Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder

AbstractObsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.

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Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder

10.1101/2020.07.23.216697 ◽

2020 ◽

Author(s):

Sean C. Piantadosi ◽

Lora L. McClain ◽

Lambertus Klei ◽

Jiebiao Wang ◽

Brittany L. Chamberlain ◽

...

Keyword(s):

Nucleus Accumbens ◽

Obsessive Compulsive Disorder ◽

Messenger Rna ◽

Functional Neuroimaging ◽

Brain Regions ◽

Synaptic Proteins ◽

Differentially Expressed ◽

Joint Analysis ◽

Obsessive Compulsive ◽

Compulsive Disorder

ABSTRACTBackgroundObsessive compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown.MethodsTo assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions.ResultsIn a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlight a smaller number of differences, which concentrate in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimate that cell type fractions of medium spiny neurons are lower whereas vascular cells and astrocyte fractions are higher in tissue of OCD subjects.ConclusionsTogether, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encode synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.

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Task-Based Functional Neuroimaging Studies of Obsessive-Compulsive Disorder: A Hypothesis-Driven Review

10.1093/med/9780190228163.003.0022 ◽

2017 ◽

Author(s):

M. M Vaghi ◽

T. W Robbins

Keyword(s):

Obsessive Compulsive Disorder ◽

Functional Neuroimaging ◽

Neural Substrates ◽

Brain Regions ◽

Cognitive Tasks ◽

Functional Magnetic Resonance ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Directed Learning ◽

Experimental Level

The neurobiological basis of Obsessive Compulsive Disorder (OCD) has been probed using functional magnetic resonance in hundreds of studies over three decades. This complex literature can be syntheized using a theory-informed approach. At a theoretical level, separable, independent, constructs of relevance to OCD have been identified. At the experimental level, extensive translational evidence has provided an account that relates specific brain systems to these neuropsychological constructs. Parallels between neural substrates implicated in OCD and functional specialization of different brain regions suggest that abnormalities within fronto-striatal circuitry impinge on executive functions, and their subcomponents, and on goal-directed learning and habit formation. In OCD, this is reflected at a functional level in patterns of abnormal activations in particular brain regions during specific cognitive tasks. However, many issues still need to be addressed. The authors suggest that the experimental context might represent a pivotal variable that should be taken into account.

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Functional Neuroimaging Studies in Obsessive-Compulsive Disorder: Overview and Synthesis

10.1093/med/9780190228163.003.0021 ◽

2017 ◽

Author(s):

Brian P. Brennan ◽

Scott L. Rauch

Keyword(s):

Obsessive Compulsive Disorder ◽

Functional Neuroimaging ◽

Critical Role ◽

Resting State Fmri ◽

Brain Regions ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Additional Information ◽

Positron Emission ◽

Cortical Circuit

Studies using functional neuroimaging have played a critical role in the current understanding of the neurobiology of obsessive-compulsive disorder (OCD). Early studies using positron emission tomography (PET) identified a core cortico-striatal-thalamo-cortical circuit that is dysfunctional in OCD. Subsequent studies using behavioral paradigms in conjunction with functional magnetic resonance imaging (fMRI) have provided additional information about the neural substrates underlying specific psychological processes relevant to OCD. More recently, studies utilizing resting state fMRI have identified abnormal functional connectivity within intrinsic brain networks including the default mode and frontoparietal networks in OCD patients. Although these studies, as a whole, clearly substantiate the model of cortico-striatal-thalamo-cortical circuit dysfunction in OCD and support the continued investigation of neuromodulatory treatments targeting these brain regions, there is also growing evidence that brain regions outside this core circuit, particularly frontoparietal regions involved in cognitive control processes, may also play a significant role in the pathophysiology of OCD.

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New Methods of Brain Stimulation Are Improving Research and Therapy in Obsessive-Compulsive Disorder

CNS Spectrums ◽

10.1017/s1092852900024986 ◽

2000 ◽

Vol 5 (S4) ◽

pp. 12-17 ◽

Cited By ~ 3

Author(s):

Mark S. George

Keyword(s):

Obsessive Compulsive Disorder ◽

Brain Stimulation ◽

Functional Neuroimaging ◽

Brain Regions ◽

Current Status ◽

Obsessive Compulsive ◽

New Techniques ◽

Compulsive Disorder ◽

The Past ◽

The Brain

AbstractOver the past decade, new functional neuroimaging tools have enabled researchers to identify the specific brain regions involved in obsessive-compulsive disorder (OCD). More recently, researchers have perfected several new techniques for stimulating the brain. With some exceptions, these new brain stimulation techniques are regionally specific and less invasive than older methods. As a class, these “somatic interventions” build on prior neuroanatomic information about OCD. This article reviews the past and current status of these brain stimulation methodologies, which promise to revolutionize neuropsychiatric research and therapy over the next 10 to 20 years. As the brain circuits in OCD and the pharmacology within those circuits become better understood, these brain stimulation techniques hold particular promise in helping to understand and perhaps treat OCD.

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Defining functional brain networks underlying obsessive–compulsive disorder (OCD) using treatment-induced neuroimaging changes: a systematic review of the literature

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-324478 ◽

2021 ◽

pp. jnnp-2020-324478

Author(s):

Kelly R. Bijanki ◽

Yagna J. Pathak ◽

Ricardo A. Najera ◽

Eric A. Storch ◽

Wayne K Goodman ◽

...

Keyword(s):

Treatment Response ◽

Obsessive Compulsive Disorder ◽

Functional Neuroimaging ◽

Current Knowledge ◽

Brain Regions ◽

Behavioural Therapy ◽

Anterior Cingulate ◽

Therapeutic Interventions ◽

Obsessive Compulsive ◽

Compulsive Disorder

Approximately 2%–3% of the population suffers from obsessive–compulsive disorder (OCD). Several brain regions have been implicated in the pathophysiology of OCD, but their various contributions remain unclear. We examined changes in structural and functional neuroimaging before and after a variety of therapeutic interventions as an index into identifying the underlying networks involved. We identified 64 studies from 1990 to 2020 comparing pretreatment and post-treatment imaging of patients with OCD, including metabolic and perfusion, neurochemical, structural, functional and connectivity-based modalities. Treatment class included pharmacotherapy, cognitive–behavioural therapy/exposure and response prevention, stereotactic lesions, deep brain stimulation and transcranial magnetic stimulation. Changes in several brain regions are consistent and correspond with treatment response despite the heterogeneity in treatments and neuroimaging modalities. Most notable are decreases in metabolism and perfusion of the caudate, anterior cingulate cortex, thalamus and regions of prefrontal cortex (PFC) including the orbitofrontal cortex (OFC), dorsolateral PFC (DLPFC), ventromedial PFC (VMPFC) and ventrolateral PFC (VLPFC). Modulating activity within regions of the cortico-striato-thalamo-cortical system may be a common therapeutic mechanism across treatments. We identify future needs and current knowledge gaps that can be mitigated by implementing integrative methods. Future studies should incorporate a systematic, analytical approach to testing objective correlates of treatment response to better understand neurophysiological mechanisms of dysfunction.

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