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Cited by 128Obsessive-Compulsive Spectrum DisordersNeurological disorders and treatmentsMemory and Neural Mechanisms

DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments

Open access
Ahmari, Susanne E., Dougherty, Darin D.·2015·Depression and Anxiety
DOI 10.1002/da.22367PMC PMC4515165
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Abstract

Obsessive-compulsive disorder (OCD) is a chronic, severe mental illness with up to 2-3% prevalence worldwide. In fact, OCD has been classified as one of the world's 10 leading causes of illness-related disability according to the World Health Organization, largely because of the chronic nature of disabling symptoms.([1]) Despite the severity and high prevalence of this chronic and disabling disorder, there is still relatively limited understanding of its pathophysiology. However, this is now rapidly changing due to development of powerful technologies that can be used to dissect the neural circuits underlying pathologic behaviors. In this article, we describe recent technical advances that have allowed neuroscientists to start identifying the circuits underlying complex repetitive behaviors using animal model systems. In addition, we review current surgical and stimulation-based treatments for OCD that target circuit dysfunction. Finally, we discuss how findings from animal models may be applied in the clinical arena to help inform and refine targeted brain stimulation-based treatment approaches.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that obsessive-compulsive disorder is linked to dysfunctional cortico-striato-thalamo-cortical circuits and that animal models, especially optogenetic and transgenic rodent models, can help identify causal circuit mechanisms. It also surveys lesion, deep brain stimulation, and transcranial magnetic stimulation treatments that target these circuits, while noting major gaps in mechanistic understanding.

Key findings

  • OCD affects roughly 2–3% of people worldwide and is among the WHO’s ten leading causes of illness-related disability, yet its pathophysiology remains incompletely understood.
  • Human structural and functional imaging consistently implicates orbitofrontal cortex, anterior cingulate cortex, striatum, and anterior thalamus, with hyperactivity in these regions at rest and during symptom provocation; successful serotonin reuptake inhibitor or cognitive behavioral therapy is often associated with reduced orbitofrontal or caudate activity.
  • Rodent models such as SAPAP3 and Slitrk5 knockouts show perseverative grooming and anxiety reversed by chronic fluoxetine, and optogenetic studies show that repeated stimulation of orbitofrontal–ventral striatal projections can produce persistent grooming in wild-type mice, while lateral orbitofrontal–striatal stimulation can restore response inhibition in SAPAP3 knockouts.
  • Circuit-based treatments show promise: stereotactic lesion success rates range from 27–86% depending on improvement criteria; ventral capsule/ventral striatum deep brain stimulation responders averaged about a 35% symptom reduction; supplementary motor area transcranial magnetic stimulation has shown benefit in sham-controlled trials, whereas dorsolateral prefrontal cortex stimulation did not.

Methods

  • Narrative review synthesizing human genetic, pharmacologic, structural and functional neuroimaging, cognitive activation, rodent model, and surgical/neuromodulation literature on OCD.
  • No new primary data, systematic search strategy, or meta-analysis is described; the evidence base is published studies and reviews cited by the author.
  • Main analysis is qualitative integration of circuit findings across species and treatment modalities, with proposed working models linking cortico-striato-thalamo-cortical dysfunction to obsessions and compulsions.

Limitations

  • The paper states that no single animal model can recreate all aspects of OCD, that candidate-gene links to human OCD remain uncertain, and that the mechanism of action for effective deep brain stimulation is still unknown.
  • It also notes that lesion success is hard to judge because double-blind studies are difficult, that only one double-blind lesion trial has been done, and that deep brain stimulation and transcranial magnetic stimulation affect unknown cell populations, fibers of passage, and broad projection systems.
  • Evident from the text: as a narrative review, it does not use a systematic search or formal quality appraisal, and it repeatedly notes inconsistent directionality across imaging studies and difficulty testing causality in humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/da.22367

Cites

150 of 150 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Cortico-striato-thalamo-cortical (CSTC) circuits are implicated in OCD pathophysiology.

    “there is remarkable convergence of neuroanatomy, circuit function, and OCD neurochemistry findings collectively implicating cortico-striato-thalamo-cortical (CSTC) circuits in OCD pathophysiology 40–43.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [40] Rauch, 1997, The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation, Biol Psychiatry source

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    • cites [41] Rotge, 2010, Anatomical alterations and symptom-related functional activity in obsessive-compulsive disorder are correlated in the lateral orbitofrontal cortex, Biol Psychiatry source

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    • cites [42] Saxena, 2001, Brain-behavior relationships in obsessive-compulsive disorder, Semin Clin Neuropsychiatry source

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    • cites [43] Maia, 2008, The neural bases of obsessive-compulsive disorder in children and adults, Dev Psychopathol source

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  • Interpretationreasoning

    Noncoding polymorphisms most likely account for the association of SLC1A1 with OCD.

    “Thus, noncoding polymorphisms most likely account for the association of SLC1A1 with OCD.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Constitutive NR2B knockout mice have an early postnatal lethal phenotype due to impaired suckling.

    “constitutive NR2B knockout mice have an early postnatal lethal phenotype due to impaired suckling 33,34.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Kutsuwada, 1996, Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice, Neuron source

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    • cites [34] Forrest, 1994, Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death, Neuron source

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  • Premisecitation

    Bridging collaterals between direct and indirect pathways may permit modulation of information transmission through CSTC circuits.

    “b) bridging collaterals between direct and indirect pathways may permit modulation of information transmission through CSTC circuits 49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Cazorla, 2014, Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry, Neuron source

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  • Premisecitation

    Structural abnormalities in CSTC circuits involving OFC, ACC, and striatum have been repeatedly demonstrated in OCD.

    “structural abnormalities in CSTC circuits involving orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and striatum have been repeatedly demonstrated in OCD 51–53.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Pittenger, 2011, Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment, Pharmacol Ther source

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    • cites [52] Rodman, 2012, Neuroimaging contributions to novel surgical treatments for intractable obsessive-compulsive disorder, Expert Rev Neurother source

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    • cites [53] Wit, 2014, Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder, Am J Psychiatry source

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  • May combine two claims. 40

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    Premisecitation

    Changing the balance of activity between direct and indirect pathways can promote or inhibit the selection of appropriate behavior sequences.

    “A popular model suggests that changing the balance of activity between direct and indirect pathways can either promote or inhibit the selection of appropriate behavior sequences 42,50.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Saxena, 2001, Brain-behavior relationships in obsessive-compulsive disorder, Semin Clin Neuropsychiatry source

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    • cites [50] Ting, 2011, Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics, Curr Opin Neurobiol source

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    Premisecitation

    OCD genome-wide association studies have generally been underpowered, and definitive genome-wide candidates have yet to be fully elucidated.

    “in general OCD genome-wide association studies have been underpowered. Definitive genome-wide candidates therefore have yet to be fully elucidated17.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Mattheisen, 2015, Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS, Mol Psychiatry source

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    • cites [16] Stewart, 2013, Genome-wide association study of obsessive-compulsive disorder, Mol Psychiatry source

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    • cites [17] Taylor, 2013, Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies, Mol Psychiatry source

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    Premisecitation

    Tic-related OCD is a biologically distinct entity with higher prevalence in males, different neurochemical features, distinct striatal pathophysiology, and earlier age of onset.

    “there is evidence that tic-related OCD is a biologically distinct entity, with increased prevalence in males, different neurochemical features, distinct striatal pathophysiology, and earlier age of onset 8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Baxter, 1988, Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder, Am J Psychiatry source

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    Premisecitation

    In mice, administration of a 5-HT1B agonist leads to OCD-relevant perseverative locomotion and prepulse inhibition deficits, both reversed with chronic but not acute fluoxetine treatment.

    “studies in mice demonstrate that administration of a 5-HT1B agonist leads to OCD-relevant perseverative locomotion and prepulse inhibition deficits, both of which are reversed with chronic, but not acute, fluoxetine treatment 38.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Shanahan, 2009, Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice, Biol Psychiatry source

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    Premisecitation

    Even partial NR2B deficits in the brain lead to significant abnormalities in functioning because NMDA receptors are essential for basic neurobiological functions necessary for learning and memory.

    “even partial NR2B deficits in the brain lead to significant abnormalities in functioning, since NMDA receptors are essential for basic neurobiological functions necessary for learning and memory 32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Akashi, 2009, NMDA receptor GluN2B (GluR epsilon 2/NR2B) subunit is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses, J Neurosci source

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    Premisecitation

    The rs301430C allele is associated with increased SLC1A1 expression in cell models and brain tissue, suggesting that overexpression contributes to OCD susceptibility.

    “most evidence for association with the rs301430C allele. In cell models and brain tissue, this allele is associated with increased SLC1A1 expression, suggesting that overexpression contributes to OCD susceptibility 19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Arnold, 2006, Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder, Arch Gen Psychiatry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some childhood-onset OCD may correspond to a distinct subtype with different genetic and environmental underpinnings.

    “there have been suggestions that some childhood-onset OCD may correspond to a distinct subtype with different genetic and environmental underpinnings 9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Eichstedt, 2001, Childhood-onset obsessive-compulsive disorder: a tic-related subtype of OCD?, Clin Psychol Rev source

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    Premisecitation

    NR2B is an important mediator of synaptic plasticity because its incorporation into NMDA receptors makes them more calcium-permeable.

    “NR2B is a conceptually attractive candidate because it is an important mediator of synaptic plasticity, since its incorporation into NMDA receptors renders them more calcium-permeable 31.”
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    • cites [31] Malenka, 1993, NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms, Trends Neurosci source

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    Premisecitation

    Coding variants in SLC1A1 are very rare and do not clearly segregate with OCD.

    “Coding variants are very rare (3/1400 subjects screened) and do not clearly segregate with OCD 26,27.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Veenstra-VanderWeele, 2012, Functional studies and rare variant screening of SLC1A1/EAAC1/EAAT3 in males with obsessive-compulsive disorder, Psychiatr Genet source

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    • cites [27] Veenstra-VanderWeele, 2001, Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder, Mol Psychiatry source

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    Premisecitation

    A recent meta-analysis showed only a modest association of 2/9 SNPs with OCD, and SLC1A1 has not emerged as a probable locus from recent GWAS studies.

    “although a recent meta-analysis showed only a modest association of 2/9 SNPs with OCD 25, and SLC1A1 has not emerged as a probable locus from recent GWAS studies 15,16”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Stewart, 2013, Meta-analysis of association between obsessive-compulsive disorder and the 3’ region of neuronal glutamate transporter gene SLC1A1, Am J Med Genet B Neuropsychiatr Genet source

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    • cites [15] Mattheisen, 2015, Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS, Mol Psychiatry source

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    • cites [16] Stewart, 2013, Genome-wide association study of obsessive-compulsive disorder, Mol Psychiatry source

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    Premisecitation

    Hoarding is now considered a separate disorder in DSM-5.

    “hoarding, which is therefore now considered a separate disorder in DSM-5 12,13”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Mataix-Cols, 2010, Hoarding disorder: a new diagnosis for DSM-V?, Depress Anxiety source

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    • cites [13] Saxena, 2007, Is compulsive hoarding a genetically and neurobiologically discrete syndrome? Implications for diagnostic classification, Am J Psychiatry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a simplified framework, direct and indirect basal ganglia pathways oppose each other, with indirect pathway activation causing net inhibition of thalamus and decreased movement, and direct pathway activation causing net disinhibition and increased movement.

    “In a simplified framework, these anatomically distinct pathways have been thought to oppose each other, resulting in net inhibition of thalamus and decrease of movement via activation of the indirect pathway, or net disinhibition (i.e. overall excitation) and increase of movement by activation of the direct pathway (Fig.1) 46,47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Kravitz, 2010, Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry, Nature source

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    • cites [47] Kravitz, 2012, Striatal mechanisms underlying movement, reinforcement, and punishment, Physiology (Bethesda) source

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Excessive selection of actions or dysfunction in screening out maladaptive behavior sequences could lead to OCD symptoms.

    “According to this theory, both excessive selection of actions or dysfunction in screening out maladaptive behavior sequences could potentially lead to OCD symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Different CSTC loops may dictate particular motor and cognitive functions, with selectivity determined by the specific frontocortical area included in the loop.

    “it is thought that different CSTC loops may be responsible for dictating particular motor and cognitive functions. Evidence from functional imaging studies suggests that selectivity is determined by the specific frontocortical area included in the loop 45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Pennartz, 2009, Corticostriatal Interactions during Learning, Memory Processing, and Decision Making, J Neurosci source

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    Premisecitation

    SLC1A1 knockout mice do not demonstrate clear OCD-relevant phenotypes and have not yet been screened in targeted behavioral tests.

    “Though SLC1A1 knockout mice do not demonstrate clear OCD-relevant phenotypes, they have not yet been screened in targeted behavioral tests 28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Aoyama, 2006, Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse, Nat Neurosci source

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    Premisecitation

    GRIN2B has been implicated in OCD, although the findings are not as strong as for SLC1A1.

    “GRIN2B, which encodes the NR2B subunit of the NMDA glutamate receptor 18,29, has also been implicated in OCD, although the findings are not as strong.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Wu, 2012, The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder, Pharmacol Biochem Behav source

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    • cites [29] Arnold, 2004, Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study, Psychopharmacology (Berl) source

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    Premisecitation

    A recent mega-analysis demonstrated reduction in ACC, dorsomedial PFC, and inferior frontal gyrus volumes, with group-by-age interactions in putamen, OFC, and insula.

    “a recent mega-analysis demonstrated a reduction in ACC, dorsomedial PFC, and inferior frontal gyrus volumes, with group-by-age interactions in putamen, OFC, and insula 53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Wit, 2014, Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder, Am J Psychiatry source

      Not checked in the free run.

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    Premisecitation

    Knockout of the developmentally expressed Hoxb8lox gene leads to perseverative grooming, which is reversed by bone marrow transplant from wild-type mice.

    “knockout of the developmentally expressed Hoxb8lox gene leads to perseverative grooming, which is surprisingly reversed by bone marrow transplant from wild-type mice 89”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Chen, 2010, Hematopoietic origin of pathological grooming in Hoxb8 mutant mice, Cell source

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    Premisecitation

    A recent meta-analysis reported reduced volumes of left ACC and bilateral OFC, increased thalamic volumes bilaterally, and no differences in basal ganglia volumes relative to controls.

    “a recent meta-analysis reported reduced volumes of left ACC and bilateral OFC, and increased thalamic volumes bilaterally, but no differences in basal ganglia volumes relative to control samples 54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Rotge, 2009, Meta-analysis of brain volume changes in obsessive-compulsive disorder, Biol Psychiatry source

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    Premisecitation

    Other regions including subthalamic nucleus, cerebellum, and temporal cortex have also been implicated in OCD, and directionality of findings varies across studies.

    “other regions including subthalamic nucleus 60, cerebellum 63,64, and temporal cortex 64 have also been implicated, and directionality of findings varies across studies”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [60] Beucke, 2013, Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder, JAMA Psychiatry source

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    • cites [63] Anticevic, 2014, Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder, Biol Psychiatry source

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    • cites [64] Hou, 2014, Resting-state functional connectivity abnormalities in patients with obsessive-compulsive disorder and their healthy first-degree relatives, J Psychiatry Neurosci source

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    • cites [61] Posner, 2014, Reduced functional connectivity within the limbic cortico-striato-thalamo-cortical loop in unmedicated adults with obsessive-compulsive disorder, Hum Brain Mapp source

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    Premisecitation

    OCD subjects demonstrate hyperactivity in these areas both at rest and with symptom provocation, with OFC showing the most robust activation.

    “OCD subjects demonstrate hyperactivity in these areas both at rest and with symptom provocation, though OFC shows the most robust activation 40.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Rauch, 1997, The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation, Biol Psychiatry source

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    Premisecitation

    OCD patients have impaired extinction recall in a fear-conditioning paradigm, with accompanying alterations in cerebellum, posterior cingulate, and putamen activity during extinction recall, and reduced hippocampus and caudate activation during fear extinction.

    “recent studies have demonstrated that OCD patients have impaired extinction recall in a fear-conditioning paradigm, with accompanying alterations in cerebellum, posterior cingulate, and putamen activity during extinction recall, and reduced hippocampus and caudate activation during fear extinction 80.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Milad, 2013, Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit, JAMA Psychiatry source

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    Premisecitation

    SAPAP3 knockout mice demonstrate anxiety and severe perseverative grooming that leads to facial lesions, reminiscent of OCD patients with contamination obsessions and washing rituals.

    “Welch et al. 91 created a transgenic knockout of SAPAP3, a corticostriatal postsynaptic density protein. Mutant mice demonstrated both anxiety and perseverative grooming that was so severe it led to facial lesions, calling to mind OCD patients with contamination obsessions and corresponding washing rituals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Welch, 2007, Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice, Nature source

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    Premisecitation

    Go/NoGo tasks in OCD show altered activation of OFC, with conflicting directionality across studies.

    “other studies have used Go/NoGo tasks to assess inhibitory control in OCD, and though the directionality of results is in conflict, both studies report altered activation of OFC [66 = increased; 67 = decreased].”
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    • cites [66] Elliott, 2010, Hedonic and informational functions of the human orbitofrontal cortex, Cereb Cortex source

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    • cites [67] Roth, 2007, Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder, Biol Psychiatry source

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    Premisecitation

    OCD animal models have classically emphasized stereotyped and compulsive behaviors, and reliance on face validity may lead to discrepancies because identical phenotypes can result from different underlying biological processes.

    “OCD animal models have classically emphasized the presence of stereotyped and compulsive behaviors, although reliance on face validity may lead to discrepancies in the field since identical phenotypes can result from different underlying biological processes (for review see Wang et al, 2009) 81.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Wang, 2009, Assessing the validity of current mouse genetic models of obsessive-compulsive disorder, Behav Pharmacol source

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    Premisecitation

    In SAPAP3 knockout mice, abnormal glutamate signaling at striatal synapses corresponds with a juvenile developmental stage, with increased NMDA-dependent and decreased AMPA-dependent fEPSPs.

    “these investigators also discovered a synaptic mechanism that correlated with the OCD-related behaviors–i.e. abnormal glutamate signaling at striatal synapses corresponding with a ‘juvenile’ developmental stage (increased NMDA-dependent and decreased AMPA-dependent fEPSPs).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Welch, 2007, Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice, Nature source

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  • May combine two claims.

    Interpretationreasoning

    Overall, cognitive activation findings support the idea that cortical-basal ganglia circuits are dysfunctional in OCD and may contribute to symptom generation.

    “Overall, these findings support the idea that cortical-basal ganglia circuits are dysfunctional in OCD, and may contribute to symptom generation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both behavioral and electrophysiologic changes in SAPAP3 knockout mice are rescued after lentiviral-mediated SAPAP3 expression broadly throughout striatum or acute treatment with low-dose fluoxetine.

    “Both behavioral and electrophysiologic changes were rescued after either lentiviral-mediated SAPAP3 expression broadly throughout striatum or acute treatment with low-dose fluoxetine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Welch, 2007, Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice, Nature source

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    Premisecitation

    Another meta-analysis demonstrated increased bilateral caudate gray matter volume and decreased bilateral ACC volume in OCD patients.

    “another meta-analysis demonstrated changes in basal ganglia (i.e. increased bilateral caudate gray matter volume) as well as decreased bilateral ACC volume, in OCD patients 55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Radua, 2009, Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder, Br J Psychiatry source

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    Premisecitation

    NAc DBS normalizes NAc activity and decreases excessive PFC-NAc connectivity.

    “Another elegant study showed normalization of NAc activity accompanied by a decrease in excessive PFC-NAc connectivity following DBS 133.”
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    • cites [133] Figee, 2013, Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder, Nat Neurosci source

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    Premisecitation

    Slitrk5 knockout mice have OFC overactivation as measured with baseline c-fos staining, paralleling findings from human neuroimaging studies.

    “Slitrk5 KOs also have OFC overactivation as measured with baseline c-fos staining, paralleling findings from human neuroimaging studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Shmelkov, 2010, Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice, Nat Med source

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    Interpretationreasoning

    Interrupting hyperactive connections and/or severing tracts between key circuit nodes with excess connectivity leads to decreased abnormal transmission and fewer symptoms.

    “they are all consistent with the theory that interrupting hyperactive connections and/or severing tracts between key circuit nodes with excess connectivity will lead to decreased abnormal transmission and fewer symptoms.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Chemogenetic technology has not yet been used to directly investigate OCD, but has been used to probe circuits underlying schizophrenia and major depressive disorder.

    “Though this technology has not yet been used to directly investigate OCD, it has already been used to probe circuits underlying complex neuropsychiatric disorders such as schizophrenia 97 and major depressive disorder 98.”
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    • cites [97] Parnaudeau, 2013, Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition, Neuron source

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    • cites [98] Soumier, 2014, Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice, Neuropsychopharmacology source

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    Premisecitation

    Only one double-blind study has been performed to date, which demonstrated symptom improvement in active gamma knife ventral capsulotomy compared to sham treatment.

    “Only one double-blind study has been performed to date 116, which demonstrated symptom improvement in active gamma knife ventral capsulotomy when compared to sham treatment.”
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    • cites [116] Lopes, 2014, Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial, JAMA Psychiatry source

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    Premisecitation

    D1CT-7 mice demonstrate perseverative climbing, leaping, and biting behaviors that are exacerbated by increased NMDA-dependent glutamatergic transmission.

    “At baseline, D1CT-7 mice demonstrate perseverative climbing, leaping, and biting behaviors that are exacerbated by increased NMDA-dependent glutamatergic transmission.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Campbell, 1999, OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons, J Neurosci source

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    Premisecitation

    A human genetics study found no association of SAPAP3 single nucleotide polymorphisms with OCD, but did find associations with grooming disorders such as pathologic skin picking, trichotillomania, and/or nail biting.

    “a recent human genetics study found no association of SAPAP3 single nucleotide polymorphisms with OCD, but did find associations with grooming disorders such as pathologic skin picking, trichotillomania, and/or nail biting 94.”
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    • cites [94] Bienvenu, 2009, Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study, Am J Med Genet B Neuropsychiatr Genet source

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    Premisecitation

    Increased grooming and evoked firing in Ahmari et al were both reversed by chronic fluoxetine treatment.

    “Increased grooming and evoked firing were both reversed by chronic fluoxetine treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Ahmari, 2013, Repeated cortico-striatal stimulation generates persistent OCD-like behavior, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Slitrk5 knockout mice demonstrate increased anxiety and perseverative grooming that are reversed by chronic fluoxetine treatment.

    “Slitrk5 KOs demonstrate increased anxiety and perseverative grooming that are reversed by chronic treatment with fluoxetine, demonstrating relevance to human OCD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Shmelkov, 2010, Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    VC/VS DBS studies showed clinical efficacy, with responders averaging a 35% reduction in symptoms.

    “These studies demonstrated clinical efficacy, with responders showing 35% reduction in symptoms on average, and some patients showing evidence for decreased OFC, ACC, and thalamus activity on PET.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112] Greenberg, 2010, Invasive circuitry-based neurotherapeutics: stereotactic ablation and deep brain stimulation for OCD, Neuropsychopharmacology source

      Not checked in the free run.

    • cites [125] Greenberg, 2010, Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chemogenetic studies have demonstrated the importance of OFC in switching between goal-directed behaviors and habits, a process that may be disrupted in OCD.

    “chemogenetic studies have demonstrated the importance of OFC in switching between goal-directed behaviors and habits, a process that may be disrupted in OCD 99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Gremel, 2013, Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions, Nat Commun

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both SAPAP3 and Slitrk5 models link molecular changes at corticostriatal synapses with abnormal repetitive behaviors and yield insight into potential molecular and cellular pathologic mechanisms in OCD.

    “Regardless, both models clearly link molecular changes at corticostriatal synapses with abnormal repetitive behaviors, and therefore yield new insight into potential molecular and cellular pathologic mechanisms in OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ahmari et al found that acute stimulation did not generate repetitive behaviors, but repeated hyperactivation for multiple days led to a progressive and persistent increase in grooming that correlated with increased evoked-firing rate at OFC-VMS synapses.

    “While acute stimulation did not generate repetitive behaviors, repeated hyperactivation for multiple days in a row led to a progressive and persistent increase in grooming that correlated with an increased evoked-firing rate at OFC-VMS synapses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Ahmari, 2013, Repeated cortico-striatal stimulation generates persistent OCD-like behavior, Science source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Differences in response and side effects might arise because DBS and TMS stimulate cortical projections, striatal cell bodies, and fibers of passage broadly.

    “Specifically, variability in treatment response and side effects may be due to the fact that DBS and TMS broadly stimulate cortical projections, striatal cell bodies, and fibers of passage; conversely, specific stimulation of particular cell types could potentially lead to more targeted symptom reduction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    VC/VS DBS probably activates OFC-originating VS projections, striatal projections from other cortical regions, and fibers passing through.

    “For example, although DBS in VC/VS likely stimulates VS projections originating in OFC, it also affects striatal projections from other cortical areas, as well as fibers of passage.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Cell-type specific treatments might work better and cause fewer side effects than DBS or TMS.

    “This is the first step in the process of performing cell-type specific interventions in people, which may have superior efficacy and fewer side effects compared to the more general stimulation afforded by DBS and TMS.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Targeting particular cell types might reduce symptoms more selectively.

    “Specifically, variability in treatment response and side effects may be due to the fact that DBS and TMS broadly stimulate cortical projections, striatal cell bodies, and fibers of passage; conversely, specific stimulation of particular cell types could potentially lead to more targeted symptom reduction.”
    Quote in the paperSubstantial claim
46 of 46

  • The paper relies on this without support.

    It is difficult or impossible to test causality of CSTC circuit dysfunction in humans.

    “it is difficult (and perhaps impossible) to test causality in humans.”

  • The paper relies on this without support.

    Performing compulsions strengthens dysfunctional neural circuits underlying OCD, leading to persistence of symptoms and overall long-term increased anxiety.

    “performing compulsions is actually believed to strengthen dysfunctional neural circuits that underlie OCD, leading to persistence of symptoms and overall long-term increased anxiety.”

  • The paper relies on this without support.

    Valid animal models are essential for identifying molecular and cellular events that lead to pathology.

    “Since valid animal models are essential for identifying molecular and cellular events that lead to pathology”

  • The paper relies on this without support.

    DBS is a relatively safe, efficacious, adjustable, and reversible treatment for many movement disorders, including Parkinson’s disease.

    “Following its success as a relatively safe, efficacious, adjustable, and reversible treatment for many movement disorders, including Parkinson’s disease”

  • The paper relies on this without support.

    Stereotactic lesions are moderately efficacious, with success rates ranging from 27–86% depending on criteria used to measure improvement.

    “Although in aggregate stereotactic lesions are moderately efficacious, with success rates ranging from 27–86% depending on criteria used to measure improvement”

  • The paper relies on this without support.

    Many independent studies have indicated that DBS for OCD is a promising approach for treatment-resistant patients.

    “many independent studies have indicated that DBS for OCD is a promising approach for treatment-resistant patients.”

  • The paper relies on this without support.

    DBS currently has a Humanitarian Device Exemption from the FDA, so that severe patients can obtain treatment before completion of the multi-center trial.

    “DBS currently has a Humanitarian Device Exemption from the FDA, so that severe patients can obtain treatment before completion of the multi-center trial.”

  • The paper relies on this without support.

    Shifting the DBS electrode toward the ventral striatum improves efficacy and allows lower voltage stimulation.

    “Based in part on the fact that shifting the electrode towards the VS led to improved efficacy and need for lower voltage stimulation, multiple groups have now focused on targeting nucleus accumbens (NAc), a structure classically involved in reward processing that lies within the VS and has extensive connectivity with both prefrontal cortical and thalamic regions.”

  • The paper relies on this without support.

    The NAc participates in reward processing and is strongly connected to prefrontal cortex and thalamus.

    “Based in part on the fact that shifting the electrode towards the VS led to improved efficacy and need for lower voltage stimulation, multiple groups have now focused on targeting nucleus accumbens (NAc), a structure classically involved in reward processing that lies within the VS and has extensive connectivity with both prefrontal cortical and thalamic regions.”

  • The paper relies on this without support.

    At present, TMS can reach only superficial brain regions.

    “Notably, though TMS is currently limited to superficial brain structures, targeting of deep structures is now being attempted in an ongoing clinical trial (NCT01343732).”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The PFC has a core role in regulating working memory, inhibitory control, and attention, and its dysfunction can impact the parietal cortex.

    “These findings emphasize the core role of the PFC in regulating working memory, inhibitory control, and attention, and how its dysfunction can impact the parietal cortex (186).”

    From Neural mechanisms underlying cognitive inflexibility in obsessive-compulsive disorder: a review (2026) · cites this paper as [186]

    The Cortico-striato-thalamo-cortical circuit function section links frontocortical circuits to inhibition and attentional allocation. The Cognitive activation studies section reports altered orbitofrontal activation during an inhibitory-control task and decreased lateral PFC and parietal activation together during reversal learning. Neither section establishes a role in working memory or says that PFC dysfunction causes changes in the parietal cortex; page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In OCD patients, clear dysfunction in the PFC is believed to impact the functioning of connected regions like the parietal cortex.

    “In OCD patients, the clear dysfunction in the PFC is believed to impact the functioning of connected regions like the parietal cortex (164, 186).”

    From Neural mechanisms underlying cognitive inflexibility in obsessive-compulsive disorder: a review (2026) · cites this paper as [186]

    The Cognitive activation studies section reports decreased activation of both the lateral PFC and parietal cortex in OCD patients during a reversal-learning task (page not provided). It does not establish that PFC dysfunction affects parietal-cortex function, so the proposed direction of influence is unsupported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

8 of the 158 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Leckman, 2010, Obsessive-compulsive disorder: a review of the diagnostic criteria and possible subtypes and dimensional specifiers for DSM-V, Depress Anxiety, 27, 507, 10.1002/da.20669 · DOI · Paper page
  2. Velzen, 2014, Response inhibition and interference control in obsessive-compulsive spectrum disorders, Front Hum Neurosci, 8, 1

Cited by

Sorted by citations

Related

Authors
Ahmari, S. E., & Dougherty, D. D.
Affiliations
  • University of Pittsburgh (US)
  • Massachusetts General Hospital (US)
Corresponding author
Ahmari, Susanne E.
ORCID
Venue
Depression and Anxiety
Publisher
Wiley
Published
2015-05-07
Volume
32
Issue
8
Pages
550-562
ISSN
1091-4269 (ISSN-L)
DOI
10.1002/da.22367
PMC
PMC4515165
OpenAlex
W1644117706
Cited by
128
References
158
Citations by year
2026: 6 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 11 · 2021: 21 · 2020: 15 · 2019: 4 · 2018: 14 · 2017: 11 · 2016: 9 · 2015: 6
FWCI
1.91
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 117 d)
Locations
  • Depression and Anxiety (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (K08MH087718, R01MH104255)
  • Burroughs Wellcome Fund (CAMS Award)
  • MQ: Transforming Mental Health (MQ Fellows Award)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
obsessive-compulsive disorder, neural circuits, animal models, repetitive behavior, deep brain stimulation, neuromodulation, surgical treatment, circuit dysfunction, pathophysiology
MeSH terms
Animals, Cerebral Cortex, Disease Models, Animal, Humans, Nerve Net, Neural Pathways, Obsessive-Compulsive Disorder, Thalamus, Ventral Striatum

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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