- Email: [email protected]
Cerebellar volume deficits in medication-naïve obsessive compulsive disorder
Author’s Accepted Manuscript Cerebellar Volume deficits in Medication-naïve Obsessive Compulsive Disorder Janardhanan C. Narayanaswamy, Dania Jose, Sunil V. Kalmady, Sri Mahavir Agarwal, Ganesan Venkatasubramanian, Y.C. Janardhan Reddy www.elsevier.com
PII: DOI: Reference:
S0925-4927(15)30175-X http://dx.doi.org/10.1016/j.pscychresns.2016.07.005 PSYN10569
To appear in: Psychiatry Research: Neuroimaging Received date: 10 December 2015 Revised date: 6 July 2016 Accepted date: 8 July 2016 Cite this article as: Janardhanan C. Narayanaswamy, Dania Jose, Sunil V. Kalmady, Sri Mahavir Agarwal, Ganesan Venkatasubramanian and Y.C. Janardhan Reddy, Cerebellar Volume deficits in Medication-naïve Obsessive Compulsive Disorder, Psychiatry Research: Neuroimaging, http://dx.doi.org/10.1016/j.pscychresns.2016.07.005 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.
Cerebellar Volume deficits in Medication-naïve Obsessive Compulsive Disorder Janardhanan C. Narayanaswamya,b, Dania Jose b, Sunil V. Kalmadyb, Sri Mahavir Agarwala,b, Ganesan Venkatasubramaniana,b*, Y.C. Janardhan Reddya a Obsessive-Compulsive Disorder Clinic, Department of Psychiatry b Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India, 560029 * Corresponding author. Dr. Ganesan Venkatasubramanian, Additional Professor, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India – 560029, Phone: +91-80-26995366. Email: [email protected] Abstract
Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD.
Keywords: Obsessive compulsive disorder; cerebellum; MRI
1.
Introduction:
Traditional neurobiological models of obsessive compulsive disorder (OCD) highlight disturbances in fronto-striatal (FS) circuits as an explanation of the recurrent thoughts and compulsive behaviours (Menzies et al., 2008; Radua et al., 2009). In the recent years, neuroimaging research has suggested involvement of regions outside the FS circuitry in OCD (Nabeyama et al., 2008; Pujol et al., 2004). A recent meta-analysis demonstrated that apart from the “conventional” fronto-striatal alterations, volume changes were present in widespread 1
brain regions (Piras et al., 2015). In addition to this, there is growing evidence of widespread alterations in white matter fiber tracts in OCD (Piras et al., 2013). Overall, recent studies employing whole-brain analyses indicate that the neuroimaging alterations are more distributed, involving insular, parietal and cerebellar regions (Nabeyama et al., 2008; Pujol et al., 2004). In particular, the role of cerebellum, a crucial yet poorly studied structure in the context of OCD is gaining prominence (Nabeyama et al., 2008; Pujol et al., 2004). Contextually, cognitive task activation based fMRI studies have reported reduced activation of the cerebellum in patients with OCD with a reversal of this along with clinical improvement due to treatment (Nabeyama et al., 2008; Nakao et al., 2005; Sanematsu et al., 2010).
In summary, on integrating the current evidence of widespread brain structural and functional abnormalities, it is now being realized that the posterior regions such as cerebellum might have an important role in OCD (Menzies et al., 2008). Even though classically described as a structure important for motor coordination, converging evidence suggest that the cerebellum, through the cerebro-cerebellar circuits, has a pivotal role in cognition and emotion in addition to motor control(Strick et al., 2009). Importantly, the cerebellum has been shown to have a modulating effect on certain cognitive functions (Allen et al., 1997; Chen and Desmond, 2005; Daum and Ackermann, 1995; Honey et al., 2000; Stoodley and Schmahmann, 2010) including the ones that are impaired in OCD (Kuelz et al., 2004).
The cerebellum is organized into ten lobules (I–X) (Schmahmann et al., 2000). There are three recognized major anterior-posterior divisions or lobes within which the lobules are sub-divided: the anterior lobe (lobules I–V) is separated from the posterior lobe by the primary fissure, and the posterior lobe (lobules VI–IX) is separated from the flocculonodular lobe (lobule X) by the posterolateral fissure. The midline region is called the vermis and the lateral cerebellar regions are called the hemispheres. Most of the lateral cerebellar regions, also referred to as the neocerebellum, comprise of the hemispheric extensions of lobules VI and VII. Interestingly, cerebellum has functionally distinct and topographically segregated organization of motor, cognitive, and limbic functions (Stoodley and Schmahmann, 2010). The cerebellar motor abnormalities are related to lesions that involve the anterior lobe and parts of lobule VI while the cognitive difficulties are related to the posterior lobe impairments that affect lobules VI and VII (including Crus I, Crus II, and lobule VIIB) occurring due to the effects on cognitive network connections with cerebral association cortices. Vermis abnormalities affect the cerebrocerebellar-limbic loops resulting in emotion related abnormalities observed in various 2
neuropsychiatric disorders. Of particular relevance to neuropsychiatric disorders such as OCD is that the association area projections from the prefrontal, parietal, and temporal, and cingulate cortices have cerebellar homunculi mainly localized to lobules VI and VII(Kelly and Strick, 2003; Stoodley and Schmahmann, 2010). The projections of the prefrontal cortical brain regions such as the anterior cingulate cortex (ACC) to Crus I/II, lateral cortical projections to lobule VI and projections from limbic cortices to posterior vermis (Stoodley and Schmahmann, 2010) would be of relevance in OCD where cognitive and emotion related abnormalities are present. Specifically, lobules VI and VII probably mediate spatial tasks, executive function and affective processing through their connections with the relevant cortical regions (Honey et al., 2000; LaBar et al., 1999; Stoodley et al., 2012).
Despite the growing evidence regarding the important role of cerebellum in OCD, wellcharacterised region of interest studies of cerebellum in medication naïve patients have not been done to date. In the present study, we aimed to examine the structural volumetric differences of cerebellum and its various sub-regions in a large sample of medication naïve OCD patients in comparison to matched healthy controls (HC). We hypothesised that OCD patients would have significantly deficient cerebellar volume compared to HC. Taking into consideration the functional and topographical representation of various networks of cerebellum as described previously, we also hypothesised that there would be volume deficits predominantly in the regions confined to the posterior lobe. 2.
Methods:
2.1 Subjects: The study participants constituted 50 medication naïve adult patients with DSM-IV OCD (APA, 1994) and 40 matched HC. The patients were recruited from the National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India. The study was conducted in accordance to the Declaration of Helsinki. The NIMHANS institute ethics committee approved the study. All the participants gave written informed consent for participation in the study. In the analysis, one subject from each group had to be excluded due to poor image quality of their MRI, thus leaving the final analysable sample to 49 OCD patients and 39 HC. None of the patients had prior exposure to psychotropic medications.
None of the subjects had any of the following: medical illness that may significantly influence CNS function or structure; significant neurologic disorder such as seizure disorder, cerebral 3
palsy; history suggestive of delayed developmental milestones (suggestive of mental retardation);a family history of hereditary neurologic disorder that may complicate diagnosis; comorbidity for DSM-IV psychoactive substance dependence; or a lifetime history of head injury associated with loss of consciousness longer than 10 minutes, seizures, neurological deficit, depressed skull fracture, surgical intervention, or central nervous system infection. Female subjects were neither pregnant nor were within the postpartum period. 2.2 Clinical measures All patients were evaluated with the Mini International Neuropsychiatric Interview plus (MINI) (Sheehan et al., 1998), a short structured diagnostic interview, designed to diagnose psychiatric disorders as per for DSM-IV and ICD-10. Severity of OCD was measured using the Yale-Brown obsessive compulsive scale (YBOCS) that includes a symptom checklist, a 10-point severity rating scale, and item 11 for insight (Goodman et al., 1989). Each item is rated from 0 (no symptoms) to 4 (extreme symptoms) (total range, 0 to 40). It provides a specific measure of the severity of OCD symptoms that is not influenced by the type of obsessions or compulsions present. YBOCS item 11 measures insight regarding the illness. Its score ranges from 0 to 4 and a higher value indicate poorer insight. The Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) was used to quantify depressive comorbidity. It is a 10-point scale, each item rated from 0 to 6 with the overall score ranging from 0 to 60. Higher score implies more severe depression. The Clinical Global Impression scale (CGI) (Guy, 1976) was used to measure the global illness severity. It is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Only subjects who had YBOCS total score of more than 16 (clinically significant OCD) were recruited for the study. All subjects were right-handed as assessed by Annett’s questionnaire (Annett, 1967), a 12-item handedness questionnaire. Healthy controls were administered the MINI (Sheehan et al., 1998) to rule out any Axis I psychiatric disorders. 2.3 MRI acquisition MRI was done with a 1.5 T scanner (Magnetom ‘Vision’, Siemens, Erhlangen, Germany).T1weighted three-dimensional magnetization prepared rapid acquisition gradient echo (MP-RAGE) sequence was performed (TR = 9.7 ms, TE = 4 ms, nutation angle = 12°, and slice thickness: 1mm with no inter-slice gap, voxel dimension 1*1*1 mm isotropic) yielding 160 sagittal slices.
2.4 Cerebellum image analysis method: 4
The origin of T1-weighted images was set to the anterior commissure using SPM8 (Wellcome Trust Centre for Neuroimaging, UCL, London; UK; http://www.fil.ion.ucl.ac.uk/spm) under MatLab 7.8.0 (The MathWorks Inc., Sherborn, MA, USA).
Infra-tentorial structures namely
cerebellum and brainstem were isolated from the surrounding tissue using the Spatially Unbiased
Infra
tentorial
Template
(SUIT)
toolbox
(Diedrichsen,
2006)
(http://www.icn.ucl.ac.uk/motorcontrol/imaging/suit.htm), which uses the tissue-type and the proximity to cortical white matter to calculate the posterior probability of each voxel to belong to cerebellum or brainstem. The cropped anatomical images were then normalized where a nonlinear deformation map to the SUIT template, using the cosine-basis function approach was performed (Ashburner and Friston, 1999). Images were then resampled into the SUIT atlas space using deformation map created in the normalization step, such that the overall probability mass were retained after normalization. Finally, using suit_lobuli_summarize function, all voxels within each cerebellar compartment were found, split by lobules and vermis/hemisphere. These 28 compartments were originally defined by the probabilistic cerebellar atlas which has been shown to enable accurate anatomical inferences for human
anatomical imaging studies
(Diedrichsen et al., 2009). 2.5 Statistical analysis: The volume measures were distributed normally (Shapiro-Wilk test, p>0.05) and hence parametric tests were employed for the analysis. Independent samples t-test and chi square test were used for continuous and discrete variables for baseline comparisons. The differences between OCD patients and healthy controls were examined using ANCOVA with age, sex and intracranial volume (ICV) as covariates. We performed Pearson’s correlation analysis for the OCD group to examine the relationship between cerebellar volumes and YBOCS severity score. To account for multiple testing, Benjamini Hochberg false discovery rate (FDR) correction was employed for the differences in the sub-regional cerebellar volumes and is reported alongside the uncorrected significance values. 3.
Results:
3.1 Demographic and clinical profile The age at assessment (26.6 ± 6.6 vs. 25.5 ± 5.5 years, t=0.8, p=0.41), mean ICV (mL) (1450.9±158.4 vs. 1418.9±148.1, t=0.9, p=0.34) and sex composition (male: female =30:19 vs. 27:12, χ2 =0.61,p=0.44) were comparable between OCD patients and HC. Among the patients with OCD, the median illness duration was 60 months (mean - 65.6 ± 58.4 months) and the mean age of onset of OCD was 21.2±7.2 years. The mean YBOCS obsession score, YBOCS 5
compulsion score, YBOCS total score, CGI-S and YBOCS item 11(insight) score were 13.2±4.1, 12.7±4.9, 25.8±8.3, 4.7±1.1 and 1.3±1.0 respectively. The symptom profile of the patients is depicted in table 1. The lifetime comorbid conditions in OCD patients were major depression (18.4%), specific phobia (5.1%), social phobia (12%) and generalized anxiety disorder (4.2%). Other comorbid conditions including tic disorders were not present in the sample. The mean MADRS score was 13.1±9.2.
3.2 Cerebellar volume differences between patients and healthy controls: The subjects with OCD had significantly smaller cerebellum (mL) compared to HC (84.2±9.8 vs. 89.4±11.0, F=9.5, p=0.003). In particular, there was significantly deficient volume (mL) of posterior lobe of cerebellum in patients compared to HC (71.2±8.0 vs. 75.5±8.84, F=10.6, p=0.002) (figure 1). The significant sub-regional (lobular) volume differences between both the groups is depicted in the table 2 and an anatomical representation of these regions on a brain image has been provided in figure 2. There was no significant sex by status interaction effect in any of the cerebellar regional volumes. The posterior lobe and sub-regional deficits were present on analysing the sample after excluding the subjects with major depressive disorder.
3.3 Correlation with the illness severity measures: Total cerebellar volume demonstrated a significant correlation with age at assessment (r = -0.6, p<0.001) but not with the duration of illness (r = -0.01, p = 0.92). Hence, partial correlation controlling for the effects of age was employed to examine the relationship between cerebellar volumes and the illness severity measures. Total and regional cerebellar volumes did not have significant correlations with YBOCS severity score [total volume, p=0.69; anterior lobe volume, p=0.82 ;posterior lobe volume, p=0.57], YBOCS item 11 (insight score) [total volume, p=0.28; anterior lobe volume, p=0.17 ;posterior lobe volume, p=0.41], CGI-severity score [total volume, p=0.74; anterior lobe volume, p=0.62 ; posterior lobe volume, p=0.55] and MADRS score [total volume, p=0.67; anterior lobe volume, p=0.99 ; posterior lobe volume, p=0.62]. 4.
Discussion:
To summarize the results, we found a significant reduction of cerebellar volume in medication naïve OCD patients compared to HC. Specifically, the posterior lobe of cerebellum was smaller among patients. Sub-regions confined to the posterior lobe which demonstrated volume reduction among OCD patients compared to HC were lobule VI and left crus 1. 6
Partially defying the conventional notion that neurobiological aberrations in OCD are restricted to the fronto-striatal circuitry, many studies have shown that there could be additional brain regions including the posterior ones involved (Piras et al., 2013; Piras et al.,2015). Tonna et al., reported an interesting case of an elderly patient who developed OCD late in life associated with a left cerebellar lesion due to an arachnoid cyst (Tonna et al., 2014). Structural MRI studies in OCD have demonstrated volume abnormalities pertaining to the cerebellum. In a study by Kim et al, there were volumetric deficits in regions confined to the posterior regions of the brain such as the left cuneus and the left cerebellum(Kim et al., 2001). Koprivová et al also demonstrated significant cerebellar volume deficits in OCD patients compared to HC (Koprivova et al., 2009). Pujol et al on the other hand reported significant grey matter volume increase in cerebellum and bilateral putamen (Pujol et al., 2004). A recent large meta-analysis of VBM studies also reported of increased cerebellar volume in OCD (de Wit et al., 2014). Recently, Brooks et al. reported that right cerebellar volume demonstrated a significant positive correlation with adverse childhood experiences among patients with OCD suggesting the role of childhood developmental pathology affecting cerebellum in OCD (Brooks et al., 2016). The variations in the direction of volume changes could be due to variations in samples across studies such as comorbidity rate, medication status and the relative composition of symptom dimensions. The present study also highlights the importance of the role of cerebellum in the neurobiology of OCD by demonstrating its volume deficit in OCD compared to HC.
Resting state functional MRI (fMRI) studies also point towards the role of cerebellum in the neurobiology of OCD. In a recent study, Anticevic et al reported of changes in connectivity of networks including cerebellum among participants with OCD (Anticevic et al., 2014). Significant changes in spontaneous neuronal activity in regions involving cerebellum and parietal cortex in resting state fMRI has been reported in OCD (Hou et al., 2012). There is growing recognition that in multi-modal information processing, the connectivity between cerebellar hemispheres, neocortical association areas and limbic cortical regions could have a crucial role (Stoodley and Schmahmann, 2010; Strick et al., 2009). Abnormalities in networks where cerebellum holds a prominent functional importance, might have a significant, yet so far poorly appreciated role in neuropsychiatric diseases including OCD. In this context, one could assume that the cognitive functions that are impaired in OCD, classically thought to be modulated by the cortical regions such as cingulate cortex, parietal cortex and dorsolateral prefrontal cortex, might have a significant modulatory effect by the cerebellum(Page et al., 2009; Woolley et al., 2008). Studies 7
have indicated that the cerebellum is also involved in a variety of cognitive functions, such as attention, verbal memory and cognitive planning (Andreasen et al., 1996; Courchesne et al., 1994; Kim et al., 1994). Impaired response inhibition and executive dysfunction which are amongst the most replicated cognitive aberrations of OCD has been found to have a substrate in cerebellum in addition to the conventional cortical areas in fMRI studies in OCD (Page et al., 2009; Woolley et al., 2008). We did not observe any significant correlation between between cerebellar volume and the severity of the illness. This could indicate that the cerebellar volume reduction might be pathogenic for OCD and not state-dependent.
The volume reduction of cerebellum pertaining to posterior lobe with distinct involvement of certain sub-regions appears interesting. Posterior lobe of cerebellum is connected to the various neo-cortical association areas and limbic cortices while the anterior lobe is connected to the motor cortical areas (Stoodley and Schmahmann, 2010) and this probably explains the differential volume abnormality of posterior lobe of cerebellum in OCD as seen in our study results. More intriguing is the fact that sub-regions of posterior lobe have distinct connectivity with the cortex. For instance, the anterior cingulate cortex projections reach Crus I/II, more lateral cortical projections reach lobule VI and posterior vermis is linked to regions that regulate affect limbic cortices (Stoodley and Schmahmann, 2010). Lobules VI and VII probably mediate spatial tasks, executive function and affective processing (Honey et al., 2000; LaBar et al., 1999; Stoodley et al., 2012). Volume deficit involving region VI merit attention since the OCD is associated with impairment in some of the above cognitive functions. This sub-region specific structural and functional topography has important implications in the understanding of neurobiology of OCD.
Studying medication naïve OCD patients is a major strength of this study. It has been reported that the medications such as selective serotonin reuptake inhibitors (SSRIs) used to treat OCD can have significant effect on the cerebellar and striatal connectivity (Anticevic et al., 2014). Thus, the potential confounding effect of medications have been averted by recruiting subjects who have never had psychotropic drug treatment in the past. Comorbid psychiatric conditions could potentially affect the results. However, the comorbidity rate is very low in the present sample. Presently OCD is considered as a heterogeneous disorder with distinct symptom dimensions. Examining the relationship between dimensional severity scores and the cerebellar regional volumes might have provided additional insights. Region of interest based single region study such as this has its advantage as well as disadvantage. Advantage is that it 8
is hypothesis driven and the disadvantage is that the region specific changes can only be explained or speculated using the previous evidence on the relevant networks/connectivity. In addition, cross-sectional evaluation of a single region of interest cannot assess the changes in that structure over various stages of the illness. However, this study gives initial evidence for region specific cerebellar volumetric deficits in OCD, thus providing novel inputs regarding the neurobiology of this disorder. More studies should systematically examine role of cerebellum using resting state as we as cognitive activation fMRI paradigms apart from evaluating the relationship of the cerebellar structural and functional alterations in accordance to the various symptom dimensions in OCD.
Acknowledgement
Ms. Dania Jose is supported by the DST-INSPIRE grant conferred by the Department of Science and Technology (DST), Government of India to Dr. Janardhanan C. Narayanaswamy. Dr. Kalmady and Dr. Agarwal are supported by the DBT-India Alliance Wellcome trust grant to Dr. Venkatasubramanian.
References: Allen, G., Buxton, R.B., Wong, E.C., Courchesne, E., 1997. Attentional activation of the cerebellum independent of motor involvement. Science 275, 1940-1943. Andreasen, N.C., O'Leary, D.S., Cizadlo, T., Arndt, S., Rezai, K., Ponto, L.L., Watkins, G.L., Hichwa, R.D., 1996. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the United States of America 93, 9985-9990. Annett, M., 1967. The binomial distribution of right, mixed and left handedness. Quarterly Journal of Experimental Psychology 19, 327-333. Anticevic, A., Hu, S., Zhang, S., Savic, A., Billingslea, E., Wasylink, S., Repovs, G., Cole, M.W., Bednarski, S., Krystal, J.H., Bloch, M.H., Li, C.S., Pittenger, C., 2014. Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biological psychiatry 75, 595-605. APA, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC.
9
Ashburner, J., Friston, K.J., 1999. Nonlinear spatial normalization using basis functions. Human brain mapping 7, 254-266. Brooks, S.J., Naidoo, V., Roos, A., Fouché, J.P., Lochner, C., Stein, D.J., 2016. Early-life adversity and orbitofrontal and cerebellar volumes in adults with obsessive-compulsive disorder: voxel-based morphometry study. British Journal of Psychiatry 208, 34-41. Chen, S.H., Desmond, J.E., 2005. Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task. Neuropsychologia 43, 1227-1237. Courchesne, E., Townsend, J., Akshoomoff, N.A., Saitoh, O., Yeung-Courchesne, R., Lincoln, A.J., James, H.E., Haas, R.H., Schreibman, L., Lau, L., 1994. Impairment in shifting attention in autistic and cerebellar patients. Behavioral neuroscience 108, 848-865. Daum, I., Ackermann, H., 1995. Cerebellar contributions to cognition. Behavioural brain research 67, 201-210. de Wit, S.J., Alonso, P., Schweren, L., Mataix-Cols, D., Lochner, C., Menchon, J.M., Stein, D.J., Fouche, J.P., Soriano-Mas, C., Sato, J.R., Hoexter, M.Q., Denys, D., Nakamae, T., Nishida, S., Kwon, J.S., Jang, J.H., Busatto, G.F., Cardoner, N., Cath, D.C., Fukui, K., Jung, W.H., Kim, S.N., Miguel, E.C., Narumoto, J., Phillips, M.L., Pujol, J., Remijnse, P.L., Sakai, Y., Shin, N.Y., Yamada, K., Veltman, D.J., van den Heuvel, O.A., 2014. Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder. The American journal of psychiatry 171, 340-349. Diedrichsen, J., 2006. A spatially unbiased atlas template of the human cerebellum. NeuroImage 33, 127-138. Diedrichsen, J., Balsters, J.H., Flavell, J., Cussans, E., Ramnani, N., 2009. A probabilistic MR atlas of the human cerebellum. NeuroImage 46, 39-46. Goodman, W.K., Price, L.H., Rasmussen, S.A., Mazure, C., Fleischmann, R.L., Hill, C.L., Heninger, G.R., Charney, D.S., 1989. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry 46, 1006-1011. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology. In: US Dept Health, Education and Welfare Publication (ADM) 76-338. Rockville, Md: National Institute of Mental Health pp. 218-222. Honey, G.D., Bullmore, E.T., Sharma, T., 2000. Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation. NeuroImage 12, 495-503.
10
Hou, J., Wu, W., Lin, Y., Wang, J., Zhou, D., Guo, J., Gu, S., He, M., Ahmed, S., Hu, J., Qu, W., Li, H., 2012. Localization of cerebral functional deficits in patients with obsessive-compulsive disorder: a resting-state fMRI study. Journal of affective disorders 138, 313-321. Kelly, R.M., Strick, P.L., 2003. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. The Journal of neuroscience 23, 8432-8444. Kim, J.J., Lee, M.C., Kim, J., Kim, I.Y., Kim, S.I., Han, M.H., Chang, K.H., Kwon, J.S., 2001. Grey matter abnormalities in obsessive-compulsive disorder: statistical parametric mapping of segmented magnetic resonance images. The British journal of psychiatry 179, 330-334. Kim, S.G., Ugurbil, K., Strick, P.L., 1994. Activation of a cerebellar output nucleus during cognitive processing. Science 265, 949-951. Koprivova, J., Horacek, J., Tintera, J., Prasko, J., Raszka, M., Ibrahim, I., Hoschl, C., 2009. Medial frontal and dorsal cortical morphometric abnormalities are related to obsessivecompulsive disorder. Neuroscience letters 464, 62-66. Kuelz, A.K., Hohagen, F., Voderholzer, U., 2004. Neuropsychological performance in obsessive-compulsive disorder: a critical review. Biological psychology 65, 185-236. LaBar, K.S., Gitelman, D.R., Parrish, T.B., Mesulam, M., 1999. Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects. NeuroImage 10, 695-704. Menzies, L., Chamberlain, S.R., Laird, A.R., Thelen, S.M., Sahakian, B.J., Bullmore, E.T., 2008. Integrating evidence from neuroimaging and neuropsychological studies of obsessivecompulsive disorder: the orbitofronto-striatal model revisited. Neuroscience and biobehavioral reviews 32, 525-549. Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to change. The British journal of psychiatry 134, 382-389. Nabeyama, M., Nakagawa, A., Yoshiura, T., Nakao, T., Nakatani, E., Togao, O., Yoshizato, C., Yoshioka, K., Tomita, M., Kanba, S., 2008. Functional MRI study of brain activation alterations in patients with obsessive-compulsive disorder after symptom improvement. Psychiatry research 163, 236-247. Nakao, T., Nakagawa, A., Yoshiura, T., Nakatani, E., Nabeyama, M., Yoshizato, C., Kudoh, A., Tada, K., Yoshioka, K., Kawamoto, M., Togao, O., Kanba, S., 2005. Brain activation of patients with obsessive-compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: a functional magnetic resonance imaging study. Biological psychiatry 57, 901-910.
11
Page, L.A., Rubia, K., Deeley, Q., Daly, E., Toal, F., Mataix-Cols, D., Giampietro, V., Schmitz, N., Murphy, D.G., 2009. A functional magnetic resonance imaging study of inhibitory control in obsessive-compulsive disorder. Psychiatry research 174, 202-209. Piras, F., Piras, F., Caltagirone, C., Spalletta, G., 2013. Brain circuitries of obsessive compulsive disorder: a systematic review and meta-analysis of diffusion tensor imaging studies. Neuroscience and biobehavioral reviews 37, 2856-2877. Piras, F., Piras, F., Chiapponi, C., Girardi, P., Caltagirone, C., Spalletta, G., 2015. Widespread structural brain changes in OCD: A systematic review of voxel-based morphometry studies. Cortex, 62, 89-108 Pujol, J., Soriano-Mas, C., Alonso, P., Cardoner, N., Menchon, J.M., Deus, J., Vallejo, J., 2004. Mapping structural brain alterations in obsessive-compulsive disorder. Archives of general psychiatry 61, 720-730. Radua, J., Mataix-Cols, D., 2009. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. The British journal of psychiatry Sanematsu, H., Nakao, T., Yoshiura, T., Nabeyama, M., Togao, O., Tomita, M., Masuda, Y., Nakatani, E., Nakagawa, A., Kanba, S., 2010. Predictors of treatment response to fluvoxamine in obsessive-compulsive disorder: an fMRI study. Journal of psychiatric research 44, 193-200. Schmahmann, J.D., Doyon, J., Toga, A., Petrides, M., Evans, A., 2000. MRI Atlas of the Human Cerebellum. San Diego: Academic Press,. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD10. J Clin Psychiatry 59 Suppl 20, 22-33;quiz 34-57. Stoodley, C.J., Schmahmann, J.D., 2010. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 46, 831-844. Stoodley, C.J., Valera, E.M., Schmahmann, J.D., 2012. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. NeuroImage 59, 1560-1570. Strick, P.L., Dum, R.P., Fiez, J.A., 2009. Cerebellum and nonmotor function. Annual review of neuroscience 32, 413-434. Tonna, M., Ottoni, R., Ossola, P., De Panfilis, C., Marchesi, C., 2014. Late-onset obsessivecompulsive disorder associated with left cerebellar lesion. Cerebellum 13, 531-535. Woolley, J., Heyman, I., Brammer, M., Frampton, I., McGuire, P.K., Rubia, K., 2008. Brain activation in paediatric obsessive compulsive disorder during tasks of inhibitory control. The British journal of psychiatry 192, 25-31. 12
Figure 1: The comparison of posterior cerebellar lobe volume between OCD patients (N=49) and healthy controls (HC=39)
13
Figure 2: A schematic brain image showing regions of significant differences between OCD patients and healthy controls in coronal (A), sagittal (B), and axial (C) sections.
Green: Left Crus I; Blue: Left VI; Yellow: Vermis VI, Red: Right VI
14
Table 1: The clinical symptom profile (YBOCS checklist –lifetime) of the participants with OCD (N=49) Clinical parameter Obsessions: Fear of contamination
N (%)
Aggressive Religious/blasphemous Sexual Symmetry Pathological doubts
14(28.0) 17(34.1) 14(28.0) 19(38.0) 28(56.8)
36 (72.0)
Compulsions: Washing Checking Arranging
36(72.0) 26(52.0) 20(40.1)
Repeating Hoarding
24(48.2) 8(16.0)
15
Table 2: The significant cerebellar regional volumetric differences between OCD patients (N=49) and healthy controls (HC) (N=39) Cerebellar region
OCD patients
Healthy (N=39)
(N=49)
(Mean±SD) (mL)
F
P
P (FDR)
(Mean±SD) (mL) Left VI
7.6±1.2
8.4±1.7
8.1
0.006
0.04
Left Crus I
9.1±1.2
9.9±1.7
8.3
0.005
0.04
Right VI
6.7±1.1
7.4±1.4
9.3
0.003
0.04
Vermis VI
1.5±0.3
1.7±0.3
8.3
0.005
0.04
F- ANCOVA controlling for the effects of age, sex and intracranial volume; P (FDR)-Benjamini Hochberg false discovery rate (FDR) correction; P-FDR < 0.05 is significant.
Highlights
Conventional neurobiological models of OCD implicate fronto-striatal circuits
Recent research propose role for cerebellum in OCD.
This study examined for status of cerebellar volume in untreated OCD patients.
Findings support posterior cerebellar volume deficit in OCD.
16
PII: DOI: Reference:
S0925-4927(15)30175-X http://dx.doi.org/10.1016/j.pscychresns.2016.07.005 PSYN10569
To appear in: Psychiatry Research: Neuroimaging Received date: 10 December 2015 Revised date: 6 July 2016 Accepted date: 8 July 2016 Cite this article as: Janardhanan C. Narayanaswamy, Dania Jose, Sunil V. Kalmady, Sri Mahavir Agarwal, Ganesan Venkatasubramanian and Y.C. Janardhan Reddy, Cerebellar Volume deficits in Medication-naïve Obsessive Compulsive Disorder, Psychiatry Research: Neuroimaging, http://dx.doi.org/10.1016/j.pscychresns.2016.07.005 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.
Cerebellar Volume deficits in Medication-naïve Obsessive Compulsive Disorder Janardhanan C. Narayanaswamya,b, Dania Jose b, Sunil V. Kalmadyb, Sri Mahavir Agarwala,b, Ganesan Venkatasubramaniana,b*, Y.C. Janardhan Reddya a Obsessive-Compulsive Disorder Clinic, Department of Psychiatry b Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India, 560029 * Corresponding author. Dr. Ganesan Venkatasubramanian, Additional Professor, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India – 560029, Phone: +91-80-26995366. Email: [email protected] Abstract
Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD.
Keywords: Obsessive compulsive disorder; cerebellum; MRI
1.
Introduction:
Traditional neurobiological models of obsessive compulsive disorder (OCD) highlight disturbances in fronto-striatal (FS) circuits as an explanation of the recurrent thoughts and compulsive behaviours (Menzies et al., 2008; Radua et al., 2009). In the recent years, neuroimaging research has suggested involvement of regions outside the FS circuitry in OCD (Nabeyama et al., 2008; Pujol et al., 2004). A recent meta-analysis demonstrated that apart from the “conventional” fronto-striatal alterations, volume changes were present in widespread 1
brain regions (Piras et al., 2015). In addition to this, there is growing evidence of widespread alterations in white matter fiber tracts in OCD (Piras et al., 2013). Overall, recent studies employing whole-brain analyses indicate that the neuroimaging alterations are more distributed, involving insular, parietal and cerebellar regions (Nabeyama et al., 2008; Pujol et al., 2004). In particular, the role of cerebellum, a crucial yet poorly studied structure in the context of OCD is gaining prominence (Nabeyama et al., 2008; Pujol et al., 2004). Contextually, cognitive task activation based fMRI studies have reported reduced activation of the cerebellum in patients with OCD with a reversal of this along with clinical improvement due to treatment (Nabeyama et al., 2008; Nakao et al., 2005; Sanematsu et al., 2010).
In summary, on integrating the current evidence of widespread brain structural and functional abnormalities, it is now being realized that the posterior regions such as cerebellum might have an important role in OCD (Menzies et al., 2008). Even though classically described as a structure important for motor coordination, converging evidence suggest that the cerebellum, through the cerebro-cerebellar circuits, has a pivotal role in cognition and emotion in addition to motor control(Strick et al., 2009). Importantly, the cerebellum has been shown to have a modulating effect on certain cognitive functions (Allen et al., 1997; Chen and Desmond, 2005; Daum and Ackermann, 1995; Honey et al., 2000; Stoodley and Schmahmann, 2010) including the ones that are impaired in OCD (Kuelz et al., 2004).
The cerebellum is organized into ten lobules (I–X) (Schmahmann et al., 2000). There are three recognized major anterior-posterior divisions or lobes within which the lobules are sub-divided: the anterior lobe (lobules I–V) is separated from the posterior lobe by the primary fissure, and the posterior lobe (lobules VI–IX) is separated from the flocculonodular lobe (lobule X) by the posterolateral fissure. The midline region is called the vermis and the lateral cerebellar regions are called the hemispheres. Most of the lateral cerebellar regions, also referred to as the neocerebellum, comprise of the hemispheric extensions of lobules VI and VII. Interestingly, cerebellum has functionally distinct and topographically segregated organization of motor, cognitive, and limbic functions (Stoodley and Schmahmann, 2010). The cerebellar motor abnormalities are related to lesions that involve the anterior lobe and parts of lobule VI while the cognitive difficulties are related to the posterior lobe impairments that affect lobules VI and VII (including Crus I, Crus II, and lobule VIIB) occurring due to the effects on cognitive network connections with cerebral association cortices. Vermis abnormalities affect the cerebrocerebellar-limbic loops resulting in emotion related abnormalities observed in various 2
neuropsychiatric disorders. Of particular relevance to neuropsychiatric disorders such as OCD is that the association area projections from the prefrontal, parietal, and temporal, and cingulate cortices have cerebellar homunculi mainly localized to lobules VI and VII(Kelly and Strick, 2003; Stoodley and Schmahmann, 2010). The projections of the prefrontal cortical brain regions such as the anterior cingulate cortex (ACC) to Crus I/II, lateral cortical projections to lobule VI and projections from limbic cortices to posterior vermis (Stoodley and Schmahmann, 2010) would be of relevance in OCD where cognitive and emotion related abnormalities are present. Specifically, lobules VI and VII probably mediate spatial tasks, executive function and affective processing through their connections with the relevant cortical regions (Honey et al., 2000; LaBar et al., 1999; Stoodley et al., 2012).
Despite the growing evidence regarding the important role of cerebellum in OCD, wellcharacterised region of interest studies of cerebellum in medication naïve patients have not been done to date. In the present study, we aimed to examine the structural volumetric differences of cerebellum and its various sub-regions in a large sample of medication naïve OCD patients in comparison to matched healthy controls (HC). We hypothesised that OCD patients would have significantly deficient cerebellar volume compared to HC. Taking into consideration the functional and topographical representation of various networks of cerebellum as described previously, we also hypothesised that there would be volume deficits predominantly in the regions confined to the posterior lobe. 2.
Methods:
2.1 Subjects: The study participants constituted 50 medication naïve adult patients with DSM-IV OCD (APA, 1994) and 40 matched HC. The patients were recruited from the National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India. The study was conducted in accordance to the Declaration of Helsinki. The NIMHANS institute ethics committee approved the study. All the participants gave written informed consent for participation in the study. In the analysis, one subject from each group had to be excluded due to poor image quality of their MRI, thus leaving the final analysable sample to 49 OCD patients and 39 HC. None of the patients had prior exposure to psychotropic medications.
None of the subjects had any of the following: medical illness that may significantly influence CNS function or structure; significant neurologic disorder such as seizure disorder, cerebral 3
palsy; history suggestive of delayed developmental milestones (suggestive of mental retardation);a family history of hereditary neurologic disorder that may complicate diagnosis; comorbidity for DSM-IV psychoactive substance dependence; or a lifetime history of head injury associated with loss of consciousness longer than 10 minutes, seizures, neurological deficit, depressed skull fracture, surgical intervention, or central nervous system infection. Female subjects were neither pregnant nor were within the postpartum period. 2.2 Clinical measures All patients were evaluated with the Mini International Neuropsychiatric Interview plus (MINI) (Sheehan et al., 1998), a short structured diagnostic interview, designed to diagnose psychiatric disorders as per for DSM-IV and ICD-10. Severity of OCD was measured using the Yale-Brown obsessive compulsive scale (YBOCS) that includes a symptom checklist, a 10-point severity rating scale, and item 11 for insight (Goodman et al., 1989). Each item is rated from 0 (no symptoms) to 4 (extreme symptoms) (total range, 0 to 40). It provides a specific measure of the severity of OCD symptoms that is not influenced by the type of obsessions or compulsions present. YBOCS item 11 measures insight regarding the illness. Its score ranges from 0 to 4 and a higher value indicate poorer insight. The Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) was used to quantify depressive comorbidity. It is a 10-point scale, each item rated from 0 to 6 with the overall score ranging from 0 to 60. Higher score implies more severe depression. The Clinical Global Impression scale (CGI) (Guy, 1976) was used to measure the global illness severity. It is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Only subjects who had YBOCS total score of more than 16 (clinically significant OCD) were recruited for the study. All subjects were right-handed as assessed by Annett’s questionnaire (Annett, 1967), a 12-item handedness questionnaire. Healthy controls were administered the MINI (Sheehan et al., 1998) to rule out any Axis I psychiatric disorders. 2.3 MRI acquisition MRI was done with a 1.5 T scanner (Magnetom ‘Vision’, Siemens, Erhlangen, Germany).T1weighted three-dimensional magnetization prepared rapid acquisition gradient echo (MP-RAGE) sequence was performed (TR = 9.7 ms, TE = 4 ms, nutation angle = 12°, and slice thickness: 1mm with no inter-slice gap, voxel dimension 1*1*1 mm isotropic) yielding 160 sagittal slices.
2.4 Cerebellum image analysis method: 4
The origin of T1-weighted images was set to the anterior commissure using SPM8 (Wellcome Trust Centre for Neuroimaging, UCL, London; UK; http://www.fil.ion.ucl.ac.uk/spm) under MatLab 7.8.0 (The MathWorks Inc., Sherborn, MA, USA).
Infra-tentorial structures namely
cerebellum and brainstem were isolated from the surrounding tissue using the Spatially Unbiased
Infra
tentorial
Template
(SUIT)
toolbox
(Diedrichsen,
2006)
(http://www.icn.ucl.ac.uk/motorcontrol/imaging/suit.htm), which uses the tissue-type and the proximity to cortical white matter to calculate the posterior probability of each voxel to belong to cerebellum or brainstem. The cropped anatomical images were then normalized where a nonlinear deformation map to the SUIT template, using the cosine-basis function approach was performed (Ashburner and Friston, 1999). Images were then resampled into the SUIT atlas space using deformation map created in the normalization step, such that the overall probability mass were retained after normalization. Finally, using suit_lobuli_summarize function, all voxels within each cerebellar compartment were found, split by lobules and vermis/hemisphere. These 28 compartments were originally defined by the probabilistic cerebellar atlas which has been shown to enable accurate anatomical inferences for human
anatomical imaging studies
(Diedrichsen et al., 2009). 2.5 Statistical analysis: The volume measures were distributed normally (Shapiro-Wilk test, p>0.05) and hence parametric tests were employed for the analysis. Independent samples t-test and chi square test were used for continuous and discrete variables for baseline comparisons. The differences between OCD patients and healthy controls were examined using ANCOVA with age, sex and intracranial volume (ICV) as covariates. We performed Pearson’s correlation analysis for the OCD group to examine the relationship between cerebellar volumes and YBOCS severity score. To account for multiple testing, Benjamini Hochberg false discovery rate (FDR) correction was employed for the differences in the sub-regional cerebellar volumes and is reported alongside the uncorrected significance values. 3.
Results:
3.1 Demographic and clinical profile The age at assessment (26.6 ± 6.6 vs. 25.5 ± 5.5 years, t=0.8, p=0.41), mean ICV (mL) (1450.9±158.4 vs. 1418.9±148.1, t=0.9, p=0.34) and sex composition (male: female =30:19 vs. 27:12, χ2 =0.61,p=0.44) were comparable between OCD patients and HC. Among the patients with OCD, the median illness duration was 60 months (mean - 65.6 ± 58.4 months) and the mean age of onset of OCD was 21.2±7.2 years. The mean YBOCS obsession score, YBOCS 5
compulsion score, YBOCS total score, CGI-S and YBOCS item 11(insight) score were 13.2±4.1, 12.7±4.9, 25.8±8.3, 4.7±1.1 and 1.3±1.0 respectively. The symptom profile of the patients is depicted in table 1. The lifetime comorbid conditions in OCD patients were major depression (18.4%), specific phobia (5.1%), social phobia (12%) and generalized anxiety disorder (4.2%). Other comorbid conditions including tic disorders were not present in the sample. The mean MADRS score was 13.1±9.2.
3.2 Cerebellar volume differences between patients and healthy controls: The subjects with OCD had significantly smaller cerebellum (mL) compared to HC (84.2±9.8 vs. 89.4±11.0, F=9.5, p=0.003). In particular, there was significantly deficient volume (mL) of posterior lobe of cerebellum in patients compared to HC (71.2±8.0 vs. 75.5±8.84, F=10.6, p=0.002) (figure 1). The significant sub-regional (lobular) volume differences between both the groups is depicted in the table 2 and an anatomical representation of these regions on a brain image has been provided in figure 2. There was no significant sex by status interaction effect in any of the cerebellar regional volumes. The posterior lobe and sub-regional deficits were present on analysing the sample after excluding the subjects with major depressive disorder.
3.3 Correlation with the illness severity measures: Total cerebellar volume demonstrated a significant correlation with age at assessment (r = -0.6, p<0.001) but not with the duration of illness (r = -0.01, p = 0.92). Hence, partial correlation controlling for the effects of age was employed to examine the relationship between cerebellar volumes and the illness severity measures. Total and regional cerebellar volumes did not have significant correlations with YBOCS severity score [total volume, p=0.69; anterior lobe volume, p=0.82 ;posterior lobe volume, p=0.57], YBOCS item 11 (insight score) [total volume, p=0.28; anterior lobe volume, p=0.17 ;posterior lobe volume, p=0.41], CGI-severity score [total volume, p=0.74; anterior lobe volume, p=0.62 ; posterior lobe volume, p=0.55] and MADRS score [total volume, p=0.67; anterior lobe volume, p=0.99 ; posterior lobe volume, p=0.62]. 4.
Discussion:
To summarize the results, we found a significant reduction of cerebellar volume in medication naïve OCD patients compared to HC. Specifically, the posterior lobe of cerebellum was smaller among patients. Sub-regions confined to the posterior lobe which demonstrated volume reduction among OCD patients compared to HC were lobule VI and left crus 1. 6
Partially defying the conventional notion that neurobiological aberrations in OCD are restricted to the fronto-striatal circuitry, many studies have shown that there could be additional brain regions including the posterior ones involved (Piras et al., 2013; Piras et al.,2015). Tonna et al., reported an interesting case of an elderly patient who developed OCD late in life associated with a left cerebellar lesion due to an arachnoid cyst (Tonna et al., 2014). Structural MRI studies in OCD have demonstrated volume abnormalities pertaining to the cerebellum. In a study by Kim et al, there were volumetric deficits in regions confined to the posterior regions of the brain such as the left cuneus and the left cerebellum(Kim et al., 2001). Koprivová et al also demonstrated significant cerebellar volume deficits in OCD patients compared to HC (Koprivova et al., 2009). Pujol et al on the other hand reported significant grey matter volume increase in cerebellum and bilateral putamen (Pujol et al., 2004). A recent large meta-analysis of VBM studies also reported of increased cerebellar volume in OCD (de Wit et al., 2014). Recently, Brooks et al. reported that right cerebellar volume demonstrated a significant positive correlation with adverse childhood experiences among patients with OCD suggesting the role of childhood developmental pathology affecting cerebellum in OCD (Brooks et al., 2016). The variations in the direction of volume changes could be due to variations in samples across studies such as comorbidity rate, medication status and the relative composition of symptom dimensions. The present study also highlights the importance of the role of cerebellum in the neurobiology of OCD by demonstrating its volume deficit in OCD compared to HC.
Resting state functional MRI (fMRI) studies also point towards the role of cerebellum in the neurobiology of OCD. In a recent study, Anticevic et al reported of changes in connectivity of networks including cerebellum among participants with OCD (Anticevic et al., 2014). Significant changes in spontaneous neuronal activity in regions involving cerebellum and parietal cortex in resting state fMRI has been reported in OCD (Hou et al., 2012). There is growing recognition that in multi-modal information processing, the connectivity between cerebellar hemispheres, neocortical association areas and limbic cortical regions could have a crucial role (Stoodley and Schmahmann, 2010; Strick et al., 2009). Abnormalities in networks where cerebellum holds a prominent functional importance, might have a significant, yet so far poorly appreciated role in neuropsychiatric diseases including OCD. In this context, one could assume that the cognitive functions that are impaired in OCD, classically thought to be modulated by the cortical regions such as cingulate cortex, parietal cortex and dorsolateral prefrontal cortex, might have a significant modulatory effect by the cerebellum(Page et al., 2009; Woolley et al., 2008). Studies 7
have indicated that the cerebellum is also involved in a variety of cognitive functions, such as attention, verbal memory and cognitive planning (Andreasen et al., 1996; Courchesne et al., 1994; Kim et al., 1994). Impaired response inhibition and executive dysfunction which are amongst the most replicated cognitive aberrations of OCD has been found to have a substrate in cerebellum in addition to the conventional cortical areas in fMRI studies in OCD (Page et al., 2009; Woolley et al., 2008). We did not observe any significant correlation between between cerebellar volume and the severity of the illness. This could indicate that the cerebellar volume reduction might be pathogenic for OCD and not state-dependent.
The volume reduction of cerebellum pertaining to posterior lobe with distinct involvement of certain sub-regions appears interesting. Posterior lobe of cerebellum is connected to the various neo-cortical association areas and limbic cortices while the anterior lobe is connected to the motor cortical areas (Stoodley and Schmahmann, 2010) and this probably explains the differential volume abnormality of posterior lobe of cerebellum in OCD as seen in our study results. More intriguing is the fact that sub-regions of posterior lobe have distinct connectivity with the cortex. For instance, the anterior cingulate cortex projections reach Crus I/II, more lateral cortical projections reach lobule VI and posterior vermis is linked to regions that regulate affect limbic cortices (Stoodley and Schmahmann, 2010). Lobules VI and VII probably mediate spatial tasks, executive function and affective processing (Honey et al., 2000; LaBar et al., 1999; Stoodley et al., 2012). Volume deficit involving region VI merit attention since the OCD is associated with impairment in some of the above cognitive functions. This sub-region specific structural and functional topography has important implications in the understanding of neurobiology of OCD.
Studying medication naïve OCD patients is a major strength of this study. It has been reported that the medications such as selective serotonin reuptake inhibitors (SSRIs) used to treat OCD can have significant effect on the cerebellar and striatal connectivity (Anticevic et al., 2014). Thus, the potential confounding effect of medications have been averted by recruiting subjects who have never had psychotropic drug treatment in the past. Comorbid psychiatric conditions could potentially affect the results. However, the comorbidity rate is very low in the present sample. Presently OCD is considered as a heterogeneous disorder with distinct symptom dimensions. Examining the relationship between dimensional severity scores and the cerebellar regional volumes might have provided additional insights. Region of interest based single region study such as this has its advantage as well as disadvantage. Advantage is that it 8
is hypothesis driven and the disadvantage is that the region specific changes can only be explained or speculated using the previous evidence on the relevant networks/connectivity. In addition, cross-sectional evaluation of a single region of interest cannot assess the changes in that structure over various stages of the illness. However, this study gives initial evidence for region specific cerebellar volumetric deficits in OCD, thus providing novel inputs regarding the neurobiology of this disorder. More studies should systematically examine role of cerebellum using resting state as we as cognitive activation fMRI paradigms apart from evaluating the relationship of the cerebellar structural and functional alterations in accordance to the various symptom dimensions in OCD.
Acknowledgement
Ms. Dania Jose is supported by the DST-INSPIRE grant conferred by the Department of Science and Technology (DST), Government of India to Dr. Janardhanan C. Narayanaswamy. Dr. Kalmady and Dr. Agarwal are supported by the DBT-India Alliance Wellcome trust grant to Dr. Venkatasubramanian.
References: Allen, G., Buxton, R.B., Wong, E.C., Courchesne, E., 1997. Attentional activation of the cerebellum independent of motor involvement. Science 275, 1940-1943. Andreasen, N.C., O'Leary, D.S., Cizadlo, T., Arndt, S., Rezai, K., Ponto, L.L., Watkins, G.L., Hichwa, R.D., 1996. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the United States of America 93, 9985-9990. Annett, M., 1967. The binomial distribution of right, mixed and left handedness. Quarterly Journal of Experimental Psychology 19, 327-333. Anticevic, A., Hu, S., Zhang, S., Savic, A., Billingslea, E., Wasylink, S., Repovs, G., Cole, M.W., Bednarski, S., Krystal, J.H., Bloch, M.H., Li, C.S., Pittenger, C., 2014. Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biological psychiatry 75, 595-605. APA, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC.
9
Ashburner, J., Friston, K.J., 1999. Nonlinear spatial normalization using basis functions. Human brain mapping 7, 254-266. Brooks, S.J., Naidoo, V., Roos, A., Fouché, J.P., Lochner, C., Stein, D.J., 2016. Early-life adversity and orbitofrontal and cerebellar volumes in adults with obsessive-compulsive disorder: voxel-based morphometry study. British Journal of Psychiatry 208, 34-41. Chen, S.H., Desmond, J.E., 2005. Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task. Neuropsychologia 43, 1227-1237. Courchesne, E., Townsend, J., Akshoomoff, N.A., Saitoh, O., Yeung-Courchesne, R., Lincoln, A.J., James, H.E., Haas, R.H., Schreibman, L., Lau, L., 1994. Impairment in shifting attention in autistic and cerebellar patients. Behavioral neuroscience 108, 848-865. Daum, I., Ackermann, H., 1995. Cerebellar contributions to cognition. Behavioural brain research 67, 201-210. de Wit, S.J., Alonso, P., Schweren, L., Mataix-Cols, D., Lochner, C., Menchon, J.M., Stein, D.J., Fouche, J.P., Soriano-Mas, C., Sato, J.R., Hoexter, M.Q., Denys, D., Nakamae, T., Nishida, S., Kwon, J.S., Jang, J.H., Busatto, G.F., Cardoner, N., Cath, D.C., Fukui, K., Jung, W.H., Kim, S.N., Miguel, E.C., Narumoto, J., Phillips, M.L., Pujol, J., Remijnse, P.L., Sakai, Y., Shin, N.Y., Yamada, K., Veltman, D.J., van den Heuvel, O.A., 2014. Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder. The American journal of psychiatry 171, 340-349. Diedrichsen, J., 2006. A spatially unbiased atlas template of the human cerebellum. NeuroImage 33, 127-138. Diedrichsen, J., Balsters, J.H., Flavell, J., Cussans, E., Ramnani, N., 2009. A probabilistic MR atlas of the human cerebellum. NeuroImage 46, 39-46. Goodman, W.K., Price, L.H., Rasmussen, S.A., Mazure, C., Fleischmann, R.L., Hill, C.L., Heninger, G.R., Charney, D.S., 1989. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry 46, 1006-1011. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology. In: US Dept Health, Education and Welfare Publication (ADM) 76-338. Rockville, Md: National Institute of Mental Health pp. 218-222. Honey, G.D., Bullmore, E.T., Sharma, T., 2000. Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation. NeuroImage 12, 495-503.
10
Hou, J., Wu, W., Lin, Y., Wang, J., Zhou, D., Guo, J., Gu, S., He, M., Ahmed, S., Hu, J., Qu, W., Li, H., 2012. Localization of cerebral functional deficits in patients with obsessive-compulsive disorder: a resting-state fMRI study. Journal of affective disorders 138, 313-321. Kelly, R.M., Strick, P.L., 2003. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. The Journal of neuroscience 23, 8432-8444. Kim, J.J., Lee, M.C., Kim, J., Kim, I.Y., Kim, S.I., Han, M.H., Chang, K.H., Kwon, J.S., 2001. Grey matter abnormalities in obsessive-compulsive disorder: statistical parametric mapping of segmented magnetic resonance images. The British journal of psychiatry 179, 330-334. Kim, S.G., Ugurbil, K., Strick, P.L., 1994. Activation of a cerebellar output nucleus during cognitive processing. Science 265, 949-951. Koprivova, J., Horacek, J., Tintera, J., Prasko, J., Raszka, M., Ibrahim, I., Hoschl, C., 2009. Medial frontal and dorsal cortical morphometric abnormalities are related to obsessivecompulsive disorder. Neuroscience letters 464, 62-66. Kuelz, A.K., Hohagen, F., Voderholzer, U., 2004. Neuropsychological performance in obsessive-compulsive disorder: a critical review. Biological psychology 65, 185-236. LaBar, K.S., Gitelman, D.R., Parrish, T.B., Mesulam, M., 1999. Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects. NeuroImage 10, 695-704. Menzies, L., Chamberlain, S.R., Laird, A.R., Thelen, S.M., Sahakian, B.J., Bullmore, E.T., 2008. Integrating evidence from neuroimaging and neuropsychological studies of obsessivecompulsive disorder: the orbitofronto-striatal model revisited. Neuroscience and biobehavioral reviews 32, 525-549. Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to change. The British journal of psychiatry 134, 382-389. Nabeyama, M., Nakagawa, A., Yoshiura, T., Nakao, T., Nakatani, E., Togao, O., Yoshizato, C., Yoshioka, K., Tomita, M., Kanba, S., 2008. Functional MRI study of brain activation alterations in patients with obsessive-compulsive disorder after symptom improvement. Psychiatry research 163, 236-247. Nakao, T., Nakagawa, A., Yoshiura, T., Nakatani, E., Nabeyama, M., Yoshizato, C., Kudoh, A., Tada, K., Yoshioka, K., Kawamoto, M., Togao, O., Kanba, S., 2005. Brain activation of patients with obsessive-compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: a functional magnetic resonance imaging study. Biological psychiatry 57, 901-910.
11
Page, L.A., Rubia, K., Deeley, Q., Daly, E., Toal, F., Mataix-Cols, D., Giampietro, V., Schmitz, N., Murphy, D.G., 2009. A functional magnetic resonance imaging study of inhibitory control in obsessive-compulsive disorder. Psychiatry research 174, 202-209. Piras, F., Piras, F., Caltagirone, C., Spalletta, G., 2013. Brain circuitries of obsessive compulsive disorder: a systematic review and meta-analysis of diffusion tensor imaging studies. Neuroscience and biobehavioral reviews 37, 2856-2877. Piras, F., Piras, F., Chiapponi, C., Girardi, P., Caltagirone, C., Spalletta, G., 2015. Widespread structural brain changes in OCD: A systematic review of voxel-based morphometry studies. Cortex, 62, 89-108 Pujol, J., Soriano-Mas, C., Alonso, P., Cardoner, N., Menchon, J.M., Deus, J., Vallejo, J., 2004. Mapping structural brain alterations in obsessive-compulsive disorder. Archives of general psychiatry 61, 720-730. Radua, J., Mataix-Cols, D., 2009. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. The British journal of psychiatry Sanematsu, H., Nakao, T., Yoshiura, T., Nabeyama, M., Togao, O., Tomita, M., Masuda, Y., Nakatani, E., Nakagawa, A., Kanba, S., 2010. Predictors of treatment response to fluvoxamine in obsessive-compulsive disorder: an fMRI study. Journal of psychiatric research 44, 193-200. Schmahmann, J.D., Doyon, J., Toga, A., Petrides, M., Evans, A., 2000. MRI Atlas of the Human Cerebellum. San Diego: Academic Press,. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD10. J Clin Psychiatry 59 Suppl 20, 22-33;quiz 34-57. Stoodley, C.J., Schmahmann, J.D., 2010. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 46, 831-844. Stoodley, C.J., Valera, E.M., Schmahmann, J.D., 2012. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. NeuroImage 59, 1560-1570. Strick, P.L., Dum, R.P., Fiez, J.A., 2009. Cerebellum and nonmotor function. Annual review of neuroscience 32, 413-434. Tonna, M., Ottoni, R., Ossola, P., De Panfilis, C., Marchesi, C., 2014. Late-onset obsessivecompulsive disorder associated with left cerebellar lesion. Cerebellum 13, 531-535. Woolley, J., Heyman, I., Brammer, M., Frampton, I., McGuire, P.K., Rubia, K., 2008. Brain activation in paediatric obsessive compulsive disorder during tasks of inhibitory control. The British journal of psychiatry 192, 25-31. 12
Figure 1: The comparison of posterior cerebellar lobe volume between OCD patients (N=49) and healthy controls (HC=39)
13
Figure 2: A schematic brain image showing regions of significant differences between OCD patients and healthy controls in coronal (A), sagittal (B), and axial (C) sections.
Green: Left Crus I; Blue: Left VI; Yellow: Vermis VI, Red: Right VI
14
Table 1: The clinical symptom profile (YBOCS checklist –lifetime) of the participants with OCD (N=49) Clinical parameter Obsessions: Fear of contamination
N (%)
Aggressive Religious/blasphemous Sexual Symmetry Pathological doubts
14(28.0) 17(34.1) 14(28.0) 19(38.0) 28(56.8)
36 (72.0)
Compulsions: Washing Checking Arranging
36(72.0) 26(52.0) 20(40.1)
Repeating Hoarding
24(48.2) 8(16.0)
15
Table 2: The significant cerebellar regional volumetric differences between OCD patients (N=49) and healthy controls (HC) (N=39) Cerebellar region
OCD patients
Healthy (N=39)
(N=49)
(Mean±SD) (mL)
F
P
P (FDR)
(Mean±SD) (mL) Left VI
7.6±1.2
8.4±1.7
8.1
0.006
0.04
Left Crus I
9.1±1.2
9.9±1.7
8.3
0.005
0.04
Right VI
6.7±1.1
7.4±1.4
9.3
0.003
0.04
Vermis VI
1.5±0.3
1.7±0.3
8.3
0.005
0.04
F- ANCOVA controlling for the effects of age, sex and intracranial volume; P (FDR)-Benjamini Hochberg false discovery rate (FDR) correction; P-FDR < 0.05 is significant.
Highlights
Conventional neurobiological models of OCD implicate fronto-striatal circuits
Recent research propose role for cerebellum in OCD.
This study examined for status of cerebellar volume in untreated OCD patients.
Findings support posterior cerebellar volume deficit in OCD.
16