Neurobiological model of obsessive compulsive disorder: Evidence from recent neuropsychological and neuroimaging findings

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1 doi: /pcn Neurobiological model of obsessive compulsive disorder: Evidence from recent neuropsychological and neuroimaging findings Tomohiro Nakao, MD, PhD,* Kayo Okada, MD and Shigenobu Kanba, MD, PhD Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Obsessive compulsive disorder (OCD) was previously considered refractory to most types of therapeutic intervention. There is now, however, ample evidence that selective serotonin reuptake inhibitors and behavior therapy are highly effective methods for treatment of OCD. Furthermore, recent neurobiological studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function. A large number of previous neuroimaging studies using positron emission tomography, single-photon emission computed tomography or functional magnetic resonance imaging (fmri) have identified abnormally high activities throughout the frontal cortex and subcortical structures in patients with OCD. Most studies reported excessive activation of these areas during symptom provocation. Furthermore, these hyperactivities were decreased after successful treatment using either selective serotonin reuptake inhibitors or behavioral therapy. Based on these findings, an orbitofrontostriatal model has been postulated as an abnormal neural circuit that mediates symptomatic expression of OCD. On the other hand, previous neuropsychological studies of OCD have reported cognitive dysfunction in executive function, attention, nonverbal memory, and visuospatial skills. Moreover, recent fmri studies have revealed a correlation between neuropsychological dysfunction and clinical symptoms in OCD by using neuropsychological tasks during fmri. The evidence from fmri studies suggests that broader regions, including dorsolateral prefrontal and posterior regions, might be involved in the pathophysiology of OCD. Further, we should consider that OCD is heterogeneous and might have several different neural systems related to clinical factors, such as symptom dimensions. This review outlines recent neuropsychological and neuroimaging studies of OCD. We will also describe several neurobiological models that have been developed recently. Advanced findings in these fields will update the conventional biological model of OCD. Key words: functional neuroimaging, neurobiology, neuropsychology, obsessive compulsive disorder, structural neuroimaging. OBSESSIVE COMPULSIVE DISORDER (OCD) was previously considered to be a typical neurotic disorder and refractory to most types of therapeutic intervention. There is now, however, ample evidence that selective serotonin reuptake inhibitors (SSRI) and cognitive behavioral therapy (CBT) are *Correspondence: Tomohiro Nakao, MD, PhD, Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi Higashi-ku, Fukuoka , Japan. tomona@npsych.med.kyushu-u.ac.jp Accepted 22 April

2 588 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: highly effective methods for treatment of OCD. Recent controlled clinical trials revealed that serotonin reuptake inhibitors (SRI), including clomipramine and SSRI, among other antidepressants, have specific anti-obsessional efficacy. 1,2 Soomro et al. 3 conducted a meta-analysis of 17 randomized controlled studies examining the efficacy of SSRI and found that treatments using SSRI were more effective than placebo in reducing the symptoms of OCD at least in the short-term, measured using the Yale Brown Obsessive Compulsive Scale (YBOCS). As for psychotherapy, Foa et al. 4 suggested that intensive exposure and ritual prevention of CBT might be superior to clomipramine and, by implication, to monotherapy with the other SRI. Recently, Olatunji et al. 5 performed a meta-analysis of 16 randomized controlled studies examining the efficacy of CBT and found that CBT outperformed control conditions on primary outcome measures at post-treatment. Recent research into the neurobiological aspects suggests that improvements of OCD due to either pharmacotherapy or psychotherapy were accompanied by functional changes of the brain network. 6 Neuropsychological studies regarding OCD and related neurological disorders have been conducted and suggest involvement of specific brain regions, including the orbitofrontal cortex (OFC) and basal ganglia, in its pathophysiology. Furthermore, recent neurobiological studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function. Since the 1980s, a large number of previous neuroimaging studies using positron emission tomography (PET) or single photon emission computed tomography (SPECT) have identified abnormally high activities throughout the frontal cortex and subcortical structures, such as the OFC, anterior cingulate cortex (ACC), caudate nucleus, and thalamus, in patients with OCD. 7 9 In addition, although there were few definite views for structural abnormalities of OCD in the early 1980s examinations using computed tomography or magnetic resonance imaging (MRI), the evidence from functional neuroimaging studies has led many researchers to examine structural abnormalities of regions, such as the OFC, caudate, and thalamus. By clarifying the biological mechanism of OCD, we could make great progress in treatment of the disorder. This review outlines recent neuropsychological and neuroimaging studies of OCD. We, furthermore, will show several neurobiological models that have been developed recently. NEUROPSYCHOLOGICAL FINDINGS OF OCD OCD-related organic and neurological disorders Before neuroimaging studies, neuropsychological studies of OCD and related neurological disorders were conducted and suggested involvement of specific brain regions, including the OFC and basal ganglia, in its pathophysiology. Several researchers showed that patients with orbitofrontal lesions consistently showed behavioral changes relating to inappropriate affect, disinhibition, and poor decision-making. 10 Recently, Figee et al. 11 reviewed 37 case reports of patients with acquired or remitted OCD due to infarctions or other brain lesions. The results suggested that lesions in the cortico-striatothalamic circuit, parietal and temporal cortex, cerebellum and brainstem may induce compulsivity. Neuropsychological studies suggest that the persistent and inflexible thought and behavior of OCD might be affected by higher cognitive impairments related to frontal function, such as executive function, spatial cognition, and nonverbal memory. Savage et al. 12 suggested that abnormal activity of the frontal-subcortical circuit might cause executive dysfunction and secondary nonverbal disturbances, and result in OC symptoms. They also insisted that sustained OC symptoms enhance abnormal activity of the neurocircuits and neuropsychological disturbance, which resulted in a vicious cycle among brain, cognition, and clinical symptoms. Neurological disorders of the basal ganglia, such as tic disorder, Tourette disorder, Sydenham s chorea, and Huntington s disease, have comorbid OCD symptoms. 13,14 Huntington s disease, an inherited neurodegenerative disorder involving atrophy of the caudate, often shows OC symptoms with personality change and depressive symptoms. Basal ganglia modulate higher cognitive functions, such as behavior planning, attention, social behavior, and decisionmaking, as well as modulate motor function by connecting with the cerebral motor cortex. Impairment of higher cognition in basal ganglia might cause the pathophysiology of OCD. Recently, Swedo et al. 15 proposed that pediatric autoimmune neuropsychiatric

3 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 589 disorders associated with group A β-hemolytic streptococcal infections (PANDAS) may cause early-onset pediatric OCD by inflammation of the basal ganglia after infection, a concept that has attracted considerable attention. Neuropsychological examination for OCD A large number of neuropsychological studies of OCD impairments have been conducted. In the 1980s, several researchers revealed impaired spatial recognition due to impairment of the nondominant hemisphere by employing the Cube Copying Test and Stylus Maze Test. 16 However, because these tests involve complicated cognitive functions, there is some doubt that decreased scores on these tests can be explained by impaired spatial recognition. Several studies found nonverbal memory dysfunction in OCD. 17 Savage et al., 18 however, suggested that memory impairment in OCD is secondary to executive function because the attention of patients to memorizing details disturbs memorizing on the whole. In addition, Radomsky et al. 19 asserted that the emotional aspects of OCD involve memory function. Zitterl et al. 20 insisted that lack of confidence, secondary to OC symptoms, might cause the lower memory score. Thus, there are various views on memory dysfunction in OCD. Kuelz et al. 21 conducted systematic electronic searches and found 50 studies showing a wide range of diverse neuropsychological disturbances, including attention, executive functions, visuospatial functions, verbal and nonverbal memories. Shin et al. 22 employed a meta-analytic approach for 88 selected studies and found significant impairments in OCD in tasks that measured visuospatial memory, executive function, verbal memory and verbal fluency, whereas auditory attention was preserved in these individuals. Recently, combinations of neuroimaging and neuropsychological methods have been employed frequently. These neuropsychological studies suggest that cognitive impairments in OCD, such as attention deficit, executive function, and working memory, which are supposed to be higher cognitive disturbances rather reflect intelligence level, educational level, or whole brain dysfunction. Impairments related to clinical OC symptoms are described below and shown in Table 1. 16,17,19,20,23 38 Attention deficit The concept of attention includes three factors information processing, attention span, and selective attention. Many researchers have examined impairments in information processing and attention span using cognitive tests, such as the trailmaking test or digit span of the Wechsler Adult Intelligence Scale Revised. Although Schmidtke et al. 26 demonstrated a decline in information processing speed, there is little evidence that suggests definite impairment of these functions in OCD. Concerning selective attention, in contrast, a number of researchers did studies based on the hypothesis that patients with OCD have difficulty in switching their attention. A PET study 24 found that glucose metabolism rates in the frontal cortices of patients with OCD were negatively correlated with subscores of the Stroop test. By using functional magnetic resonance imaging (fmri), we also found decreased activation in the ACC and right caudate compared to the healthy volunteers during the Chinese letter version of the Stroop task. 27 Gu et al. 28 employed a task-switching paradigm during an event-related fmri and found that patients with OCD exhibited a significantly higher error rate in the trials and decreased activation in the dorsal frontal-striatal regions, ventromedial prefrontal, and right OFC regions. Thus, neuroimaging studies might provide some evidence of disturbance of the attention process in OCD. Executive function Executive function is a higher cognitive function that controls and manages other cognitive processes. It includes planning, cognitive flexibility, rule acquisition, set shifting, and problem-solving ability. The concept of executive function might be reasonable to explain the persistent and inflexible thought and behavior of OCD, so many researchers have examined executive function in OCD. The Wisconsin Card Sorting Test (WCST) is appropriate to check setshifting ability. Head reported lower scores of WCST in patients with OCD compared to matched volunteers. 29 Lucey conducted SPECT scanning while patients with OCD performed the WCST and found a correlation between cerebral blood flow in the caudate and inferior frontal cortex and the number of errors on the WCST. 32 Abbruzzese et al., 30 however, found no impairment of this ability. On the other

4 590 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: Table 1. Neuropsychological findings Neuropsychological function Spatial cognition Authors (date) Subjects (number) Hollander et al. (1990) 16 OCD n = 41 HC n = 20 Memory Christensen et al. (1992) 17 OCD n = 18 HC n = 18 Radomsky et al. (1999) 19 OCD n = 10 HC n = 20 Savage et al. (2000) 23 OCD n = 33 HC n = 30 Zitterl et al. (2001) 20 OCD n = 27 HC n = 27 Attention Martinot et al. (1990) 24 OCD n = 16 HC n = 17 Executive function Working memory Nelson et al. (1993) 25 OCD n = 15 HC n = 15 Schmidtke et al. (1998) 26 OCD n = 29 HC n = 58 Nakao et al. (2005) 27 OCD n = 24 HC n = 14 Gu et al. (2008) 28 OCD n = 21 HC n = 21 Head et al. (1989) 29 OCD n = 19 HC n = 19 Abbruzzese et al. (1995) 30 OCD n = 33 HC n = 33 Gross-Isseroff et al. (1996) 31 OCD n = 15 HC n = 15 Lucey et al. (1997) 32 OCD n = 15 HC n = 15 Cavedini et al. (1998) 33 OCD n = 28 HC n = 29 Pujol et al. (1999) 34 OCD n = 20 HC n = 20 Purcell et al. (1998) 35 OCD n = 23 HC n = 23 Mataix-Cols et al. (1999) 36 OCD n = 35 HC n = 35 van der Wee et al. (2003) 37 OCD n = 11 HC n = 11 Nakao et al. (2009) 38 OCD n = 40 HC n = 25 Tests (and imaging techniques) employed Cube Copying Test WMS-R WCST WMS-R/Memory for contaminated stimuli ROCFT/California Verbal Learning Test Lern- und Gedachtnistest Corsi Block-Tapping Test Stroop test (+PET) Posner task Spatial-linguistic conflict task Trail Making Test A Stroop test (+fmri) Task-switching paradigm (+fmri) WCST Block Design (WAIS-R) WCST WCST Object Alternation Test WCST (+SPECT) WCST Object Alternation Test Word generation test (+fmri) Cambridge Neuropsychological Test Automated Battery Tower of Hanoi Spatial n-back task (+fmri) n-back task (+fmri) Findings Declined spatial cognition induced by indominant hemisphere Nonverbal memory dysfunction Memory impairment caused by emotional disturbance Memory impairment secondary to executive function Lower memory score due to lack of confidence, secondary to OCD Selective attention deficit Negative correlation between frontal metabolism and Stroop test subscores Selective attention deficit on visual stimulation Loss of information processing speed Sustained psychological scores Decreased activation in the ACC and the right caudate Higher error rate in the trial Decreased activation in the dorsal frontal-striatal regions, ventromedial prefrontal and right OFC Lower WCST scores No significant impairment Set-shifting disability caused by OFC dysfunction Correlation between cerebral blood flow in the caudate and inferior frontal and number of errors in WCST Set-shifting disability due to OFC dysfunction Stronger activation of left frontal cortex Decreased spatial working memory Decreased working memory Poor performance at highest level of task difficulty Same set of brain regions as HC in areas of medial, prefrontal, and parietal cortices Greater activation in right DLPFC and left STG and insula ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; fmri, fuctional magnetic resonance imaging; HC, healthy controls; OCD, obsessive compulsive disorder; OFC, orbitofrontal cortex; PET, positron emission tomography; ROCFT, Rey Osterrieth Complex Figure Test; STG, superior temporal gyrus; SPECT, single-photon emission computed tomography; WAIS-R, Wechsler Adult Intelligence Scale Revised; WCST, Wisconsin Card Sorting Test; WMS-R, Wechsler Memory Scale-Revised.

5 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 591 hand, a few researchers have suggested that dysfunction of the OFC may impair set shifting by employing the Object Alternation Test, which reflects OFC function. 31,33 There are several reports that found cognitive inflexibility and problem-solving deficits by using the Tower of Hanoi or Tower of London test. 35 An fmri study 34 showed significantly stronger activation of the left frontal cortex in patients with OCD compared with normal controls during performance of the Word Generation Test. Impairment of executive function has still been the most reasonable explanation of behaviors such as inadequate behavioral choice or inflexibility of behavioral change that are often seen in OCD. Working memory Working memory is one of the higher cognitive functions that involves interim integration, processing, disposal, and retrieval of information. It is distinguished from general memory function in the aspect of including active monitoring and manipulation of information. Several researchers found impaired working memory in OCD by using the Tower of London Test. 35,36 Recently, several studies 37,39,40 examined working memory function in OCD using both neuropsychological and functional neuroimaging methods. An fmri study 37 found that patients with OCD performed poorly at the highest level of task difficulty and engaged the same set of brain regions as the matched healthy controls in the areas of the medial, prefrontal, and parietal cortices, which are specifically involved in working memory, during the N-back task. We applied neuropsychological batteries to demonstrate a working memory deficit in OCD by comparison with normal controls in combination with functional imaging studies. 38 On the neuropsychological tests, the OCD patients had significantly lower scores on the delayed recall section of the Wechsler Memory Scale-Revised (WMS-R) and the immediate recall section of the Rey Osterrieth Complex Figure Test compared to the controls. On fmri, the patients showed greater activation in the right dorsolateral prefrontal cortex (DLPFC), left superior temporal gyrus (STG), left insula, and cuneus during the twoback task compared to the controls. In addition, we examined the correlation between working memory and brain activation by symptom-based analysis. Right OFC activity showed a significant positive correlation with Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores in OCD. Furthermore, patients with obsessions/checking rituals showed severer memory deficits and decreased activity in the postcentral gyrus than patients with cleanliness/washing rituals. Our results indicated that patients with OCD might have visual working memory dysfunction related to the functional brain network. OCD patients demonstrate difficulties in visual organization and mental manipulation of visual information, which might cause repetitive thoughts and behavior of OCD. STRUCTURAL NEUROIMAGING OF OCD Region of interest Although there were few definite views in the early 1980s examinations using computed tomography or MRI, the evidence from functional neuroimaging studies has led many researchers to examine brain structures of regions that showed abnormal activation, such as the OFC, caudate, and thalamus. We summarized the structural imaging findings in Table Researchers employed region of interest (ROI) methods until voxel-based morphometry (VBM) methods were developed. Most ROI studies 42 44,53,54 reported volume reduction in the regions such as the OFC, caudate, thalamus, amygdala, and ACC. Rotge et al. 55 conducted a meta-analysis of 14 ROI studies and found a reduced volume of the left ACC and bilateral OFC and an increase of bilateral thalamic volumes. Szeszko et al. 42 found that patients with OCD had significantly reduced bilateral OFC and amygdala volumes compared with healthy control subjects and lacked the normal hemispheric asymmetry of the hippocampus-amygdala complex. Researchers also took an interest in structural abnormalities of pediatric patients with OCD. Interestingly, Gilbert reported that thalamic volumes were significantly greater in treatment-naive patients with OCD than in controls, 43 but that they declined significantly to levels comparable with those of controls after paroxetine monotherapy. Rosenberg et al. 41 found that treatment-naive children aged 7 18 years with OCD had significantly smaller striatal volumes and significantly larger third ventricle volumes than controls. It would be meaningful to examine pediatric patients in the early stage from onset with little influence of medication. ROI methods, however, have a major limitation. ROI methods measure volumes of the brain regions

6 592 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: Table 2. Findings of structural neuroimaging Technique/ Design MRI ROI MRI VBM MRI DTI MRI DTI + VBM Authors (date) Subjects (number) Rosenberg et al. (1997) 41 OCD n = 19 HC n = 19 Szeszko et al. (1999) 42 OCD n = 26 HC n = 26 Gilbert et al. (2000) 43 OCD n = 21 HC n = 21 Kwon et al. (2003) 44 OCD n = 22 HC n = 22 Sc n = 22 Kim et al. (2001) 45 OCD n = 25 HC n = 25 Pujol et al. (2004) 46 OCD n = 72 HC n = 72 Valente et al. (2005) 47 OCD n = 19 HC n = 15 van den Heuvel et al. (2009) 48 OCD n = 55 HC n = 50 Togao et al. (2010) 49 OCD n = 23 HC n = 26 Okada (submitted) OCD n = 37 HC n = 37 Szeszko et al. (2005) 50 OCD n = 15 HC n = 15 Nakamae et al. (2008) 51 OCD n = 15 HC n = 15 Zarei et al. (2011) 52 OCD n = 26 HC n = 26 Findings Smaller striatal volumes and significantly larger third ventricle volumes Reduced bilateral OFC and amygdala volumes Greater thalamic volumes Declined significantly after paroxetine monotherapy Reduced bil. hippocampal volume in both OCD and Sc Enlarged left amygdala volume in OCD Increased GM density in left OFC and thalamus Reduced GM density in left cuneus and left cerebellum Reduced GM volume in medial frontal gyrus, medial OFC, and left insulo-opercular region Increased GM volume in ventral part of the putamen and in anterior cerebellum Increased GM in posterior OFC and parahippocampal regions Decreased GM in left ACC in OCD Decreased GM volume in left lateral OFC, left inferior frontal, left DLPFC and right medial prefrontal cortices Decreased bilateral prefrontal WM volume Significant reduction of GM volume in bilateral medial prefrontal cortex, right premotor area, right OFC, right DLPFC, and bilateral temporal and occipital regions. Significant WM volume increase in right anterior limb of internal capsule, right orbitofrontal region, and significant WM volume reduction in left anterior cingulate gyrus Specific negative correlations between symptomatic dimension scores and regional GM volumes, mainly as decreased right cerebellum in aggression and decreased right insula in contamination Significant lower FA bilaterally in ACC white matter in OCD Higher FA in bilateral semioval center extending to subinsular white matter Increased GM volume in caudate bilaterally and right putamen. Higher FA values in regions including left inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, right inferior fronto-occipital fasciculus, and bilateral corticospinal tract ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; DTI, diffusion tensor imaging; FA, fractional anisotropy; GM, grey matter; HC, healthy controls; MRI, magnetic resonance imaging; OCD, obsessive compulsive disorder; OFC, orbitofrontal cortex; ROI, region of interest; VBM, voxel-based morphometry; WM, white matter.

7 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 593 defined a priori as being implicated in OCD, therefore preventing the exploration of other brain regions potentially implicated in the disorder. Voxel-based morphometry Recently, several interesting findings that employed VBM, a whole-brain approach to the imaging analysis of MRI scanning, have been reported. Kim et al. found increased regional grey matter density in multiple cortical areas, including the left OFC and in subcortical areas, including the thalamus, while regions of reduction were confined to posterior parts of the brain, such as the left cuneus and left cerebellum. 45 Pujol et al. conducted MRI scanning and VBM analysis on 72 patients with OCD and matched controls. 46 They found that the patients with OCD showed reduced gray matter volume in the medial frontal gyrus, medial OFC, and left insulo-opercular region. A relative increase in gray matter volume was observed bilaterally in the ventral part of the putamen and anterior cerebellum. Recently, van den Heuvel et al. 48 found that OCD patients showed decreased grey matter (GM) volume in the left lateral OFC, left inferior frontal, left DLPFC, and right medial prefrontal (BA10) cortices and decreased bilateral prefrontal white matter (WM) volume. They also found symptom dimension-specific GM and WM alterations. Our group also compared 23 patients with OCD to 26 healthy controls by using VBM analysis. 49 The patients with OCD demonstrated a significant reduction of GM volume in the bilateral medial prefrontal cortex, right premotor area, right OFC, right DLPFC and bilateral temporal and occipital regions, while they showed a significant WM volume increase in the right anterior limb of the internal capsule and right orbitofrontal region, and a significant WM volume reduction in the left anterior cingulate gyrus. Although the findings of VBM studies were inconsistent, Radua et al. 56 conducted a meta-analysis of 12 VBM studies and found that individuals with OCD had increased bilateral regional grey matter volumes in the lenticular nucleus (mainly ventral anterior putamen) extending to the caudate nucleus, as well as decreased bilateral regional grey matter volumes in dorsal mediofrontal/anterior cingulate gyri, extending to the supplementary motor area and frontal eye fields. Interestingly, this meta-analysis did not reveal significant between-group differences in the OFC, a region that has been consistently implicated in functional neuroimaging studies of OCD, and constitutes the basis of the most widely accepted neurobiological model of OCD. The authors pointed out that it would be possible that recruitment of the OFC in functional neuroimaging studies in OCD reflects secondary, perhaps compensatory, neural responses to cognitive or emotional challenges, rather than being critically implicated in the etiopathogenesis of the disorder. Diffusion tensor imaging Diffusion tensor imaging (DTI) has lately attracted considerable attention. DTI can be used to examine the white matter microstructure, permitting quantification of the directionality and coherence of water self-diffusion. Tissues with highly regular fibers have high fractional anisotropy (FA), while those with less regular fibers, such as gray matter, have low anisotropy. Szeszko et al. 50 compared patients with OCD to healthy volunteers and found that the patients demonstrated significantly lower FA bilaterally in ACC white matter. Nakamae et al. 51 found that patients with OCD had higher FA in the bilateral semioval center extending to the subinsular white matter and a higher apparent diffusion coefficient (ADC) in the left medial frontal cortex compared with healthy volunteers. Recently, Koch et al. 57 identified a negative correlation between FA and ordering as well as between FA and obsessing, suggesting that stronger white matter deficits are associated with higher severity of ordering/obsessing symptoms. Further, Zarei 52 examined structural GM volume and WM microstructure by employing both DTI and VBM and found that patients had increased GM volume in the bilateral caudate and right putamen and higher FA values in several regions, including the left inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, and right inferior fronto-occipital fasciculus. 52 Although the findings from DTI are inconsistent at present, DTI might have implications for understanding the anatomical organization of white matter and anatomical connectivity in OCD. FUNCTIONAL NEUROIMAGING OF OCD Findings from PET and SPECT Since the 1980s, a large number of neuroimaging studies using PET or SPECT have identified abnor-

8 594 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: mally high activities throughout the frontal cortex and subcortical structures, such as the OFC, ACC, caudate nucleus, and thalamus, in patients with OCD. We summarized the findings of functional imaging using PET and SPECT in Table ,58 69 Baxter et al. 7 showed elevated metabolic rates in the OFC and caudate nucleus in their early work by using PET scanning. Zohar et al. 9 reported that increased anxiety was correlated with hyperperfusion in the caudate nucleus and OFC by using SPECT during a symptom-provocation task. Although these findings of hyperactivities in the OFC and caudate nucleus have been replicated repeatedly, some studies showed different findings. Busatto et al. 66 found decreased perfusion in the right OFC and left ACC. Machlin et al. 65 showed no difference between OCD and healthy volunteers in OFC activation, though they found medial prefrontal hyperperfusion in OCD during SPECT scanning. Swedo et al. 8 found elevated metabolic rates in the right prefrontal cortex (PFC) and left ACC. Perani et al. 59 also found elevated metabolism in the bilateral ACC. Although there are some inconsistencies among studies, these findings concerning abnormal activities throughout the frontal cortex and subcortical regions were replicated by many researchers using both resting and symptom-provocation paradigms Recently, Whiteside et al. 74 performed meta-analysis of 13 studies that were carried out by using PET or SPECT and found significant functional abnormality in the OFC and head of the caudate. Dysfunction of the ventromedial system and subcortical structures, including the OFC and caudate nucleus, has been strongly implicated in OCD symptomatology and related emotional responses. 75 Findings from fmri In the later 1990s, numerous fmri studies of OCD were performed. fmri shows regional changes that reflect blood perfusion as contrast images by MRI. fmri has been suggested to be one of the most effective methods for following changes in local brain regions throughout various activation paradigms because of its comparatively high temporal and spatial resolution. fmri investigations identified related frontal brain regions with OCD in detail and reported various new findings that were not identified in PET or SPECT studies. We summarized the findings of functional imaging using fmri in Table Several studies reported extreme activation in the OFC and ACC during symptom provocation tasks using items such as pictures of violence, sexual photographs, and unclean towels to induce fear of contamination. 76,77 Shapira et al. 78 reported increased activation in the insula, parahippocampus, and inferior frontal cortex during symptom provocation of patients with washing rituals by using fmri, while Cannistraro et al. 79 found that OCD subjects exhibited a weaker response to human faces than control subjects in the bilateral amygdala. The fmri findings varied widely, mainly due to the wide range of paradigms employed by these studies. Recently, Harrison et al. 82 found that patients with OCD had significantly increased functional connectivity along a ventral corticostriatal axis, implicating the OFC and surrounding areas by using resting-state fmri, which provides a more sensitive measurement of functional connectivity in large-scale brain networks. Their findings emphasized the abnormal and heightened functional connectivity of ventro-limbic-cortico-striatal regions in patients with OCD. Menzies et al. 85 conducted a meta-analysis that included 15 fmri studies and found various activation abnormalities in the lateral frontal, cingulate, middle occipital and parietal cortices, and cerebellum. Rotge et al. 86 also conducted a voxel-based metaanalysis of eight imaging studies, including four by PET and four by fmri to provide a quantitative estimation of cerebral activation patterns related to the performance of a symptom provocation task by OCD patients. They found significant likelihoods of activation in cortical and subcortical regions of the OFC and ACC loops. The left dorsal fronto-parietal network, including the DLPFC and precuneus, and the left superior temporal gyrus also demonstrated significant likelihoods of activation. The results of the meta-analysis suggest that more-widely distributed large-scale brain systems may be involved in OCD. Molecular imaging Recently, several researchers reported a new approach to molecular imaging that estimates receptors and transporters of neurotransmitters quantitatively. Hesse et al. 67 reported decreased availability of dopamine transporters in the striatum and decreased availability of serotonin transporters in the thalamus and midbrain by using SPECT scanning with [ 123 I]β- CIT, which labels both dopamine transporter (DAT) and serotonin transporter (SERT). Moresco et al. 64 reported that [ 11 C]-Raclopride, which is a selective D2

9 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 595 Table 3. Functional neuroimaging (PET/SPECT) findings Technique PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET 18 F-FDG PET [ 11 C]Rac SPECT 133 Xe SPECT m99 Tc SPECT m99 Tc SPECT [ 123 I]β-CIT Xe CT Proton-MRS Authors (year) Subjects (number) Design/task Findings Baxter et al. OCD n = 14 (1987) 7 Depression n = 14 HC n = 14 Swedo et al. OCD n = 18 (1989) 8 HC n = 18 Baxter et al. OCD n = 18 (1992) 58 HC n = 4 Resting state Resting state Before and after CBT and fluoxetine OCD n = 11 Perani et al. Resting state (1995) 59 HC n = 15 Brody et al. OCD = 27 Before and after BT (1998) 60 and fluoxetine Saxena et al. OCD = 20 Before and after (1999) 61 taking paroxetine Rauch et al. OCD n = 9 Resting state, (2002) 62 before fluvoxamine treatment Saxena et al. (2003) 63 OCD = 27 MDD = 27 OCD + MDD = 17 Moresco et al. OCD n = 8 (2007) 64 HC n = 8 Resting state, before paroxetine treatment Before and after treatment Zohar et al. (1989) 9 OCD n = 10 Symptom provocation task Machlin et al. OCD n = 10 Resting state (1991) 65 HC n = 8 Busatto et al. OCD n = 26 Resting state (2000) 66 HC n = 22 Hesse et al. OCD n = 15 Resting state (2005) 67 HC n = 10 Nakatani et al. (2003) 68 OCD n = 22 Before and after treatment Sumitani et al. OCD n = 20 Before and after (2007) 69 HC n = 26 treatment Elevated metabolic rates in OFC and caudate nucleus Elevated metabolic rates in right PFC and left ACC Correlation between OCD symptom improvement and reduction of metabolism in right caudate Metabolic correlation between right OFC, caudate, and thalamus disappeared after treatment Increased in ACC, thalamus and pallidum/ putamen complex Higher normalized metabolism in left OFC was associated with greater improvement with BT treatment, but worse outcome with fluoxetine Lower pretreatment metabolism in bilateral OFC predicted greater improvement of clinical severity after treatment Lower rcbf values in OFC and higher rcbf values in posterior cingulate cortex predicted better treatment response Clinical improvement was correlated to higher pretreatment glucose metabolism in right caudate nucleus in OCD, while improvement of MDD symptoms were correlated with pretreatment metabolism in amygdala, thalamus, and medial prefrontal cortex Increased [ 11 C]Rac binding potential in basal ganglia corresponding to clinical improvement Increasing anxiety correlated with hyper-perfusion in caudate nucleus and OFC Medial prefrontal hyperperfusion Decreased perfusion in right OFC and left ACC Decreased availability of dopamine transporter in striatum and decreased availability of serotonin transporter in thalamus and midbrain Decreased rcbf in right head of caudate nucleus after treatment Decreased N-acetyl aspartate concentration in ACC corresponding to augmentation of SRI with atypical neuroleptics CBT, cognitive behavioral therapy; HC, healthy controls; MDD, major depressive disorder; OCD, obsessive compulsive disorder; OFC, orbitofrontal cortex; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

10 596 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: Table 4. Functional neuroimaging (fmri) findings Technique fmri fmri fmri fmri fmri fmri fmri fmri fmri Authors (date) Subjects (number) Design/task Findings Breiter et al. OCD n = 10 Symptom Increased activation in OFC, ACC and (1996) 76 HC n = 5 provocation task caudate Adler et al. OCD n = 7 Symptom Increased activation in OFC, DLPFC, (2000) 77 provocation task temporal, and ACC Shapira et al. OCD n = 8 Symptom Increased activation in insula, (2003) 78 HC n = 8 provocation task parahippocampus, and inferior frontal cortex Cannistraro et al. (2004) 79 OCD n = 10 HC n = 10 Provocation task for recognition of human faces Nakao et al. (2005) 80 OCD n = 10 Symptom provocation task and neurocognitive task before and after treatment Nabeyama et al. OCD n = 11 Neurocognitive (2008) 81 task before and after BT Harrison et al. (2009) 82 OCD n = 21 HC n = 21 Resting state Sanematsu et al (2010) 83 OCD n = 17 Symptom provocation task before taking fluvoxamine Murayama et al. (2013) 84 OCD/check n = 10 OCD/wash n = 12 HC/check n = 10 HC/wash n = 9 Symptom provocation task Weak response in bilateral amygdala Decreased activation in bilateral OFC, DLPFC and ACC during symptom provocation and increased activation in parietal and cerebellum during Stroop task after symptom improvement Increased activation in cerebellum and parietal and decreased activation in the OFC, middle frontal gyrus, and temporal regions after symptom improvement Increased functional connectivity along a ventral corticostriatal axis, implicating the OFC and surrounding areas Correlation between pre-treatment activation in right cerebellum and left STG and Y-BOCS %improvement Hypoactivation in left caudate and left ACC in Checkers. Hyperactivation in several bilateral cortico-cerebellar regions in Checkers ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; fmri, functional magnetic resonance imaging; HC, healthy controls; OCD, obsessive compulsive disorder; OFC, orbitofrontal cortex; STG, superior temporal gyrus; Y-BOCS, Yale Brown Obsessive Compulsive Scale. receptor antagonist, increased the D2-binding potential significantly in the basal ganglia of OCD patients, corresponding to clinical improvement. Sumitani et al. 69 employed proton-mrs and found that the concentration of N-acetyl aspartate in the ACC was significantly decreased in patients who responded to augmentation therapy using atypical neuroleptics. Some OCD patients respond to neuroleptics, although they do not respond sufficiently to SSRI. Molecular imaging studies might be useful to clarify the involvement of various neurotransmitters, including serotonin and dopamine, in OCD pathophysiology. Brain changes before and after treatment Comparative studies before and after treatment make it possible to estimate the correlation between changes of brain function and clinical improvement after pharmacological or psychological treatment.

11 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 597 Benkelfat et al. 87 reported that hypermetabolism in the OFC and caudate nucleus observed by pretreatment PET scanning was normalized after successful treatment with clomipramine. Baxter et al. 58 also reported that hypermetabolism in the right caudate and pathological metabolic correlation between the OFC, caudate, and thalamus improved significantly in responders to both drug and behavior therapy. They suggested that presence of the pathological metabolic correlation might predict treatment response. Several studies using ROI methods have found that a lower pre-treatment metabolism rate within the OFC 60,61,88 or higher activity in the right caudate nucleus 62,63,89 was associated with better subsequent response to SRI. Saxena et al. 61 reported that lower metabolism in the bilateral OFC predicts a better treatment response to paroxetine. Rauch et al. 62 used SPM methods with PET to investigate predictors of fluvoxamine treatment response with contaminationrelated OCD patients in the context of a symptom provocation paradigm, and reported that lower rcbf values in the OFC and higher rcbf values in the posterior cingulate cortex predicted better treatment response. As for effects of psychotherapy, Linden et al. 6 mentioned in his review that psychological intervention led to decreased metabolism in the caudate and a decreased correlation of the right OFC with the ipsilateral caudate and thalamus. They found that in four studies 58,68,80,90 discussed in the review that compared pharmacological and psychological interventions, the effects on cerebral metabolism were rather similar. However, Saxena et al. 91 maintained that response to intensive cognitive behavior therapy (CBT) might require activation of the dorsal ACC, a region involved in reappraisal and suppression of negative emotions, although a reduction of thalamic activity may be a final common pathway for improvement in OCD. NEUROBIOLOGICAL MODEL OF OCD Orbitofronto-subcortical circuits Neuroimaging findings accumulated since the 1980s led us to a biological hypothesis regarding the pathophysiology of OCD. The orbitofronto-subcortical circuits (OCD-loop) model that Saxena et al. 92 proposed might be a principal one to account for OCD phenomenology. In the OCD-loop model, the existence of a (+) OFC (+) Mediodorsal thalamus (+) OCD loop ( ) GPi SNR Ventromedial caudate Subthalamic nucleus lateral orbitofrontal loop was proposed, involving projections from the OFC to the head of the caudate nucleus and ventral striatum, then to the mediodorsal thalamus via the internal pallidus, and finally returning from the thalamus to the OFC. Furthermore, Saxena et al. proposed that OCD is mediated by an imbalance between the direct (excitatory, OFCstriatum-globus pallidus-thalamus-cortical) and indirect (inhibitory, DLPFC-striatum-globus pallidussubthalamic nucleus-cortical) pathways within this circuit, which causes brain lock in the caudate nucleus and a mutual hyperactivation between the OFC and thalamus (Fig. 1). Each of these regions might play its characteristic role and work in close cooperation, the OFC as a monitor of appropriate behavior in social life, the ACC as an action monitor and regulator, the caudate as a gate for the limbic and frontal cortices, and the thalamus as a filter of information. The OCD-loop model explained OCD-specific phenomenology as a functional abnormality in the orbitofronto-subcortical circuits in contrast to other hypotheses, such as hypofrontality in depression or limbic system impairments of hippocampus and amygdala in other anxiety disorders, such as panic disorder or post-traumatic stress disorder. Structural imaging studies showing volume changes of the regions, including the OFC, ACC, thalamus, and caudate nucleus, also support the OCD-loop model. A recent meta-analysis demon- ( ) ( ) ( ) GPe Figure 1. Cortico-striatal-thalamic-cortical circuit in obsessive compulsive disorder (OCD). The cortico-striatalthalamic-cortical circuit (OCD-loop) model that Saxena proposed might be a principal one to account for OCD phenomenology. In this model, the existence of a lateral orbitofrontal loop was proposed, involving projections from the orbitofrontal cortex (OFC) to the head of the caudate nucleus and ventral striatum, then to the mediodorsal thalamus via the internal pallidus and finally returning from the thalamus to the OFC. Although the OCD-loop model explains OCDspecific phenomenology, we should examine the pathophysiology of OCD in more detail. Saxena et al. 92 ( )

12 598 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: strated the biological independency of OCD from other anxiety disorders by showing that individuals with OCD had increased bilateral GM volumes in the lenticular/caudate nuclei, while patients with other anxiety disorders had decreased gray matter volumes in the left lenticular nucleus. 93 Executive function DLPFC Visuospatial information Occipital cortex cerebellum Basal ganglia ACC Conflict anxiety Decision-making OFC OCD loop Thalamus Figure 2. Functional neuroanatomy in obsessive compulsive disorder (OCD) brain: Correlation between brain activation and clinical improvement. A network including the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) and posterior regions may be related to cognitive processes in OCD, while orbitofronto-striatal regions (OCD-loop) may be involved with OCD symptomatology. Clinical improvement of OCD might accompany functional improvement of brain and cognitive improvement, such as visuospatial information, decision-making, working memory, and executive function. OFC, orbitofrontal cortex. Integrated model of neuroimaging and neuropsychology Savage proposed a hypothesis concerning the correlation among clinical symptoms, neuropsychological function, and brain function as follows. Orbitofronto-subcortical circuits (OCD-loop) in the brain cause executive dysfunction and secondary nonverbal dysfunction in OCD, and lead to the emergence of OC behaviors. Sustained OC behaviors, furthermore, reinforce the OCD-loop in the brain and strengthen neuropsychological impairment. A vicious cycle among brain-cognition-clinical symptoms finally develops. They also insisted that neuropsycho-pharmacotherapy at the brain level, behavior therapy at the clinical level, and cognitive training at the cognitive level might be useful for breaking this vicious cycle. 12 Recently, we realized we should consider further evidence regarding brain areas outside the orbitofronto-striatum circuits. Menzies et al. 85 provided a revised model for OCD in which the underlying pathology is not limited to the orbitofronto-striatal regions and associated limbic structures, such as the amygdala, but also involves abnormalities in additional brain systems, particularly including more dorsolateral frontal and parietal regions that may be considered to represent the dorsolateral prefrontostriatal circuit involving cognitive networks, such as spatial or attentional cognition. Our findings also suggest that posterior regions, including the parietal and occipital lobes and cerebellum, showed increased activation during a cognitive task with clinical improvement, while hyperactivation in orbitofronto-striatal regions had decreased. 80,81 This means that clinical improvement of OCD might accompany functional improvement of the brain and cognitive improvement of functions such as attention, working memory, and executive function. Involvement of both orbitofronto-striatum circuits and prefronto-limbic-posterior circuits would constitute a complicated pathophysiological state of OCD (Fig. 2). Although neuropsychological findings have been inconsistent so far, inspection of the neuropsychological function of the OCD plays a crucial role as a state marker for clinical improvement and as an endophenotype connecting clinical features to the biological model. A combination of neuropsychological methods with neuroimaging methods could be expected to reveal the correlation among clinical symptoms, neuropsychological functions, and the brain. Assessment of treatment response using functional neuroimaging Functional imaging revealed that there are functional changes in several regions, including the OFC, thala-

13 Psychiatry and Clinical Neurosciences 2014; 68: Review of neurobiology for OCD 599 ACC/insula Emotion SSRI NLP BG Obsession OFC OCD loop Compulsion Thalamus CBT Cognition DLPFC Figure 3. Brain networks and treatment effects in obsessive compulsive disorder (OCD). Although there may be a specific biological basis for OCD, such as the OCD-loop, complex involvements of various neural networks relevant to cognition and emotion might cause its clinical diversity and result in deviation of treatment response. In our hypothesis, cognitive behavioral therapy (CBT) may improve compulsive behavior and cognition by acting on cortical regions, including the dorsolateral prefrontal cortex (DLPFC), and result in improvement of obsession. On the other hand, selective serotonin reuptake inhibitors (SSRI) and neuroleptics will decrease obsession and emotion by acting on limbic and basal ganglia. BG, basal ganglia; NLP, neuroleptic; OFC, orbitofrontal cortex. mus, and basal ganglia, involved in clinical improvement. Furthermore, the existence of pathological activation of specific regions, such as the OFC and caudate nucleus, before treatment might predict a treatment response. To assess treatment response, our research group has conducted fmri studies of OCD patients that examine brain function of the participants before and after behavior therapy or psychopharmacology with fluvoxamine. We found that untreated patients show increased activation in the OFC and thalamus during the symptom provocative task and decreased activation in the parietal cortex and cerebellum during the Stroop task, which is relevant to selective attention, compared to healthy volunteers. 27 Furthermore, we observed that these abnormal activations, hyperactivation of the frontal lobe and hypoactivation of posterior regions, normalized after improvement of OCD with either fluvoxamine or behavioral therapy. 80,81 In assessment of the treatment response, we also found that pre-treatment activation in the right cerebellum and left STG was positively correlated with improvement in the Y-BOCS score. 83 Our result suggested that pretreatment activation in the right cerebellum and left STG predict a subsequent reduction in OCD symptom severity. In the present review, we have outlined recent neuropsychological and neuroimaging studies of OCD and an advanced neurobiological model of OCD pathophysiology. Although we hypothesize a specific biological basis in OCD, such as an OCD-loop, complicated involvement of various neural networks relevant to cognition and emotion might cause its clinical diversity and result in deviation of treatment response. Further, in our hypothesis, CBT will alleviate compulsive behavior and cognition by acting on cortical regions, including the DLPFC, and result in amelioration of the obsession. On the other hand, SSRI and neuroleptics will decrease obsessions and emotions by acting on limbic and basal ganglia (Fig. 3). However, we have not revealed the difference in pathways between psychotherapy and pharmacotherapy; although, in depression, psycho- and pharmacotherapy seem to operate through different pathways, one more top-down and the other more bottom-up. 6 We need further investigation to clarify the correlation between treatment and brain changes. Recent studies, however, suggest that more widely distributed large-scale brain systems, including the parietal, occipital, and cerebellar areas, rather than only the orbitofronto-striatal regions, might be involved in the treatment of OCD. 37,85,81 Multi-dimensional model Patients with OCD present various types of symptoms, such as washing rituals for contamination fear, checking rituals for harm avoidance, or hoarding rituals. In recent studies, researchers proposed a revised multi-dimensional model involving a brain network model. Mataix-Cols et al. found functional brain differences among OCD subtypes by using fmri methods. 94 They hypothesized that checking rituals were more connected with a frontalsubcortical network related to impulse and that washing rituals were more affected by a frontallimbic system related to emotional discomfort 95 (Fig. 4). Recently, by using resting fmri methods, Harrison et al. 96 found that aggression symptoms modulated connectivity between the ventral striatum,

14 600 T. Nakao et al. Psychiatry and Clinical Neurosciences 2014; 68: Symptom dimension CHECKING WASHING Functional impairment Inhibition/suppression of urges to check Emotional processing/disgust Neural systems Basal ganglia Thalamus Brainstem Prefrontal cortex Limbic system Figure 4. Multidimensional model of obsessive compulsive disorder (OCD). Different obsessive compulsive symptom dimensions may be mediated by relatively distinct components of neural circuits. Aberration of the basal ganglia system may be attributed to difficulty in inhibition of unwanted impulses, such as urges to check, while neural components of the limbic system are likely to process emotional dimensions, such as disgust for uncleanness. OCD thus seems best conceptualized as a spectrum of multiple, overlapping syndromes rather than a unitary disease entity. amygdala, and ventromedial frontal cortex, while sexual/religious symptoms had a specific effect on ventral striatal-insular connectivity. Our group 84 also found that patients with checking rituals showed hypoactivation in the left caudate and left ACC compared to normal controls, while the patients with washing rituals showed hyperactivation in several bilateral cortico-cerebellar regions. Based on our results, we can revise the traditional OCD-loop network (Fig. 5). In this revised model, we assume that the caudate and ACC are associated with checking rituals and that large cortical brain regions are related to washing rituals in OCD patients. We, furthermore, found specific negative correlations between symptomatic dimension scores and regional GM volumes, mainly as decreased right cerebellum in aggression and decreased right insula in contamination by using VBM methods. In the multi-dimensional model, Mataix-Cols et al. 94 suggest that different obsessive compulsive symptom dimensions are mediated by relatively distinct components of fronto-striato-thalamic circuits implicated in cognitive and emotion processing and that OCD may be best conceptualized as a spectrum of multiple, potentially overlapping syndromes rather than a unitary nosologic entity. The concept of WASHING-RELATED Temporal cortex Cerebellum DLPFC Somatic perception CHECKING-RELATED Cortico-cerebellarthalamic circuit Higher cognition VLPFC OFC Mediodorsal thalamus OCD loop GPi SNR ACC Striatum Impulsiveness GPe Subthalamic nucleus Figure 5. Obsessive compulsive disorder (OCD)-loop and subtyperelated circuits. Based on our results, we revised the traditional OCD-loop network. In this new model, we assume that the caudate and anterior cingulate cortex (ACC) are associated with checking rituals and large cortical brain regions are related to washing rituals in OCD patients. DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex.