, cuneus and angular gyrus, while regional cerebral blood flow was unchanged in non-responders. In addition, decreases in symptom scores correlated to a decrease in OFC activity. Previous or current comorbid mental disorder was an exclusion criterion. The lack of a control group limited the ability to establish specificity of the effects of BT compared with other treatment strategies. This methodological problem is further complicated by the fact that all participants were also taking SSRIs. In summary, resting state studies comparing regional cerebral blood flow (rCBF) before and after therapy have mostly reported decreased rCBF in areas such as the OFC, ACC, thalamus and caudate nucleus after treatment in responders. However, divergent findings of increased activity in these same structures have also been reported, where comorbid depression, concurrent SSRI administration and different methodologies may be important confounders. 3.2. Task-related functional imaging Table 2 about here Nakao et al. (2005) used fMRI to investigate blood oxygen level dependent (BOLD) response during symptom provocation and Stroop tasks in six OCD participants receiving behavioral therapy and four receiving fluvoxamine. Provocation tasks involved participants thinking of pre-selected words and images (contrasted against neutral mental imagery) that caused distress and OCD symptoms. Due to low power, both treatment groups had to be

combined, precluding analysis between treatment modalities. After treatment, patients showed increased activation in the right dorsolateral PFC, bilateral putamen, parietal cortex and cerebellum, as well as the left temporal cortex, during incongruent blocks of the Stroop task. Decreased activation was found in other parts of the right frontal cortex, bilateral cingulate cortex, left cerebellum, right hippocampus, temporal cortex and parietal cortex. During the provocation tasks, after treatment activation was decreased in bilateral frontal and occipital cortex, thalamus, cerebellum, left ACC and temporal cortex. The lack of a control group is a limitation, as is the small number of participants. A strength of this study is the exclusion of comorbid diagnoses and concurrent pharmacotherapy. Nabeyama et al. (2008) used fMRI to measure changes of activity during a Stroop task in a study of 11 OCD participants receiving BT and 19 healthy controls. After treatment, compared with pre-treatment, OCD participants exhibited significantly decreased activation during incongruent blocks of the Stroop task in the right OFC, left middle frontal gyrus, left fusiform gyrus, bilateral hippocampal gyrus, and left parietal lobe. Increased activation was seen in the right parietal lobe and bilateral cerebellum. Comorbid diagnoses and medication use were excluded. The small number of participants is a limitation of this study. Also, controls were only scanned once, hampering investigations into the potential learning effects of repeated testing. Freyer et al. (2011) used fMRI to investigate activity during a reversal learning task before and after CBT treatment in 10 OCD participants and 10 healthy controls. The learning task involved choosing between two abstract shapes, where a correct response garnered a happy pictogram, while an incorrect response resulted in a sad pictogram. Analysis with uncorrected significance thresholds found decreased activity in the left OFC and right putamen during strategy changes after treatment, along with increased activity in the caudate nucleus. In addition, greater symptom reduction was correlated with more stable globus

pallidus activation. In addition, mean depression ratings were within the normal range for the sample. Andreou et al. (2013) used EEG to measure event-related potentials to auditory stimuli in an oddball paradigm. Their sample included previously unmediated 71 OCD participants who received combined treatment with sertraline and BT, as well as 71 healthy controls. The authors reported non-significant reduction in P300 amplitude and latency after treatment, as well as a reduction of current density signal power localized to the left PFC. The relatively large sample size and exclusion of participants who had received past treatment or were suffering from comorbid disorders constituted strengths of this study. Although the use of EEG permits low latency measurements, findings are difficult to compare with those obtained in the other neuroimaging studies. Baioui et al. (2013) investigated functional changes using fMRI and both standardized and individualized visual images designed to provoke symptoms. Their sample included 12 OCD participants who mainly had washing symptoms and who were receiving CBT, as well as 12 healthy controls. Results showed reduced activation in the bilateral nucleus accumbens and left supramarginal gyrus (SMG) in response to the individualized provocation. Standardized provocation was associated with reduced activation in the left OFC, right caudate, left PFC and bilateral SMG after treatment. Exclusion criteria were past or current mental disorders, while concurrent medication use was allowed. The small number of participants is a limitation of this study. Morgiève et al. (2013) used fMRI during generic and individualized visual symptom provocation for 31 OCD participants with mainly checking symptoms. They also carried out neuroimaging mid-therapy and 6 months after CBT treatment, as well as standard pre- and post-treatment imaging. After treatment, fMRI results indicated reduced activation in the

bilateral ACC and left OFC in response to individualized images. This study also indicated that neural changes continue after the end of treatment in the left OFC and ACC. The use of both generic and standardized symptom provocation, four fMRI sessions and exclusion of participants with comorbid mental disorders are important strengths of this study. Concurrent medication use was not an exclusion criterion. Schiepek et al. (2013) applied a similar paradigm of symptom provocation via individualized visual images combined with fMRI imaging for nine OCD participants receiving CBT and nine healthy controls. However, the authors also used assessment of the ongoing therapy process along with three to four fMRI scans. The goal was to account for phase transitions in the therapy process and self-assessment of the disorder, the relation between them and changes in task-related brain activation. Imaging results indicated that changes in brain activity were greater during phase transitions, especially in the ACC, supplementary motor area, bilateral DLPFC and right insula. The use of qualitative measures and three to four fMRI sessions is a strength of this study, as well as the relatively treatmentnaive and drug-free sample, where one participant had a comorbid diagnosis and medication treatment. The small sample size is a limitation of this study, as is the use of multiple MRI scanners. Functional studies of OCD treatment have focused on both cognitive functioning and symptom provocation, which are reflected in both their paradigms and subsequent findings. The two cognitive studies report both increased and decreased activity and task performance, possibly reflecting increased neural engagement and lessening of neural inefficiency. Meanwhile, the studies using symptom provocation mostly report decreased activity after treatment, in areas such as the OFC, ACC and thalamus. The potential role of task difficulty or provoked emotional intensity has not been explored in detail.

3.3. Neurochemistry Table 3 about here Whiteside et al. (2012) used proton magnetic resonance spectroscopy (MRS) to investigate possible differences in neural markers in the head of the caudate nucleus and orbital frontal white matter in OCD, using a sample of 15 OCD participants receiving BT and 15 healthy controls. Results showed that although no baseline differences in metabolites in the caudate were found between OCD and control participants, successful treatment was associated with an increase in N-acetyl-l-aspartic acid (NAA) levels in the head of the left caudate nucleus. Exploratory analysis also indicated lower levels of Cr (creatine) and NAA in the right orbital frontal white matter in OCD participants, findings that did not significantly change after treatment. The function of NAA is not clear, but it is regarded as a marker of neural health, viability and neuronal number (Moffett et al., 2007). A strength of this study is the exclusion of participants with depression. Two limitations of this study are the small sample size and concomitant pharmacological treatment. O'Neill et al. (2013) applied proton MRS in eight OCD participants receiving CBT, an approach that also included aspects of mindfulness training. Eight healthy controls were included as well. Results showed lower levels of NAA in the right pregenual ACC in OCD patients compared with controls. After treatment right pregenual ACC levels of tNAA (Nacetylaspartate + N-acetyl-aspartyl-glutamate) increased, while Glx (glutamate + glutamine) in the left anterior middle cingulate cortex was reduced. Concurrent medication use and depression as a secondary diagnosis were allowed in the study, which may have confounded the study findings. The few existing studies of neural metabolites concur in their findings of increased NAA after treatment, which may reflect induced neuroplasticity and neural changes. Although

findings of changes in metabolites such as Cr and Glx require replication, they do fit previous reports of baseline differences in metabolites between OCD participants and controls (Brennan et al., 2013), and they indicate that effective psychotherapy may affect several metabolites and their associated neural systems. 3.4. Structural imaging Table 4 about here Hoexter et al. (2012) investigated treatment effects of fluoxetine treatment (n=19) versus CBT (n=19) on brain structure, using T1-weighted MRI to measure gray matter volume in OCD participants compared with 36 healthy controls. Analysis of treatment-naive participants revealed smaller grey matter volumes in the left putamen, medial OFC and left ACC compared with controls. Post-treatment results did not reveal any differences in the left putamen when treatment and control groups were compared. Exploratory analysis indicated that only fluoxetine-treated participants exhibited a significant increase in left putamen grey matter volume. The number of participants in this study was relatively high compared with the other reviewed studies. However, 13 OCD participants met diagnostic criteria for major depression or other comorbidities, complicating the generalizability of the findings. There is clearly a need for more studies on structural changes, but the current study indicates that at least some areas normalize following successful therapy. 4. Discussion The aim of this review was to examine the evidence for neural changes following psychotherapy in participants with OCD. In general, all the reviewed studies reported neural changes following therapy-related clinical improvement. The studies using resting state or symptom provocation conditions largely support the hypothesis of normalized (reduced)

activation in areas related to affective processing after therapy, while studies using cognitive tasks mostly support the hypothesis of normalized (mainly increased) task-related brain activation after treatment. Reduction of activity in the caudate nucleus, orbitofrontal, prefrontal and anterior cingulate regions is most often reported in the resting state and provocation studies, followed by the thalamus, temporal and occipital cortices. These results fit the prevailing empirical and theoretical framework of altered recruitment of the dorsal and ventral CSTC circuits, and indicate that abnormal activity and structure in OCD are, at least partly, state-dependent and reversible. Also, while the current studies do not explain the etiology of OCD, they do support the link between neural correlates related to brain structure, function and chemistry, as well as the phenomenology of successful treatment (Aouizerate et al., 2004). Although fewer studies have investigated cognitive than symptomatic improvement after treatment, the studies largely suggest improved neurocognitive performance and normalization of task-related neural activity (Nabeyama et al., 2008; Freyer et al., 2011), conclusions that are also supported by a recent naturalistic study (Vriend et al., 2013). Increases in activity were mostly reported in the putamen, parietal cortex and cerebellum, while only the study of Nakao et al. (2005) found increased DLPFC activity; stable or decreased activity in other regions such as the OFC, ACC and parahippocamal gyri has also been reported. Treatment-induced alterations in task-related brain activity could be linked to increased neurocognitive performance due to reduction in distracting obsessions, compulsions and anxiety (Simon et al., 2014). One might expect that treatment-induced changes in symptom scores would correlate with changed recruitment of specific brain regions. However, only some of the studies reported such correlations, in regions such as the right OFC, ACC and caudate (Saxena et al., 2009;

Yamanishi et al., 2009; Apostolova et al., 2010; Whiteside et al., 2012). A reason for the relatively small number of significant associations between symptoms and neural findings may be the clinical heterogeneity of OCD, as well the varying stringency in excluding comorbid disorders and concurrent pharmacological treatment. Unfortunately, few of the reviewed studies have reported neural changes specific to a symptom dimension, but one finding of post-treatment changes in insula activity during exposure to disgust-generating pictures (Schiepek et al., 2013) provides some evidence for how therapy may affect emotional processing of specific stimuli. Also, while two studies only included patients with either washing (Baioui et al., 2013) or checking symptoms (Morgiève et al., 2013), their findings do not substantially differ from other studies involving participants with mixed symptoms. Several of the reviewed studies attempted to investigate whether different types of treatment have distinct neural effects, but few found significant differences. (Baxter et al., 1992; Nakao et al., 2005; Saxena et al., 2009; Apostolova et al., 2010; Hoexter et al., 2012), suggesting that pre-post treatment changes are more related to symptom reduction than to treatment modality per se. However, Baxter et al. (1992) found a significant decrease in right anterior cingulate gyrus and left thalamus blood flow for those undergoing drug treatment, but not for those undergoing psychotherapy. Furthermore, Hoexter et al. (2012) reported that only fluoxetine-treated OCD participants exhibited an increase in left putamen grey matter after exploratory analysis. The fact that few differences in neural activity that emerged for the two forms of treatment is surprising, considering the differences in each treatment’s mechanism of effect. Psychotherapy often involves strategies aimed at strengthening the patient’s selfefficacy, willingness to face fears, and tolerate uncertainty. Pharmacotherapy, on the other hand, involves direct modulation of the neural circuits by targeting the relevant neurotransmitter systems involved in OCD. The few functional neural differences between pharmacotherapy and psychotherapy suggest that the neural correlates of symptom

improvements are similar across treatment strategies. Alternatively, the current functional paradigms may not reflect any phenomenological differences between pharmacotherapy and psychotherapy, as these effects might be dependent on other tasks than the ones currently used. Also, differences could be too small to be reliably detected in the current sample sizes. Future research should focus on the overlap and differentiation across the behavioral and neural changes in the circuits targeted by psychotherapy, and changes as result of pharmacological treatment. A clinical relevant question is, for any treatment modality, what the neurobiological mechanisms of the treatment effect are. When variance in symptom profile (symptom dimensions, cognitive functioning, and co-morbidity), neural profile (structure, function, and chemistry), eventually combined with the genetic profile, and treatment mechanisms for various forms of psychotherapeutic and pharmacological treatment is more clear, one might use the individual ‘fingerprint’ to determine the most effective treatment strategy. Although little is known about the mechanisms of treatment effects, one might hypothesize that the various forms of psychotherapy and pharmacotherapy have diverse effects on the various implicated neurotransmitter systems, involving serotonin (Linden, 2006), dopamine (Koo et al., 2010), and glutamate (Pittenger et al., 2006), and their reciprocal influences, which could affect neural circuits in terms of both function and structure. Neural predictors of treatment efficacy may also be useful in informing models of psychopathology and recovery (see Shin et al., 2013, for a recent review). Olatunji et al. (2013b) reported that neural measures of increased emotional processing in the anterior temporal pole and amygdala positively predicted outcome, while excessive cognitive control and activity in the dorsolateral PFC negatively predicted therapy outcome. In addition, orbitofrontal, medial prefrontal and anterior cingulate regions, which are brain regions related to fear processing, seem to predict treatment outcome (Brody et al., 1998; Hoexter et al.,

2013; Fullana et al., 2014). Although the predictive power of these findings is limited, they may indicate the importance of emotional exposure in psychotherapy, and the negative effect of inflexible cognitive control in fear extinction and inhibitory learning. This may be at odds with evidence for the effectiveness of cognitive and mindfulness-based treatments of OCD (Fairfax, 2008; Calkins et al., 2013), which arguably emphasize other factors than exposure and fear conditioning. Finally, the proposed prognostic value of emotional activity for psychotherapy outcome may be at odds with research that emphasizes the top-down effects of psychotherapy on prefrontal regions, compared with bottom-up effects of pharmacotherapy in limbic regions (DeRubeis et al., 2008; Barsaglini et al., 2014), while the concept is in line with evidence that better treatment outcome of CBT for depression is associated with higher levels of amygdala activity and lower levels of activity in the subgenual cingulate cortex (Siegle et al., 2006). Unfortunately, current treatment studies have not included the amygdala in their regions of interest, which hinders a further understanding of neural mechanisms during fear processing in exposure therapy. Neurobiological changes after treatment are probably only partly related to the specific therapeutic characteristics, since emotional, cognitive and behavioral changes following therapy are quite often more related to other factors than psychotherapy itself (Wampold, 2001, 2005; Miller et al., 2013). The effect of common and specific treatment factors in OCD has been investigated in terms of treatment characteristics such as length, intensity and focus (Keeley et al., 2008; Rosa-Alcázar et al., 2008; Olatunji et al., 2013a). In addition, some research has investigated the role of the working alliance and motivation (Vogel et al., 2006; Keeley et al., 2008), process-outcome factors (Polman et al., 2010) and characteristics of the therapist (Baldwin and Imel, 2013). It seems that what matters in and outside of therapy is relatively unexplored using neuroimaging, and designs that delineate potential neural differences between patient coping styles, treatment modalities and the qualitative experience

of recovery are needed. Also, some argue that focusing on the neurobiological substrates of OCD frames its sufferers in a disease-based medical framework, which may result in patient alienation, authoritarian therapy, and greater stigma towards mental illness (e.g., Shafran and Speckens, 2005; Elkins, 2009). Though certainly a possibility, this need not be the case (as has also been stated by Shafran and Speckens, 2005). Obsessions and unwanted thoughts are a normal occurrence, but the appraisal, intensity and duration of these thoughts and obsessions may differentiate normal occurrences and OCD (Rachman and de Silva, 1978). However, why some experience more intrusions or obsessions, and appraise them more negatively than others, is rooted in an interaction between genetics, neural processing, and life experiences (Pauls et al., 2014). Therefore, seeking to understand the neurobiological aspect of OCD needs not reduce OCD to abnormalities in the brain, but may rather be an attempt to better understand the neural aspect of obsessions, compulsions, and experiences associated with the disorder. This provides a complementary dimension to behavior, cognition, and phenomenology, instead of monopolizing OCD as a brain disorder. Recurring limitations in the reviewed studies are the mostly small sample sizes, concurrent SSRI treatment, lack of wait-list control groups, and poor randomization to treatment groups. The low numbers of participants found in several studies may have influenced statistical power, along with difficulties in isolating possible differences for psychotherapy and drug treatment. The lack of wait-lists or non-treatment conditions excludes the possibility of controlling for time as an influence on neural changes. However, changes in brain activity after treatment have been demonstrated for both long (up to 4 months; Baioui et al., 2013) and shorter periods (4 weeks; Saxena et al., 2009). This may indicate that the length of therapy is not critical for neural changes, an interpretation that fits with the possible nonsignificance of treatment length for symptom changes (Olatunji et al., 2013a). The lack of proper randomization in many studies is a potential problem, although the reviewed studies

that do use randomization do not report clear critical differences compared with those that do not use proper randomization. Future research should attempt to investigate neural changes in light of symptom dimensions and heterogeneity, and might benefit from more integrated multi-modal analyses combining structural, functional and effective connectivity measurements (Eickhoff and Grefkes, 2011), as well as investigating how phenomenon such as thalamocortical dyshrytmia and its relation to other CSTC circuitry may change during treatment (Schulman et al., 2011). Eric Kandel (2005) formulated the idea that psychotherapy affects the brain as follows: When a therapist speaks to a patient and the patients listens, the therapist is not only making eye contact and voice contact, but the action of neural machinery in the therapist’s brain is having an indirect, and one hopes, long-lasting effect on the neural machinery in the patient’s brain; and quite likely, vice versa. Insofar as our words produce changes in our patients mind, it is likely that these psychotherapeutic interventions produce changes in the patient’s brain. (p. 52). The current review concurs with Kandel in saying that psychotherapy can produce changes in the patient’s brain, though the mechanisms behind these changes are still quite unclear. The use of neuroimaging in psychotherapy research may radically change how we think about OCD. Its use has already had a large impact on models of pathophysiology, and may provide indicators for how therapy should be applied. One way this could come to pass is if the symptom profile of patients (i.e., symptom dimensions) and their neural substrates can predict which treatment, including psychotherapy, drugs, or a combination of both, is most effective for the individual patient. However, such practical applicability requires improvements in many areas, both in terms of better understanding patient heterogeneity

regarding symptom profile and disease stage, and not least in improving imaging analyses by translating group findings to the individual level. Acknowledgements Thanks to Karsten Specht and Håkan Sundberg for guidance, suggestions and proofreading, as well the invaluable friends and colleagues that supported and proof-read the manuscript. The authors report no conflicts of interest.

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Table 1 Studies of resting state activity Authors

Participants

Treatment effect

Neuroimaging

Treatment

(Cohen’s d)

method -

period

Main finding

Direction of change

condition

between imaging Baxter et al. (1992)

9 BT

2.17

FDG-PET

9 fluoxetine

R caudate

↓

rCBF,

4 HC 10±2 weeks Normalization of synchronized hemispheric rCBF Schwartz et al. (1996)

9 BT (+9 from

Responders

Baxter et al.,

(n=6): 4.97

1992)

Non-responders

10±2 weeks

(n=3): 1.71

FDG-PET

Bilateral

↓

caudate rCBF,

Normalization of synchronized hemispheric rCBF Saxena et al. (2009)

10 CBT

3.31

FDG-PET

12 HC

Bilateral

↓

thalamic rCBF

4 weeks

Apostolova et al. (2010)

9 CBT

R ACC rCBF

↑

1.52

FDG-PET

R caudate rCBF

↑

2.94

Xe-CT

R caudate rCBF

↓

7 paroxetine 14±4 weeks CBT 14±3 weeks paroxetine Nakatani et al. (2003)

31 BT 31 HC Varying duration based on clinical

improvement Yamanishi et al. (2009)

45 BT,

Responders

99mTc ECD

L middle

treatment-

(N=33):

SPECT

frontal gyrus, R

resistant to

4.22

medial PFC and

SSRI

Nonresponders

R OFC rCBF

12 weeks

(N=12): 1.01

R fusiform

↓

↑

gyrus, cuneus and angular gyrus rCBF BT=behavior therapy, HC=healthy controls, FDG-PET=18F-fluorodeoxyglucose positron emission tomography, rCBF=regional cerebra blood flow, CBT=cognitive behavioral therapy, R=right, ACC=anterior cingulate cortex, BT=behavior therapy, Xe-CT=xenon enhanced computed tomography, SSRI=selective serotonin reuptake inhibitor, ECD SPECT=technetium single-photon emission computed tomography, PFC=prefrontal cortex, OFC=orbitofrontal cortex.

Table 2 Studies of task-related activity Authors

Participants

Treatment effect

Neuroimaging

Treatment

(Cohen’s d)

method -

period

Main finding

Direction of change

condition

between imaging Nakao et al. (2005)

6 BT

2.05

fMRI - Stroop

Stroop task: R

4 fluvoxamine

task &

DLPFC,

12 weeks

individualized

bilateral

symptom

putamen,

provocation

parietal cortex

↑

and cerebellum and L temporal cortex activity

Stroop task: R

↓

frontal cortex, bilateral cingulate cortex, L cerebellum, and R hippocampus, temporal and parietal cortex activity Provocation

↓

task: bilateral frontal and occipital cortex, thalamus and cerebellum activity Nabeyama et al. (2008)

11 BT 19 HC 12 weeks

4.26

fMRI - Stroop

R OFC, L

task

middle frontal gyrus, L fusiform gyrus, bilateral hippocampal gyrus and L

↓

parietal lobe activity

R parietal lobe

↑

and bilateral cerebellum activity

Freyer et al. (2011)

10 CBT

2.02

10 HC

fMRI - reversal

L OFC and R

learning task

putamen

10±2 weeks

↓

activity Caudate

↑

nucleus activity

Andreou et al. (2013)

71 BT +

1.59

EEG - oddball

Current density

↓

power in L PFC

sertraline 71 HC 10 weeks Baioui et al. (2013)

12 CBT

1.20

fMRI –

Bilateral

12 HC

standardized &

nucleus

4 months

individualized

accumbens, L

symptom

SMG activity

↓

provocation Standardized

↓

provocation: L OFC, R caudate, L PFC, bilateral SMG activity Morgiève et al. (2013)

31 CBT

Mid therapy:

fMRI –

Bilateral ACC

3 months

1.22

standardized &

and L OFC

After therapy:

individualized

1.77

symptom

↓

provocation Schiepek et al. (2013)

9 CBT 9 HC

0.89

fMRI –

ACC/SMA,

individualized

bilateral

↓

8 weeks

symptom

DLPFC and R

provocation

insula activity

↑=increase, ↓=decrease, BT=behavior therapy, fMRI=functional magnetic resonance imaging, R=right, DLPFC=dorsolateral prefrontal cortex, L=left, OFC=Orbitofrontal cortex, CBT=cognitive behavioral therapy, HC=healthy controls, EEG=electroencephalography, PFC=prefrontal cortex, SMG=supramarginal gyrus, SMA=supplemental motor area, ACC=anterior cingulate cortex.

Table 3 Studies of neural metabolites Authors

Participants

Treatment effect

Neuroimaging

Treatment

(Cohen’s d)

method -

period

Main finding

Direction of change

condition

between imaging Whiteside et al. (2012)

15 BT

3.77

1

H-MRS

15 HC

NAA in L

↑

caudate

8 weeks O'Neill et al. (2013)

8 CBT

3.91

1

H-MRS

8 HC

tNAA in R

↓

pACC

4 weeks Glx in L middle

↑

cingulate cortex

↑=increase, ↓=decrease, BT=behavior therapy, HC=healthy controls, 1H-MRS=proton magnetic resonance spectroscopy, NAA= N-acetyl-l-aspartic acid, , L=left, CBT=cognitive behavioral therapy, tNAA= Nacetylaspartate + N-acetyl-aspartyl-glutamate, Glx= glutamate + glutamine.

Table 4 Study of structural changes Authors

Participants

Treatment effect

Neuroimaging

Treatment

(Cohen’s d)

method -

period

Main finding

Direction of change

condition

between imaging Hoexter et al. (2012)

19 CBT 19 fluoxetine

1.14

MRI

L putamen GM

↑

volume

36 HC 12 weeks ↑=increase, CBT=cognitive behavioral therapy, HC=healthy controls, MRI=magnetic resonance imaging, GM=gray matter.

Highlights: • OCD is associated with neural dysfunction in frontal-striatal dorsal and ventral circuits. • After successful cognitive behavioral therapy functional and resting state activity normalizes, with some evidence for gray matter growth as well. • Neural normalization is often associated with symptomatic and cognitive recovery. • Pharmacotherapy and psychotherapy may have similar effects on neural functioning.