Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder

Background: the assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. Methods: eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. Results: in comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. Conclusions: this study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively

Brain structural alterations in obsessive-compulsive disorder patients with autogenous and reactive obsessions

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although structural brain alterations have been consistently reported in OCD, their interaction with particular clinical subtypes deserves further examination. Among other approaches, a two-group classification in patients with autogenous and reactive obsessions has been proposed. The purpose of the present study was to assess, by means of a voxel-based morphometry analysis, the putative brain structural correlates of this classification scheme in OCD patients. Ninety-five OCD patients and 95 healthy controls were recruited. Patients were divided into autogenous (n = 30) and reactive (n = 65) sub-groups. A structural magnetic resonance image was acquired for each participant and pre-processed with SPM8 software to obtain a volume-modulated gray matter map. Whole-brain and voxel-wise comparisons between the study groups were then performed. In comparison to the autogenous group, reactive patients showed larger gray matter volumes in the right Rolandic operculum. When compared to healthy controls, reactive patients showed larger volumes in the putamen (bilaterally), while autogenous patients showed a smaller left anterior temporal lobe. Also in comparison to healthy controls, the right middle temporal gyrus was smaller in both patient subgroups. Our results suggest that autogenous and reactive obsessions depend on partially dissimilar neural substrates. Our findings provide some neurobiological support for this classification scheme and contribute to unraveling the neurobiological basis of clinical heterogeneity in OCD

Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder

Background: cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. Methods: we investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. Results: we included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. Limitations: we used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. Conclusion: in this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders

Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Conclusion: Our results provide evidence for structural network-level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders

Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder

Background: sensory phenomena (SP) are uncomfortable feelings, including bodily sensations, sense of inner tension, 'just-right' perceptions, feelings of incompleteness, or 'urge-only' phenomena, which have been described to precede, trigger or accompany repetitive behaviours in individuals with obsessive-compulsive disorder (OCD). Sensory phenomena are also observed in individuals with tic disorders, and previous research suggests that sensorimotor cortex abnormalities underpin the presence of SP in such patients. However, to our knowledge, no studies have assessed the neural correlates of SP in patients with OCD. Methods: we assessed the presence of SP using the University of São Paulo Sensory Phenomena Scale in patients with OCD and healthy controls from specialized units in São Paulo, Brazil, and Barcelona. All participants underwent a structural magnetic resonance examination, and brain images were examined using DARTEL voxel-based morphometry. We evaluated grey matter volume differences between patients with and without SP and healthy controls within the sensorimotor and premotor cortices. Results: we included 106 patients with OCD and 87 controls in our study. Patients with SP (67% of the sample) showed grey matter volume increases in the left sensorimotor cortex in comparison to patients without SP and bilateral sensorimotor cortex grey matter volume increases in comparison to controls. No differences were observed between patients without SP and controls. Limitations: most patients were medicated. Participant recruitment and image acquisition were performed in 2 different centres. Conclusion: we have identified a structural correlate of SP in patients with OCD involving grey matter volume increases within the sensorimotor cortex; this finding is in agreement with those of tic disorder studies showing that abnormal activity and volume increases within this region are associated with the urges preceding tic onset

Caracterització de les alteracions cerebrals associades a l’heterogeneïtat clínica del Trastorn obsessivocompulsiu mitjançant ressonància magnètica estructural i funcional

[cat] El trastorn obsessivocompulsiu (TOC) es caracteritza per la presència de pensaments, imatges o impulsos intrusos i egodistònics que provoquen ansietat (obsessions) i que generalment porten a la realització de conductes repetitives amb l'objectiu de disminuir-la (compulsions). Estudis clínics han demostrat que el TOC no és un trastorn homogeni. S'han descrit diferències significatives en característiques clíniques del trastorn, com el contingut de les obsessions i les compulsions, la comorbilitat o la resposta al tractament, que han donat lloc a que diversos autors suggereixin diferents classificacions per al trastorn. L'etiologia del TOC, que encaixa en el model etiopatològic d'interacció gen-ambient acceptat per a la majoria de trastorns psiquiàtrics, inclou l'alteració dels circuits cerebrals corticoestriatals com a substrat neurobiològic més acceptat. De tota manera, encara que els estudis de neuroimatge han descrit de forma consistent alteracions a nivell estructural i funcional en els pacients amb TOC, els treballs que han intentat descriure les alteracions sotjacents als diferents subtipus clínics suggerits han reportat resultats poc consistents. En aquesta tesi, s'intenta aprofundir en el coneixement de la neurobiologia del TOC i descriure possibles característiques de neuroimatge estructural i funcional comuns a subgrups de pacients que s'han descrit homogenis a nivell clínic. D'aquesta manera, aquestes alteracions podrien constituir possibles marcadors de neuroimatge per aquests subgrups. Amb aquest objectiu, s'han portat a terme quatre treballs. En els tres primers, s'ha realitzat una anàlisi de ressonància magnètica (RM) estructural de les alteracions en el volum regional de substància grisa cerebral (SG) associada a tres propostes de classificació dels pacients, definides prèviament a nivell clínic. Així, s'ha comparat la distribució regional de SG entre els pacients amb obsessions autògenes i reactives, d'acord al model proposat per Lee & Kwon, entre aquells pacients que presenten o no fenòmens sensorials com a part de la seva simptomatologia obsessivocompulsiva i entre els pacients que refereixen algun factor vital estressant associat a l'inici del trastorn i aquells que no. Per altra banda, en el quart treball, ens hem proposat aprofundir en els correlats neurals sotjacents al model clínic multidimensional del TOC, el més estès tant a nivell clínic com d'investigació, mitjançant un estudi de la connectivitat funcional corticoestriatal durant un paradigma de provocació de símptomes. En resum, els resultats obtinguts permeten concloure que la classificació dels pacients en funció de les característiques de les seves obsessions (en autògenes i reactives), la presència de fenòmens sensorials precedint o acompanyant les compulsions, o la presència o absència d'algun antecedent vital estressant previ a l'inici del trastorn, s'associa a diferències específiques en la distribució regional de SG analitzada mitjançant RM estructural, involucrant sobretot estructures de tipus sensorimotor. Així mateix, l'expressió clínica del TOC estaria mediada per alteracions específiques en la connectivitat corticoestriatal, i alhora modulada, amb un grau d'especificitat variable, per la inducció de símptomes obsessivocompulsius. Així doncs, els resultat obtinguts reforcen la idea de que l'heterogeneïtat clínica observada en la pràctica diària podria tenir una traducció a nivell neural. Aquest accent en el caràcter biològic de la variabilitat fenotípica del TOC enllaça amb algunes perspectives a curt i mitjà termini. Per exemple, el plantejament d'estudis longitudinals, l'avaluació de diferents escenaris d'estrès sobre el desenvolupament de la simptomatologia obsessivocompulsiva, la caracterització àmplia dels pacients a nivell clínic però també cognitiu i neuropsicològic mitjançant protocols el més homogenis possibles entre grups de recerca, així com el coneixement de les estructures i circuits cerebrals implicats en manifestacions clíniques concretes ens haurien de permetre aconseguir una major personalització dels abordatges terapèutics. Alhora, es podria plantejar, en possibles assaigs clínics futurs, l'actuació sobre aquestes determinades regions o circuits cerebrals a través de teràpies físiques poc invasives com l'estimulació cerebral profunda, l'estimulació magnètica transcranial, l'estimulació per corrent elèctrica directa transcranial, o bé tècniques com la neuroretroalimentació en temps real mitjançant RM funcional.[eng] Obsessive compulsive disorder (OCD) is characterized by the presence of intrusive, egodystonic and anxiogenic thoughts or images (obsessions) and/or ritualized behaviors or mental acts (compulsions), performed to relieve such anxiety. Clinical studies have described a high heterogeneity for the disorder in terms of the content of the obsessions and compulsions, comorbidity or treatment response. Based on such variability, several authors have suggested different classifications for OCD. Although neuroimaging studies have consistently reported structural and functional brain alterations in OCD patients, mostly involving cortico-striatal regions and circuits, attempts to describe neural alterations associated to the OCD subgroups already described at a clinical level, have reported less consistent results. In this doctoral thesis, we aim to describe common structural and functional neuroimaging characteristics in clinically homogeneous subgroups. In this way, these alterations could be considered as neuroimaging biomarkers for such subgroups. With this objective, we developed four studies. In three, structural magnetic resonance analyses were performed to assess regional brain gray matter (GM) volume alterations associated with three different clinical classifications for the disorder. We compared the regional GM distribution between OCD-patient subgroups according to the presence of autogenous or reactive obsessions, sensory phenomena symptoms preceding or accompanying compulsions and stressful life events at the disorder's onset. On the other hand, in the fourth study, we tried to assess the neural correlates of the clinical multidimensional model of OCD, the most extensively used model at a clinical and research levels, via a functional connectivity study during a symptom provoking paradigm. In sum, our results suggest that the classification of the patients based on the content of their obsessions, the presence of sensory phenomena or the presence of any stressful life events as a trigger of the disorder are associated with specific differences in the GM distribution, mostly involving sensorimotor structures. Moreover, OCD clinical expression may be mediated by specific alterations in cortico-striatal connectivity, that in turn could be modulated, with a variable degree of specificity, by the induction of OCD symptoms

Brain structural alterations in obsessive-compulsive disorder patients with autogenous and reactive obsessions

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although structural brain alterations have been consistently reported in OCD, their interaction with particular clinical subtypes deserves further examination. Among other approaches, a two-group classification in patients with autogenous and reactive obsessions has been proposed. The purpose of the present study was to assess, by means of a voxel-based morphometry analysis, the putative brain structural correlates of this classification scheme in OCD patients. Ninety-five OCD patients and 95 healthy controls were recruited. Patients were divided into autogenous (n = 30) and reactive (n = 65) sub-groups. A structural magnetic resonance image was acquired for each participant and pre-processed with SPM8 software to obtain a volume-modulated gray matter map. Whole-brain and voxel-wise comparisons between the study groups were then performed. In comparison to the autogenous group, reactive patients showed larger gray matter volumes in the right Rolandic operculum. When compared to healthy controls, reactive patients showed larger volumes in the putamen (bilaterally), while autogenous patients showed a smaller left anterior temporal lobe. Also in comparison to healthy controls, the right middle temporal gyrus was smaller in both patient subgroups. Our results suggest that autogenous and reactive obsessions depend on partially dissimilar neural substrates. Our findings provide some neurobiological support for this classification scheme and contribute to unraveling the neurobiological basis of clinical heterogeneity in OCD

Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Conclusion: Our results provide evidence for structural network-level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders

Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Conclusion: Our results provide evidence for structural network-level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders