Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention‐deficit/hyperactivity disorder

The quote only partly states this claim.

The COI revealed a pattern of functional connectivity comprising the bilateral VLPFC (bilateral inferior frontal gyrus 47 and left BA 44), DLPFC (superior and middle frontal gyrus, BA 9), frontopolar cortex (middle frontal gyrus, BA 10), cingulate cortex (BA 24 and 32), superior frontal cortex (BA 6 and 8), inferior parietal lobule (BA 40), precuneus, striatum (putamen and caudate), right thalamus

“The COI revealed a pattern of functional connectivity comprising the bilateral VLPFC (bilateral inferior frontal gyrus 47 and left BA 44), the DLPFC (superior and middle frontal gyrus, BA 9), the frontopolar cortex (middle frontal gyrus, BA 10), the cingulate cortex (BA 24 and 32), the superior frontal cortex (BA 6 and 8), the inferior parietal lobule (BA 40), the precuneus, the striatum (putamen”

May combine two claims.

Regional activation differences between ADHD adults and healthy controls were confined to the delay period of the activation task and were not detected during the encoding or during the probe phase.

“Regional activation differences were confined to the delay period of the activation task and were not detected during the encoding or during the probe phase.”

May combine two claims.

Compared with healthy controls, ADHD adults showed lower activation during the delay period in the left VLPFC (BA 47), right insula, right middle occipital gyrus (BA 18), right medial frontal gyrus (BA 6), and right cerebellum.

“Delay period. Compared with healthy controls, ADHD adults showed lower activation of the left VLPFC (inferior frontal gyrus, BA 47), the right insula, the right middle occipital gyrus (BA 18), the right medial frontal gyrus (BA 6), and the right cerebellum; Figure 2 (right), see also Table IV for detailed stereotaxic coordinates and Z -scores.”

May combine two claims.

Lower activation in ADHD adults was found in the left VLPFC (BA 47) and the right cerebellum.

“As predicted, lower activation in ADHD adults was found in the left VLPFC (BA 47) and the right cerebellum.”

The quote only partly states this claim.

A similar parametric activation pattern to healthy controls was found in ADHD adults during the encoding period.

“A similar parametric activation pattern was found in ADHD adults; see also Supporting Information Figure S1a.”

The quote only partly states this claim.

Both groups showed a linearly increasing activation pattern with increasing WM processing during the delay period in bilateral brain regions including the VLPFC (BA 44, 45, 47), DLPFC (BA 9, 46, 10), cingulate gyrus (BA 24/32, 31), premotor cortex, supplementary motor area, insula, superior and inferior parietal lobule (BA 7 and 40), precuneus, middle and inferior temporal gyrus (BA 21 and 22),中间

“Delay period. Both groups showed a linearly increasing activation pattern with increasing WM processing in bilateral brain regions including the VLPFC (BA 44, 45, 47), the dorsolateral prefrontal cortex (DLPFC; BA 9, 46, 10), the cingulate gyrus (BA 24/32, 31), the premotor cortex, the supplementary motor area, the insula, the superior and inferior parietal lobule (BA 7 and 40), the precuneus, the”

May combine two claims.

ADHD adults included in this study did not differ from healthy controls with regard to IQ, years of education, and behavioral performance during a broad range of cognitive domains.

“The ADHD adults included in this study did not differ from healthy controls with regard to IQ, years of education, and behavioral performance during a broad range of cognitive domains, indicating well-preserved cognitive function and academic achievement similar to healthy controls as demonstrated by the fact that verbal and spatial WM, card sorting, and inhibition during the Stroop task were not”

May combine two claims.

ADHD adults did not significantly differ from healthy controls with respect to both RT and accuracy at higher WM load levels during fMRI.

“With regard to task performance during fMRI, ADHD adults did not significantly differ from healthy controls with respect to both RT and accuracy at higher WM load levels, in accordance with previous behavioral findings in adult ADHD patients during verbal WM performance [Hale et al., 2007; Valera et al., 2005].”

May combine two claims.

Verbal and spatial WM, card sorting, and inhibition during the Stroop task were not significantly impaired in the ADHD patient group compared with healthy controls.

“The ADHD adults included in this study did not differ from healthy controls with regard to IQ, years of education, and behavioral performance during a broad range of cognitive domains, indicating well-preserved cognitive function and academic achievement similar to healthy controls as demonstrated by the fact that verbal and spatial WM, card sorting, and inhibition during the Stroop task were not”

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

The stimuli were pseudorandomized and counterbalanced for the relative frequency of each letter per WM load, position, and probe.

“The stimuli were pseudorandomized and counterbalanced for the relative frequency of each letter per WM load, position, and probe.”

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

Valera et al. reported no activation differences in an a priori identified right prefrontal region and decreased activation in cerebellar regions during n-back task performance in a relatively large sample of ADHD adults.

“In contrast, Valera et al. reported no activation differences in an a priori identified right prefrontal region and decreased activation in cerebellar regions during n -back task performance in a relatively large sample of ADHD adults [Valera et al., 2005].”

• cites Valera et al., 2005Not checked yet

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

Differences between controls and ADHD patients on neuropsychological tests were assessed by eight separate t tests, and all t tests were Bonferroni-corrected to avoid alpha-error accumulation.

“Differences between controls and ADHD patients were assessed by calculating eight separate t tests ( P < 0.05). In order to avoid a -error accumulation, all t tests were Bonferroni-corrected ( P < 0.0064).”

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

In ADHD adults, increased activation in prefrontal areas associated with language processing was found in a recent fMRI study using the forward and backward digit span.

“In ADHD adults, increased activation in prefrontal areas associated with language processing was found in a recent functional magnetic resonance imaging (fMRI) study using the forward and backward digit span [Hale et al., 2007].”

• cites Hale et al., 2007Not checked yet

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Frontoparietal, striatal, and cerebellar activation abnormalities have been frequently reported during tasks that tap executive function including response inhibition and WM.

“In addition to the inferior frontal cortex, frontoparietal, striatal, and cerebellar activation abnormalities have been frequently reported during tasks that tap executive function including response inhibition and WM [Castellanos and Tannock, 2002; Clark et al., 2007; Dickstein et al., 2006].”

• cites Castellanos and Tannock, 2002Not checked yet

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• cites Clark et al., 2007Not checked yet

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• cites Dickstein et al., 2006Not checked yet

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Only a few functional imaging studies have attempted to examine the functional neuroanatomy underlying WM function in ADHD adults, yielding ambiguous results with regard to prefrontal and cerebellar activation abnormalities.

“Although WM dysfunction is recognized as an important cognitive correlate of the disorder, only a few functional imaging studies have attempted to examine the functional neuroanatomy underlying WM function in ADHD adults [Hale et al., 2007; Schweitzer et al., 2000; Valera et al., 2005], yielding ambiguous results with regard to prefrontal and cerebellar activation abnormalities”

• cites Hale et al., 2007Not checked yet

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• cites Schweitzer et al., 2000Not checked yet

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• cites Valera et al., 2005Not checked yet

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

The appearance of probes from the two immediately preceding trials was avoided in order to prevent proactive interference from preceding stimuli.

“The appearance of probes from the two immediately preceding trials was avoided in order to prevent proactive interference from preceding stimuli [Jonides et al., 1998].”

• cites Jonides et al., 1998Not checked yet

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The healthy control group consisted of 12 right-handed males matched for age, education and intelligence.

“The healthy control group was recruited from the University of Ulm campus and consisted of 12 right-handed males matched for age, education and intelligence.”

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

For between-group analyses, the statistical threshold was set at P < 0.005, and a spatial contiguity criterion of 25 adjacent voxels was used.

“Being a priori driven, the statistical threshold for this between-group comparison was set at P &lt; 0.005, and a spatial contiguity criterion of 25 adjacent voxels [Forman et al., 1995].”

• cites Forman et al., 1995Not checked yet

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To ensure diagnostic validity, additional information was collected from partners, relatives, friends, and from school report certificates.

“To ensure diagnostic validity, additional information was collected from partners, relatives, friends, and from school report certificates.”

Classified as probably not a substantial claim.

To account for interindividual variance and in order to generalize inferences, random-effects analyses were computed on the 2nd level.

“To account for interindividual variance and in order to generalize inferences, random-effects analyses were computed on the 2nd level [Holmes and Friston, 1998].”

• cites Holmes and Friston, 1998Not checked yet

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

ICA is a statistical technique that maximizes the independence between output components, thus identifying a set of spatially nonoverlapping and temporally synchronous brain networks.

“ICA is a statistical technique that maximizes the independence between the output components [Calhoun et al., 2001, 2004], thus identifying a set of spatially nonoverlapping and temporally synchronous brain networks.”

• cites Calhoun et al., 2001, 2004Not checked yet

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

ADHD patients were excluded if they had a current axis-I mood, substance-related, psychotic, or anxiety disorder and/or a concurrent axis-II disorder, a history of dependence on illicit drugs or alcohol, current psychotropic medication other than psychostimulants, or sensorimotor deficits or other neurological disorders.

“ADHD patients were excluded from participation if they (1) had a current axis-I mood, substance-related, psychotic, or anxiety disorder and/or a concurrent axis-II disorder according to DSM-IV”

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

In a PET study using a paced auditory serial addition task, task-related changes in rCBF in men without ADHD were more prominent in prefrontal and temporal regions.

“using positron emission tomography (PET) and a paced auditory serial addition task, Schweitzer et al. found that task-related changes in regional cerebral blood flow (rCBF) in men without ADHD were more prominent in prefrontal and temporal regions [Schweitzer et al., 2000].”

• cites Schweitzer et al., 2000Not checked yet

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

Controls were excluded if they had a current axis-I and/or concurrent axis-II disorder, a first-degree relative with a neurologic or psychiatric disorder, a history of dependence on illicit drugs or alcohol, current psychotropic medication, or sensorimotor deficits or other neurological disorders.

“Controls were excluded from participation if they (1) had a current axis-I and/or a concurrent axis-II disorder according to DSM-IV”

Classified as probably not a substantial claim.

All patients were diagnosed by an experienced consultant in psychiatry.

“All patients were diagnosed by an experienced consultant in psychiatry (C.J.).”

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

WM function has been widely studied on the behavioral level in children and adults with ADHD, showing both verbal and spatial WM deficits in affected individuals.

“WM function has been widely studied on the behavioral level in children and adults with ADHD, showing both verbal and spatial WM deficits in affected individuals [Dowson et al., 2004; Lui and Tannock, 2007; Martinussen et al., 2005].”

• cites Dowson et al., 2004Not checked yet

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• cites Lui and Tannock, 2007Not checked yet

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• cites Martinussen et al., 2005Not checked yet

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The estimation of the number of independent components performed directly on the data has been proven to effectively reduce the occurrence of over/underfitting the data.

“The estimation of the number of the ICs performed directly on the data has been proven to effectively reduce the occurrence of over/underfitting the data [Li et al., 2007].”

• cites Li et al., 2007Not checked yet

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Brain activation abnormalities of the VLPFC, the anterior cingulate, and the cerebellum in children with ADHD have been associated with a deficit in inhibitory control.

“Specifically, brain activation abnormalities of the ventrolateral prefrontal cortex (VLPFC), the anterior cingulate, and the cerebellum in children with ADHD have been associated with a deficit in inhibitory control [Durston et al., 2006; Schulz et al., 2004; Tauscher et al., 2002].”

• cites Durston et al., 2006Not checked yet

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• cites Schulz et al., 2004Not checked yet

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• cites Tauscher et al., 2002Not checked yet

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May combine two claims.

These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing.

“These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing.”

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

Functional activation changes of the VLPFC have been associated with ADHD symptom persistence and genetic vulnerability for ADHD.

“With regard to the VLPFC, functional activation changes of this region have been associated with ADHD symptom persistence [Schulz et al., 2005] and genetic vulnerability for ADHD [Durston et al., 2006].”

• cites Schulz et al., 2005Not checked yet

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• cites Durston et al., 2006Not checked yet

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Distinct WM subprocesses are mediated by frontoparietal, striatal and cerebellar regions.

“distinct WM subprocesses have been shown to be mediated by frontoparietal, striatal and cerebellar regions [Baddeley, 2003; Owen et al., 2005; Postle and D'Esposito, 2000].”

• cites Baddeley, 2003Not checked yet

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• cites Owen et al., 2005Not checked yet

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• cites Postle and D'Esposito, 2000Not checked yet

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

At the time of the fMRI scanning, six patients were removed from medication for at least 6 weeks, and the remaining six discontinued their treatment with MPH at least 3 days prior to the scanning procedure.

“At the time of the fMRI scanning, six patients were removed from medication for at least 6 weeks, whereas the remaining six patients discontinued their treatment with MPH at least 3 days prior to the scanning procedure.”

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

Previous studies in children and adults with ADHD have reported abnormal activation of the VLPFC and the anterior cingulate cortex during response inhibition and WM, as well as hypoactivation of the parietal cortex associated with task switching.

“Moreover, previous studies in children and adults with ADHD have reported abnormal activation of the VLPFC and the anterior cingulate cortex during response inhibition [Bush et al., 1999; Durston et al., 2006] and WM [Schweitzer et al., 2000], as well as hypoactivation of the parietal cortex associated with task switching [Smith et al., 2006].”

• cites Bush et al., 1999Not checked yet

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• cites Durston et al., 2006Not checked yet

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• cites Schweitzer et al., 2000Not checked yet

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

Evidence from functional neuroimaging studies of memory processes in humans suggests that the implementation of an intended act or plan to recall or remember a specific stimulus set may be the lowest common denominator of VLPFC activation.

“Evidence from functional neuroimaging studies of memory processes in humans have suggested that the implementation of an intended act or plan to recall or remember a specific stimulus set may be the lowest common denominator of VLPFC activation [Courtney et al., 1997; Henson et al., 1999; Owen, 2000].”

• cites Courtney et al., 1997Not checked yet

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• cites Henson et al., 1999Not checked yet

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• cites Owen, 2000Not checked yet

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May combine two claims.

VLPFC activation in healthy subjects occurs during tasks that require the active comparison of stimuli held in both working memory and long-term memory, stimulus selection, and holding online of both spatial and nonspatial information.

“Consistent with this notion, VLPFC activation in healthy subjects has been demonstrated to occur during tasks that require the active comparison of stimuli held in both WM and long-term memory [Owen et al., 2005; Petrides, 1994; Wolf et al., 2006], stimulus selection [Rushworth et al., 1997], and holding online of both spatial and nonspatial information [Goldman-Rakic, 1990, 1996].”

• cites Owen et al., 2005Not checked yet

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• cites Petrides, 1994Not checked yet

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• cites Wolf et al., 2006Not checked yet

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The functional connectivity results support the notion that in addition to regional activation abnormalities in the left VLPFC, a functional decoupling of right hemisphere VLPFC regions is also present during WM processing.

“Our functional connectivity results support this notion by showing that in addition to regional activation abnormalities in the left VLPFC, a functional decoupling of right hemisphere VLPFC regions is also present during WM processing.”

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

Cerebellar contributions to cognition have been linked to the representation of precise temporal relationships and timing processes during sensory anticipation, and the role of the cerebellum during WM has been increasingly recognized.

“Cerebellar contributions to cognition have been linked to the representation of precise temporal relationships and timing processes during sensory anticipation [Castellanos and Tannock, 2002], and the role of the cerebellum during WM has been increasingly recognized [Owen et al., 2005].”

• cites Castellanos and Tannock, 2002Not checked yet

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• cites Owen et al., 2005Not checked yet

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Classified as probably not a substantial claim.

In its application to fMRI data, ICA has been demonstrated to be a viable method for revealing functionally related brain regions in healthy controls and patients with neuropsychiatric disorders.

“In its application to fMRI data, ICA has been demonstrated to be a viable method for revealing functionally related brain regions in healthy controls and patients with neuropsychiatric disorders [Celone et al., 2006; Garrity et al., 2007; Sambataro et al., 2008].”

• cites Celone et al., 2006Not checked yet

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• cites Garrity et al., 2007Not checked yet

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• cites Sambataro et al., 2008Not checked yet

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A common neural mechanism for both WM and response inhibition deficits in ADHD adults has been suggested previously given common behavioral deficits during WM and inhibition processes in ADHD adults and patients with damage to the right inferior prefrontal cortex.

“Indeed, a common neural mechanism for both WM and response inhibition deficits in ADHD adults has been suggested previously given common behavioral deficits during WM and inhibition processes in ADHD adults and patients with damage to the right inferior prefrontal cortex [Clark et al., 2007].”

• cites Clark et al., 2007Not checked yet

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

The combination of univariate (GLM) and multivariate (ICA) statistical methods has been previously shown to explore different aspects of brain activity, where GLM-based methods are more sensitive to detect functional specificity, while ICA is better suited to define aspects of functional connectivity.

“The combination of both univariate (GLM) and multivariate (ICA) statistical methods has been previously shown to explore different aspects of brain activity [Esposito et al., 2006], where GLM-based methods are thought to be more sensitive to detect functional specificity, while an ICA approach is better suited to define aspects of functional connectivity [Esposito et al., 2006; Sambataro et al., 2”

• cites Esposito et al., 2006Not checked yet

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• cites Sambataro et al., 2008Not checked yet

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

There is abundant evidence from functional neuroimaging studies suggesting that inhibitory control is associated with an activation pattern including the VLPFC, the anterior cingulate and the parietal cortex, and that these functionally heterogeneous regions also subserve WM processes.

“There is abundant evidence from functional neuroimaging studies suggesting that inhibitory control is associated with an activation pattern including the VLPFC, the anterior cingulate and the parietal cortex, e.g. [Durston et al., 2002, 2006; Konishi et al., 1999; Smith et al., 2006], and that these functionally heterogeneous regions also subserve WM processes [Owen et al., 2005; Wolf and Walter,”

• cites Durston et al., 2002, 2006Not checked yet

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• cites Konishi et al., 1999Not checked yet

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• cites Smith et al., 2006Not checked yet

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Regional activation changes in both the VLPFC and the cerebellum have been linked to familial vulnerability to ADHD.

“Furthermore, regional activation changes in both the VLPFC and the cerebellum have been linked to familial vulnerability to ADHD [Durston et al., 2006; Mulder et al., 2008].”

• cites Durston et al., 2006Not checked yet

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• cites Mulder et al., 2008Not checked yet

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The ICA-derived results support the notion of aberrant ventrolateral prefrontal, cingulate, parietal, and cerebellar connectivity in ADHD and provide evidence for a common pathophysiologic mechanism underlying commonly observed deficits in cognitive and inhibitory control in ADHD patients.

“Our ICA-derived results support the notion of aberrant ventrolateral prefrontal, cingulate, parietal, and cerebellar connectivity in ADHD [Castellanos and Tannock, 2002; Dickstein et al., 2006; Valera et al., 2005], and provide evidence for a common pathophysiologic mechanism underlying commonly observed deficits in cognitive and inhibitory control in ADHD patients.”

• cites Castellanos and Tannock, 2002Not checked yet

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• cites Dickstein et al., 2006Not checked yet

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• cites Valera et al., 2005Not checked yet

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Inferior frontal and cingulate regions have also been associated with attentional processes within the default-mode network.

“However, inferior frontal and cingulate regions have also been associated with attentional processes within the so called ''default-mode'' network [Raichle et al., 2001; Weissman et al., 2006].”

• cites Raichle et al., 2001Not checked yet

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• cites Weissman et al., 2006Not checked yet

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Classified as probably not a substantial claim.

Including only correctly performed trials in the functional analyses based on the GLM minimized the potentially relevant activation bias resulting from decreased task accuracy in both groups.

“Eventually, as we included only correctly performed trials in the functional analyses based on the GLM, we sought to minimize the potentially relevant activation bias resulting from decreased task accuracy in both groups.”

Classified as probably not a substantial claim.

The statistical threshold for between-group comparisons was set at P < 0.05 corrected for multiple comparisons using the false discovery rate (qFDR).

“The statistical threshold for these comparisons was set at P &lt; 0.05 corrected for multiple comparisons using the false discovery rate (qFDR) [Genovese et al., 2002; Storey and Tibshirani, 2003].”

• cites Genovese et al., 2002Not checked yet

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• cites Storey and Tibshirani, 2003Not checked yet

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

All ADHD patients included in this study had a history of MPH medication.

“Moreover, all ADHD patients included in this study had a history of MPH medication.”

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

We sought to exclude manifest reading disability in the patient sample by assessing subjective complaints and by obtaining independent information from parents, relatives, and school reports, thus minimizing potential inclusion bias.

“However, we sought to exclude manifest reading disability in the patient sample not only by assessing subjective complaints but also by obtaining independent information from parents, relatives, and school reports and thus additionally minimizing potential inclusion bias.”

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

A nonparametric analysis was chosen in order to minimize potential effects of data outliers and of a nonGaussian distribution of the data.

“A nonparametric analysis was chosen in order to minimize potential effects of data outliers and of a nonGaussian distribution of the data.”

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

We cannot rule out a motivational bias which may have additionally contributed to negative group effects in cognitive performance.

“As such, we cannot rule out a motivational bias which may have additionally contributed to negative group effects in cognitive performance.”

May combine two claims.

The behavioral results are potentially limited by the relatively small sample size and by the patient group consisting of highly motivated ADHD patients who received monetary compensation.

“However, the behavioral results are potentially limited by the relatively small sample size included in this study and by the fact that the patient group consisted of highly motivated ADHD patients, who received monetary compensation for their participation in this project.”

May combine two claims.

This study suggests both regional brain activation deficits and functional connectivity changes of ventrolateral prefrontal and cerebellar regions in ADHD adults during cognitive processing.

“Keeping these limitations in mind, this study suggests both regional brain activation deficits and functional connectivity changes of ventrolateral prefrontal and cerebellar regions in ADHD adults during cognitive processing.”

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

Although all patients were removed from medication at least three days prior to scanning, the long-term effects of medication on brain function are not yet well known and may have had an impact on cerebral activation and connectivity differences observed in the ADHD group.

“Nevertheless, although all patients investigated in this study were removed from medication at least three days prior to scanning, the long-term effects of medication on brain function are not yet well known [Langleben et al., 2002], and may have had an impact on cerebral activation and connectivity differences observed in the ADHD group.”

• cites Langleben et al., 2002Not checked yet

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Classified as probably not a substantial claim.

All 2nd level analyses were recalculated including individual IQ values as a nuisance variable.

“In addition, although IQ measures did not significantly differ between ADHD patients and healthy controls ( P &lt; 0.31), all 2nd level analyses were nevertheless recalculated including the individual IQ values as a nuisance variable.”

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

Reading disability was not formally tested in the patient group.

“Another potential limitation of this study is that although patients with manifest subjective reading disability were excluded from participation, reading disability was not formally tested in the patient group.”