Task-related deactivation and functional connectivity of the subgenual cingulate cortex in major depressive disorder.
Davey Christopher G,Yücel Murat,Allen Nicholas B,Harrison Ben J
Frontiers in psychiatry
BACKGROUND:Major depressive disorder is associated with functional alterations in activity and resting-state connectivity of the extended medial frontal network. In this study we aimed to examine how task-related medial network activity and connectivity were affected in depression. METHODS:18 patients with major depressive disorder, aged 15- to 24-years-old, were matched with 19 healthy control participants. We characterized task-related activations and deactivations while participants engaged with an executive-control task (the multi-source interference task, MSIT). We used a psycho-physiological interactions approach to examine functional connectivity changes with subgenual anterior cingulate cortex. Voxel-wise statistical maps for each analysis were compared between the patient and control groups. RESULTS:There were no differences between groups in their behavioral performances on the MSIT task, and nor in patterns of activation and deactivation. Assessment of functional connectivity with the subgenual cingulate showed that depressed patients did not demonstrate the same reduction in functional connectivity with the ventral striatum during task performance, but that they showed greater reduction in functional connectivity with adjacent ventromedial frontal cortex. The magnitude of this latter connectivity change predicted the relative activation of task-relevant executive-control regions in depressed patients. CONCLUSION:The study reinforces the importance of the subgenual cingulate cortex for depression, and demonstrates how dysfunctional connectivity with ventral brain regions might influence executive-attentional processes.
10.3389/fpsyt.2012.00014
Serotonin transporter gene promoter hypomethylation in obsessive-compulsive disorder - Predictor of impaired response to exposure treatment?
Schiele Miriam A,Thiel Christiane,Weidner Magdalena,Endres Dominique,Zaudig Michael,Berberich Götz,Domschke Katharina
Journal of psychiatric research
Treatment resistance is common in obsessive-compulsive disorder (OCD) and associated with a significant burden for the individual patient. Accordingly, the identification of biomarkers as early predictors of the clinical response has become a central goal in the search for more efficacious and personalized treatments. Epigenetic mechanisms such as DNA methylation of the serotonin transporter gene (SLC6A4) have been suggested to predict therapy outcome in mental disorders closely related to OCD, but have not yet been investigated as such in OCD. The present therapy-epigenetic study therefore sought to address the potential role of SLC6A4 promoter methylation in the prediction of treatment response for the first time in OCD. Overall, 112 patients with primary OCD were investigated over the course of 8-10-week OCD-specific, cognitive behavioral therapy (CBT) comprising exposure and response prevention/management (phase I) and in vivo exposure exercises ('flooding', phase II). OCD symptoms were measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline as well as before and after the in vivo exposure phase. SLC6A4 promoter methylation at baseline was analyzed via pyrosequencing of sodium bisulfite-treated DNA extracted from blood cells. Lower baseline SLC6A4 promoter methylation predicted impaired treatment response (defined as reduction in Y-BOCS scores) in phase II (but not phase I) of CBT (β = -0.359, p = .002). SLC6A4 methylation may thus constitute a potential early biomarker predicting biologically mediated clinical changes elicited specifically by exposure treatment. These results carry promise for clinical application and in the future could aid in early treatment modification and personalized treatment efforts.
10.1016/j.jpsychires.2020.09.034
Altered anatomical connections of associative and limbic cortico-basal-ganglia circuits in obsessive-compulsive disorder.
Haynes William I A,Clair Anne-Hélène,Fernandez-Vidal Sara,Gholipour Bahar,Morgiève Margot,Mallet Luc
European psychiatry : the journal of the Association of European Psychiatrists
BACKGROUND:Current neurocognitive models suppose dysfunctions of associative and limbic cortico-basal ganglia circuits to be at the core of obsessive-compulsive disorder (OCD). As little is known about the state of underlying anatomical connections, we investigated whether these connections were reduced and/or not properly organised in OCD patients compared to control. METHODS:Diffusion magnetic resonance images were obtained in 37 OCD patients with predominant checking symptoms and 37 matched healthy controls. We developed indices to characterise the quantity (spatial extent and density) and the organisation (topography and segregation) of 24 anatomical connections between associative and limbic cortical (anterior cingulate, dorsolateral prefrontal, orbitofrontal cortices and the frontal pole), and subcortical (caudate nucleus, putamen and thalamus) areas in each hemisphere. RESULTS:Associative and limbic cortico-basal-ganglia connections were reduced in OCD patients compared to controls: 19/24 connections had a reduced subcortical spatial extent, 9/24 had a reduced density. Moreover, while the general topography was conserved, the different cortical projection fields in the striatum and thalamus were hyper-segregated in OCD patients compared to controls. CONCLUSION:These quantitative and qualitative differences of anatomical connections go beyond the current model of a reduced cortical control of automatic behaviour stored in the basal ganglia. The hyper-segregation in OCD could also impair the integration of cortical information in the thalamus and striatum and distort the subsequent behavioural selection process. This provides new working hypotheses for functional and behavioural studies on OCD.
10.1016/j.eurpsy.2018.01.005
A Microglia Sublineage Protects from Sex-Linked Anxiety Symptoms and Obsessive Compulsion.
Tränkner Dimitri,Boulet Anne,Peden Erik,Focht Richard,Van Deren Donn,Capecchi Mario
Cell reports
Aberrant microglia activity is associated with many neurological and psychiatric disorders, yet our knowledge about the pathological mechanisms is incomplete. Here, we describe a genetically defined microglia sublineage in mice which has the ability to suppress obsessive compulsion and anxiety symptoms. These microglia derive from precursors expressing the transcription factor Hoxb8. Selective ablation of Hoxb8-lineage microglia or the Hoxb8 gene revealed that dysfunction in this cell type causes severe over-grooming and anxiety-like behavior and stress responses. Moreover, we show that the severity of the pathology is set by female sex hormones. Together, our findings reveal that different microglia lineages have distinct functions. In addition, our data suggest a mechanistic link between biological sex and genetics, two major risk factors for developing anxiety and related disorders in humans.
10.1016/j.celrep.2019.09.045
Basolateral amygdala input to the medial prefrontal cortex controls obsessive-compulsive disorder-like checking behavior.
Sun Tingting,Song Zihua,Tian Yanghua,Tian Wenbo,Zhu Chunyan,Ji Gongjun,Luo Yudan,Chen Shi,Wang Likui,Mao Yu,Xie Wen,Zhong Hui,Zhao Fei,Luo Min-Hua,Tao Wenjuan,Wang Haitao,Li Jie,Li Juan,Zhou Jiangning,Wang Kai,Zhang Zhi
Proceedings of the National Academy of Sciences of the United States of America
Obsessive-compulsive disorder (OCD) affects ∼1 to 3% of the world's population. However, the neural mechanisms underlying the excessive checking symptoms in OCD are not fully understood. Using viral neuronal tracing in mice, we found that glutamatergic neurons from the basolateral amygdala (BLA) project onto both medial prefrontal cortex glutamate (mPFC) and GABA (mPFC) neurons that locally innervate mPFC neurons. Next, we developed an OCD checking mouse model with quinpirole-induced repetitive checking behaviors. This model demonstrated decreased glutamatergic mPFC microcircuit activity regulated by enhanced BLA inputs. Optical or chemogenetic manipulations of this maladaptive circuitry restored the behavioral response. These findings were verified in a mouse functional magnetic resonance imaging (fMRI) study, in which the BLA-mPFC functional connectivity was increased in OCD mice. Together, these findings define a unique BLA→mPFC circuit that controls the checking symptoms of OCD.
10.1073/pnas.1814292116
Reducing Astrocyte Calcium Signaling In Vivo Alters Striatal Microcircuits and Causes Repetitive Behavior.
Neuron
Astrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used two-photon laser scanning microscopy, electrophysiology, MINIscopes, RNA-seq, and a genetic approach to explore the effects of reduced striatal astrocyte Ca signaling in vivo. In wild-type mice, reducing striatal astrocyte Ca-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation facilitated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington's disease, dysregulation of GABA and astrocyte Ca signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca signaling in a cell-autonomous and non-cell-autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling mouse obsessive-compulsive-like behavior.
10.1016/j.neuron.2018.08.015
Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity.
Voon Valerie,Droux Fabien,Morris Laurel,Chabardes Stephan,Bougerol Thierry,David Olivier,Krack Paul,Polosan Mircea
Brain : a journal of neurology
Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation.
10.1093/brain/aww309
Genetic and environmental sources of familial coaggregation of obsessive-compulsive disorder and suicidal behavior: a population-based birth cohort and family study.
Molecular psychiatry
Obsessive-compulsive disorder (OCD) is associated with high risk of suicide. It is yet unknown whether OCD and suicidal behaviors coaggregate in families and, if so, what are the mechanisms underlying this coaggregation. In a population-based birth cohort and family study, we linked individuals born in Sweden in 1967-2003 (n = 3,594,181) to their parents, siblings, and cousins, and collected register-based diagnoses of OCD, suicide attempts, and deaths by suicide and followed them until December 31, 2013. We also applied quantitative genetic modeling to estimate the contribution of genetic and environmental factors to the familial coaggregation of OCD and suicidal behavior. An elevated risk of suicide attempts was observed across all relatives of individuals with OCD, increasing proportionally to the degree of genetic relatedness, with odds ratios (OR) ranging from 1.56 (95% confidence interval (CI) 1.49-1.63) in parents to 1.11 (95% CI 1.07-1.16) in cousins. The risk of death by suicide also increased alongside narrowing genetic distance, but was only significant in parents (OR 1.55; 95% CI 1.40-1.72) and full siblings (OR 1.80; 95% CI 1.43-2.26) of individuals with OCD. Familial coaggregation of OCD and suicide attempts was explained by additive genetic factors (60.7%) and non-shared environment (40.4%), with negligible contribution of shared environment. Similarly, familial coaggregation with death by suicide was attributed to additive genetics (65.8%) and nonshared environment (34.2%). Collectively, these observations indicate that OCD and suicidal behaviors coaggregate in families largely due to genetic factors. The contribution of unique environment is also considerable, providing opportunities to target high-risk groups for prevention and treatment.
10.1038/s41380-019-0417-1