Disorder‐specific inferior prefrontal hypofunction in boys with pure attention‐deficit/hyperactivity disorder compared to boys with pure conduct disorder during cognitive flexibility

May combine two claims.

Across all subjects, switch trials produced more errors and slower reaction times than repeat trials.

“Repeated measures ANOVA with trial type as within‐subject variable and group as dependent variable showed that within all subjects there was a significant linear effect of trial type on errors and reaction times, with all subjects making more errors and having slower reaction times during the switch compared to the repeat trials [F(1,45) = 45; P < 0.0001 for both reaction time and errors].”

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

All participants were slower and made more errors during Switch trials.

“Although all participants were slower and made more errors during Switch trials”

May combine two claims.

CD patients activated right medial frontal, pre/postcentral gyri, inferior/superior parietal lobes, and left inferior parietal and pre/postcentral gyri.

“Patients with CD activated right medial frontal, pre and postcentral gyri, and inferior/superior parietal lobes, and left‐inferior parietal and pre and postcentral gyri.”

May combine two claims.

The visual-spatial switch task only elicited performance deficits and brain underactivation in inferior prefrontal cortex in the ADHD compared to the healthy or CD groups.

“only elicited performance deficits and brain underactivation in inferior prefrontal cortex in the ADHD compared to the healthy or CD groups.”

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

CD patients showed disorder-specific activation reductions in paralimbic system regions (orbitofrontal cortex during reward, insula/hippocampus/anterior cingulate during sustained attention, superior temporal lobe during motor inhibition).

“CD patients, on the other hand, demonstrated disorder‐specific activation reductions of the paralimbic system, such as the orbitofrontal cortex during reward [Rubia et al., 2009c], the insula, hippocampus, and anterior cingulate during sustained attention [Rubia et al., 2009c] and the superior temporal lobe during motor inhibition [Rubia et al., 2008].”

• cites Rubia et al., 2009cNot checked yet

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• cites Rubia et al., 2008Not checked yet

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

One fMRI study of cognitive flexibility in CD children with psychopathic traits during a reversal task found abnormally enhanced ventromedial orbitofrontal activation during errors.

“Only one fMRI study, however, has investigated the neurofunctional substrates of cognitive flexibility in the CD subtype of children with psychopathic traits during a reversal task, finding abnormally enhanced ventromedial orbitofrontal activation during errors in the task [Finger et al., 2008].”

• cites Finger et al., 2008Not checked yet

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

Prior studies observed enhanced, presumably compensatory cerebellar activation in ADHD that was reduced in CD.

“We also observed enhanced, presumably compensatory activation in the cerebellum in children with ADHD that was reduced in children with CD [Rubia et al., 2009c].”

• cites Rubia et al., 2009cNot checked yet

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

Children with CD and callous-unemotional traits showed reduced amygdala and hippocampus activation during processing of fearful facial expressions compared to healthy children.

“In two more recent studies, children with CD and callous‐unemotional traits showed reduced amygdala and hippocampus activation during the processing of fearful facial expressions compared to healthy children [Jones et al., 2009; Marsh et al., 2008].”

• cites Jones et al., 2009Not checked yet

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• cites Marsh et al., 2008Not checked yet

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May combine two claims.

The majority of fMRI studies in CD have been on emotion-processing tasks, finding abnormal activation in limbic and paralimbic regions.

“The majority of fMRI studies in CD, however, have been on emotion‐processing tasks, finding abnormal activation in limbic and paralimbic regions.”

• cites Sterzer et al., 2005Not checked yet

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• cites Jones et al., 2009Not checked yet

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• cites Marsh et al., 2008Not checked yet

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

Structural studies have found reduced volume and gray matter of temporal and orbitofrontal cortices in children with CD.

“Thus, structural studies have found reduced volume and gray matter of the temporal and orbitofrontal cortices in children with CD [Huebner et al., 2008; Kruesi et al., 2004].”

• cites Huebner et al., 2008Not checked yet

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• cites Kruesi et al., 2004Not checked yet

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

Children with CD showed more pronounced deactivation in right dorsal anterior cingulate gyrus during viewing of negative valence pictures.

“Thus, children with CD have shown to have more pronounced deactivation in right dorsal anterior cingulate gyrus during the viewing of pictures with negative valence, which was interpreted by the authors as reduced inhibition of emotional behavior [Sterzer et al., 2005].”

• cites Sterzer et al., 2005Not checked yet

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May combine two claims.

Cognitive switching activates ventrolateral prefrontal brain regions, which are impaired in ADHD and with some evidence in CD during cognitive flexibility tasks.

“Furthermore, cognitive switching has been shown to activate ventrolateral prefrontal brain regions [Derrfuss et al., 2005; Rubia et al., 2006; Smith et al., 2004] that are known to be impaired in children with ADHD [Dickstein et al., 2006; Rubia et al., 1999, 2005b, 2008; Smith et al., 2006] with some evidence for impairment in children with CD during tasks of cognitive flexibility [Finger et al.,”

• cites Derrfuss et al., 2005Not checked yet

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• cites Rubia et al., 2006Not checked yet

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• cites Smith et al., 2004Not checked yet

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

CD overlaps clinically, behaviorally, and cognitively with ADHD.

“Conduct disorder (CD) is defined by the violation of the rights of others and societal rules (DSM IV) [American Psychiatric Association, 1994]; it overlaps clinically, behaviorally, and cognitively with ADHD.”

• cites Banaschewski et al., 2005Not checked yet

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• cites Spencer et al., 1999Not checked yet

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Classified as probably not a substantial claim.

Few studies have compared the neurofunctional substrates between ADHD and CD.

“Few studies have compared the neurofunctional substrates between the two disorders.”

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

Prior fMRI studies of motor and interference inhibition in ADHD found predominantly frontostriatal underactivations.

“Although many functional magnetic resonance imaging (fMRI) studies have used tasks of motor and interference inhibition, finding predominantly frontostriatal underactivations [Dickstein et al., 2006; Durston et al., 2003, 2006; Rubia et al., 1999, 2005]”

• cites Dickstein et al., 2006Not checked yet

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• cites Durston et al., 2003, 2006Not checked yet

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• cites Rubia et al., 1999, 2005Not checked yet

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

In CD, anterior cingulate deactivation correlated negatively with aggressive behavior scores and remained when controlling for attention scores.

“The anterior cingulate deactivation furthermore correlated negatively with the aggressive behavior scores and remained when controlling for attention scores [Sterzer et al., 2005].”

• cites Sterzer et al., 2005Not checked yet

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

About 30% of children with CD have comorbid ADHD, rising to up to 50% when ODD is also present.

“About 30% of children with CD have comorbidity with ADHD, which can reach up to 50%, when oppositional defiant disorder (ODD) is also present [Banaschewski et al., 2005; Spencer et al., 1999].”

• cites Banaschewski et al., 2005Not checked yet

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• cites Spencer et al., 1999Not checked yet

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May combine two claims.

Only one previous study (Smith et al., 2006) investigated neural substrates of cognitive switching in ADHD, reporting reduced activation in bilateral inferior prefrontal and temporoparietal regions.

“to our knowledge, only a previous study from our own group has investigated the neural substrates of cognitive switching in ADHD patients, reporting reduced activation in bilateral inferior prefrontal and temporoparietal brain regions [Smith et al., 2006].”

• cites Smith et al., 2006Not checked yet

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

Structural and functional studies have shown abnormalities of the paralimbic system (orbitofrontal cortex, superior temporal lobe, limbic regions) in CD.

“Structural and functional studies have shown abnormalities of the paralimbic system that comprises the orbitofrontal cortex, superior temporal lobe, and underlying limbic brain regions, known to mediate emotion and motivation [Blair et al., 2006].”

• cites Blair et al., 2006Not checked yet

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

Limbic volume reductions have been observed in hippocampus, insula, and amygdala in CD.

“Limbic volume reductions have been observed in the hippocampus, the insula, and the amygdala [Huebner et al., 2008; Sterzer et al., 2004].”

• cites Huebner et al., 2008Not checked yet

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• cites Sterzer et al., 2004Not checked yet

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

Two studies comparing CD children with psychopathic traits to ADHD and controls found enhanced orbitofrontal activation during errors in a reversal task and reduced amygdala activation during fear.

“Two studies compared the CD subgroup of severely disruptive children with psychopathic traits with children with ADHD as well as controls; one found enhanced orbitofrontal activation compared to healthy and ADHD children during errors in a reversal task [Finger et al., 2008] and the other reduced amygdala activation during fear [Marsh et al., 2008].”

• cites Finger et al., 2008Not checked yet

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• cites Marsh et al., 2008Not checked yet

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May combine two claims.

There were no significant group or group × motion effects in head movement.

“Repeated measures ANOVA showed no significant group or group × motion effects in the extent of three‐dimensional motion in x, y, and z translation and rotation.”

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

Deficits in children with CD seem to be more consistently observed during reversal tasks that involve reward processing.

“Deficits seem to be more consistently observed during reversal tasks that involve reward processing [Aronowitz et al., 1994; Budhani and Blair, 2005; Fisher and Blair, 1998]”

• cites Aronowitz et al., 1994Not checked yet

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• cites Budhani and Blair, 2005Not checked yet

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• cites Fisher and Blair, 1998Not checked yet

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May combine two claims.

Previous findings showed disorder-specific underactivations in the same patients with CD when compared with a larger group of ADHD patients and controls in the orbitofrontal cortex during reward, in limbic and paralimbic regions during sustained attention, and in superior temporal and inferior parietal lobes during inhibition failures.

“It differs from our previous findings of disorder‐specific underactivations in the same patients with CD when compared with a larger group of ADHD patients and controls in the orbitofrontal cortex during reward, in limbic and paralimbic regions during sustained attention [Rubia et al., 2009c], and in superior temporal and inferior parietal lobes during inhibition failures [Rubia et al., 2008].”

• cites Rubia et al., 2009cNot checked yet

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• cites Rubia et al., 2008Not checked yet

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

The fMRI analysis method (XBAM) uses median statistics and permutation-based inference, making no normality assumptions, and allows a mixed effects approach.

“This method of analysis makes no normality assumptions, which are usually violated in fMRI data, but instead uses median statistics to control outlier effects and permutation rather than normal theory based inference. Furthermore, the most common test statistic is computed by standardizing for individual difference in residual noise before embarking on second level, multisubject testing using”

• cites Thirion et al., 2007Not checked yet

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

The largest study did not find deficits in the more difficult WCST in children with CD.

“and the largest study did not find deficits in the more difficult WCST [Klorman et al., 1999].”

• cites Klorman et al., 1999Not checked yet

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May combine two claims.

The findings extend previous evidence for disorder-specificity of inferior prefrontal dysfunction in patients with ADHD compared to CD to another domain of cognitive control and suggest that inferior prefrontal dysfunction may be a disorder-specific neurofunctional biomarker of ADHD that is pervasive across cognitive control tasks.

“The findings of this study therefore extend our previous evidence for disorder‐specificity of inferior prefrontal dysfunction in patients with ADHD compared to CD to yet another domain of cognitive control and hence suggest that inferior prefrontal dysfunction may be a disorder‐specific neurofunctional biomarker of ADHD that is pervasive across cognitive control tasks.”

Classified as probably not a substantial claim.

Reversal tasks that involve reward processing are mediated by the orbitofrontal cortex.

“known to be mediated by the orbitofrontal cortex [Rolls, 2000]”

• cites Rolls, 2000Not checked yet

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May combine two claims.

Interference inhibition in the Simon task and attention allocation seem not to be key dysfunctions in patients with CD.

“Like with cognitive switching, interference inhibition in the Simon task and attention allocation seem not to be key dysfunctions in patients with CD [Banaschewski et al., 2005; Herba et al., 2006].”

• cites Banaschewski et al., 2005Not checked yet

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• cites Herba et al., 2006Not checked yet

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May combine two claims.

Left and right inferior prefrontal cortex has consistently been found to be underactivated in children with ADHD compared to healthy controls during the same switch task as well as during other tasks of inhibitory control.

“Left and right inferior prefrontal cortex has consistently been found to be underactivated in children with ADHD compared to healthy controls during the same switch task [Smith et al., 2006] as well as during other tasks of inhibitory control [Dickstein et al., 2006; Durston et al., 2006; Pliszka et al., 2006; Rubia et al., 1999, 2005].”

• cites Smith et al., 2006Not checked yet

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• cites Dickstein et al., 2006Not checked yet

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• cites Durston et al., 2006Not checked yet

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

The permutation-based methods used are more suitable for fMRI data analysis in samples similar to ours.

“Instead of relying on asymptotic distributions such as t or F that assume data normality, we use data‐driven, permutation‐based methods with minimal distributional assumptions that have been shown to be more suitable for fMRI data analysis in samples sizes similar to the ours [Zhang et al., 2009].”

• cites Zhang et al., 2009Not checked yet

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

No deficits in cognitive switching were found in children with CD in simpler visual spatial switching tasks.

“No deficits were found in simpler visual spatial switching tasks [Blair, 2001]”

• cites Blair, 2001Not checked yet

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

Previous studies found enhanced Switch costs during the same task in younger children with ADHD but not in younger children with CD.

“we have previously found enhanced Switch costs during the same task in younger children with ADHD [Rubia et al., 2007b], but not in younger children with CD [Hobson, 2008].”

• cites Rubia et al., 2007bNot checked yet

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• cites Hobson, 2008Not checked yet

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Classified as probably not a substantial claim.

Switching tasks without reward elements are mediated by the inferior prefrontal cortex.

“rather than switching tasks without reward elements, that are mediated by the inferior prefrontal cortex [Derrfuss et al., 2005; Rubia et al., 2006; Smith et al., 2004].”

• cites Derrfuss et al., 2005Not checked yet

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• cites Rubia et al., 2006Not checked yet

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• cites Smith et al., 2004Not checked yet

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

Meta-analyses show that children with ADHD have difficulties with cognitive switching in more difficult switching tasks such as the Wisconsin Card Sorting task (WCST).

“Meta‐analyses show that children with ADHD have difficulties with cognitive switching in more difficult switching tasks such as the Wisconsin Card Sorting task (WCST) [Willcutt et al., 2005].”

• cites Willcutt et al., 2005Not checked yet

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

Right and left inferior prefrontal cortex was also specifically underactivated in ADHD children when compared with healthy and OCD children during the same switching task and a response inhibition task.

“Right and left inferior prefrontal cortex was also specifically underactivated in ADHD children when compared with healthy and OCD children during the same switching task and a response inhibition task [Rubia et al., in press].”

• cites Rubia et al., in pressNot checked yet

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

All subjects were within acceptable limits for head movement (below 1.5 mm).

“All subjects were within acceptable limits for head movement (below 1.5 mm).”

May combine two claims.

Groups differed significantly in SDQ hyperactivity/inattention and conduct problems subscale scores, with ADHD scoring higher than controls and CD on hyperactivity/inattention, and CD scoring higher than controls and ADHD on conduct problems.

“As expected, groups differed significantly in the hyperactivity/inattention and conduct problems subscale scores of the SDQ.”

• Also stated in: § METHODS · plain

  “Post hoc t‐test [corrected using least significance difference (LSD)] revealed that ADHD boys scored significantly higher than both controls and CD boys on the hyperactivity/inattention subscale. CD boys scored significantly higher on the conduct problems subscale than both control and ADHD boys (see Table I).”

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

The absence of switching deficits in ADHD children compared to controls in this study may be because the fMRI adaptation was easier than neuropsychological task versions, due to a higher number of repeat trials interspersed with switch trials to allow for hemodynamic separability of switch trials.

“In this study, we may not have found switching deficits in the ADHD children compared to controls, because the fMRI adaptation was easier than neuropsychological task versions, due to a higher number of repeat trials interspersed with switch trials to allow for hemodynamic separability of switch trials.”

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

Precuneus and cuneus are important areas for visual-spatial attention to saliency.

“and are important areas for visual–spatial attention to saliency [Mesulam et al., 2001; Small et al., 2003].”

• cites Mesulam et al., 2001Not checked yet

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• cites Small et al., 2003Not checked yet

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

The parietal lobes are thought to mediate visual-spatial executive attention, necessary for cognitive switching.

“The parietal lobes are thought to mediate visual–spatial executive attention, necessary for cognitive switching [Rushworth, 2006; Smith et al., 2004].”

• cites Rushworth, 2006Not checked yet

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• cites Smith et al., 2004Not checked yet

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

We did not test for psychopathic traits, as our sample would have been too small for further subtype analyses.

“We did not test for psychopathic traits, as our sample would have been too small for further subtype analyses.”

Classified as probably not a substantial claim.

CD is considered a highly heterogeneous disorder.

“CD is considered a highly heterogenous disorder [Frick and Ellis, 1999]”

• cites Frick and Ellis, 1999Not checked yet

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

Reduced temporoparietal and precuneus/posterior cingulate activation is a consistent finding in ADHD patients during tasks that require visual-spatial attention to saliency such as reward, error monitoring, and oddball tasks.

“Reduced temporoparietal and precuneus/posterior cingulate activation is a consistent finding in ADHD patients during tasks that require visual–spatial attention to saliency such as reward, error monitoring, and oddball tasks [Rubia et al., 2005, 2007a, 2008, 2009a, b, c; Stevens et al., 2007; Tamm et al., 2006]”

• cites Rubia et al., 2005Not checked yet

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• cites Stevens et al., 2007Not checked yet

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• cites Tamm et al., 2006 sourceNot checked yet

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

A limitation of this study is the relatively small subject numbers.

“A limitation of this study is the relatively small subject numbers.”

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

This deficit in reduced temporoparietal and precuneus/posterior cingulate activation may be shared with CD.

“and it appears that this deficit may be shared with CD.”

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

It is conceivable that disruptive patients with psychopathic traits show different neurobiological abnormalities than those with predominant impulsive-aggressive traits during cognitive switching.

“It is conceivable, however, that disruptive patients with psychopathic traits show different neurobiological abnormalities than those with predominant impulsive‐aggressive traits during cognitive switching.”

• AssumptionThe authors state this as an assumption: Patients in this study exhibited overt rather than just covert antisocial behavior and would fit criteria for the impulsive-aggressive subtype of CD.

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

The temporal lobe has been found to be reduced in size in children with CD and associated with aggression.

“The temporal lobe has been found to be reduced in size in children with CD [Huebner et al., 2008; Kruesi et al., 2004] and been associated with aggression [Herzberg and Fenwick, 1988].”

• cites Huebner et al., 2008Not checked yet

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• cites Kruesi et al., 2004Not checked yet

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• cites Herzberg and Fenwick, 1988Not checked yet

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

A typical design feature of cognitive switching tasks is that switch trials are typically less in number than repeat trials.

“A typical design feature of cognitive switching tasks is that switch trials are typically less in number than repeat trials.”

Classified as probably not a substantial claim.

In this study, the childhood-onset CD subtype was tested to maximize homogeneity.

“and, in this study, we have tested the childhood‐onset CD subtype to maximize homogeneity.”

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

A weakness of the activation in the temporoparietal junction could possibly be related to visual-spatial executive attention deficits in patients with CD.

“A weakness of the activation in the temporoparietal junction could possibly be related to visual–spatial executive attention deficits in patients with CD.”

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

Shared abnormal precuneus activation has also been observed in children with psychopathic traits and with ADHD during errors in a reversal task.

“Shared abnormal precuneus activation has also been observed in children with psychopathic traits and with ADHD during errors in a reversal task [Finger et al., 2008].”

• cites Finger et al., 2008Not checked yet

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

Other subtypes of CD have been suggested, such as those associated with predominant psychopathic and those with predominant impulsive-aggressive traits.

“Other subtypes, however, have been suggested, such as those associated with predominant psychopathic and those with predominant impulsive‐aggressive traits [Frick and Ellis, 1999].”

• cites Frick and Ellis, 1999Not checked yet

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May combine two claims.

The findings extend previous findings of disorder specificity of these brain regions in ADHD patients when compared with patients with CD during three other executive function tasks, of sustained attention, and of motor and interference inhibition, and when compared with patients with OCD during the same task.

“This extends our previous findings of disorder specificity of these brain regions in ADHD patients when compared with patients with CD during three other executive function tasks, of sustained attention, and of motor and interference inhibition [Rubia et al., 2008, 2009b, c] and when compared with patients with OCD during the same task [Rubia et al., in press].”

• cites Rubia et al., 2008Not checked yet

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• cites Rubia et al., 2009bNot checked yet

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• cites Rubia et al., in pressNot checked yet

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

Abnormal activation in relation to switch trials in the patient groups could therefore potentially at least in part also reflect abnormalities in visual-spatial attention allocation systems.

“Abnormal activation in relation to switch trials in the patient groups could therefore potentially at least in part also reflects abnormalities in visual–spatial attention allocation systems.”