Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

May combine two claims.

In a four-week follow-up of methylphenidate administration, Coghill et al. (2007) found a significant behavioral response to medication versus placebo on parent and teacher Conners ratings in 59% of children at some dose, but the effect of dose was not significant and optimal dose varied across children (33% at 0.3 mg/kg, 43% at 0.6 mg/kg).

“In the follow-up study of chronic (four-week) MP administration (Coghill et al, 2007), a significant behavioral response to medication compared with placebo was documented by parent and teacher ratings on the Conners' 10-item rating scale in 59% of the children at some dose, but the effect of dose was not significant and the optimal dose varied across children (33% when treated with a lowF0.3mg/kg”

• cites Coghill et al, 2007 sourceNot checked yet

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This well-designed study did not confirm expectations that stimulant response would correct executive function deficits, but also did not document a dose-related impairment on any battery task.

“This well-designed and implemented study of the cognitive effects of stimulant medication did not confirm expectations that the response would correct EF deficits, but also did not document a dose-related impairment on any of the tasks in the battery.”

May combine two claims.

The pattern of ANT fMRI findings suggests that some controls have expected activation of frontalstriatal circuitry, whereas the ADHD group manifests compensatory activation of different brain regions.

“This pattern suggested that some individuals in the control group have the expected activation of the frontalstriatal circuitry, whereas the ADHD group manifest compensatory activation of different brain regions.”

• cites Konrad et al (2006) sourceNot checked yet

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The percentage of children who benefit from stimulants depends on the task used to assess improvement, with highest response rates for activity and lowest for learning or problem solving.

“A basic finding is that the percentage of children who benefit depends on the task used to assess improvement, with the highest response rates for the assessment of activity (with decreases considered beneficial) and the lowest response rates for the assessment of learning or problem solving (with increases considered beneficial).”

• cites Conners, 2002 sourceNot checked yet

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• cites Ottenbacher and Cooper, 1983 sourceNot checked yet

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• cites Rapport and Kelley, 1993Not checked yet

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Pietrzak et al. (2006) meta-analysis found that higher doses of methylphenidate produced greater improvements than lower doses on attention, vigilance, memory, and working memory tasks, but no additional improvements on planning, cognitive flexibility, inhibitory control, naming, and motor speed tasks.

“Pietrzak et al (2006) provides a meta-analysis of the recent literature on placebo-controlled studies of the effects of MP on a variety of neuropsychological tasks, and in studies comparing effects for more than one clinical dose, higher doses produced greater improvements than lower doses for some tasks (attention, vigilance, memory, and working memory), but no additional improvements on others (”

• cites Pietrzak et al (2006) sourceNot checked yet

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Some fMRI studies of ADHD confirm a wide range of brain regions with deficits (hypoactivation relative to controls), while others suggest ADHD children may compensate for cognitive deficits by using alternative neural processes, producing patterns of hyperactivation as well as hypoactivation in different brain regions.

“Some fMRI studies of ADHD confirmed a wide range of brain regions with the evidence of deficits (hypoactivation relative to controls), but others suggest that ADHD children may compensate for cognitive deficits by using alternative neural processes to perform these tasks compared with control children, which may produce patterns of hyperactivation as well as hypoactivation in different brain”

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

Konrad et al. (2006) found that in ANT trials, anterior cingulate activation was greater in controls than ADHD for alerting, putamen activation was greater in ADHD than controls for orienting, and frontal activation was greater in controls than ADHD for executive control, while brainstem and parietal activation was greater in ADHD than controls.

“Konrad et al (2006) also used fMRI to evaluate brain regions activated by trials requiring alerting (anterior cingulate gyrus activation was greater in the control than in the ADHD group, but the brainstem activation was greater in the ADHD than in the control group), orienting trials (putamen activation was greater in the ADHD than in the control group), and executive control (frontal activation”

• cites Konrad et al (2006) sourceNot checked yet

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Scheres et al. (2003) found in a double-blind, placebo-controlled, crossover study of three methylphenidate doses (5, 10, 20 mg) that the overall effect of medication was significant due to faster Stop-signal reaction times and lower reaction time variability, but the dose effect was not significant, suggesting maximum cognitive benefit may be elicited by a low dose.

“Scheres et al (2003) provides an example of the use of a specific task (the STOP task) to evaluate dose-response to MP in a double-blind, placebo-controlled, crossover study of three doses (5, 10, and 20 mg).The overall effect of medication was significant owing to faster SSRTs and lower RT variability, but the dose effect was not significant, suggesting that the maximum cognitive benefit may be”

• cites Scheres et al (2003) sourceNot checked yet

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

Sprague and Sleator (1977) suggested that the optimal dose for cognitive effects of methylphenidate is lower than that for behavioral effects.

“An early study of dose-related effects (Sprague and Sleator, 1977) had suggested that the optimal dose for cognitive effects was lower than that for behavioral effects of MP”

• cites Sprague and Sleator, 1977 sourceNot checked yet

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Go-NoGo fMRI studies reveal hypoactivation in inferior frontal cortex, anterior cingulate cortex, and precentral gyrus, and hyperactivation in medial frontal gyrus and right paracentral lobule in ADHD compared with controls.

“These Go-NoGo fMRI studies reveal hypoactivation involving relatively smaller regions within the inferior frontal cortex, anterior cingulate cortex, and precentral gyrus, as well as hyperactivation in medial frontal gyrus and right paracentral lobule.”

May combine two claims.

Methylphenidate and amphetamine are particularly effective for clinical treatment of ADHD, and have been prescribed for over seven decades.

“Stimulant drugs (methylphenidate (MP) and amphetamine (AMP)) are particularly effective for the clinical treatment of ADHD, and accordingly, pediatricians and psychiatrists have been prescribing them for over seven decades (Bradley, 1937).”

• cites Bradley, 1937 sourceNot checked yet

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In the same chronic methylphenidate study, cognitive response was shown on visual memory tests (pattern matching, delayed matching to sample, spatial memory) but not on executive function tests except the Go-NoGo test.

“The chronic cognitive response to MP was shown on visual memory tests (pattern matching, delayed matching to sample, and spatial memory), but not on EF tests (except the Go-NoGo test).”

• cites Coghill et al, 2007 sourceNot checked yet

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Spencer et al. (2009) found in a double-blind, dose-response, crossover study that methylphenidate produced a significant reduction of the mode and SD from the mode for low and high doses, not due to a speed-accuracy tradeoff, reflecting increased efficiency of responding.

“Spencer et al (2009) evaluated the cognitive response of children with ADHD to stimulant medication based on an RT task of discriminating two stimuli (X or O) in a double-blind, dose-response, crossover study of placebo, low (0.9 mg/kg/day) and high (1.8 mg/kg/day) MP doses delivered by controlled-release formulations.Medication produced a significant reduction of the mode and SD from the mode”

• cites Spencer et al (2009) sourceNot checked yet

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Comparisons of Go-NoGo performance between ADHD and control children reveal significant differences in commission errors, variability of reaction times, omission errors, and perceptual sensitivity (d').

“Comparisons of Go-NoGo performance of ADHD and control children revealed significant differences in commission errors, as well as variability of RTs, omission errors, and a derived measure of perceptual sensitivity (d 0 ) based on signal detection theory.”

May combine two claims.

Various versions of the ANT revealed deficits in ADHD versus control groups on measures of the executive function network, but observed response patterns did not reflect impulsive responding.

“Various versions of the ANT have revealed deficits in ADHD vs control groups on measures of the executive function network, but the observed response patterns (slower RTs and more errors, particularly on conflict trials), did not reflect impulsive responding (Johnson et al, 2008;Konrad et al, 2006).”

• cites Johnson et al, 2008 sourceNot checked yet

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• cites Konrad et al, 2006 sourceNot checked yet

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Studies combining the STOP task with fMRI showed differential activation patterns of a distributive nature, which do not support models hinging on dysfunction in any one frontal subregion.

“Studies that combined the STOP task with fMRI also showed differential activation patterns of a distributive nature, which do not support models that hinge on the dysfunction in any one frontal subregion (Dickstein et al, 2006).”

• cites Dickstein et al, 2006 sourceNot checked yet

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In stimulant-naive children with ADHD, Rhodes et al. (2006) found improvement on some tasks without a major executive function component (complex reaction time, spatial recognition memory reaction time, delayed matching-to-sample) but not on tasks designed to assess executive function components (inhibition, working memory, strategy formation, planning, set-shifting).

“In stimulant-naı ¨ve children with ADHD, controlling for practice effects in a randomized clinical trial (RCT) with between-subject comparisons (Rhodes et al, 2006), improvement was documented on some tasks without a major executive function (EF) component (complex reaction time, spatial recognition memory reaction time, and delayed matchingto-sample) but surprisingly not those designed to assess”

• cites Rhodes et al, 2006 sourceNot checked yet

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

Alderson et al. (2007) reported effect sizes for Stop-signal reaction time (0.63), mean reaction time (0.45), and Stop Signal Delay (-0.025) in ADHD children.

“A recent review (Alderson et al, 2007) contrasted the es for the Stop-signal reaction time (SSRT, es ¼ 0.63) and mean RT (MRT, es ¼ 0.45), as well as on a measure of Stop Signal Delay (SSD) defined as the difference between them (ie, SSD ¼ MRTFSSRT, es ¼ À0.025)”

• cites Alderson et al, 2007 sourceNot checked yet

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At some doses and on some tasks, stimulant drugs may produce cognitive enhancement in some individuals without ADHD as well as in those with ADHD.

“At some doses and on some tasks (Dodds et al, 2008), stimulant drugs may have the same direction of effect (cognitive enhancement) in some individuals without ADHD (Clatworthy et al, 2009) as well as in those with ADHD.”

• cites Dodds et al, 2008 sourceNot checked yet

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• cites Clatworthy et al, 2009 sourceNot checked yet

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In Epstein et al.'s Ex-Gaussian analysis, the faster and less variable result was due to a reduction in tau and an increase in mu.

“but the Ex-Gaussian analysis revealed that this was owing to a reduction in t (suggesting fewer long RTs in the inattentive state) and an increase in m (slower RTs in the attentive state).”

• cites Epstein et al (2006) sourceNot checked yet

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• AssumptionThe authors state this as an assumption: Reaction-time distributions are generated by two underlying processes: a normal process and an exponential process for infrequent long responses.

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Dose-response studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function, with high doses tending to produce greater enhancement on some domains (e.g., vigilance) but not others (e.g., planning), without clear evidence of completely correcting cognitive deficits associated with ADHD.

“Doseresponse studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function, with high doses tending to produce greater enhancement on some (eg, vigilance) but not others (eg, planning), without clear evidence of completely correcting cognitive deficits associated with ADHD.”

May combine two claims.

Standard reaction-time analysis suggests inefficient responding, whereas Ex-Gaussian analysis suggests impulsive responding combined with interspersed long reaction times from attention lapses.

“The former analysis would suggest inefficient responding (slow, inaccurate, and variable), whereas the latter analysis might suggest impulsive responding (fast and inaccurate) combined with interspersed long RTs owing to lapses of attention.”

May combine two claims.

In nearly all studies using reaction time as a performance measure, ADHD individuals differ from controls in overall speed, being slower on average, and in variability, with greater within-individual standard deviation.

“In almost all studies that used RT as a measure of performance, ADHD individuals differ from controls in overall speed (slower average RT) and variability (increased within individual SD).”

May combine two claims.

In Epstein et al.'s MTA 2-year assessment, traditional reaction-time analysis showed the medicated subgroup responded faster and was less variable than the off-medication subgroup.

“A comparison of the self-selected subgroups evaluated by traditional analysis of RT (mean and SD) revealed that the subgroup on medication responded faster and was less variable than the subgroup off medication”

• cites Epstein et al (2006) sourceNot checked yet

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Observational follow-up studies that compare self-selected naturalistic subgroups suggest long-term cognitive and behavioral benefit from stimulant medication.

“In some observational follow-up studies of children into adulthood, comparison of self-selected naturalistic subgroups suggest a long-term benefit of stimulant medication on cognition as well as behavior”

May combine two claims.

Powers et al. (2008) reported in a 9-year follow-up that self-selected subgroups of children with ADHD differed on three measures of academic achievement and grade point average, with the medication group outperforming the non-medication group.

“Powers et al (2008) recently reported on a longterm (about 9 year) follow-up of a cohort of 169 children with ADHD.Of these, 90 were assessed at follow-up, and 48 had a history of medication use for more than 1 year (average 5.33 years) and 42 had a history of no treatment or short-term treatment (less than 1 year).The self-selected subgroups differed on three measures of academic achievement and”

• cites Powers et al (2008) sourceNot checked yet

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

The NIMH brain imaging program defined the pattern for typical brain development (roughly linear increase in white matter volumes and inverted U-shaped trajectories for some gray matter structures) and suggested that some childhood onset disorders may be disorders of neuroplasticity.

“The NIMH brain imaging program also provides the essential background of normal brain development in a large cohort of singletons (see Giedd et al (2001)) and twins (see Lenroot and Giedd (2008)), which have defined the pattern for typical brain development (ie, roughly linear increase in white matter volumes and inverted U-shaped trajectories for some gray matter structures), and suggest that”

• cites Giedd et al (2001) sourceNot checked yet

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• cites Lenroot and Giedd (2008)Not checked yet

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• cites Rapoport and Gogtay, 2008 sourceNot checked yet

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NIMH longitudinal brain imaging provided evidence of a global reduction in brain volume and multiple regional differences in brain anatomy, suggesting approximately 10% reduction in prefrontal, basal ganglia, corpus callosum, and cerebellum.

“A program of longitudinal brain imaging was established in the child psychiatry branch of the National Institute of Mental Health (NIMH), and the ADHD component of this program has provided evidence of a global reduction in brain volume, as well as multiple regional differences in brain anatomy, suggesting an approximately 10% reduction in prefrontal, basal ganglia, corpus callosum, and cerebellum”

• cites Castellanos et al, 2002aNot checked yet

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• cites Giedd et al, 2001 sourceNot checked yet

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• cites Shaw et al, 2006 sourceNot checked yet

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Castellanos et al. hypothesized that reaction times varied systematically over time with a slow cycle of about 10-20 seconds reflecting underlying variation at the synaptic level of the dopamine system.

“Castellanos et al (2005) hypothesized that RTs varied systematically over time with a slow cycle of about 10-20 s that reflected underlying variation at the synaptic level of the DA system (Walters et al, 2001).”

• cites Castellanos et al (2005) sourceNot checked yet

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• cites Walters et al, 2001Not checked yet

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In Hervey et al.'s Go-NoGo study, standard analyses showed the ADHD group had longer mean reaction time and greater standard deviation and skewness than controls.

“On the basis of standard analyses, the ADHD group had a longer MRT and greater SD and skewness.”

• cites Hervey et al (2006) sourceNot checked yet

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One hypothesis holds that the skewness and infrequent long reaction times arise from periodic lapses in attention.

“One hypothesis is that the skewness and infrequent long RTs are the result of periodic lapses in attention (Douglas et al, 1995).”

• cites Douglas et al, 1995 sourceNot checked yet

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Selection biases in the observational follow-up studies have not been adequately addressed, so a firm conclusion about long-term benefit is not justified.

“but selection biases have not been adequately addressed to justify a firm conclusion about this hopeful hypothesis.”

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

Response variability is a ubiquitous finding in ADHD research across speeded reaction-time tasks, laboratories, and cultures.

“An influential review by Castellanos and Tannock (2002b) noted that 'yresponse variability is one of the ubiquitous findings in ADHD research across a variety of speededreaction-time tasks, laboratories, and cultures' (p 624).”

• cites Castellanos and Tannock (2002b)Not checked yet

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In Castellanos et al.'s FFT analysis, the magnitude of systematic waxing and waning was greater for ADHD than controls; oscillations centered at 0.05 Hz were present in both groups, but power at that frequency was 50% greater in ADHD.

“the FFT analysis revealed that the magnitude of the systematic waxing and waning was greater for the ADHD than the control group (ie, oscillations centered at 0.05 Hz were present in both groups, but the power at this frequency was 50% greater for the ADHD than the control group).”

• cites Castellanos et al (2005) sourceNot checked yet

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The group treated consistently with stimulant medication appeared to show normalization in the trajectory of brain development, but this group was self-selected and may differ on other factors related to outcome.

“Surprisingly, the group that had been treated consistently with stimulant medication appeared to show normalization in the trajectory of brain development (for a review see Shaw et al (2010)), but this group was self-selected and may differ on other factors related to outcome.”

• cites Shaw et al (2010) sourceNot checked yet

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Reviews emphasize that both the trajectory and the endpoint are important in evaluating brain anatomy, and that the most important differences between normal and abnormal brain development are likely dependent on age and stage of development at the time of evaluation.

“These reviews emphasize that the journey (trajectory) as well as the destination (end point) are important to consider in the evaluation of brain anatomy, and that the most important differences between normal and abnormal brain development are likely to be dependent on age and stage of development at the time of the evaluation.”

May combine two claims.

Both environmental (history of stimulant medication treatment) and genetic (dopamine D4 receptor genotype) factors affected the developmental trajectory of cortical thickness.

“Both environmental (history of treatment with stimulant medication) and genetic (genotype of the dopamine (DA) receptor D4 gene) factors affected the developmental trajectory.”

• cites Shaw et al (2006) sourceNot checked yet

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• cites Shaw et al (2007) sourceNot checked yet

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Krain and Castellanos (2006) suggested that these brain deficits were non-progressive and associated with ADHD (presumably from early genetic and/or environmental factors), rather than consequences of stimulant treatment.

“Krain and Castellanos (2006) suggested that these brain deficits were non-progressive and associated with the disorder (presumably from the result of early genetic and/or environmental factors), rather than consequences of treatment of the disorder with stimulant drugs.”

• cites Krain and Castellanos (2006) sourceNot checked yet

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In Hervey et al.'s Ex-Gaussian analysis, the ADHD group had lower mu, indicating faster reaction times, but greater tau, indicating more long reaction times, than controls.

“an Ex-Gaussian analysis revealed that, compared with controls, the ADHD group had lower estimates of m (ie, faster RTs) but a greater t (ie, more long RTs).”

• cites Hervey et al (2006) sourceNot checked yet

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• AssumptionThe authors state this as an assumption: Reaction-time distributions are generated by two underlying processes: a normal process and an exponential process for infrequent long responses.

May combine two claims.

In the same study, the ADHD subgroup on medication had better performance on sustained attention (CPT) and verbal learning (California Verbal Learning Test) than the ADHD subgroup not on medication.

“A comparison of ADHD subgroups revealed that the subgroup on medication had better performance on sustained attention (measured by the CPT) and verbal learning (measured by the California Verbal Learning Test).”

• cites Biederman et al (2008) sourceNot checked yet

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The Ex-Gaussian results suggested that ADHD children had more attention lapses marked by long reaction times, but otherwise responded similarly to control children.

“This suggested that the ADHD children had more lapses of attention marked by long RTs, but otherwise they responded about the same as the control children.”

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

Sonuga-Barke and Castellanos proposed the default-mode interference hypothesis to account for the systematic increased intraindividual variance in reaction-time tasks.

“Sonuga-Barke and Castellanos (2007)) proposed the default-mode interference hypothesis to account for the systematic increased intraindividual variance in RT tasks”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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Classified as probably not a substantial claim.

During the resting state, the theory proposes recurrent toggling between a self-reflective Introspective state and an attentive-readiness Extrospective state.

“During the resting state, this theory proposes a recurrent toggling or switching (Fransson, 2005) between a state of self-reflection (an 'Introspective' state) and a state of attentive readiness (an 'Extrospective' state).”

• cites Fransson, 2005 sourceNot checked yet

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

Brain regions typically activated by task performance also show highly correlated cyclical BOLD fluctuations, but this activity is out of phase with the default mode network's BOLD waxing and waning.

“Brain regions that are typically activated by task performance also show highly correlated cyclical fluctuations in BOLD signals (or functional connectivity), although this activity is out of phase with the waxing and waning of the BOLD signals from the DMN.”

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

Task characteristics affect reaction-time distributions and analyses, but this additional variation may be informative about underlying cognitive processes.

“Task characteristics affect RT distributions and analyses, but this additional source of variation may be informative of the underlying cognitive processes.”

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

The discovery of intrinsic brain activity organization and fMRI methods for characterizing networks and functional connectivity offer a new way to map brain organization and investigate disorders such as ADHD.

“the discovery of the intrinsic organization of brain activity and the development of fMRI methods to characterize networks and functional connectivity offer the exciting possibility of an important new way to map brain organization and to investigate disorders (such as ADHD).”

May combine two claims.

Although the group differences in Yang et al. may be compounded by large IQ differences, the regions involved could be tentatively interpreted as reflecting abnormalities in intrinsic frontal-cortex brain organization in ADHD children at rest.

“Even though these group differences may be compounded by large differences in IQ, the nature of the regions involved could be tentatively interpreted as a reflection of abnormalities in intrinsic brain organization in the frontal cortex in ADHD children in the resting state.”

May combine two claims.

Fassbender and Schweitzer found the ADHD group had greater intraindividual variability, which was negatively correlated with activity in the posterior cingulate cortex.

“The ADHD group also showed greater intraindividual variability, which was negatively correlated with activity in the PCC.”

• cites Fassbender and Schweitzer (2006) sourceNot checked yet

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Use of global regression techniques warrants extra caution when interpreting the directionality or meaning of resting-state relationships.

“Clearly, the use of global regression techniques warrants extra caution when interpreting the directionality, or even the meaning of resting state relationships.”

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

Evidence from several studies indicates that spontaneous BOLD fluctuations during task performance are related to trial-to-trial variability in task-related evoked signals.

“There is evidence from several studies that spontaneous BOLD fluctuations during task performance are related to trial-to-trial variability in task-related evoked signals (Fox et al, 2006b;Fransson, 2006).”

• cites Fox et al, 2006bNot checked yet

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• cites Fransson, 2006 sourceNot checked yet

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Some experts suggested that global regression techniques might introduce spurious negative correlations when whole-brain signals are regressed out.

“Some experts have suggested that these techniques might introduce spurious negative correlations upon regressing out whole brain signals (Murphy et al, 2009;Van Dijk et al, 2009).”

• cites Murphy et al, 2009 sourceNot checked yet

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• cites Van Dijk et al, 2009 sourceNot checked yet

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Resting-state fMRI studies consistently show within-subject positive correlations of slow cyclical BOLD fluctuations among regions within the default mode network.

“Fox and Raichle (2007) provide a review of resting state fMRI studies, which consistently show within-subject positive correlations of the slow cyclical fluctuations of BOLD signals from the brain regions within the DMN”

• cites Fox and Raichle (2007) sourceNot checked yet

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Fox et al. proposed dorsal-ventral distinctions between a dorsal task mode network and a ventral default mode network.

“Fox et al (2006) proposed dorsal-ventral distinctions between a dorsal TMN and ventral DMN.”

• cites Fox et al (2006)Not checked yet

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Kelly et al. 2008 observed high negative correlations for all 26 subjects, ranging from -0.80 to -0.97, and inter-subject variation in anticorrelation was related to reaction-time variance, with higher anticorrelations associated with lower reaction-time variance.

“High negative correlations (see Figure 2b for an individual example) were observed for all of the 26 subjects evaluated, with a range from À0.80 to À0.97, and this inter-subject variation in the degree of anticorrelation was related to inter-subject variation in performance measures of the task (RT variance): the subjects with the higher anticorrelations had lower RT variances in performance of”

• cites Kelly et al (2008) sourceNot checked yet

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This suggested the possibility of linking temporal variation in brain states to variability in behavior or task performance.

“This suggested the exciting possibility of linking temporal variation in brain states to variability in behavior or performance on a task”

May combine two claims.

This was interpreted as a relative weakness in ADHD individuals to suppress default mode network activity during a working memory task, supporting the default mode interference hypothesis as a cause of periodic attention lapses and long reaction times.

“This was interpreted as a relative weakness in the ADHD individuals to suppress activity in the DMN during performance of a working memory task, and it provided support for the hypothesis of Sonuga-Barke and Castellanos (2007) of default mode interference as a cause of periodic attentional lapses and long RTs.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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Tian et al. 2006 found the ADHD group had greater resting-state connectivity than controls in multiple brain regions, including bilateral dorsal anterior cingulate, pons, insula, cerebellum, and thalamus, interpreted as abnormalities in autonomic control areas.

“The ADHD group had greater resting state connectivity than the controls in multiple brain regions (bilaterally in the dorsal anterior cingulate, pons, insula, cerebellum, and thalamus), which was interpreted as abnormalities in areas involved in autonomic control.”

• cites Tian et al (2006) sourceNot checked yet

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De Luca et al. identified five resting-state networks, one of which, RSN-2, was equivalent to the default mode network.

“De Luca et al (2006) identified five resting state networks (RSNs), and one of these (RSN-2) was equivalent to the DMN described by Raichle (2010) and Fox et al (2006a) and depicted in Figure 1.”

• cites De Luca et al (2006) sourceNot checked yet

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Classified as probably not a substantial claim.

They considered the task-positive and task-negative networks together as a default mode state in which spontaneous fluctuations are synchronized in an opposing anticorrelated relationship.

“They considered the task-positive and task-negative networks together as a default mode state in which spontaneous fluctuations are synchronized in the opposing (anticorrelated) relationship described in Figure 1.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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Several characteristics of anticorrelated networks cannot be readily attributed to global signal removal, supporting the notion that these signals represent a true biological phenomenon rather than a statistical artifact.

“several of the characteristics of anticorrelated networks (eg, spatial distribution, cross-subject consistency, presence with modified whole brain masks, and existence before global regression) cannot be attributed readily to global signal removal, which supports the notion that these signals represent a true underlying biological phenomenon instead of a statistical artifact (Fox et al, 2009).”

• cites Fox et al, 2009 sourceNot checked yet

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Raw resting-state fMRI data must be edited to remove motion artifacts and other sources of physiological noise.

“It is important to mention that raw fMRI data from the resting state must be edited to remove contaminating motion artifacts and various other sources of physiological noise.”

May combine two claims.

In individuals with ADHD, recovery and default mode interference is faster and attention lapses are more frequent than in non-ADHD individuals during tasks, resulting in increased intraindividual reaction-time variance and a skewed distribution.

“In individuals with ADHD, the recovery and 'default mode interference' is faster and the lapses of attention are more frequent than in non-ADHD individual when performing a task (such as the Go-NoGo, STOP, or ANT), resulting in an increase in the intraindividual variance of RTs that creates a skewed distribution.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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

The proposed ventral network, equivalent to the default mode network, included medial prefrontal, posterior cingulate, and lateral parietal regions, assumed to be activated when not performing a task.

“The proposed ventral network (equivalent to the DMN) included the MPF, posterior cingulate, and lateral parietal brain regions, which are assumed to be activated when not performing a task (in the 'resting state').”

• cites Fox et al (2006)Not checked yet

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• AssumptionThe authors state this as an assumption: The ventral network regions equivalent to the default mode network are activated when a task is not being performed.

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

Fransson presented a similar framework of cognitive control and proposed that the brain switches between the default mode network and the task mode network.

“Fransson (2006) presented a similar conceptual framework of cognitive control and proposed the brain switches ('toggles') between the DMN and TMN.”

• cites Fransson (2006) sourceNot checked yet

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

When a task is initiated, the magnitude of fluctuations in Introspective and Extrospective states decreases, but over time it increases and crosses a threshold labeled the default mode interference threshold.

“When a task is initiated, they propose the magnitude of the fluctuations in Introspective and Extrospective states is decreased but, over time, this magnitude increases, crossing a threshold at some point that they label the 'default mode interference threshold'.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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

The observation of a difference between a subtraction and a reverse subtraction is not evidence for the importance of the baseline.

“it is necessary to contend with the claim that 'ythe observation of a difference between a subtraction and a reverse subtraction is not evidence for the importance of the baseline' (Morcom and Fletcher, 2007).”

• cites Morcom and Fletcher, 2007 sourceNot checked yet

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

Sonuga-Barke and Castellanos used the concept of anticorrelated networks to propose an alternative to the traditional top-down model of ADHD based on executive function deficits.

“Sonuga-Barke and Castellanos (2007) used the concept of anticorrelated networks (which we have outlined in Figures 1 and 2) to propose an alternative to the traditional topdown model of ADHD based on executive function deficits”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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

There are multiple task mode networks depending on cognitive demands, and each may be related or anticorrelated with the same or different default mode networks.

“Of course, there are multiple TMNs dependent on the cognitive demands of tasks, and each may be related (or anticorrelated) with the same or different DMNs.”

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

Models of reaction-time analysis have been used to investigate underlying processes such as randomly occurring attention lapses in the Ex-Gaussian model and systematic waxing and waning of attention in the FFT model.

“models of RT analysis have been applied to investigate underlying processes, such as randomly occurring lapses of attention (the Ex-Gaussian model) or systematic waxing and waning of attention (the FFT model) that affect RT.”

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

The posterior cingulate cortex/precuneus, medial prefrontal cortex, and lateral parietal cortex show correlated increases in BOLD activity during the resting state when no task is performed, in slow 0.1 Hz cycles.

“these brain regionsFposterior cingulate cortex (PCC)/precuneus, medial prefrontal (MPF), and the lateral parietal cortex (LP)Fhave correlated increases in BOLD activity during the resting state when a task is not being performed shown in slow wave (0.1 Hz) cycles.”

• cites Raichle (2010) sourceNot checked yet

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Classified as probably not a substantial claim.

When the default mode interference threshold is crossed, a lapse of attention results in a long reaction time.

“When this occurs, they propose a lapse of attention results in a long RT.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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

The intrinsic activity in the task-positive network is out of phase with the default mode network, so the correlation of spontaneous cyclical activity between the two networks over time is high but negative or anticorrelated.

“The intrinsic brain activity in the task-positive network is out of phase with the intrinsic activity of the DMN, so the correlation of the spontaneous cyclical activity in the two networks over time is highFbut negative or anticorrelated”

• cites Fox and Raichle (2007) sourceNot checked yet

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

The default mode network approach is consistent with a hierarchical organization of brain networks, with the default mode network possibly a hub at the top.

“This DMN approach is consistent with a hierarchical organization of brain networks (Raichle, 2010): the DMN may be a 'hub' at the top of a hierarchal organization”

• cites Raichle, 2010 sourceNot checked yet

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

Sonuga-Barke and Castellanos proposed that the skewed reaction-time distributions in ADHD may result from interference by the default mode network.

“Sonuga-Barke and Castellanos (2007) proposed that the skewed RT distributions of individuals with ADHD (see above) may be a consequence of interference by the default mode network (DMN) of the brain.”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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

The idea that ADHD involves an underlying dysfunction in reward and motivation was proposed over two decades ago, revived a decade ago, and emphasized in some current theories.

“The notion that ADHD involves an underlying dysfunction in reward and motivation was proposed over two decades ago (Haenlein and Caul, 1987), revived a decade ago (Iaboni et al, 1997), and emphasized in some current theories of ADHD”

• cites Haenlein and Caul, 1987 sourceNot checked yet

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• cites Iaboni et al, 1997 sourceNot checked yet

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May combine two claims.

Rubia et al. found that off medication, the ADHD group had significant CPT performance deficits, reduced activation of a frontal-striatal-parietal-cerebellar network, and increased activation of orbitofrontal and superior temporal regions.

“Off medication, the ADHD group had significant performance deficits on CPT, and reduced activation of a brain network that connected frontal, striatal, parietal, and cerebellar brain regions and increased activation of orbitofrontal and superior temporal brain regions.”

• cites Rubia et al (2009) sourceNot checked yet

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

In ADHD, abnormalities in functional connectivity have been documented, but both increases and decreases relative to controls have been observed.

“In ADHD, abnormalities in functional connectivity have been documented, but both increases and decreases relative to controls have been observed.”

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

The ventral attention network orients attention to internal or Introspective processes and is part of the default mode network activated in the resting state.

“the ventral attention network orients attention to internal or Introspective processes and is part of the DMN that is activated in the so-called resting state”

May combine two claims.

Shiels et al. found motivational incentives enhanced performance on the backward span task but not the forward span task.

“Motivational incentives enhanced performance on the backward span, but not the forward span task.”

• cites Shiels et al (2008) sourceNot checked yet

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May combine two claims.

The difference in delay aversion compared with the familial control group was not significant, but the sibling control average fell midway between the ADHD and normal control groups.

“even though the difference compared to the familial control group was not significant, the average for the sibling control fell midway between the average for the ADHD and the normal control groups.”

• cites Bitsakou et al (2009) sourceNot checked yet

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

Tripp and Wickens proposed the dopamine transfer deficit theory and suggested that children with ADHD have diminished cellular responses of dopamine cells to cues preceding reinforcement.

“Tripp and Wickens (2008) proposed the DA transfer deficit theory and suggested that children with ADHD have diminished cellular responses of DA cells to cues that precede reinforcement.”

• cites Tripp and Wickens (2008) sourceNot checked yet

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Bitsakou et al. found a significant difference in delay aversion between the ADHD and normal control groups, with an effect size of 0.9.

“The contrasts revealed a significant difference between the ADHD and normal control group (es ¼ 0.9)”

• cites Bitsakou et al (2009) sourceNot checked yet

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May combine two claims.

Rubia et al. found medication normalized the attentional network by upregulating activity and the motivational network by downregulating reward-induced overactivity.

“Medication normalized the attentional network (upregulating activity) and in the motivational network (downregulating reward-induced overactivity).”

• cites Rubia et al (2009) sourceNot checked yet

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May combine two claims.

Stimulant medication may facilitate deactivation of the default mode network and alleviate ADHD inattention symptoms and their variable manifestation over time.

“Stimulant medication may facilitate the deactivation of the DMN and alleviate the ADHD symptoms of inattention and their variable manifestation over time.”

May combine two claims.

Several brain regions and circuits involved in specific cognitive processes that impact attention are modulated by the catecholaminergic system and are affected by stimulant medications.

“Several brain regions and circuits are involved in the orchestration of specific cognitive processes that impact attention; these circuits are modulated by the catecholaminergic system and thus are affected and modulated by stimulant medications (Wilens, 2008).”

• cites Wilens, 2008 sourceNot checked yet

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To evaluate cognitive deficits in ADHD, both Introspective and Extrospective processes appear important, and neuropsychological and brain imaging methods are being developed to characterize these deficits and the effects of stimulant medication.

“To evaluate cognitive deficits in ADHD, both Introspective and Extrospective processes appear to be important, and neuropsychological and brain imaging methods are being developed to characterize ADHD-related cognitive deficits and effects of stimulant medication that may correct them”

• cites Sonuga-Barke and Castellanos (2007) sourceNot checked yet

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May combine two claims.

Shanahan et al. documented significant main effects of motivation on overall reaction time, reaction-time variability, and stop-signal reaction time, but the critical group by motivation interaction was not significant.

“This study documented significant main effects of motivation on overall RT, variability of RT, and SSRT, but the critical group by motivation interaction was not significant.”

• cites Shanahan et al (2008) sourceNot checked yet

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

BOLD activity from fMRI signals may be related to variation in reaction times.

“The BOLD activity from fMRI signals may be related to variation in RTs.”

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

Impaired ability to suppress ongoing actions or pre-potent responses is one hallmark of the core inhibition deficit theory of ADHD and one of the most disruptive aspects of ADHD.

“We have focused on the impaired ability to suppress ongoing actions or pre-potent responses that is one of the hallmarks of the theory of a core inhibition deficit of ADHD (Barkley, 1997) and is one of the most disruptive aspects of ADHD (Kenemans et al, 2005).”

• cites Barkley, 1997 sourceNot checked yet

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• cites Kenemans et al, 2005 sourceNot checked yet

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May combine two claims.

Increased default mode network activity was present in some studies, consistent with the hypothesis that ADHD individuals may have increased intrusions during task performance manifested as attention lapses and variable responses reflecting improper default mode network deactivation.

“Increased activity in the DMN was present in some studies, which is consistent with the hypothesis that ADHD individuals may have increased intrusions during task performance that are manifested as lapses of attention and variable patterns of response that reflect in part improper deactivation of the DMN.”

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

Sonuga-Barke proposed a theory based on the premise that some ADHD children have an aversion to delay of reinforcement.

“Sonuga-Barke (2002) proposed a theory based on the premise that some ADHD children have an aversion to delay of reinforcement.”

• cites Sonuga-Barke (2002) sourceNot checked yet

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

Johansen et al. proposed a theory based on the premise that ADHD children have a steeper than normal delay-of-reinforcement gradient.

“Johansen et al (2002) proposed a theory based on the premise that ADHD children have a steeper than normal delay-of-reinforcement gradient”

• cites Johansen et al (2002) sourceNot checked yet

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May combine two claims.

In Kuntsi et al., the combination of a fast event rate and incentive condition normalized speed of response (mean RT 653 vs 648 ms) and intraindividual variability (SD 217 vs 203 ms).

“Compared with the performance on the task with a slow event rate and no incentive, the combination of a fast event rate and the incentive condition normalized speed of response (mean RT ¼ 653 vs 648 ms) and intraindividual variability (SD ¼ 217 vs 203 ms).”

• cites Kuntsi et al (2009) sourceNot checked yet

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May combine two claims.

The default mode network is deactivated during cognitive operations but not completely suppressed as the dorsal task mode network is activated, resulting in anticorrelation of BOLD activity even during the task state.

“The DMN is deactivated during cognitive operations but not completely suppressed, as the dorsal TMN is activated (see Figure 2), resulting in anticorrelation of BOLD activity even during the task state (Fox et al, 2006a).”

• cites Fox et al, 2006aNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The literature on brain states suggests spontaneous cyclical activity is correlated across cognition-related brain regions and organized in opposing task mode and default mode networks.

“The literature on brain states suggests that spontaneous cyclical activity is correlated across brain regions related to cognition, and is organized in opposing TMN and DMN (ie, task-positive and task-negative networksFsee Figures 1 and 2).”

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

Motivation and reward may represent another core deficit of ADHD.

“Motivation and reward may represent another 'core' deficit of ADHD (Luman et al, 2005).”

• cites Luman et al, 2005 sourceNot checked yet

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May combine two claims.

Wolf et al. 2009 found that ADHD and control groups did not differ in working memory task performance, but differed in brain activation patterns and functional connectivity during the delay phase.

“The groups did not differ in performance of this task, but they did differ in the patterns of brain activation elicited by the task (ie, in the task-positive networks for working memory) and in the functional connectivity estimates during the delay phase of the task.”

• cites Wolf et al (2009) sourceNot checked yet

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

Another model of attention proposes two networks: a dorsal network for top-down orienting and a ventral attention network for reorienting to salient sensory stimuli.

“Another model of attention proposes two networks; a dorsal network involved in top-down orienting of attention and a ventral attention network involved in reorienting attention in response to salient sensory stimuli (Corbetta and Shulman, 2002;Fox et al, 2006a).”

• cites Corbetta and Shulman, 2002 sourceNot checked yet

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• cites Fox et al, 2006aNot checked yet

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May combine two claims.

In Kuntsi et al.'s baseline slow event rate condition, the ADHD group had longer average reaction time and higher intraindividual variability (mean RT 1018 vs 943 ms; SD 495 vs 404 ms).

“In the baseline task, with a slow event rate (8 s), the ADHD group had longer average RT and higher intraindividual variability (average mean RT ¼ 1018 vs 943 ms; average SD ¼ 495 vs 404 ms).”

• cites Kuntsi et al (2009) sourceNot checked yet

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The literature based on multiple reaction-time paradigms suggests ADHD individuals have an increased proportion of infrequent long reactions that skew the reaction-time distribution and may reflect attention lapses.

“The literature based on multiple RT paradigms suggests that ADHD individuals have an increased proportion of infrequent long reactions that skew the distribution of RTs and may reflect lapses of attention.”

May combine two claims.

Peterson et al. 2009 found significant differences in brain activation for the ADHD group off medication compared with controls, suggesting the ADHD group could not suppress default mode network activity to the same degree as controls.

“They found significant differences in brain activation for the ADHD group off medication compared with the control group, suggesting that the ADHD group was not able to suppress activity in the DMN to the same degree as the control group”

• cites Peterson et al (2009) sourceNot checked yet

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Wolf et al. found the ADHD group had less functional connectivity for some brain regions and greater functional connectivity for others.

“The ADHD group had less functional connectivity for some brain regions (ventrallateral PFC, anterior cingulate gyrus, superior parietal, and cerebellum) and greater functional connectivity for other brain regions (right PFC and left dorsal anterior cingulate gyrus, and cuneus).”

• cites Wolf et al (2009) sourceNot checked yet

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May combine two claims.

PET studies confirmed that stimulants increase synaptic DA, first with intravenous MP and later with oral clinical doses.

“PET study confirmed this hypothesis, first with intravenous doses of MP (Volkow et al, 1995(Volkow et al, , 1999a) ) and then with oral clinical doses of MP (Swanson et al, 1999;Volkow et al, 1999bVolkow et al, , 2002)).”

• cites Volkow et al, 1995 sourceNot checked yet

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• cites Swanson et al, 1999 sourceNot checked yet

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• cites Volkow et al, 1999bNot checked yet

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May combine two claims.

The DA hypothesis of ADHD was proposed decades ago, partly because stimulants were thought to act as DA agonists and increased synaptic DA was thought critical for stimulant response.

“The DA hypothesis of ADHD was proposed decades ago (Levy, 1991;Wender, 1971), based partially on the hypothesis that stimulants acted as DA agonist drugs and that the increase in synaptic DA was a critical factor in the response to stimulant medication.”

• cites Levy, 1991 sourceNot checked yet

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• cites Wender, 1971Not checked yet

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

A generally accepted biological theory of ADHD has been that the disorder involves abnormally high DAT density, suggested by SPECT studies in small adult ADHD samples.

“For the past decade, a generally accepted underpinning of biological theories of ADHD has been that this disorder is associated with abnormally high levels of DAT density, which were suggested by studies using single photon emission tomography to evaluate small samples of ADHD adults (Dougherty et al, 1999;Krause, 2008).”

• cites Dougherty et al, 1999 sourceNot checked yet

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• cites Krause, 2008 sourceNot checked yet

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

It remains unclear and debated whether DA activity is enhanced or depressed in ADHD.

“Surprisingly, it is still unclear and debated whether DA activity is enhanced or depressed in individuals with ADHD.”

May combine two claims.

Based on animal models, the optimum alert state appears related to moderate activation of NE alpha-2A and DA D1 receptors in PFC, while stress-related increases in NE and DA release activate NE alpha-1 and beta-1 receptors and excessively activate D1 receptors.

“On the basis of animal models (Berridge et al, 2006;Robbins and Arnsten, 2009), the optimum alert state (see Figure 4) appears to be related to more moderate levels of activation of NE a-2A and DA D1 receptors in the PFC, but that stress-related increases of release of NE and DA and results in the activation of NE a-1 and b-1 receptor and excessive activation of D1 receptors (Arnsten, 2009).”

• cites Berridge et al, 2006 sourceNot checked yet

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• cites Robbins and Arnsten, 2009 sourceNot checked yet

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• cites Arnsten, 2009 sourceNot checked yet

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In non-ADHD adults, MP's effects on the brain depend on the task, attenuating BOLD activity in ventral striatum during reversal learning after negative feedback and modulating PFC BOLD during distractions when response set is maintained.

“Dodds et al (2008) showed that the effects of MP on the brain depended on the task being performed, with attenuation of BOLD activity in the ventral striatum during phase of a reversal learning task (after negative feedback) and modulation of the BOLD signal in the PCF in the face of distractions when response set was maintained.”

• cites Dodds et al, 2008 sourceNot checked yet

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May combine two claims.

The PET imaging literature supports the DA hypothesis of ADHD, but specific details remain unclear.

“In summary, the literature on PET imaging supports the DA hypothesis of ADHD, but the specific details are not yet clear.”

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

PET imaging studies have led to the hypothesis that stimulants may act by facilitating a dorsal task-positive attention network and deactivating the ventral resting-state network or DMN.

“On the basis of PET imaging studies, it has been hypothesized that stimulant medications may act by facilitating the engagement of a dorsal task-positive attention network and the deactivation of the ventral resting state network or DMN (Volkow et al, 2008).”

• cites Volkow et al, 2008 sourceNot checked yet

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

Stimulant effects depend on the context of administration and the type of task.

“it is intriguing that stimulant medications appear to have different effects depending on the context of administration and the type of task required”

• cites Clatworthy et al, 2009 sourceNot checked yet

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• cites Dodds et al, 2008 sourceNot checked yet

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Oral MP induces significant DAT blockade in the striatum, with an estimated ED50 of 0.25 mg/kg.

“Imaging studies have corroborated the ability of oral MP to induce significant levels of DAT blockade in the striatum, with an estimated ED50 (dose required to block 50% of the DAT) of 0.25 mg/kg (Volkow et al, 1999a).”

• cites Volkow et al, 1999aNot checked yet

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

Lapses of attention could reflect either a deficit in maintaining DMN deactivation or overactivation of the DMN.

“Lapses of attention could reflect either a deficit in ability to maintain deactivation of the DMN or to an overactivation of this network.”