Altered inhibition-related frontolimbic connectivity in obsessive–compulsive disorder

May combine two claims.

Mean connection strength was positive in patients and controls but negative in siblings.

“The mean connection strength was positive in patients with obsessive-compulsive disorder and controls, but was negative in siblings.”

May combine two claims.

BMS did not identify a winning model in healthy controls; several models with bottom-up connections had equally high exceedance probabilities.

“Results of the BMS did not reveal a winning model in the healthy control group, as the exceedance probabilities for multiple models that included bottom-up connections were equally high (see Supporting Information Table S3 and Fig. S1), indicating multiple winning models in this group.”

May combine two claims.

SSRT was significantly longer in patients than controls, while siblings did not differ from either group.

“As reported previously [de Wit et al., 2012], SSRT was significantly increased in patients compared to controls (t 5 2.07, P 5 0.04), whereas siblings did not differ in SSRT from both patients and controls.”

• cites de Wit et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

In siblings, the same relationship appeared (r = -0.650, P = 0.005), but after removing an outlier it was only trend-level (r = -0.459, P = 0.074).

“The relationship between IFG-amygdala connectivity and pre-SMA activity was also seen in siblings (r 5 20.650, P 5 0.005), but was after removal of an outlier only seen at trend-level (r 5 20.459, P 5 0.074).”

May combine two claims.

In siblings, the winning model had bidirectional IFG-amygdala connections in both hemispheres (exceedance probability 28%); the patients' winning model was only slightly worse in siblings (21%).

“In siblings, the winning model included bidirectional connections between the IFG and amygdala in both hemispheres (see Supporting Information Fig S1) and had an exceedance probability of 28%.However, the winning model for patients (i.e., top-down connection in the left hemisphere) was only slightly worse in siblings, with an exceedance probability of 21%.”

• AssumptionThe authors state this as an assumption: Parallel connections between the same regions across hemispheres were assumed to be bidirectional in every model.

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

The IFG and pre-SMA are essential for response inhibition and appear to initiate the neural stop signal.

“The inferior frontal gyrus (IFG) and presupplementary motor area (pre-SMA) are crucial for response inhibition [Chambers et al., 2006;Chen et al., 2009] and appear to initiate the neural stop signal [Aron, 2011].”

• cites Chambers et al., 2006Not checked yet

  Not checked in the free run.

• cites Chen et al., 2009Not checked yet

  Not checked in the free run.

• cites Aron, 2011Not checked yet

  Not checked in the free run.

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

The authors previously reported reduced activation in the right inferior parietal cortex and right IFG in OCD patients during a response inhibition task.

“We have also previously reported decreased activation of the right inferior parietal and right IFG in OCD patients during performance of a response inhibition task [ de Wit et al., 2012].”

• cites de Wit et al., 2012Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Neurobiological models of OCD implicate dysfunction in frontal-striatal, frontoparietal, and frontolimbic circuits in the disorder's etiology.

“Current neurobiological models implicate dysfunction of frontal-striatal, frontoparietal and frontolimbic circuits in the etiology of this disorder [Milad and Rauch, 2012;van den Heuvel et al., in press].”

• cites Milad and Rauch, 2012Not checked yet

  Not checked in the free run.

• cites van den Heuvel et al., in pressNot checked yet

  Not checked in the free run.

May combine two claims.

The authors previously found greater task-related left pre-SMA activation in OCD patients and their siblings, suggesting compensatory pre-SMA hyperactivity may be an endophenotype of OCD.

“We additionally found increased task-related activation of the left pre-SMA in OCD patients and their siblings, indicating that compensatory pre-SMA hyperactivity during response inhibition may be an endophenotype of obsessive-compulsive disorder.”

• cites de Wit et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Patients with OCD exhibit impaired response inhibition, shown by more commission errors on go/no-go tasks and longer stop signal reaction times on the stop signal task.

“Studies have shown response inhibition deficits in patients with this disorder, as indicated by increased commission errors during go-no go task performance [Bannon et al., 2002] and increased stop signal reaction times (SSRT) in the stop signal task [Chamberlain et al., 2006].”

• cites Bannon et al., 2002Not checked yet

  Not checked in the free run.

• cites Chamberlain et al., 2006Not checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Impaired response inhibition may underlie repetitive behaviors such as compulsions.

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

Those models posit an imbalance among affective, cognitive, and sensorimotor CSTC circuits, plus altered connectivity linking these circuits with the amygdala.

“The models propose an imbalance between interacting affective, cognitive, and sensorimotor corticostriato-thalamo-cortical (CSTC) circuits, and altered connectivity between these circuits and the amygdala [Milad and Rauch, 2012;van den Heuvel et al., in press].”

• cites Milad and Rauch, 2012Not checked yet

  Not checked in the free run.

• cites van den Heuvel et al., in pressNot checked yet

  Not checked in the free run.

May combine two claims.

Unaffected siblings of OCD patients also show response inhibition deficits, which suggests the impairment is state-independent and supports it as a neurocognitive endophenotype of OCD.

“Deficits in response inhibition have also been observed in unaffected siblings of patients with obsessive-compulsive disorder, suggesting that the response inhibition impairment is state-independent and strengthening the notion of impaired response inhibition as a neurocognitive endophenotype of obsessive-compulsive disorder [Chamberlain et al., 2007].”

• cites Chamberlain et al., 2007Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

In healthy people, the amygdala contributes to motor inhibition triggered by threat.

“Studies in healthy samples showed that the amygdala plays a role in motor inhibition in response to threat [Sagaspe et al., 2011]”

• cites Sagaspe et al., 2011Not checked yet

  Not checked in the free run.

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

No correction for multiple comparisons was applied in the DCM analyses, to reduce the risk of type-2 errors.

“To also reduce the risk for type-2 errors, we used no correction for multiple comparisons in the DCM analyses.”

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

Prior work has suggested that the amygdala may mediate detection of salient or goal-relevant stimuli, or vigilance to uncertain events such as the stop signal.

“This is in line with previous suggestions that detection of salient or goalrelevant stimuli (in this case the stop signal) or vigilance in response to uncertain events (the presentation of the stop signal) may be mediated by the amygdala”

• cites Davis and Whalen, 2001Not checked yet

  Not checked in the free run.

• cites Schaefer et al., 2006Not checked yet

  Not checked in the free run.

• cites Schaefer and Gray, 2007Not checked yet

  Not checked in the free run.

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

The IFG is essential for response inhibition and participates in detecting the stop signal and generating inhibitory output.

“The inferior frontal gyrus is crucial for response inhibition [Chambers et al., 2006] and is involved in both the detection of the stop signal and generation of inhibitory output [Chikazoe et al., 2009;Levy and Wagner, 2011].”

• cites Chambers et al., 2006Not checked yet

  Not checked in the free run.

• cites Chikazoe et al., 2009Not checked yet

  Not checked in the free run.

• cites Levy and Wagner, 2011Not checked yet

  Not checked in the free run.

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

The met allele of the COMT gene has been associated with increased connectivity between the amygdala and orbitofrontal cortex during processing of emotional stimuli.

“and increased connectivity between the amygdala and orbitofrontal cortex [Rasch et al., 2010]”

• cites Rasch et al., 2010Not checked yet

  Not checked in the free run.

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

In healthy people, the amygdala contributes to detecting behaviorally relevant or salient stimuli in cognitive tasks.

“and in the detection of behaviorally relevant or salient stimuli in other cognitive tasks [Kiehl et al., 2005;Ousdal et al., 2008].”

• cites Kiehl et al., 2005Not checked yet

  Not checked in the free run.

• cites Ousdal et al., 2008Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

For the PPI analysis, results were considered significant after multiple-testing correction at P < 0.0001723.

“For the PPI analysis, results survive correction for multiple testing if P 0.0001723.”

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

In the DCM subset, groups remained matched on demographic measures and performance, but included siblings were significantly younger than excluded siblings.

“Groups were still matched for demographic measures and performance, siblings included in the DCM analysis were significantly younger (mean age 33.2; standard deviation 10.87) than siblings not included in the DCM analysis (mean age 50.54; standard deviation 11.15) (t[15] 5 2.975, P 5 0.009, see Supporting Information Table S3).”

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

The met allele of the COMT gene has been associated with increased connectivity between the amygdala and inferior frontal gyrus during processing of emotional stimuli.

“and between the amygdala and IFG [Drabant et al., 2006] during processing of emotional stimuli.”

• cites Drabant et al., 2006Not checked yet

  Not checked in the free run.

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

The met allele of the COMT gene has been associated with increased extracellular dopamine levels.

“Furthermore, the met allele of the COMT gene has been associated with increased extracellular dopamine levels [Lachman et al., 1996]”

• cites Lachman et al., 1996Not checked yet

  Not checked in the free run.

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

Although many studies link inhibition to the right IFG, the left IFG also appears involved.

“Although many studies implicate the right IFG in inhibition, the left IFG seems also involved [Duann et al., 2009;Swick et al., 2008].”

• cites Duann et al., 2009Not checked yet

  Not checked in the free run.

• cites Swick et al., 2008Not checked yet

  Not checked in the free run.

May combine two claims.

Both right and left IFG have been found hypoactive during response inhibition in OCD patients, possibly reflecting reduced attention to the stop signal or impaired generation of the neural stop signal.

“Both the right IFG [Page et al., 2009;de Wit et al., 2012;Woolley et al., 2008] and left IFG [Maltby et al., 2005;Page et al., 2009] have been found to be hypoactive during response inhibition in patients with obsessive-compulsive disorder, which may reflect decreased attention allocation to the stop signal or an impairment in generating the neural stop signal.”

• cites Page et al., 2009Not checked yet

  Not checked in the free run.

• cites de Wit et al., 2012Not checked yet

  Not checked in the free run.

• cites Woolley et al., 2008Not checked yet

  Not checked in the free run.

May combine two claims.

Over half of the patients met criteria for at least one additional axis-I disorder, but comorbid disorders were not associated with task performance or OCD severity.

“More than half of the patients also met criteria for one or more other axis-I disorders (54%), but the presence of comorbid disorders was not associated with task performance or obsessive-compulsive disorder severity.”

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

Some studies have found increased amygdala activation in obsessive-compulsive disorder during decision making and processing of emotional faces or disease-relevant emotional stimuli.

“and increased amygdala activation during decision making and processing of emotional faces or disease-relevant emotional stimuli [Cardoner et al., 2011;Stern et al., 2013;van den Heuvel et al., 2004].”

• cites Cardoner et al., 2011Not checked yet

  Not checked in the free run.

• cites Stern et al., 2013Not checked yet

  Not checked in the free run.

• cites van den Heuvel et al., 2004Not checked yet

  Not checked in the free run.

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

Previous studies have shown altered brain activation in response to salient stimuli using oddball tasks in patients with obsessive-compulsive disorder.

“Previous studies strengthen this notion by showing altered brain activation in response to salient stimuli using oddball tasks in patients with obsessive-compulsive disorder [Kim et al., 2003;Rubia et al., 2011].”

• cites Kim et al., 2003Not checked yet

  Not checked in the free run.

• cites Rubia et al., 2011Not checked yet

  Not checked in the free run.

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

OCD patients had higher depression scores than controls.

“Patients with obsessive-compulsive disorder scored higher on clinical measures of depression than controls (Montgomery-A ˚sberg Depression Rating Scale scores: patients: mean 11.5 (8.1); siblings: mean 1.9 (3.5); controls: mean 0.8 (1.0) (F[2,92] 5 0.26, P < 0.001).”

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

Some studies have found structural abnormalities of the amygdala in obsessive-compulsive disorder.

“Some studies, however, have observed structural abnormalities of the amygdala in obsessive-compulsive disorder [Kwon et al., 2003;Szeszko et al., 1999]”

• cites Kwon et al., 2003Not checked yet

  Not checked in the free run.

• cites Szeszko et al., 1999Not checked yet

  Not checked in the free run.

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

Studies have shown that the limbic system, including the amygdala, is involved in obsessive-compulsive disorder.

“system, including the amygdala [Admon et al., 2012;Cardoner et al., 2011;Milad and Rauch, 2012] in the disorder.”

• cites Admon et al., 2012Not checked yet

  Not checked in the free run.

• cites Cardoner et al., 2011Not checked yet

  Not checked in the free run.

• cites Milad and Rauch, 2012Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Prior work has suggested that the amygdala may send modulatory signals to the cortex that affect attention allocation or cause behavioral adaptation.

“and that the amygdala may send modulatory signals to the cortex affecting attention allocation or causing behavioral adaptation [Davis and Whalen, 2001;Schaefer et al., 2006;Schaefer and Gray, 2007].”

• cites Davis and Whalen, 2001Not checked yet

  Not checked in the free run.

• cites Schaefer et al., 2006Not checked yet

  Not checked in the free run.

• cites Schaefer and Gray, 2007Not checked yet

  Not checked in the free run.

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

In OCD patients, resting-state connectivity is greater between the right middle cingulate cortex and right parahippocampal cortex, and between the right middle cingulate cortex and left caudate; middle cingulate-parahippocampal connectivity correlates negatively with SSRT.

“This group found greater connectivity between the right middle cingulate cortex and right parahippocampal cortex, and between the right middle cingulate cortex and left caudate at rest in patients with obsessive-compulsive disorder.Connectivity between the middle cingulate cortex and the parahippocampal cortex correlated negatively with SSRT.”

• cites Kang et al., 2013Not checked yet

  Not checked in the free run.

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

Previous imaging genetics studies in obsessive-compulsive disorder showed that the dopamine receptor D2 polymorphism is associated with altered functional connectivity between the amygdala and the dorsolateral prefrontal cortex during emotional processing.

“Previous imaging genetics studies in obsessive-compulsive disorder showed that the dopamine receptor D2 polymorphism is associated with altered functional connectivity between the amygdala and the dorsolateral prefrontal cortex during emotional processing [Blasi et al., 2009].”

• cites Blasi et al., 2009Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

Altered IFG-amygdala connectivity in patients and siblings leads to inefficient frontal-striatal processing, producing compensatory task-related pre-SMA hyperactivation.

“We hypothesize that altered connectivity between the IFG and amygdala in patients and siblings leads to inefficient processing in frontal-striatal circuits, resulting in compensatory taskrelated hyperactivation of the pre-SMA.”

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

Both the dopamine receptor D2 gene and the COMT gene have been associated with obsessive-compulsive disorder in several studies.

“Both abovementioned genes have been associated with obsessive-compulsive disorder in several studies [Denys et al., 2006;Karayiorgou et al., 1997;Schindler et al., 2000].”

• cites Denys et al., 2006Not checked yet

  Not checked in the free run.

• cites Karayiorgou et al., 1997Not checked yet

  Not checked in the free run.

• cites Schindler et al., 2000Not checked yet

  Not checked in the free run.

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

A DCM study of the Stroop task found increased inhibition-related connectivity between the anterior cingulate cortex and dorsolateral prefrontal cortex in OCD patients.

“Another study examined connectivity during performance of a related inhibition task, the Stroop task, using dynamic causal modeling and found increased inhibitionrelated connectivity between the anterior cingulate cortex and the dorsolateral prefrontal cortex in patients with obsessive-compulsive disorder [Schl€ osser et al., 2010].”

• cites Schl€ osser et al., 2010Not checked yet

  Not checked in the free run.

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

Polymorphisms of the serotonin transporter gene affect fronto-limbic connectivity.

“Additionally, polymorphisms of the serotonin transporter gene affect fronto-limbic connectivity [Long et al., 2013;Surguladze et al., 2012]”

• cites Long et al., 2013Not checked yet

  Not checked in the free run.

• cites Surguladze et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

The participant groups were matched on age, gender, and educational level.

“To briefly summarize, participants were matched for age (patients: mean 38.6 y (standard deviation 9.8); siblings: mean 38.3 y (13.4); controls: mean 39.7 y (11.6); (F[2,92] =0.01, P 5 0.871), gender (patients: 21/41 males; siblings: 12/17 males; controls: 18/37 males); (v 2 5 2.4, P 5 0.297), and educational level”

Classified as probably not a substantial claim.

The present study used two complementary techniques, PPI and DCM, to assess functional connectivity.

“Strengths of the present study are the inclusion of medication-free subjects and use of two complementary techniques to assess functional connectivity (PPI and DCM).”

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

Polymorphisms of the serotonin transporter gene have been associated with obsessive-compulsive disorder.

“and have been associated with obsessive-compulsive disorder [Lin, 2007].”

• cites Lin, 2007Not checked yet

  Not checked in the free run.

May combine two claims.

The findings suggest that altered inferior frontal gyrus-amygdala connectivity in obsessive-compulsive disorder, and to a lesser extent in unaffected siblings, interferes with the task-related efficiency of the response inhibition network, resulting in compensatory pre-supplementary motor area hyperactivation.

“To conclude, our findings suggest that altered IFGamygdala connectivity in obsessive-compulsive disorder, and to a lesser extent in their unaffected siblings, interferes with the task-related efficiency of the response inhibition network resulting in compensatory pre-SMA hyperactivation.”

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

Because DCM used subject-specific regions of interest, not all subjects from the PPI analysis could be included in the DCM analysis, which may warrant replication in a larger sample.

“Because of the use of subject-specific regions of interest in DCM, not all subjects in the PPI analysis could be included in our DCM analysis, which may warrant replication in a larger sample.”