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Cited by 7Attention Deficit Hyperactivity DisorderNeural and Behavioral Psychology StudiesNeurotransmitter Receptor Influence on Behavior

Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis

Open access
Pan, Nanfang, Ma, Tianyu, Liu, Yixi, Zhang, Shufang, Hu, Samantha, Shekara, Aniruddha, Cao, Hengyi, Gong, Qiyong +1 more·2024·Psychological Medicine
DOI 10.1017/s003329172400285xPMC PMC11769909
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Abstract

Abstract Background Psychostimulants and nonstimulants have partially overlapping pharmacological targets on attention-deficit/hyperactivity disorder (ADHD), but whether their neuroimaging underpinnings differ is elusive. We aimed to identify overlapping and medication-specific brain functional mechanisms of psychostimulants and nonstimulants on ADHD. Methods After a systematic literature search and database construction, the imputed maps of separate and pooled neuropharmacological mechanisms were meta-analyzed by Seed-based d Mapping toolbox, followed by large-scale network analysis to uncover potential coactivation patterns and meta-regression analysis to examine the modulatory effects of age and sex. Results Twenty-eight whole-brain task-based functional MRI studies (396 cases in the medication group and 459 cases in the control group) were included. Possible normalization effects of stimulant and nonstimulant administration converged on increased activation patterns of the left supplementary motor area (Z = 1.21, p < 0.0001, central executive network). Stimulants, relative to nonstimulants, increased brain activations in the left amygdala (Z = 1.30, p = 0.0006), middle cingulate gyrus (Z = 1.22, p = 0.0008), and superior frontal gyrus (Z = 1.27, p = 0.0006), which are within the ventral attention network. Neurodevelopmental trajectories emerged in activation patterns of the right supplementary motor area and left amygdala, with the left amygdala also presenting a sex-related difference. Conclusions Convergence in the left supplementary motor area may delineate novel therapeutic targets for effective interventions, and distinct neural substrates could account for different therapeutic responses to stimulants and nonstimulants.

AI snapshot

Written from the paper’s full text.

TL;DR

This comparative meta-analysis of 28 task-based fMRI studies found that stimulants and nonstimulants share normalization effects in the left supplementary motor area, while stimulants show greater activation changes in the left amygdala, middle cingulate gyrus, and superior frontal gyrus. These overlapping and distinct neural substrates may help explain shared efficacy and differential therapeutic responses in ADHD.

Key findings

  • Across 28 whole-brain task-based fMRI studies (396 medication cases, 459 control cases), stimulant and nonstimulant effects converged on increased left supplementary motor area activation (Z = 1.206, p < 0.0001, cluster size = 44; 43.18% relative distribution in the central executive network).
  • Stimulants, relative to nonstimulants, increased activation in the left amygdala (Z = 1.295, p = 0.0006, cluster size = 199), left middle cingulate gyrus (Z = 1.222, p = 0.0008, cluster size = 174; and Z = 1.271, p = 0.0006, cluster size = 63), and left superior frontal gyrus (Z = 1.243, p = 0.0007, cluster size = 68), distributed within the ventral attention network.
  • Stimulant-specific effects versus control included increased left cerebellum (Z = 1.449, p = 0.0001), right supplementary motor area (Z = 1.266, p = 0.0007), right anterior cingulate gyrus (Z = 1.560, p < 0.0001), right postcentral gyrus (Z = 1.132, p = 0.0016), and left middle frontal gyrus (Z = 1.100, p = 0.0020), plus reduced left supplementary motor area (Z = −1.307, p = 0.0013).
  • Nonstimulant-specific effects versus control included reduced left middle cingulate gyrus extending to bilateral supplementary motor area (Z = −1.808, p < 0.0001), left amygdala (Z = −1.345, p = 0.0010), left superior frontal gyrus (Z = −1.819, p < 0.0001), and right caudate nucleus (Z = −1.540, p = 0.0002); meta-regression linked younger age to stimulant-induced reduced right supplementary motor area activation and male sex with greater age to nonstimulant-related reduced left amygdala activation.

Methods

  • Preregistered systematic review and meta-analysis (OSF; PRISMA) searched PubMed, Medline, and Web of Science before May 8, 2022, including 28 task-based fMRI studies: 19 stimulant-specific and 9 nonstimulant-specific, with 396 medication-group and 459 control-group cases.
  • Extracted whole-brain activation coordinates and analyzed them with AES-SDM/Seed-based d Mapping random-effects meta-analysis, including conjunction and comparative SDM linear models; medication-specific threshold was p < 0.005 with clusters > 10 voxels, and two-modality analyses used corrected p < 0.0025.
  • Performed large-scale network decoding using seven Yeo networks, meta-regression for age and sex, subgroup analyses for cognitive control and child samples, publication-bias tests, and Jackknife sensitivity analyses.

Limitations

  • The paper states heterogeneity from included tasks (most assessed cognitive control, others working memory and attention), mixed child/adult samples, and varied designs including randomized controlled and cross-sectional trials; it also states it could not differentiate short- versus long-term medication effects, nonstimulant pathways are diverse, and clinical ratings were unavailable to infer treatment response or disorder/diagnostic specificity.
  • Evident from the text: nonstimulant evidence came from only 9 studies versus 19 stimulant studies, limiting power for nonstimulant-specific and comparative conclusions.
  • Evident from the text: medication effects were pooled across within-subject, between-subject, and mixed designs, which the authors note may contribute to heterogeneity.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1017/s003329172400285x

Cites

118 of 118 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

36 of 91 cited sources checked · 5 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    The normalization effects of stimulants could also modulate frontolimbic abnormalities.

    “the normalization effects of stimulants could also modulate the frontolimbic abnormalities (Wiguna, Guerrero, Wibisono, & Sastroasmoro, 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wiguna, Guerrero, Wibisono, & Sastroasmoro, 2014 source

      The Results report reduced glutamate-to-creatine ratios in both amygdalae after 12 weeks of methylphenidate, and the Introduction discusses prefrontal–limbic abnormalities in children with ADHD. But the study measured the amygdala, not frontolimbic circuitry, and had no healthy control group to establish normalization (Discussion). It supports a possible limbic effect, not the broader normalization claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Both stimulants and nonstimulants may act on brain frontoparietal circuitry to ameliorate the dysfunction of cognitive control and attention in ADHD individuals.

    “Taken together, both stimulants and nonstimulants may act on brain frontoparietal circuity to ameliorate the dysfunction of cognitive control and attention in ADHD individuals (Cubillo et al., 2014; Fu et al., 2022; Tomasi et al., 2011)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Cubillo et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Fu et al., 2022

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tomasi et al., 2011 source

      The Results and Discussion (page numbers unavailable) report that methylphenidate, a stimulant, increased activation in frontal and parietal attention-network regions during attention and working-memory tasks. The study tested healthy controls, not people with ADHD; it did not test nonstimulants or show that either drug class ameliorates cognitive-control dysfunction in ADHD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Stimulants may upregulate neuroimaging activation patterns in the left cerebellum compared to controls given their indirect phosphorylation of the glutamate receptor through modulating the release of norepinephrine.

    “Our study reveals that stimulants may upregulate neuroimaging activation patterns in the left cerebellum compared to controls given their indirect phosphorylation of the glutamate receptor through modulating the release of norepinephrine”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Arnsten & Dudley, 2005 source

      The Background and Discussion (pages unavailable) say that methylphenidate and amphetamine increase norepinephrine in the rat prefrontal cortex. The paper does not link this effect to glutamate-receptor phosphorylation or report increased left-cerebellar neuroimaging activation relative to controls; the latter is framed as the citing authors’ own finding. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Cutando et al., 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Interpretationcitation

    Underactivated MCC in ADHD individuals may be connected with the core symptom of inattention.

    “Underactivated MCC in ADHD individuals may be construed as connected with the core symptom of inattention”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Emond, Joyal, & Poissant, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rolls, 2019 source

      In the section “Midcingulate cortex, the cingulate motor area, and action–outcome learning” (page unavailable), the paper suggests that anterior MCC activity helps direct attention and is relevant to ADHD. It does not report that the MCC is underactivated in people with ADHD or specifically link such underactivation to inattention. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Vossel, Geng, & Fink, 2014 source

      The Introduction and Conclusions discuss attention networks, while the Dorsal–Ventral Interactions section discusses altered activity in patients with spatial neglect. Searches for ADHD, MCC or midcingulate cortex, and inattention found no passage connecting MCC underactivation in ADHD to inattention. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The overlapping mechanism between the neuropharmacological effects of stimulants and nonstimulants was mapped in the inhibited activation patterns of the left SMA that coactivated with the CEN.

    “the overlapping mechanism between the neuropharmacological effects of stimulants and nonstimulants was mapped in the inhibited activation patterns of the left SMA that coactivated with the CEN.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Schulz et al., 2012 source

      The Results (Neural Correlates of Symptomatic Improvement; page unavailable) link improvement with reduced activation in the left and right motor cortices for both treatments. But they report divergent changes in the left anterior cingulate/supplementary motor area—activation increased with atomoxetine and decreased with methylphenidate. Our copy does not identify coactivation with the CEN. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 19
  • May combine two claims. 25

  • Classified as probably not a substantial claim.

    Premisecitation

    It remains unknown whether dissociable therapeutic responses to medications are mediated by shared or distinct neural underpinnings.

    “However, it remains unknown whether dissociable therapeutic responses to medications are mediated by shared or distinct neural underpinnings”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Chou, Chia, Shang, & Gau, 2015 source
    • cites Schulz et al., 2012 source

      The Results (Neural Correlates of Symptomatic Improvement; page unavailable) report both common and unique changes in neural activation associated with improvement under atomoxetine and methylphenidate. The Comment likewise identifies a common motor-cortex mechanism and distinct frontoparietal mechanisms in youth with ADHD. For these medications and this population, the paper addresses rather than leaves unknown whether the neural underpinnings are shared or distinct. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Smith et al., 2013 source

  • May combine two claims.

    Premisecitation

    Age and sex influence the effectiveness of medication treatment.

    “At the same time, the factors of age and sex also complicate individual medication selection as they influence the effectiveness of medication treatment (Childress, Newcorn, & Cutler, 2019; Dafny & Yang, 2006; Wigal, Kollins, Childress, & Adeyi, 2010).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Childress, Newcorn, & Cutler, 2019 source

      The Conclusion (page not provided) says boys and girls with ADHD responded equally well to racemic amphetamine sulfate, with comparable onset and duration of effect. The Results found no significant or consistent difference in effect size by gender, apart from isolated treatment-by-gender interactions at 2 hours. The paper does not establish that age influences treatment effectiveness. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Dafny & Yang, 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Wigal, Kollins, Childress, & Adeyi, 2010 source

      The Background describes mixed evidence on whether age and sex moderate ADHD medication response, including a study reporting sex differences in response to methylphenidate. But this paper’s Discussion (Effects of age; Effects of Sex, pages unavailable) says both age groups responded to lisdexamfetamine and found no consistent treatment-by-sex interactions. It therefore does not establish the broad claim that both factors influence medication effectiveness or complicate individual medication selection. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ADHD is characterized by problems of inattention, impulsivity, and hyperactivity.

    “attention-deficit/hyperactivity disorder (ADHD) is characterized by problems of inattention, impulsivity, and hyperactivity (Battle, 2013)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Battle, 2013 source

      The passage listing DSM-V neurodevelopmental disorders names Attention Deficit/Hyperactivity Disorder but does not describe its symptoms. Searches for inattention, impulsivity, hyperactivity, and ADHD diagnostic criteria found no passage in our copy that characterizes ADHD as the claim does. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    The systematic review and meta-analysis followed PRISMA guidelines.

    “This preregistered systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher, Liberati, Tetzlaff, & Altman, 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Moher, Liberati, Tetzlaff, & Altman, 2009 source

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

    Premisecitation

    Psychostimulants, such as methylphenidate, are widely prescribed to ameliorate ADHD symptoms, at least in improving attention span and reducing distractibility.

    “Psychostimulants, such as methylphenidate, are widely prescribed to ameliorate ADHD symptoms, at least in improving attention span and reducing distractibility (Janssen et al., 2016).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Janssen et al., 2016 source

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

    Study design and conductcitation

    A Jackknife analysis was performed to assess the robustness of the main findings.

    “To assess the robustness of our main findings, we performed a Jackknife analysis, which consists of repeating the statistical analyses by discarding one study each time, thus demonstrating the stability of the results (Müller et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Müller et al., 2018 source

  • May combine two claims.

    Interpretationcitation

    The normalization of SMA activation patterns may correspond directly to drug action given the massive presence of DAT and NET expression in the motor cortex, while also being associated with indirect and downstream effects modulated by responses of the prefrontal cortex.

    “The normalization of SMA activation patterns may correspond directly to drug action given the massive presence in DAT and NET expression in the motor cortex, while also being associated with indirect and downstream effects modulated by responses of the prefrontal cortex”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Lewis et al., 2001

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Peterson et al., 2009 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Schulz et al., 2012 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Abnormalities of the anterior cingulate cortex and supplementary motor area regions were normalized along with improved capacity of self-regulatory control in stimulant treatment.

    “Due to localized effects at DAT sites corresponding to the action of stimulants (Ciliax et al., 1999; Schou et al., 2005), abnormalities of the anterior cingulate cortex (ACC) and supplementary motor area (SMA) regions were normalized along with improved capacity of self-regulatory control (Baldaçara, Borgio, De Lacerda, & Jackowski, 2008; Fan, McCandliss, Fossella, Flombaum, & Posner, 2005; Posn”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Baldaçara, Borgio, De Lacerda, & Jackowski, 2008 source

      Section 6 (Attention deficit hyperactivity disorder; page unavailable) reports anterior cingulate cortex abnormalities in adults with ADHD. It does not report supplementary motor area abnormalities or improved self-regulatory control with stimulant treatment. The section says the brain-volume findings it discusses appeared unrelated to stimulant treatment, so it does not support the claimed treatment-related normalization. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Fan, McCandliss, Fossella, Flombaum, & Posner, 2005 source
    • cites Rubia et al., 2014 source

      The Results (Normalization Effects; page not provided) report that methylphenidate eliminated the SMA activation difference from controls in a timing task, but a smaller ACC difference remained. The same section reports faster stop-signal responses under methylphenidate, while the Discussion notes that only some studies found performance improvements. The source therefore supports some neural and behavioral effects, but not full normalization of both regions alongside a general improvement in self-regulatory control. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    The shared and distinct substrates of stimulant and nonstimulant effects may delineate a novel therapeutic target for effective interventions and could account for different therapeutic responses to stimulants and nonstimulants among individuals with ADHD.

    “These shared and distinct substrates may delineate a novel therapeutic target for effective interventions and could account for different therapeutic responses to stimulants and nonstimulants among individuals with ADHD”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Newcorn et al., 2008 source
    • cites Schulz et al., 2012 source

  • May combine two claims.

    Premisecitation

    Nonstimulants have downstream effects that modulate activation patterns of frontoparietal regions through extracellular catecholamine and indirect effects that regulate brain connectivity patterns of the central executive network and default mode network.

    “Besides, they also have downstream effects that modulate the activation patterns of frontoparietal regions through extracellular catecholamine and indirect effects that regulate the brain connectivity patterns of the central executive network and default mode network (Borchert et al., 2019; Farr et al., 2014; Lin & Gau, 2015; Schulz et al., 2012; Shafritz et al., 2004).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Borchert et al., 2019 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Farr et al., 2014 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Lin & Gau, 2015 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Stimulants may improve cingulate dysfunction through bidirectional remediation by dopaminergic modulation, and the DA system controlled by cholinergic receptors in the MCC is a likely target.

    “the normalization effects of stimulants aligning with the underactivity of MCC echoes previous evidence that stimulants may improve cingulate dysfunction through bidirectional remediation by dopaminergic modulation, and the DA system controlled by cholinergic receptors in the MCC is a likely target”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Murray et al., 2019 source

      The Discussion (page not provided) reports that dopaminergic drugs reduced exaggerated anterior cingulate prediction-error responses in patients with OCD. The study used pramipexole and amisulpride, not stimulants, and does not identify cholinergic receptors in the MCC as a target. It also concerns anterior cingulate overactivity rather than MCC underactivity. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Vogt, 2019 source

  • May combine two claims.

    Premisecitation

    Stimulants and nonstimulants act to alter the abnormal neural responses in ADHD patients through α2-adrenergic and dopamine D1 receptors to improve cognitive functions through the reactivity of the prefrontal cortex based on its high sensitivity to catecholamines.

    “stimulants and nonstimulants act to alter the abnormal neural responses in ADHD patients through α2-adrenergic and dopamine D1 receptors to improve cognitive functions through the reactivity of the prefrontal cortex based on its high sensitivity to catecholamines”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Gamo, Wang, & Arnsten, 2010 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Schulz et al., 2012 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In the ADHD group with nonstimulants, activation in the right caudate was inhibited, unlike stimulant action in the same region.

    “In the ADHD group with nonstimulants, activation in the right caudate was inhibited, unlike stimulant action in the same region”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rubia et al., 2014 source

      The Discussion (page unavailable) says methylphenidate enhanced caudate activation during inhibition, supporting the stimulant side of the comparison. The paper does not report that nonstimulants inhibited right caudate activation in ADHD; its meta-analysis compares stimulants with placebo or off-medication, not with nonstimulants. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The MCC is considered a key area of emotion and cognition processing and subserves bottom-up attention diversion.

    “the MCC is considered a key area of emotion and cognition processing and subserves bottom-up attention diversion”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Emond, Joyal, & Poissant, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rolls, 2019 source

      The section on the midcingulate cortex (page unavailable) links it to emotion, action–outcome learning, error monitoring, and modulation of executive regions that direct attention. It does not describe the MCC as subserving bottom-up attention diversion; the attention passage instead concerns goal and feedback information modulating executive regions. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Vossel, Geng, & Fink, 2014 source

      The section “Reorienting Responses and Filtering in the Ventral System” discusses stimulus-driven attention, but does not assign that function to the MCC. Searches for “MCC,” “midcingulate,” and emotion-and-cognition processing found no passage in our copy addressing the claimed role of the MCC; page numbers were not available. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Stimulants act on the amygdala, which is distributed with monoamine transporters, and strengthen the current of cortico-amygdala synapses, which enhance emotional memory retention and learning performance.

    “stimulants act on the amygdala, which is distributed with monoamine transporters (i.e. DAT and NET inhabitation) and strengthen the current of cortico-amygdala synapses, which enhance emotional memory retention and learning performance”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Smith & Porrino, 2008 source
    • cites Tye et al., 2010 source

      The Results and Discussion (page not available) show that methylphenidate and a selective DAT inhibitor strengthen cortico-amygdala synapses and improve cue-reward learning performance in rats. They distinguish this acute effect from the improved memory retention observed with NET inhibition; the paper does not show that synaptic strengthening enhances emotional memory retention. The claim also generalizes findings about methylphenidate and specific inhibitors to stimulants broadly. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Nineteen stimulant-specific and nine nonstimulant-specific studies were included.

    “In total, 19 studies specific to stimulants and 9 studies specific to nonstimulants were included after a systematic literature search”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The treatment responses to stimulants and nonstimulants showed inverse activation patterns in the amygdala, MCC and SFG for ADHD individuals, and the distinct patterns mainly overlaid brain networks of the VAN and AFN.

    “The treatment responses to stimulants and nonstimulants showed inverse activation patterns in the amygdala, MCC and SFG for ADHD individuals, and the distinct patterns mainly overlaid brain networks of the VAN and AFN.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The brain networks (VAN, AFN, CEN) used to interpret the findings are valid constructs.

  • May combine two claims.

    Findingown data

    Subgroup analysis on children with ADHD yielded consistent findings in the increased activation in the left cerebellum induced by stimulants and the reduced activation in the left SFG induced by nonstimulant compared to the pooling findings.

    “Subgroup analysis on children with ADHD yielded consistent findings in the increased activation in the left cerebellum induced by stimulants and the reduced activation in the left SFG induced by nonstimulant compared to our pooling findings.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Egger's tests revealed no potential publication bias in the separate analysis of the stimulant group, and funnel plots were symmetric across all clusters.

    “Egger's tests revealed no potential publication bias (p > 0.10) identified in the separate analysis of the stimulant group, and funnel plots were found to be symmetric across all clusters (Online Supplementary Table S2).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    AES-SDM is a statistical technique and toolbox to identify neural abnormalities on account of voxel-based neuroimaging meta-analysis.

    “AES-SDM is a statistical technique and toolbox to identify neural abnormalities on account of voxel-based neuroimaging meta-analysis (Zhao, Yang, Gong, Cao, & Liu, 2022).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao, Yang, Gong, Cao, & Liu, 2022

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductcitation

    All included studies were evaluated with a 12-point Imaging Methodology Quality Assessment Checklist.

    “We evaluated all included studies with a 12-point Imaging Methodology Quality Assessment Checklist for their quality and limitations to infer the importance of those findings (Shepherd, Matheson, Laurens, Carr, & Green, 2012)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shepherd, Matheson, Laurens, Carr, & Green, 2012 source

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

    Premisecitation

    ADHD approximately affects 84.7 million individuals worldwide.

    “which approximately affect 84.7 million individuals worldwide (Collaborators, 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Collaborators, 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    For individuals who respond poorly to stimulants, nonstimulant alternatives may be considered, including norepinephrine modulators like atomoxetine and certain antidepressants such as bupropion.

    “For individuals who respond poorly to stimulants, nonstimulant alternatives may be considered, including norepinephrine modulators like atomoxetine and certain antidepressants such as bupropion. (Mechler, Banaschewski, Hohmann, & Häge, 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mechler, Banaschewski, Hohmann, & Häge, 2022 source

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

    Premisecitation

    The seven brain networks used in large-scale network analysis represent a typical integration and segmentation of cerebral functional parcellation.

    “We dropped those identified clusters to seven brain networks that represent a typical integration and segmentation of the cerebral functional parcellation, including the default mode network (DMN), dorsal attention network (DAN), central executive network (CEN), affective network (AFN), sensorimotor network (SMN), ventral attention network (VAN), and visual network (VN) (Yeo et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yeo et al., 2011 source

  • May combine two claims.

    Interpretationreasoning

    These findings documented similarities in the neural pharmacological effects of stimulants and nonstimulants, which refined the understanding of brain alterations from medication effects that lead to the shared efficacy of both classes of ADHD medications.

    “These findings documented similarities in the neural pharmacological effects of stimulants and nonstimulants, which refined the understanding of brain alterations from medication effects that lead to the shared efficacy of both classes of ADHD medications.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The research protocol was pre-registered on the Open Scientific Framework before obtaining datasets.

    “We pre-registered the research protocol on the Open Scientific Framework (https://osf.io/65vn4, registration DOI: https://doi.org/10.17605/OSF.IO/65VN4) before obtaining datasets.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The literature search was systematically and comprehensively conducted in PubMed, Medline and Web of Science before May 8, 2022.

    “The literature search was systematically and comprehensively conducted in the PubMed, Medline and Web of Science databases before May 8, 2022”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Approximately 56% of ADHD cases may achieve clinical improvement with stimulants, while 45% of cases achieve so with non-stimulants.

    “approximately 56% of ADHD cases may achieve clinical improvement with stimulants, while 45% of cases achieve so with non-stimulants (Mechler et al., 2022; Newcorn et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mechler et al., 2022 source
    • cites Newcorn et al., 2008 source

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

    Study design and conductcitation

    Funnel plots and Egger's test were used to detect potential publication biases.

    “We used funnel plots and Egger's test to detect potential publication biases (Egger, Davey Smith, Schneider, & Minder, 1997; Peters, Sutton, Jones, Abrams, & Rushton, 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Egger, Davey Smith, Schneider, & Minder, 1997 source
    • cites Peters, Sutton, Jones, Abrams, & Rushton, 2008 source

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The neuroimaging findings may have implications for individualized medication strategies and enhance treatment response by precisely matching therapeutic targets.

    “Our neuroimaging findings may have implications for individualized medication strategies and enhance treatment response by precisely matching therapeutic targets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The convergence of psychostimulant and nonstimulant effects on the left SMA may delineate a novel therapeutic target for effective interventions for ADHD, and these distinct neural substrates could account for individual differences in therapeutic responses.

    “The convergence of psychostimulant and nonstimulant effects on the left SMA may delineate a novel therapeutic target for effective interventions for ADHD, and these distinct neural substrates could account for individual differences in therapeutic responses.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The authors were unable to obtain clinical ratings to speculate treatment responses of ADHD medications based on reanalyzed neuroimaging datasets.

    “we were unable to obtain clinical ratings to speculate treatment responses of ADHD medications based on reanalyzed neuroimaging datasets”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The SMA sends its output to the primary motor cortex to produce motor sequences.

    “SMA sends its output to the primary motor cortex to produce motor sequences”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Côté, Elgbeili, Quessy, & Dancause, 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Dum & Strick, 2002 source

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

    Premisecitation

    The AFN (also called the limbic system) has long been regarded as having an integral role in emotion-based decision-making, reward and motivation.

    “The AFN (also called the limbic system) has long been regarded as having an integral role in emotion-based decision-making, reward and motivation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites LeDoux, 2000 source
    • cites Phelps, 2006 source

  • May combine two claims.

    Premisecitation

    Longitudinal studies on ADHD patients reported age-dependent amelioration of symptoms of hyperactivity, and those adults may develop hypo-responsiveness or resistance to psychostimulants induced by specified developmental trajectories.

    “Longitudinal studies on ADHD patients reported age-dependent amelioration of symptoms of hyperactivity, and those adults may develop hypo-responsiveness or resistance to psychostimulants induced by specified developmental trajectories”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Biederman, Mick, & Faraone, 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rubia et al., 2000 source
    • cites Santosh & Taylor, 2000 source

  • May combine two claims.

    Premisecitation

    The SMA acts as a top-down hub that integrates information from the parietal and frontal lobes, corresponding to task selection and behavior control of CEN functioning.

    “SMA acts as a top-down hub that integrates information from the parietal and frontal lobes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bari & Robbins, 2013 source

  • May combine two claims.

    Premisecitation

    Both stimulant and nonstimulant medications used for ADHD have been shown to decrease cortical inhibition and increase cortical facilitation in the SMA.

    “Both stimulant and nonstimulant medications used for ADHD have been shown to decrease cortical inhibition and increase cortical facilitation in the SMA”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gilbert et al., 2006 source

  • May combine two claims.

    Interpretationcitation

    Reduced activations of the right SMA play a role in compensatory mechanisms in ADHD adults and they may not need the intervention of stimulants to improve hyperactivity deficits.

    “suggesting that reduced activations of the right SMA play a role in compensatory mechanisms in ADHD adults and that they may not need the intervention of stimulants to improve hyperactivity deficits”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hart, Radua, Nakao, Mataix-Cols, & Rubia, 2013 source

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

    Premisecitation

    The neuropharmacological pathways of nonstimulants are notably diverse, yet they all converge on targeting the norepinephrine transporter in some capacity for the treatment of ADHD.

    “the neuropharmacological pathways of nonstimulants are notably diverse, yet they all converge on targeting the norepinephrine transporter in some capacity for the treatment of ADHD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Newcorn, Krone, & Dittmann, 2022 source
39 of 39

  • The paper relies on this without support.

    Psychostimulants exert their therapeutic effects as indirect catecholamine agonists by blocking the dopamine transporter (DAT) and norepinephrine transporter (NET), and atomoxetine is a selective NET inhibitor.

    “From a neurobiological perspective, psychostimulants exert their therapeutic effects as indirect catecholamine agonists by blocking the dopamine transporter (DAT) and norepinephrine transporter (NET), and atomoxetine, the most commonly used nonstimulant for ADHD treatment, is a selective NET inhibitor.”

  • The paper relies on this without support.

    Treatment with methylphenidate and atomoxetine produces clinical improvement for ADHD via both common and divergent neurophysiologic actions in frontoparietal regions.

    “Functional magnetic resonance imaging (fMRI) studies have found that treatment with methylphenidate and atomoxetine produces clinical improvement for ADHD via both common and divergent neurophysiologic actions in frontoparietal regions.”

  • The paper relies on this without support.

    Psychostimulants work by increasing levels of specific neurotransmitters in the brain, especially dopamine and norepinephrine.

    “These medications work by increasing levels of specific neurotransmitters in the brain, especially dopamine and norepinephrine.”

  • The paper relies on this without support.

    Individualized management for ADHD cases in clinical settings is still hard to achieve due to the elusive neuropsychological mechanisms of first-line medications.

    “However, individualized management for ADHD cases in clinical settings is still hard to achieve due to the elusive neuropsychological mechanisms of first-line medications.”

  • The paper relies on this without support.

    The lack of evidence linking pharmacologic actions to neural correlates and therapeutic improvement provides limited opportunity to understand how these medications work in the brain.

    “The lack of evidence linking pharmacologic actions to neural correlates and therapeutic improvement provides limited opportunity to understand how these medications work in the brain, which is an essential step in developing targeted approaches to treatment.”

  • The paper relies on this without support.

    Pooling neuroimaging studies that used different cognitive tasks (cognitive control, working memory, attention) yields interpretable medication effects.

    “most included studies evaluated cognitive control function, while others measured working memory and attention problems”

  • The paper relies on this without support.

    Pooling randomized controlled and cross-sectional trials yields interpretable medication effects.

    “various protocol designs of the included studies with both randomized controlled and cross-sectional trials may also contribute to the heterogeneity”

  • The paper relies on this without support.

    The brain networks (VAN, AFN, CEN) used to interpret the findings are valid constructs.

    “These regions are distributed within the VAN (%RD: 15.08%, Table 2 and Fig. 2).”
    “the distinct patterns mainly overlaid brain networks of the VAN and AFN.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Out of the nine meta-analyzed fMRI studies that examined non-stimulants, eight studies tested atomoxetine and only one study tested guanfacine.

    “However, out of the nine meta-analyzed fMRI studies that examined non-stimulants, eight studies tested atomoxetine and only one study tested guanfacine.”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [93]

    The Results (‘Included studies and sample characteristics’; page unavailable) report nine nonstimulant studies, but Table 1 lists one fluoxetine study as well as the guanfacine study. It lists seven distinct atomoxetine studies; Fan et al. (2017) appears twice for different tasks. The claimed eight-atomoxetine, one-guanfacine breakdown therefore omits fluoxetine and counts Fan twice. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Tailoring pharmacotherapy to comorbidity patterns (anxiety, insomnia, cardiovascular disease) enhances both safety and efficacy.

    “Tailoring pharmacotherapy to comorbidity patterns—such as anxiety, insomnia, or cardiovascular disease—enhances both safety and efficacy [155,158].”

    From ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives (2025) · cites this paper as [158]

    The Introduction and Conclusion (pages unavailable) suggest that neuroimaging findings may inform individualized ADHD medication strategies and improve treatment response. They do not address tailoring treatment to anxiety, insomnia, or cardiovascular disease, assess safety, or show that such tailoring enhances efficacy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A recent fMRI comparative meta-analysis of 29 fMRI studies of stimulants (20 studies) and non-stimulants (9 studies) showed overlapping but also differential drug effects.

    “Furthermore, a recent fMRI comparative meta-analysis of 29 fMRI studies of stimulants (20 studies) and of non-stimulants (9 studies) showed overlapping but also differential drug effects.”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [93]

    The Results (Included studies and sample characteristics; page unavailable) report 19 stimulant studies and 9 nonstimulant studies, for 28 studies—not 20 and 9, for 29. The Discussion reports overlapping and distinct effects on brain activation, so the substantive finding is supported, but the study counts are not. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Non-stimulants on their own reduced left prefrontal and caudate activations.

    “Non-stimulants on their own reduced left prefrontal and caudate activations which could potentially be an underlying mechanism for the here observed worsening of cognitive attention measures of RTV (and eventual sustained attention) with guanfacine.”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [93]

    The Results section (‘Stimulant- and nonstimulant-specific brain effects’; page unavailable) reports reduced activation in the left superior frontal gyrus, a prefrontal region, and the right caudate in ADHD youth receiving nonstimulants. If ‘left’ modifies both regions in the claim, the caudate laterality is incorrect: the paper reports the right caudate, not the left. The proposed link to worsening attention with guanfacine is the citing authors’ speculation, not a finding attributed to this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In the meta-analysis, both drugs normalized left SMA activation which overlapped with regions of the central executive control, but only non-stimulants normalized regions of the ventral attention and limbic systems (i.e. left superior frontal and mid-cingulate cortices and left amygdala).

    “While both drugs normalized left SMA activation which overlapped with regions of the central executive control, only non-stimulants normalized regions of the ventral attention and limbic systems (i.e. left superior frontal and mid-cingulate cortices and left amygdala).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [93]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Not confirmedz = 1.21reported p < .0001 · recomputed p = .226

    “(Z = 1.21, p < .0001”

  • Not confirmedz = 1.3reported p = .0006 · recomputed p = .194

    “(Z = 1.30, p = .0006”

  • Not confirmedz = 1.22reported p = .0008 · recomputed p = .222

    “(Z = 1.22, p = .0008”

  • Not confirmedz = 1.27reported p = .0006 · recomputed p = .204

    “(Z = 1.27, p = .0006”

4 of 4

Self-check

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

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

  • Shared left SMA effect is described with opposite directions

    Minor

    The Results describe the shared stimulant and nonstimulant effect as increased left SMA activation, whereas the Discussion calls the overlapping effect inhibited activation.

  • Right SMA Z value differs between Results and Table 2

    Minor

    The medication-specific Results give Z = 1.226 for the right SMA cluster at 18, −6, 68; Table 2 gives Z = 1.266 for the same cluster.

  • Subcluster counts exceed the reported cluster size

    Minor

    The three listed subclusters contain 402 voxels in total, exceeding the reported 356-voxel cluster.

    Reported 356 · recomputed 402

  • Abstract misreports the superior frontal gyrus statistics

    Minor

    The abstract assigns the superior frontal gyrus Z = 1.27 and p = 0.0006, but Table 2 reports Z = 1.243 and p = 0.0007 for that region.

  • Nonstimulant cingulate peak has conflicting z-coordinates

    Minor

    The Results place the 2557-voxel nonstimulant cingulate cluster's peak at z = −10, while Table 2 places it at z = 16.

  • Cluster-size inclusion thresholds conflict

    Minor

    The Methods say medication-specific clusters were counted only if they exceeded 10 voxels, but Table 2 states that suprathreshold clusters required more than 20 voxels.

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. 10.1016/j.euroneuro.2015.08.024 · DOI · Paper page
  2. Prehn-Kristensen, 2011, Brain Research, 1388, 56
  3. Battle, 2013, CoDAS, 25, 191
  4. 10.1093/cercor/bhs296 · DOI · Paper page
  5. 10.1016/j.euroneuro.2019.07.139 · DOI · Paper page
  6. 10.1093/cercor/bhs296 · DOI · Paper page
  7. 10.1017/s0033291713000676 · DOI · Paper page
  8. 10.1176/appi.ajp.2009.08050724 · DOI · Paper page
  9. 10.1016/j.euroneuro.2015.08.024 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Pan, N., Ma, T., Liu, Y., Zhang, S., Hu, S., Shekara, A., Cao, H., Gong, Q., & Chen, Y.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Sichuan University (CN)
  • University of Cincinnati (US)
  • Feinstein Institute for Medical Research (US)
Corresponding author
  • Gong, Qiyong
  • Chen, Ying
ORCID
Venue
Psychological Medicine
Publisher
Cambridge University Press (CUP)
Published
2024-12
Volume
54
Issue
16
Pages
4676-4690
ISSN
  • 0033-2917 (ISSN-L)
  • 1469-8978
DOI
10.1017/s003329172400285x
PMC
PMC11769909
OpenAlex
W4406382006
Semantic Scholar
3a2dc5427db744aa3b3e5667a4c91f0509a63908
Cited by
7
References
114
Citations by year
2026: 3 · 2025: 4
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Psychological Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
National Natural Science Foundation of China (81801358, 823B2041, 81820108018, 81621003, 82027808)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
attention deficit hyperactivity disorder, psychostimulants, non-stimulant medication, supplementary motor area, amygdala, ventral attention network, frontoparietal network, brain activation patterns, sex differences, age effects, neurodevelopmental trajectories, therapeutic target
MeSH terms
Amygdala, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Brain, Child, Female, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Functional Neuroimaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-29.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-29.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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