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Cited by 362Obsessive-Compulsive Spectrum DisordersNeural and Behavioral Psychology StudiesPsychoanalysis and Psychopathology Research

The neural bases of obsessive-compulsive disorder in children and adults

Open access
Maia, Tiago V., Cooney, Rebecca E., Peterson, Bradley S.·2008·Development and Psychopathology
DOI 10.1017/s0954579408000606PMC PMC3079445
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Abstract

Functional imaging studies have reported with remarkable consistency hyperactivity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and caudate nucleus of patients with obsessive–compulsive disorder (OCD). These findings have often been interpreted as evidence that abnormalities in cortico–basal ganglia–thalamo–cortical loops involving the OFC and ACC are causally related to OCD. This interpretation remains controversial, however, because such hyperactivity may represent either a cause or a consequence of the symptoms. This article analyzes the evidence for a causal role of these loops in producing OCD in children and adults. The article first reviews the strong evidence for anatomical abnormalities in these loops in patients with OCD. These findings are not sufficient to establish causality, however, because anatomical alterations may themselves be a consequence rather than a cause of the symptoms. The article then reviews three lines of evidence that, despite their own limitations, permit stronger causal inferences: the development of OCD following brain injury, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and neurosurgical lesions that attenuate OCD. Converging evidence from these various lines of research supports a causal role for the cortico–basal ganglia–thalamo–cortical loops that involve the OFC and ACC in the pathogenesis of OCD in children and adults.

Integrity signals

Registry

Crossref · 10.1017/s0954579408000606

Cites

299 of 299 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 338 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    One study of children with OCD failed to detect differences between pre- and post-treatment scans.

    “The other study (Castillo et al., 2005) failed to detect any differences between pre- and post-treatment scans.”
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    • cites Castillo et al., 2005

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  • Premisecitation

    The age of onset of OCD has a bimodal distribution, with one peak in childhood around age 10 and another in early adulthood.

    “The age of onset of OCD seems to have a bimodal distribution, with a peak in childhood (at approximately 10 years of age) and another in early adulthood (Geller, 2006; Geller, Biederman, Jones, Shapiro et al., 1998).”
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    • cites Geller, 2006

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    • cites Geller et al., 1998

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  • Premisecitation

    One-third to one-half of adults with OCD had symptom onset in childhood or adolescence.

    “Conversely, one-third to one-half of adults with OCD have the onset of their symptoms in childhood or adolescence (Eichstedt & Arnold, 2001).”
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    • cites Eichstedt & Arnold, 2001

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  • Interpretationreasoning

    Many studies report only the mean and standard deviation of age of illness onset, which is inadequate for likely bimodal distributions.

    “In addition, many studies report only the mean and standard deviation of age of illness onset, which are inadequate to characterize what are likely to be bimodal distributions.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Cognitive activation studies can reveal neural activity differences reflecting compensatory strategies even without obvious behavioral performance differences.

    “These studies show that even in the absence of obvious differences in behavioral performance, cognitive activation studies may highlight differences in neural activity that reflect compensatory strategies.”
    Quote in the paperSubstantial claim
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  • Classified as probably not a substantial claim. 39
  • The quote only partly states this claim. 1

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    Premisecitation

    About 40% of childhood-onset OCD cases continue into adulthood, and this rises to 60% when subthreshold presentations are included.

    “Approximately 40% of cases of childhood-onset OCD continue into adulthood, and that number increases to 60% when subthreshold presentations of OCD are also considered (Stewart et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stewart et al., 2004

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    Premisecitation

    In treatment-naïve children with OCD, the caudate and ACC are hyperactive at rest, and this hyperactivity declines after treatment, largely consistent with adult findings.

    “The findings of this study were largely consistent with the findings in adults, including hyperactivity at rest in the caudate and ACC of treatment-naïve children, which declined following treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Diler et al., 2004

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    Interpretationnone given

    Few studies have compared the neural correlates of OCD across children and adults, severely limiting knowledge of their similarities and differences.

    “In addition, few studies have compared the neural correlates of OCD across children and adults, severely limiting our knowledge of their similarities and differences.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The authors were not aware of any symptom provocation studies in children with OCD.

    “We are not aware of any symptom provocation studies in children with OCD.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It remains unclear why OCD patients would have difficulty using the striatal habit-learning system to learn other habits, even if compulsions are exaggerated habits.

    “Even if compulsions are maladaptive, exaggerated habits (Graybiel & Rauch, 2000), why patients with OCD would have difficulty using the striatal habit-learning system (Packard & Knowlton, 2002) to learn other habits remains unclear.”
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    • cites Graybiel & Rauch, 2000

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    • cites Packard & Knowlton, 2002

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    Interpretationcitation

    Most brain imaging studies of adults with OCD use mixed samples of childhood- and adult-onset cases, which may compromise statistical power and confound findings.

    “Most brain imaging studies that include adults with OCD use mixed samples that include adults with childhood- and adult-onset OCD. Given the evidence that brain activity differs in adults with childhood- versus adult-onset OCD (Busatto et al., 2001), such heterogeneous samples may compromise statistical power and confound findings.”
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    • cites Busatto et al., 2001

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    Premisecitation

    Each CBGTC loop receives inputs from multiple cortical areas and projects back to one of its cortical areas of origin, partly closing the loop.

    “Each of these loops receives inputs from multiple cortical areas and then projects back to one of its cortical areas of origin, thereby partly closing the loop (Alexander et al., 1986).”
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    • cites Alexander et al., 1986

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    Premisecitation

    Cognitive activation studies in adults with OCD have generally found functional disturbances in the OFC, ACC, basal ganglia, and related areas, consistent with resting, symptom provocation, and pre/post-treatment studies.

    “The findings of these studies have generally been consistent with the findings of resting, symptom provocation, and pre/post-treatment studies, highlighting functional disturbances in the OFC, ACC, basal ganglia, and related areas (Menzies et al., 2008).”
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    • cites Menzies et al., 2008

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    Interpretationnone given

    The pathogenic relation, if any, of implicit learning deficits to OCD symptoms remains unclear.

    “On the other hand, the pathogenic relation, if any, of deficits in implicit (habit) learning and the symptoms of OCD remains unclear.”
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    Interpretationreasoning

    Because inhibitory control deficits occur in many disorders with widely varying phenotypes, caution is warranted in interpreting them as the root cause of OCD.

    “The presence of deficits in inhibitory control in so many disorders with such widely varying phenotypes suggests caution in interpreting such deficits as the root cause of OCD.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Several CBGTC loops exist and run largely parallel courses through the basal ganglia.

    “Several CBGTC loops exist, and they seem to run largely parallel courses through the basal ganglia (Alexander et al., 1986; Mega & Cummings, 2001; Middleton & Strick, 2001b).”
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    • cites Alexander et al., 1986

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    • cites Mega & Cummings, 2001

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    • cites Middleton & Strick, 2001b

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    Premisecitation

    If OCD patients use declarative learning to compensate, their performance should suffer more than controls when a secondary working memory task is added, and this was confirmed experimentally.

    “If so, the performance of patients with OCD should suffer more than that of healthy controls when a secondary task that taxes working memory is introduced, and this was confirmed experimentally (Deckersbach et al., 2002).”
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    • cites Deckersbach et al., 2002

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    Premisecitation

    A more recent formulation adds two loops targeting the medial OFC and inferotemporal/posterior parietal cortex, and suggests each loop may be further subdivided.

    “A more recent formulation adds two additional loops with target areas in the medial OFC and in the inferotemporal/posterior parietal cortex, and suggests that each of the loops may actually be further subdivided into multiple parallel loops (Middleton & Strick, 2001b).”
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    • cites Middleton & Strick, 2001b

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    Premisecitation

    An influential formulation proposes five CBGTC loops targeting the supplementary motor area, frontal eye fields, dorsolateral prefrontal cortex, lateral OFC, and ACC.

    “but a particularly influential formulation proposes the existence of five loops, whose target areas are (a) the supplementary motor area, (b) the frontal eye fields, (c) the dorsolateral prefrontal cortex (DLPFC), (d) the lateral OFC; and (e) the ACC (Alexander et al., 1986).”
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    • cites Alexander et al., 1986

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    Premisecitation

    The OFC, ACC, and head of the caudate nucleus are consistently implicated in resting, symptom provocation, and pre/post-treatment studies of adults with OCD; they are hyperactive at rest, become more active with symptom provocation, and lose resting hyperactivity after successful medication or cognitive-behavioral therapy.

    “Three brain areas – the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), and the head of the caudate nucleus – have been consistently implicated in a large number of resting, symptom provocation, and pre/post-treatment studies of adults with OCD. These areas (a) are hyperactive at rest in adults with OCD relative to healthy controls, (b) become more active with symptom provocation,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Baxter et al., 2001

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    • cites Saxena et al., 2001

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    • cites Saxena et al., 1998 source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    From the idea that OCD involves exaggerated habits, one could equally predict the opposite pattern-that the habit learning system in OCD should be especially powerful and effective.

    “However, from the idea that OCD prominently involves exaggerated habits (the compulsions), one could equally plausibly have predicted the opposite pattern of findings – that the habit learning system in OCD should be especially powerful and effective.”
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  • Classified as probably not a substantial claim.

    Premisecitation

    Excessive relative activity in the direct pathway in OFC/ACC CBGTC loops has been suggested to create a positive feedback loop in which obsessive thoughts become trapped.

    “In particular, excessive relative activity in the direct pathway in OFC/ACC CBGTC loops has been suggested to result in a positive feedback loop in which obsessive thoughts become “trapped” (Baxter et al., 2001; Saxena et al., 2001; Saxena et al., 1998; Saxena & Rauch, 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Baxter et al., 2001

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    • cites Saxena et al., 2001

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    • cites Saxena et al., 1998 source

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    Premisecitation

    Animal models have been criticized because they only model repetitive behaviors, whereas compulsions in OCD are tied to obsessions, and there is no way to assess whether animals have obsessions.

    “These have, however, been criticized because they only model repetitive behaviors, whereas compulsive behaviors in OCD are intimately tied to obsessions (Shafran & Speckens, 2005) – and we have no way of assessing whether animals have obsessions.”
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    • cites Shafran & Speckens, 2005

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    Interpretationcitation

    Genetic, phenomenological, and pathophysiological similarities between TS and OCD suggest that excessive activity in these areas in OCD might reflect inhibition of compulsions.

    “The genetic, phenomenological, and pathophysiological similarities between TS and OCD (Fineberg, Saxena, Zohar, & Craig, 2007; Marsh, Leckman, Bloch, Yazgan, & Peterson, 2008) suggest that excessive activity in these areas in patients with OCD might reflect the inhibition of compulsions.”
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    • cites Fineberg et al., 2007

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    • cites Marsh et al., 2008

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    Premisecitation

    Excessive relative activity in the indirect pathway inhibits cortical motor programs, producing hypokinetic symptoms such as difficulty initiating movement in Parkinson's disease.

    “Conversely, excessive relative activity in the indirect pathway inhibits cortical motor programs, producing hypokinetic symptoms, such as the difficulty initiating movement in Parkinson’s disease.”
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    • cites Wichmann & DeLong, 1996

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    Interpretationreasoning

    Functional imaging findings are inherently correlational and demonstrate only that activity in these areas correlates with a symptomatic state in OCD.

    “The problem with interpreting these activations as the cause of the symptoms is that these functional imaging findings are inherently correlational: they demonstrate only that activity in these areas correlates with a symptomatic state in OCD.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Hyperactivation of the OFC, ACC, and caudate may simply reflect the need to inhibit compulsive behavior during the scan.

    “A related, though slightly different idea is that hyperactivation of the OFC, ACC, and caudate nucleus simply reflects the need to inhibit compulsive behavior during the scan (Peterson, 2003).”
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    • cites Peterson, 2003

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    Interpretationcitation

    The validity of the PANDAS construct remains controversial, with substantial difficulties in establishing a causal relation between streptococcal infection and neuropsychiatric disorders.

    “Second, the validity of the PANDAS construct remains controversial (Harris & Singer, 2006; Kurlan, 2004; Kurlan & Kaplan, 2004; Singer & Loiselle, 2003), with substantial difficulties involved in establishing a causal relation between infection with Group-A beta-hemolytic streptococcus and the development of neuropsychiatric disorders (and additional difficulties in proving that the possible”
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    • cites Harris & Singer, 2006

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    • cites Kurlan, 2004

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    • cites Singer & Loiselle, 2003

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    Interpretationreasoning

    The vast majority of anatomical imaging studies of OCD were conducted after early functional imaging findings implicated the OFC, ACC, and caudate, and were strongly influenced by the theory that OFC/ACC CBGTC loops are centrally involved.

    “The vast majority of anatomical imaging studies of OCD have been conducted after the early functional imaging findings implicated the OFC, ACC, and caudate nucleus in the pathophysiology of OCD. Those studies were therefore strongly influenced by the theory that OFC/ACC CBGTC loops are centrally involved in the pathogenesis of OCD, and have therefore tended to look specifically at brain regions”
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    Premisecitation

    Excessive relative activity in the direct pathway disinhibits cortical motor programs, producing hyperkinetic symptoms such as chorea in Huntington's disease.

    “The idea is that excessive relative activity in the direct pathway disinhibits cortical motor programs, producing hyperkinetic symptoms, such as the chorea in Huntington’s disease.”
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    • cites Wichmann & DeLong, 1996

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    Interpretationnone given

    Studies of OCD as a consequence of brain injury typically involve small numbers of subjects with diffuse lesions that vary greatly across subjects.

    “First, studies of OCD as a consequence of brain injury typically involve a small number of subjects who have diffuse lesions that vary greatly across subjects.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    If OFC hyperactivity caused symptoms, greater OFC activation during provocation should be associated with a greater, not lesser, increase in symptoms.

    “If OFC hyperactivity played a role in causing, rather than in inhibiting symptoms, then greater activation of the OFC during symptom provocation should be associated with a greater, not a lesser, increase in symptoms.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The OFC responds to a variety of positive and negative emotional stimuli, as well as to neutral stimuli previously paired with positive or negative outcomes.

    “However, the OFC responds to a variety of both positive and negative emotional stimuli, as well as to neutral stimuli that have been previously paired with positive or negative outcomes (Elliott & Deakin, 2005; Elliott, Dolan, & Frith, 2000; Kringelbach & Rolls, 2004; O’Doherty, 2007; Rolls, 1996, 1999, 2004; Schultz, Tremblay, & Hollerman, 2000; Zald & Kim, 2001).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Elliott & Deakin, 2005

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    • cites Kringelbach & Rolls, 2004

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    • cites O’Doherty, 2007

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    Interpretationreasoning

    Although each line of evidence alone is insufficient to establish causality, their convergence with functional imaging studies in implicating OFC/ACC CBGTC loops would provide reassurance that those loops may play a causal role in OCD.

    “Although each of the aforementioned lines of evidence – anatomical imaging, OCD as a consequence of brain injury, PANDAS, and neurosurgery – in isolation is insufficient to establish causality, their convergence with functional imaging studies in implicating OFC/ACC CBGTC loops in OCD would provide some reassurance that those loops may indeed play a causal role in OCD.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Hyperactivity in OFC/ACC may be a consequence of patients' attempts to regulate anxiety rather than the cause of symptoms.

    “so again, hyperactivity in these areas may be a consequence of an attempt by patients with OCD to regulate their anxiety, rather than being the cause of their symptoms.”
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    Interpretationreasoning

    One possible interpretation is that OFC/ACC regions become hyperactive as a normal consequence of obsessional content rather than being its origin.

    “One possible interpretation of these findings is that rather than being the origin of obsessional content, these regions become hyperactive as a normal consequence of the obsessional content (Shafran & Speckens, 2005).”
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    • cites Shafran & Speckens, 2005

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    Premisecitation

    An influential idea is that OCD results from an imbalance between the direct and indirect pathways through the basal ganglia.

    “An influential idea based on these observations is that OCD results from an imbalance between the so-called “direct” and “indirect” pathways through the basal ganglia (Figure 1; Baxter et al., 2001; Saxena et al., 2001; Saxena et al., 1998; Saxena & Rauch, 2000).”
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    • cites Baxter et al., 2001

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    • cites Saxena et al., 2001

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    • cites Saxena et al., 1998 source

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  • May combine two claims.

    Interpretationreasoning

    All the alternative interpretations are consistent with the findings that the OFC, ACC, and caudate are hyperactive at rest, more active under provocation, and less active after treatment.

    “Instead, we wish to emphasize that all are consistent with the findings that the OFC, ACC, and caudate nucleus are hyperactive at rest, become more active under symptom provocation, and show less activity following treatment.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    It is unclear why socioterritorial concerns in particular should become locked in the OCD positive feedback loop.

    “Why, then, “socioterritorial concerns” in particular should become locked in the OCD positive feedback loop is unclear.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Functional imaging evidence for OFC involvement in response inhibition using the Go/NoGo task is inconclusive, with block designs typically showing OFC activation but event-related designs failing to show it.

    “The evidence from functional imaging for an involvement of the OFC in response inhibition, as studied using the Go/NoGo task, also remains inconclusive, with block designs typically showing OFC activation, but event-related designs failing to show such activation (Elliott & Deakin, 2005).”
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    • cites Elliott & Deakin, 2005

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    Interpretationnone given

    OCD is often diagnosed long after symptom onset, making it relatively impractical to study patients close to onset.

    “OCD is, however, often diagnosed long after the onset of symptoms, making this strategy relatively impractical.”
    Quote in the paperSubstantial claim

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    Interpretationnone given

    Neurosurgical studies lack appropriate controls, and the mechanisms by which they attenuate OCD symptoms are not fully understood.

    “Third, neurosurgical studies lack appropriate controls, and the mechanisms by which they attenuate OCD symptoms are not fully understood.”
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    Premisecitation

    Decreased NAA levels are a more sensitive indicator of neuronal loss or dysfunction than traditional volumetric measurements.

    “To the extent that decreased levels of NAA are a more sensitive indicator of neuronal loss or dysfunction than are traditional volumetric measurements (Bartha et al., 1998; Cendes et al., 1994; Ebisu et al., 1994)”
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    • cites Bartha et al., 1998

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    • cites Cendes et al., 1994

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    • cites Ebisu et al., 1994

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    Premisecitation

    In children with OCD, medication treatment reduced thalamic volume, and this reduction correlated with symptom improvement.

    “a study that scanned children with OCD before and after medication treatment did detect medication-induced reductions in thalamic volume that moreover correlated with symptom improvement (Gilbert et al., 2000)”
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    • cites Gilbert et al., 2000

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    Interpretationcitation

    Overall caudate volume could be normal or reduced in adults with OCD, while head of caudate and ventral striatum volumes could be increased.

    “Thus, the overall volume of the caudate could be normal (Atmaca et al., 2006; Atmaca et al., 2007; Aylward et al., 1996; Kang et al., 2004; Kellner et al., 1991; Riffkin et al., 2005) or even reduced (Luxenberg et al., 1988; D. Robinson et al., 1995) in adults with OCD, whereas the volumes of the head of the caudate (Scarone et al., 1992) and ventral striatum (Cardoner et al., 2007) could be incre”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both left and right OFC volumes correlate inversely with severity of OCD symptoms.

    “Both left and right OFC volumes have been found to correlate inversely with the severity of OCD symptoms (Atmaca et al., 2007; Kang et al., 2004)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Atmaca et al., 2007

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    • cites Kang et al., 2004

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    Premisecitation

    A study dividing the OFC into anterior and posterior regions found volume reduction in the left anterior OFC but not in the left posterior or right anterior or posterior OFC.

    “Another study that divided the OFC into anterior and posterior regions reported a volume reduction in the left anterior OFC, but not in the left posterior or right anterior or posterior OFC (Choi et al., 2004).”
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    • cites Choi et al., 2004

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  • May combine two claims.

    Interpretationreasoning

    Considerable evidence suggests that OFC volumes are significantly reduced in adults with OCD, with greater reductions accompanying more severe symptoms.

    “In summary, considerable evidence suggests that OFC volumes are significantly reduced in adults with OCD, with greater reductions accompanying more severe symptoms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Failure of some studies to detect thalamic differences could be due to medication effects.

    “the failure of these studies to detect differences between adults with OCD and controls could conceivably be due to the effects of medication.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Volume reductions have been reported for superior temporal gyrus and hippocampus in adults with OCD.

    “volume reductions have been reported for both the superior temporal gyrus (Choi et al., 2006) and hippocampus (Kwon et al., 2003) in adults with OCD.”
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    • cites Choi et al., 2006

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    • cites Kwon et al., 2003

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    Premisecitation

    Amygdala projects strongly to mediodorsal nucleus of thalamus and is positioned to influence output of OFC/ACC CBGTC loops.

    “The amygdala also projects strongly to the mediodorsal nucleus of the thalamus (Amaral et al., 1992), the final relay station before the OFC/ACC CBGTC loops project back to the cortex (Alexander et al., 1986; Middleton & Strick, 2001b), and it is therefore critically positioned to influence the output of these loops.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Amaral et al., 1992

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    • cites Alexander et al., 1986

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    • cites Middleton & Strick, 2001b

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

    Premisecitation

    Voxel-based morphometry is a popular whole-brain approach that gives voxel-by-voxel measurements.

    “Voxel-based morphometry is a popular whole-brain approach that gives voxel-by-voxel measurements (Ashburner & Friston, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ashburner & Friston, 2000

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    Interpretationcitation

    Thinning in parahippocampal cortex may point to broader abnormalities in tissue surrounding hippocampus, consistent with volume reductions reported for hippocampus proper.

    “the finding of thinning in the parahippocampal cortex may point to broader abnormalities in the tissue surrounding the hippocampus that would be consistent with the volume reductions that have been reported for the hippocampus proper (Kwon et al., 2003).”
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    • cites Kwon et al., 2003

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    Premisenone given

    Automated methods to delimit ROIs partly alleviate this problem but are significantly less accurate than manual methods.

    “Automated methods to delimit ROIs partly alleviate this problem, but they are significantly less accurate than manual methods.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Considering each nucleus as a whole misses distinctions between different loops within the nucleus and the fact that portions of one nucleus should be considered together with portions of the other.

    “Considering each nucleus – caudate or putamen – as a whole misses both the distinctions between different loops within the nucleus and the fact that portions of one nucleus should be considered together with portions of the other.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Insula is contiguous with posterior OFC and heavily interconnected with both OFC and ACC.

    “The insula is contiguous with the posterior OFC and is heavily interconnected with both the OFC and the ACC (Mesulam & Mufson, 1982; Mufson & Mesulam, 1982; Ongur & Price, 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mesulam & Mufson, 1982

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    • cites Mufson & Mesulam, 1982

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    • cites Ongur & Price, 2000

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    Interpretationcitation

    These surface analysis results are surprising because these are not the striatal regions through which OFC/ACC CBGTC loops run.

    “These results are surprising, given that these are not the striatal regions through which the OFC/ACC CBGTC loops run (Alexander et al., 1986; Haber, 2003; Lehericy et al., 2004; Middleton & Strick, 2001b).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Alexander et al., 1986

      Not checked in the free run.

    • cites Haber, 2003

      Not checked in the free run.

    • cites Lehericy et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cerebellum and frontal cortex are interconnected in parallel cortico-cerebellar loops, and cerebellum can influence striatum via disynaptic connection through thalamus.

    “The cerebellum and frontal cortex are interconnected in parallel cortico-cerebellar loops (R. M. Kelly & Strick, 2003; Middleton & Strick, 1997, 2000, 2001a), and the cerebellum can also influence the striatum via a disynaptic connection through the thalamus (Hoshi, Tremblay, Feger, Carras, & Strick, 2005).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites R. M. Kelly & Strick, 2003 source

      Not checked in the free run.

    • cites Middleton & Strick, 1997

      Not checked in the free run.

    • cites Hoshi et al., 2005

      Not checked in the free run.

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

    Premisereasoning

    Surface analyses still require prior delimitation of ROIs.

    “Surface analyses, however, still require the prior delimitation of ROIs, as it is within a previously-delimited ROI that surface analysis gives detailed, point-by-point measurements.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Surface analysis results need to be interpreted with care because neither study corrected for multiple comparisons and majority of patients had medication history.

    “The results of these surface analysis studies need to be interpreted with care because neither study corrected for multiple comparisons, and in both studies the majority of patients had a history of medication (although all were medication-free for at least 4 weeks prior to scanning).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    VBM studies have reported both increases and decreases in gray matter in superior temporal gyrus, as well as increases in gray matter in parahippocampal gyrus extending to amygdala.

    “VBM studies have reported both increases (J. J. Kim et al., 2001) and decreases (Yoo et al., 2008) in gray matter in the superior temporal gyrus, as well as increases in gray matter in the parahippocampal gyrus, extending to the amygdala (Valente et al., 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites J. J. Kim et al., 2001

      Not checked in the free run.

    • cites Yoo et al., 2008

      Not checked in the free run.

    • cites Valente et al., 2005

      Not checked in the free run.

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

    Premisenone given

    Tensor-based morphometry is used to analyze local morphological changes on the surface of cortical or subcortical structures or to measure cortical thickness.

    “Tensor-based morphometry is used to analyze local morphological changes on the surface of cortical or subcortical structures (a procedure often termed “surface analysis”) or to measure cortical thickness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Amygdala's role in fear/anxiety and involvement in anxiety disorders highlight its potential relevance for OCD pathophysiology.

    “The amygdala’s key role in mediating normal fear and anxiety (LeDoux, 2000, 2007; Phelps & LeDoux, 2005) and its prominent involvement in anxiety disorders (Bremner, 2004; Miller, Taber, Gabbard, & Hurley, 2005; Rauch, Shin, & Wright, 2003) highlight its potential relevance for understanding the pathophysiology of OCD, a disorder in which anxiety plays a crucial role (Foa, Steketee, & Ozarow, 1985”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites LeDoux, 2000

      Not checked in the free run.

    • cites Phelps & LeDoux, 2005

      Not checked in the free run.

    • cites Bremner, 2004

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    ROI studies often analyze only a small number of regions due to laborious manual delimitation, limiting opportunity to find abnormalities in unanticipated regions.

    “because manual delimitation of ROIs is laborious, ROI studies often analyze only a small number of regions for which there are prior suspicions of abnormality, which limits the opportunity to find abnormalities in unanticipated regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several CBGTC loops run through the caudate nucleus and each also partly through the putamen.

    “several CBGTC loops run through the caudate nucleus (Alexander et al., 1986; Middleton & Strick, 2001b) and each of those loops also partly seems to run through the putamen (Haber, 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Alexander et al., 1986

      Not checked in the free run.

    • cites Middleton & Strick, 2001b

      Not checked in the free run.

    • cites Haber, 2003

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The cortical thickness findings should be interpreted with care because most patients were medicated.

    “The findings from this study should be interpreted with care because most patients were medicated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shin et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cortical thickness study detected no abnormalities in the ACC or anywhere in the right hemisphere.

    “No abnormalities were detected in the ACC or anywhere in the right hemisphere.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shin et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Few studies of amygdala volumes in adults with OCD have yielded inconsistent findings.

    “The few studies that have examined volumes of the amygdala in adults with OCD have, however, yielded inconsistent findings”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of PET and SPECT studies found reliable differences between OCD patients and controls in orbital gyrus and head of caudate nucleus, but not in OFC or caudate nucleus as a whole.

    “A meta-analysis of PET and SPECT studies of OCD that found reliable differences between patients with OCD and normal controls in the orbital gyrus and the head of the caudate nucleus, but not in the OFC or caudate nucleus as a whole (Whiteside et al., 2004)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Whiteside et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The only extant study of cortical thickness in OCD found cortical thinning in several left hemisphere areas of adults with OCD, including OFC, ventrolateral prefrontal, middle frontal, precentral, superior temporal, parahippocampal, and lingual cortices.

    “This study found cortical thinning in several areas of the left hemisphere of adults with OCD, including not only the OFC but also the ventrolateral prefrontal, middle frontal, precentral, superior temporal, parahippocampal, and lingual cortices.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shin et al., 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    We are not aware of any volumetric studies of the OFC in pediatric OCD.

    “We are not aware of any volumetric studies of the OFC in pediatric OCD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Findings of increased ACC volumes in children with OCD are in contrast to findings in adults, which have generally failed to detect volumetric abnormalities in ACC, although they are consistent with several 1H-MRS studies reporting decreased NAA levels in ACC of adults with OCD.

    “The findings of increased ACC volumes in children with OCD, however, are in contrast to the findings in adults with OCD, which have generally failed to detect volumetric abnormalities in the ACC, although they are consistent with several 1H-MRS studies that have reported decreased NAA levels in the ACC of adults with OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Establishing a clear and definitive causal role for GAS infections in these cases has proven difficult, in part because GAS infections are common in childhood.

    “Establishing a clear and definitive causal role for GAS infections in these cases has, however, proven difficult, in part because GAS infections are so common in childhood (T. K. Murphy, Sajid, & Goodman, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites T. K. Murphy, Sajid, & Goodman, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GAS infection was first observed to produce Sydenham's chorea, an illness associated with rheumatic fever and characterized primarily by involuntary rapid, jerky movements, often accompanied by obsessive-compulsive symptoms and OCD.

    “GAS infection was first observed to produce Sydenham’s chorea, an illness associated with rheumatic fever and characterized primarily by involuntary rapid, jerky movements, which are, however, often accompanied by other motor, behavioral, and emotional problems, including obsessive-compulsive symptoms and OCD (Swedo et al., 1993; Swedo et al., 1989).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Swedo et al., 1993

      Not checked in the free run.

    • cites Swedo et al., 1989 source

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

    Interpretationreasoning

    A possible explanation for this difference is that ACC may develop differently in patients with OCD and healthy controls.

    “A possible explanation for this difference in findings across age groups is that the ACC may develop differently in patients with OCD and healthy controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    If confirmed, this could mean ACC volumes are larger in children with OCD but stay relatively constant with age, whereas healthy children's ACC volumes might be smaller but increase with age, resulting in similar ACC volumes by adulthood.

    “If this finding is confirmed, ideally in a longitudinal study, it could mean that ACC volumes are larger in children with OCD but then stay relatively constant with advancing age, whereas ACC volumes in healthy children might be smaller but then increase with age, resulting in similar ACC volumes in patients with OCD and healthy controls by adulthood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Abnormalities in other areas, such as increased NAA levels in left but not right DLPFC of children with OCD and decreased pituitary volumes in boys but not girls with OCD, have been reported sporadically but need replication.

    “Abnormalities in other areas – e.g., increased NAA levels in the left but not right DLPFC of children with OCD (Russell et al., 2003) and decreased pituitary volumes in boys but not girls with OCD (MacMaster et al., 2006) – have been reported sporadically, but need to be replicated.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Russell et al., 2003

      Not checked in the free run.

    • cites MacMaster et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Two findings receive convergent support from more than one study of children with OCD: increased volumes of ACC and abnormal metabolite concentrations in thalamus.

    “two findings receive convergent support from more than one study of children with OCD: increased volumes of the ACC and abnormal metabolite concentrations in the thalamus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Other large clusters of decreased gray matter were found in middle frontal gyrus, with cluster in right middle frontal gyrus remaining significant after correcting for multiple comparisons.

    “Other large clusters of decreased gray matter were found in the middle frontal gyrus, with the cluster in the right middle frontal gyrus remaining significant after correcting for multiple comparisons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carmona et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Volumetric studies in adults with OCD have generally not measured putamen, so whether reduced putamen volumes are found in adults with OCD remains unclear.

    “Volumetric studies in adults with OCD have generally not measured the putamen, so whether reduced putamen volumes are found in adults with OCD remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Two studies detected no significant differences in caudate volumes between children with OCD and matched controls, although one reported smaller putamen volumes in children with OCD.

    “Two studies detected no significant differences in caudate volumes between children with OCD and matched controls (Rosenberg et al., 1997; Szeszko, MacMillan, McMeniman, Chen et al., 2004), although one of these studies reported smaller putamen volumes in children with OCD (Rosenberg et al., 1997).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rosenberg et al., 1997

      Not checked in the free run.

    • cites Szeszko, MacMillan, McMeniman, Chen et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This absence is a major gap in the literature given that reduced OFC volumes are the most consistent finding in adult OCD.

    “This is a major gap in the literature, given that reduced volumes in the OFC are the most consistent finding in the volumetric literature on adult OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    This CBT study did not include a control group, so possibility that children with OCD might not have significantly enlarged thalami prior to treatment cannot be excluded.

    “This study, however, did not include a control group, so the possibility that the children with OCD in this study might not have significantly enlarged thalami prior to treatment cannot be excluded.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Controversy remains regarding the causal hypothesis that PANDAS are autoimmune disorders and the validity of the PANDAS construct itself.

    “Controversy remains, however, regarding not only this causal hypothesis but the validity of the PANDAS construct itself (Harris & Singer, 2006; Kurlan, 2004; Kurlan & Kaplan, 2004; Singer & Loiselle, 2003).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Harris & Singer, 2006

      Not checked in the free run.

    • cites Kurlan, 2004

      Not checked in the free run.

    • cites Kurlan & Kaplan, 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This finding is consistent with similar findings in VBM studies of adults with OCD but contrasts with volumetric studies in children with OCD, which have generally found increased ACC volumes.

    “Although this is consistent with similar findings in VBM studies of adults with OCD, it contrasts with the findings of volumetric studies in children with OCD, which have generally found increased ACC volumes (Rosenberg & Keshavan, 1998; Szeszko, MacMillan, McMeniman, Chen et al., 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rosenberg & Keshavan, 1998

      Not checked in the free run.

    • cites Szeszko, MacMillan, McMeniman, Chen et al., 2004

      Not checked in the free run.

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

    Premisecitation

    Another potential line of evidence for involvement of basal ganglia in OCD comes from study of PANDAS.

    “Another potential line of evidence for the involvement of the basal ganglia in OCD comes from the study of PANDAS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Another study found no differences in volumes of thalamus measured before and after successful cognitive-behavioral therapy, suggesting that reduction in thalamic volumes seen with paroxetine treatment is not necessary for symptom improvement.

    “Another study found no differences in volumes of the thalamus measured before and after successful cognitive-behavioral therapy (Rosenberg, Benazon, Gilbert, Sullivan, & Moore, 2000), suggesting that the reduction in volumes of the thalamus seen with paroxetine treatment is not necessary for symptom improvement.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rosenberg, Benazon, Gilbert, Sullivan, & Moore, 2000

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The finding of a putamen abnormality is somewhat surprising from perspective of pathophysiological model emphasizing OFC/ACC CBGTC loops, given those loops run mostly through caudate.

    “The finding of a putamen abnormality is somewhat surprising from the perspective of the pathophysiological model of OCD that emphasizes the OFC/ACC CBGTC loops, given that those loops run mostly (though not exclusively) through the caudate”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    One study reported larger volumes of ACC in treatment-naïve children with OCD than in matched controls, with larger ACC volumes accompanying more severe symptoms.

    “One study reported larger volumes of the ACC in treatment-naïve children with OCD than in matched controls, with larger ACC volumes accompanying more severe symptoms (Rosenberg & Keshavan, 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rosenberg & Keshavan, 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One VBM study reported decreased gray matter in left ACC and medial frontal gyrus bilaterally in children with OCD, consistent with similar findings in adults and with hypothesized involvement of ACC in OCD.

    “One of these (Gilbert et al., 2008) reported decreased gray matter in the left ACC and in the medial frontal gyrus bilaterally in children with OCD, consistent with similar findings in adults (Pujol et al., 2004; Valente et al., 2005; Yoo et al., 2008) and with the hypothesized involvement of the ACC in OCD.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gilbert et al., 2008

      Not checked in the free run.

    • cites Pujol et al., 2004

      Not checked in the free run.

    • cites Valente et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Subsequent studies reported increases in choline and creatine/phosphocreatine levels in medial thalami of children with OCD, suggesting earlier findings reflected elevated choline and creatine/phosphocreatine rather than decreased NAA.

    “Indeed, subsequent studies from the same group did report increases in choline (Rosenberg, Amponsah, Sullivan, MacMillan, & Moore, 2001; Smith et al., 2003) and creatine/phosphocreatine levels (Mirza et al., 2006) in the medial thalami of children with OCD, suggesting that the earlier findings reflected elevated levels of choline and creatine/phosphocreatine rather than decreased levels of NAA.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rosenberg et al., 2001

      Not checked in the free run.

    • cites Smith et al., 2003

      Not checked in the free run.

    • cites Mirza et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two studies failed to detect significant differences in amygdala volumes between children with OCD and healthy controls, although one found children with OCD had significantly larger left than right amygdalae.

    “Two studies failed to detect significant differences in amygdala volumes between children with OCD and healthy controls (Rosenberg & Keshavan, 1998; Szeszko, MacMillan, McMeniman, Lorch et al., 2004), although one of these studies found that children with OCD, unlike healthy controls, had significantly larger left than right amygdalae (Szeszko, MacMillan, McMeniman, Lorch et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rosenberg & Keshavan, 1998

      Not checked in the free run.

    • cites Szeszko, MacMillan, McMeniman, Lorch et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One VBM study states its findings concern gray matter densities, not volumes, and that this may explain discrepancy with prior volumetric studies.

    “In fact, one of the studies (Gilbert et al., 2008) states precisely that its findings concern gray matter densities, not volumes, and that this may explain their discrepancy with prior volumetric studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gilbert et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The other VBM study reported a large cluster of decreased gray matter in cingulate cortex, but that finding did not remain significant after correcting for multiple comparisons.

    “The other VBM study in children with OCD (Carmona et al., 2007) also reported a large cluster of decreased gray matter in the cingulate cortex, although that finding did not remain significant after correcting for multiple comparisons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carmona et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Additional clusters were reported but were substantially smaller and none remained significant after correcting for multiple comparisons.

    “Additional clusters were also reported, but they were substantially smaller and none remained significant after correcting for multiple comparisons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carmona et al., 2007

      Not checked in the free run.

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

    Premisenone given

    Simply because a lesion in a given brain region can produce OCD, that does not necessarily imply that all or even some cases of non-lesion-related OCD involve impairments in that region.

    “In principle, simply because a lesion in a given brain region can produce OCD, that does not necessarily imply that all or even some cases of non-lesion-related OCD involve impairments in that region.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The Grados study lacked matched non-injured controls, precluding inferences about the extent to which symptom changes were caused by the injury.

    “The non-inclusion of a group of matched non-injured controls in the study precludes any inferences regarding the extent to which the changes in symptoms were caused by the injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grados et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Childhood- and adult-onset obsessive-compulsive disorder may have differing etiologies, and the case reports mostly involve adults, so they may bear mainly on adult-onset illness.

    “To the extent that childhood- and adult-onset OCD may have differing etiologies, these cases may also bear mostly on adult-onset illness, as the vast majority of them involve adults”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Grados study finding is consistent with neurosurgical treatments that disrupt the orbitofrontal cortex or its connections, but contrasts with case reports implicating orbitofrontal cortex lesions in obsessive-compulsive disorder onset.

    “This is consistent with neurosurgical treatments for OCD that disrupt the OFC or its connections, but contrasts with the case reports that have implicated lesions of the OFC in the onset of OCD”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several studies have reported elevated anti-basal ganglia antibodies in sera of patients with TS or OCD, although at least one study failed to detect differences between PANDAS patients and healthy controls.

    “Several studies have reported elevated anti-basal ganglia antibodies in the sera of patients with TS or OCD (Dale, Heyman, Giovannoni, & Church, 2005; Kiessling, Marcotte, & Culpepper, 1994; Rizzo, Gulisano, Pavone, Fogliani, & Robertson, 2006; Singer et al., 1998; Wendlandt, Grus, Hansen, & Singer, 2001), although at least one study failed to detect differences in anti-basal ganglia antibodies”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dale et al., 2005

      Not checked in the free run.

    • cites Kiessling et al., 1994

      Not checked in the free run.

    • cites Singer et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A case study of an adolescent boy with exacerbation of OCD symptoms after streptococcal pharyngitis showed reduction in basal ganglia volumes accompanied by reduction in symptom severity.

    “A case study of an adolescent boy with exacerbation of OCD symptoms after a streptococcal pharyngitis showed precisely that, and the reduction in basal ganglia volumes was also accompanied by a reduction in symptom severity (Giedd, Rapoport, Leonard, Richter, & Swedo, 1996).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Giedd et al., 1996

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The Grados study suggests a role for the orbitofrontal cortex in obsessive-compulsive symptoms after brain injury, although orbitofrontal cortex lesions were inversely related to symptom severity.

    “A larger, prospective study (Grados et al., 2008) also suggests a role for the OFC in obsessive-compulsive symptoms following brain injury, although in that study lesions to the OFC were inversely related to symptom severity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grados et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The specific CGBTC loops affected may determine the neuropsychiatric presentation, with disturbances in motor loops causing TS or Sydenham's chorea and disturbances in OFC/ACC CBGTC loops causing OCD.

    “The specific CGBTC loops affected may determine the neuropsychiatric presentation, with disturbances in motor loops causing TS or Sydenham’s chorea and disturbances in OFC/ACC CBGTC loops causing OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Existing evidence suggests but does not prove that a GAS infection may, in some cases, trigger an autoimmune response that attacks the basal ganglia, leading to OCD, TS, Sydenham's chorea, or a combination.

    “To summarize, the existing evidence suggests but does not prove that a GAS infection may, in some cases, trigger an autoimmune response that attacks the basal ganglia, leading to OCD, TS, Sydenham’s chorea, or a combination of these disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Medial prefrontal and temporal lobe lesions were associated with new-onset obsessions, but the effect disappeared when obsessions and compulsions were considered together.

    “Medial prefrontal and temporal lobe lesions were associated with new-onset obsessions, but this effect disappeared when obsessions and compulsions were considered conjointly.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grados et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One study reported that immunomodulatory treatment of PANDAS led to improvements in both OCD and TS symptoms, although this study has been criticized.

    “One study reported that immunomodulatory treatment of PANDAS led to improvements in both OCD and TS symptoms (Perlmutter et al., 1999), although this study has been criticized on multiple grounds (Singer, 1999).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Perlmutter et al., 1999

      Not checked in the free run.

    • cites Singer, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two studies reported that antibiotic prophylaxis and treatment was effective in reducing symptoms in PANDAS, although these studies should be considered preliminary because neither included a placebo group.

    “Two studies have reported that antibiotic prophylaxis and treatment was effective in reducing symptoms in PANDAS (M. L. Murphy & Pichichero, 2002; Snider, Lougee, Slattery, Grant, & Swedo, 2005), although these studies should be considered preliminary because neither of them included a placebo group.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites M. L. Murphy & Pichichero, 2002

      Not checked in the free run.

    • cites Snider et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mediodorsal thalamic nucleus has the densest reciprocal connections with the orbitofrontal cortex and is the primary thalamic nucleus in cortico-basal ganglia-thalamo-cortical loops connecting to the orbitofrontal cortex.

    “which is the thalamic nucleus with densest reciprocal connections with the OFC and the primary nucleus in the thalamus involved in CBGTC loops that connect to the OFC”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fuster, 1997

      Not checked in the free run.

    • cites Ongur & Price, 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The caudate, putamen, and globus pallidus are enlarged in patients with PANDAS, just as they are in Sydenham's chorea.

    “The caudate, putamen, and globus pallidus are enlarged in patients with PANDAS (Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000), just as they are in Sydenham’s chorea (Giedd et al., 1995).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Giedd et al., 2000

      Not checked in the free run.

    • cites Giedd et al., 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anterior capsulotomy lesions are placed in the anterior limb of the internal capsule and are believed to interrupt connections between the orbitofrontal cortex and the mediodorsal thalamic nucleus.

    “The lesions in anterior capsulotomy are placed in the anterior limb of the internal capsule. Such lesions are believed to interrupt the connections between the OFC and the mediodorsal nucleus of the thalamus”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Greenberg et al., 2000

      Not checked in the free run.

    • cites Mindus et al., 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infusion of sera from TS patients with elevated antineuronal antibodies into rat striatum has been reported to produce an increase in stereotypies, although these findings have not always been replicated.

    “Finally, infusion of sera from TS patients who have elevated antineuronal antibodies into the striatum of rats has been reported to produce an increase in stereotypies (Hallett, Harling-Berg, Knopf, Stopa, & Kiessling, 2000; J. R. Taylor et al., 2002), although these findings have not always been replicated (Loiselle, Lee, Moran, & Singer, 2004; Singer et al., 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hallett et al., 2000

      Not checked in the free run.

    • cites J. R. Taylor et al., 2002

      Not checked in the free run.

    • cites Loiselle et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Evaluating the success of neurosurgical procedures is complicated by small subject numbers and ethical difficulties with randomized double-blind studies involving neurosurgical lesions.

    “Evaluating the success of these procedures is complicated by the small number of subjects in each study and the obvious ethical difficulties with conducting randomized double-blind studies involving neurosurgical lesions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Earp, 1979

      Not checked in the free run.

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

    Premisecitation

    Some authors have argued that development of the anterior cingulate cortex during infancy, childhood, and adolescence may underlie improvements in self-regulatory capacities.

    “Some authors have argued that development of the ACC during infancy, childhood, and adolescence may underlie the improvements in self-regulatory capacities that characterize these periods”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Posner & Rothbart, 1998

      Not checked in the free run.

    • cites Posner, Rothbart, Sheese, & Tang, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortical thickness and size of the dorsal anterior cingulate cortex seem to change relatively little between 5 and 11 years of age, although cortical thickness and size of the ventral anterior cingulate cortex may increase in that age range.

    “cortical thickness and size of the dorsal ACC seem to change relatively little between 5 and 11 years of age, although cortical thickness and size of the ventral ACC may increase in that age range”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sowell et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neurosurgical lesions for treatment-refractory obsessive-compulsive disorder suggest lesions in key components of orbitofrontal and anterior cingulate cortico-basal ganglia-thalamo-cortical loops can attenuate symptoms, but improvement is often gradual, raising the possibility it is due to degeneration or plasticity elsewhere rather than the primary lesion.

    “neurosurgical lesions used for treatment-refractory OCD suggest that lesions placed in key components of the OFC/ACC CBGTC loops can be effective in attenuating the symptoms of OCD; however, the improvement in symptoms is often gradual, raising the possibility that it may be due to degeneration or plasticity elsewhere in the brain, rather than an effect of the primary lesion itself.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Some of these developmental changes seem to affect primarily boys, which may explain the higher prevalence of obsessive-compulsive disorder among boys than girls.

    “some of those changes seem to affect primarily boys, which may explain the higher prevalence of OCD among boys than girls”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All lines of research reviewed suggest a role for orbitofrontal and anterior cingulate cortico-basal ganglia-thalamo-cortical loops in obsessive-compulsive disorder pathogenesis, but each suffers from important limitations.

    “All of the lines of research reviewed herein – anatomical imaging, PANDAS, OCD as a consequence of brain injury, and neurosurgery for treatment-refractory OCD – suggest a role for OFC/ACC CBGTC loops in the pathogenesis of OCD, but each suffers from important limitations.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The volume of the right anterior cingulate cortex has been reported to increase during childhood and adolescence.

    “the volume of the right ACC has been reported to increase during childhood and adolescence”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Casey et al., 1997

      Not checked in the free run.

    • cites Marquardt et al., 2005

      Not checked in the free run.

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

    Premisecitation

    Larger volumes of the right anterior cingulate cortex have been associated with better performance on an attentional task in children and adolescents.

    “larger volumes of the right ACC have been associated with better performance on an attentional task in children and adolescents”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Casey et al., 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Childhood and adolescence may be particularly critical for development of the basal ganglia in boys, which may explain why boys are more susceptible to obsessive-compulsive disorder and other cortico-basal ganglia-thalamo-cortical circuitry disorders.

    “Childhood and adolescence may therefore be particularly critical for the development of the basal ganglia in boys, which may explain why boys are more susceptible than girls to OCD and other disorders of CBGTC circuitry”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Existing evidence suggests both the caudate and the orbitofrontal cortex differ markedly and develop differently in boys and girls.

    “existing evidence suggests that both the caudate and the OFC – two key components of the OFC/ACC CGBTC loops – differ markedly and develop differently in boys and girls.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Many studies have reported sexual dimorphisms in the human brain.

    “Many studies have reported sexual dimorphisms in the human brain”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gilmore et al., 2007

      Not checked in the free run.

    • cites Goldstein et al., 2001

      Not checked in the free run.

    • cites Luders et al., 2005

      Not checked in the free run.

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

    Premisecitation

    Growth of the prefrontal cortex during childhood and adolescence may be largely driven by development of white matter.

    “The growth of the PFC during childhood and adolescence may be largely driven by the development of white matter”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Barnea-Goraly et al., 2005

      Not checked in the free run.

    • cites Reiss et al., 1996

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Similar success rates are often seen in open trials of medication or psychotherapy and typically drop substantially in blinded controlled treatment trials.

    “Similar rates are, however, often seen in open trials of medication or psychotherapy, and typically drop substantially in blinded, controlled treatment trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Studies of PANDAS suggest an autoimmune insult to the basal ganglia may cause obsessive-compulsive disorder, but controversy remains about this mechanism and even the existence of PANDAS.

    “studies of PANDAS suggest that an autoimmune insult to the basal ganglia may cause OCD; however, controversy remains regarding this putative pathogenic mechanism and even the very existence of PANDAS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Studies of obsessive-compulsive disorder as a consequence of brain injury suggest lesions in key components of these loops may cause obsessive-compulsive disorder, but much evidence is based on case reports.

    “Studies of OCD as a consequence of brain injury suggest that lesions in key components of these loops may also cause OCD; however, much of this evidence is based on case reports.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Female rats have more extensive dendritic fields in the orbitofrontal cortex than male rats, but those differences are abolished by neonatal gonadectomy.

    “female rats have more extensive dendritic fields in the OFC than do male rats, but those differences are abolished by neonatal gonadectomy”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kolb, Pellis, & Robinson, 2004

      Not checked in the free run.

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

    Premisecitation

    One study reported that white matter volume in dorsal prefrontal cortex increased throughout childhood and adolescence, while white matter volume in the orbitofrontal cortex decreased.

    “One study reported that while the volume of white matter in dorsal PFC increased throughout childhood and adolescence, the volume of white matter in the OFC decreased”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reiss et al., 1996

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Studies mapping prefrontal cortex growth did not include the ventral surface of the brain, so orbitofrontal cortex growth patterns remain to be elucidated.

    “the studies that have mapped the growth of the PFC did not include the ventral surface of the brain, so the growth patterns of the OFC remain to be elucidated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sensorimotor areas mature earlier and higher-order areas, including the orbitofrontal cortex, mature later.

    “In general, sensorimotor areas mature earlier and higher-order areas, including the OFC, mature later”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Benes, 1989

      Not checked in the free run.

    • cites Gogtay et al., 2004

      Not checked in the free run.

    • cites Yakovlev & Lecours, 1967

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    No anatomical abnormalities have yet been reported in other structures affected in adults with obsessive-compulsive disorder, including the orbitofrontal cortex and caudate, but this may be because those structures have not been properly studied in children with obsessive-compulsive disorder.

    “No anatomical abnormalities have yet been reported in the other structures that are affected in adults with OCD, including the OFC and caudate, but that may be attributable either in whole or in part to the fact that those structures have not yet been properly studied in children with OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisenone given

    Existing studies clearly point to anatomical abnormalities in the anterior cingulate cortex and metabolite abnormalities in the thalamus in children with obsessive-compulsive disorder.

    “Existing studies clearly point to anatomical abnormalities in the ACC and metabolite abnormalities in the thalamus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Even though the most consistent finding for the striatum of adults with obsessive-compulsive disorder is reduced NAA levels, no studies have analyzed NAA levels in the striatum of children with obsessive-compulsive disorder.

    “even though the most consistent finding for the striatum of adults with OCD is a reduction in NAA levels, no studies have analyzed NAA levels in the striatum of children with OCD.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Differences between findings in children and adults with obsessive-compulsive disorder could be due to multiple factors including comparison across childhood- and adult-onset subtypes, differing types and rates of comorbidity, differing ascertainment biases, and differing durations of illness.

    “Differences between findings in children and adults OCD could, however, be due to multiple factors, including a comparison across childhood- and adult-onset subtypes, differing types and rates of comorbidity, differing ascertainment biases, and differing durations of illness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Even though the most consistently replicated volumetric finding in adults with obsessive-compulsive disorder is reduced orbitofrontal cortex volume, no region-of-interest studies have analyzed orbitofrontal cortex volume in children with obsessive-compulsive disorder.

    “even though the most consistently replicated volumetric finding in adults with OCD is a reduction in volume of the OFC, no ROI studies have analyzed the volume of the OFC in children with OCD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Of the two voxel-based morphometry studies of pediatric obsessive-compulsive disorder, one had fairly small samples and in the other the majority of children were on medication.

    “of the two VBM studies of pediatric OCD, one had fairly small samples (Gilbert et al., 2008), and in the other the majority of children were on medication (Carmona et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gilbert et al., 2008

      Not checked in the free run.

    • cites Carmona et al., 2007

      Not checked in the free run.

131 of 131

  • The authors state this as an assumption.

    The symptoms of OCD relate directly to a deficit in inhibitory control.

    “the relevance of those studies to understanding the symptoms of OCD depends on the unproven assumption that those symptoms relate directly to a deficit in inhibitory control.”

  • The authors state this as an assumption.

    Obsessive-compulsive disorder is caused by abnormalities in orbitofrontal and anterior cingulate cortico-basal ganglia-thalamo-cortical loops.

    “Assuming that OCD is indeed caused by abnormalities in OFC/ACC CBGTC loops”
2 of 2

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?

  • An imbalance between the direct and indirect pathways, specifically overactivity in the direct pathway, is thought to contribute to OCD pathology by creating a positive feedback loop resulting in CSTC circuit hyperactivity.

    “An imbalance between these two pathways is thought to contribute to OCD pathology, that is, overactivity in the direct pathway (critical for initiation and suppression of behavior) creating a positive feedback loop resulting in CSTC circuit hyperactivity (Saxena et al., 2001; see also Maia et al., 2008; Ting & Feng, 2011) (Vahabzadeh & McDougle, 2014; van den Heuvel et al., 2016).”

    From Obsessive-compulsive disorder: Etiology, neuropathology, and cognitive dysfunction (2023) · cites this paper as Maia et al., 2008

  • 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.”

    From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [43]

  • Findings from a wide range of studies suggest that disturbances in orbitofrontal cortex may play a causal role in producing OCD symptoms.

    “Nevertheless, findings from a wide range of studies suggest that disturbances in orbitofrontal cortex may play a causal role in producing the symptoms of OCD (67).”

    From Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies (2009) · cites this paper as [67]

  • Evidence for abnormalities in components of a goal-directed system in OCD, particularly the caudate nucleus, aligns with a suggestion that key manifestations of this condition reflect an overdominance of a habitual system.

    “Furthermore, evidence for abnormalities in components of a goal-directed system in OCD, particularly the caudate nucleus, aligns with a suggestion that key manifestations of this condition reflect on overdominance of a habitual system (Maia et al., 2008).”

    From Goals and Habits in the Brain (2013) · cites this paper as Maia et al., 2008

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A pediatric study is listed among adult cognitive-activation studies

    Minor

    The discussion presents its task list as studies of adults with OCD and includes Woolley et al. (2008) for the Stop Signal task. The cited reference explicitly identifies its participants as pediatric.

1 of 1

Cites

Flagged first, then by citations

19 of the 318 references couldn’t be matched to a known paper.

Research works printed but not linked: 7

  1. 2000, Diagnostic and statistical manual of mental disorders
  2. Yakovlev, 1967, Regional development of the brain in early life, 3
  3. Kretschmann, 1986, Brain growth, 1
  4. Marsh, 2008, Handbook of developmental cognitive neuroscience, 717
  5. Rachman, 1980, Obsessions and compulsions
  6. Mega, 2001, The frontal lobes and neuropsychiatric illness, 15
  7. Talairach, 1949, Recherches sur la coagulation thérapeutique des structures sous-corticales chez l'homme, Revue Neurologique, 81, 4

Cited by

Sorted by citations

Related

Authors
Maia, T. V., Cooney, R. E., & Peterson, B. S.
Affiliations
New York State Psychiatric Institute (US)
Corresponding author
Peterson, Bradley S.
ORCID
Venue
Development and Psychopathology
Publisher
Cambridge University Press (CUP)
Published
2008
Volume
20
Issue
4
Pages
1251-1283
ISSN
  • 0954-5794 (ISSN-L)
  • 1469-2198
DOI
10.1017/s0954579408000606
PMC
PMC3079445
OpenAlex
W2125861950
Cited by
362
References
318
Citations by year
2026: 19 · 2025: 25 · 2024: 26 · 2023: 23 · 2022: 25 · 2021: 25 · 2020: 21 · 2019: 27 · 2018: 16 · 2017: 22 · 2016: 11 · 2015: 22 · 2014: 19 · 2013: 24 · 2012: 22
FWCI
1.95
Type
journal article
Language
en
Open access
Licence
www.cambridge.org/core/terms (unspecified, 280 d)
Locations
  • Development and Psychopathology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5k02mh074677-05)
  • U.S. Public Health Service (NIMH K02 74677)
  • National Institute of Mental Health (2 T32 MH 16434, T32MH016434, R01MH068318, MH 068318, K02-MH-074677)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
Keywords
obsessive-compulsive disorder, orbitofrontal cortex, anterior cingulate cortex, caudate nucleus, cortico-basal ganglia-thalamo-cortical loop, brain injury, PANDAS, pediatric autoimmune neuropsychiatric disorders, neurosurgical lesions, causal inference, pathogenesis, children
MeSH terms
Adult, Brain, Brain Mapping, Child, Cognition, Humans, Magnetic Resonance Imaging, Models, Biological, Obsessive-Compulsive Disorder, Reproducibility of Results, Prevalence, Age of Onset

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.

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