Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress.
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ABSTRACT:
SUBMITTER: Swanson J
PROVIDER: S-EPMC3055506 | biostudies-other | 2011 Jan
REPOSITORIES: biostudies-other
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Project description:The cerebellum is emerging as a key anatomical structure underlying normal attentional and cognitive control mechanisms. Dysregulation within cerebellar circuits may contribute to the core symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). In the present study we aimed to characterize surface morphological features of the cerebellum in ADHD and healthy comparison youths. Further, we studied the association of cerebellar morphology with the severity of ADHD symptoms and the effects of stimulant treatment. We examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional, case-control study using magnetic resonance imaging. Measures of cerebellar surface morphology were the primary outcome. Relative to comparison participants, youths with ADHD exhibited smaller regional volumes corresponding to the lateral surface of the left anterior and the right posterior cerebellar hemispheres. Stimulant medication was associated with larger regional volumes over the left cerebellar surface, whereas more severe ADHD symptoms were associated with smaller regional volumes in the vermis. We used optimized measures of morphology to detect alterations in cerebellar anatomy specific to ADHD, dimensions of symptomology, and stimulant treatment. Duration of treatment correlated positively with volumes of specific cerebellar subregions, supporting a model whereby compensatory morphological changes support the effects of stimulant treatment.
| S-EPMC3895250 | biostudies-literature
Project description:Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence (ND). It remains unclear whether and how stimulant treatment may affect this risk. We aimed to investigate how stimulant use profiles influence the risk of SUDs and ND, using a novel data-driven community detection analysis to construct different stimulant use profiles. Comprehensive lifetime stimulant prescription data and data on SUDs and ND were available for 303 subjects with ADHD and 219 controls, with a mean age 16.3 years. Community detection was used to define subgroups based on multiple indicators of treatment history, start age, treatment duration, total dose, maximum dose, variability, stop age. In stimulant-treated participants, three subgroups with distinct medication trajectories were distinguished (late-and-moderately dosed, n?=?91; early-and-moderately dosed, n?=?51; early-and-intensely dosed, n?=?103). Compared to stimulant-naïve participants (n?=?58), the early-and-intense treatment group had a significantly lower risk of SUDs and ND (HR?=?0.28, and HR?=?0.29, respectively), while the early-and-moderate group had a significantly lower risk of ND only (HR?=?0.30). The late-and-moderate group was at a significantly higher risk of ND compared to the other two treatment groups (HR?=?2.66 for early-and-moderate, HR?=?2.78 for early-and-intense). Our findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.
| S-EPMC6751155 | biostudies-literature
Project description:We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD.
| S-EPMC4484811 | biostudies-literature
Project description:Symptoms of attention-deficit/hyperactivity disorder (ADHD) run a variable course through adolescence. While most affected individuals show some improvement, particularly of hyperactivity-impulsivity, symptoms of inattention are more persistent, and some individuals may meet diagnostic criteria for the first time during adolescence. Genetic factors affect adolescent symptom trajectories; those showing persistence likely carry a greater burden of common risk alleles. Rare structural genomic variants, such as copy number variants and point mutations, might also play a role. Although psychostimulant medication is associated with better functional outcomes, an impact on underlying adolescent symptom trajectories has been hard to demonstrate. At a neural level, several studies report that adolescents whose childhood ADHD symptoms have remitted are indistinguishable from neurotypical individuals. This finding could reflect the "carrying forward" of relatively typical childhood neural features among those destined for adolescent remission or the correction of early childhood anomalies with a convergence toward typical dimensions. Other studies have noted unique, possibly compensatory patterns of neural activity among adolescents whose ADHD has improved. Finally, different neural processes might occur in different brain regions. Thus, some functional imaging studies find that subcortical anomalies reflect the onset of ADHD and remain throughout life regardless of symptom change, whereas the variable clinical course of adolescent ADHD is determined by plasticity of the cerebral cortex. Integrating an understanding of the neural processes with genomic risk could elucidate the mechanisms underlying the complex course of adolescent ADHD.
| S-EPMC7736482 | biostudies-literature
Project description:ObjectiveBecause models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.MethodAn 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.ResultsA total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.ConclusionCOMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273.
| S-EPMC4976782 | biostudies-literature
Project description:Working memory impairments are commonly found in attention-deficit/hyperactivity disorder (ADHD) and often improve with psychostimulant treatment. Little is known about how these medications affect the function of frontoparietal brain regions engaged for working memory. This study used functional magnetic resonance imaging (fMRI) to examine medication-related changes in brain activation and functional connectivity in ADHD.Eighteen ADHD-combined subtype youths (ages 11-17) twice completed a Sternberg working memory fMRI task in a randomized, double-blind, placebo-controlled design. Medications were individualized as patients' standard, clinically effective psychostimulant (e.g., methylphenidate or dextroamphetamine/amphetamine combination) dose. Brain activity and functional connectivity were characterized using group independent component analysis. SPM5 repeated-measures t tests compared ADHD patients' network engagement and regional functional connectivity on and off medication.Independent component analysis identified six frontoparietal networks/components with hemodynamic responses to encoding/maintenance or retrieval phases of the Sternberg fMRI task. On medication, three of these networks significantly increased activation. Functional connectivity analyses found medication led to recruitment of additional brain regions that were not engaged into the networks when participants were on placebo. Also, medication strengthened connectivity of some frontoparietal regions. Many connectivity changes were directly related to improved working memory reaction time. Overall, there was strong evidence for regional functional connectivity changes following medication in structures previously implicated as abnormal in ADHD, such as anterior cingulate, ventrolateral prefrontal cortex, and precuneus.Stimulant medication has widespread effects on the functional connectivity of frontoparietal brain networks, which might be a mechanism that underlies their beneficial effects on working memory performance.
| S-EPMC4120250 | biostudies-literature
Project description:This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions.
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Project description:ObjectiveThe purposes of this study were to examine the impact of 3 weeks of amphetamine administration on intrinsic connectome-wide connectivity patterns in adults with attention-deficit/hyperactivity disorder (ADHD) and explore the association between stimulant-induced symptom improvement and functional connectivity alteration.MethodsParticipants included 19 adults (age 20-55 years) diagnosed with ADHD using the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria per the Adult Clinician Diagnostic Scale taking part in amphetamine trials. For each patient, two 6-minute resting-state functional magnetic resonance imaging (R-fMRI) scans were acquired at baseline and after treatment. A fully data-driven multivariate analytic approach (i.e., multivariate distance matrix regression [MDMR]) was applied to R-fMRI data to characterize the distributed pharmacological effects in the entire functional connectome. Clinical efficacy was assessed using ADHD rating scale with adult prompts and the Adult Self-Report Scale v1.1 Symptom Checklist. We linked stimulant-induced functional connectivity changes to symptom amelioration using Spearman's correlation.ResultsThree weeks of administration of a stimulant significantly reduced ADHD symptoms. MDMR-based analyses on R-fMRI data highlighted the left dorsolateral prefrontal cortex (DLPFC, a key cognitive control region) and the medial prefrontal cortex (MPFC, the anterior core of default network) whose distributed patterns of functional connectivity across the entire brain were altered by psychostimulants. Follow-up intrinsic functional connectivity revealed that stimulants specifically decreased the positive functional connectivity between DLPFC-insula, DLPFC-anterior cingulate cortex, and MPFC-insula. Importantly, these functional connectivity changes are associated with symptom improvement.ConclusionThese results suggested that ADHD is associated with increased functional integration or decreased functional segregation between core regions of cognitive control, default, and salience networks. The apparent normalization of intrinsic functional interaction in these circuits (i.e., increased functional segregation) may underlie the clinical benefits produced by 3 weeks of amphetamine treatment.
| S-EPMC4991601 | biostudies-literature
Project description:BackgroundWhile the neuroanatomic substrates of symptoms of attention deficit hyperactivity disorder (ADHD) have been investigated, less is known about the neuroanatomic correlates of cognitive abilities pertinent to the disorder, particularly in adults. Here we define the neuroanatomic correlates of key cognitive abilities and determine if there are associations with histories of psychostimulant medication.MethodsWe acquired neuroanatomic magnetic resonance imaging data from 264 members of 60 families (mean age 29.5; s.d. 18.4, 116 with ADHD). Using linear mixed model regression, we tested for associations between cognitive abilities (working memory, information processing, intelligence, and attention), symptoms and both cortical and subcortical volumes.ResultsSymptom severity was associated with spatial working memory (t = -3.77, p = 0.0002), processing speed (t = -2.95, p = 0.004) and a measure of impulsive responding (t = 2.19, p = 0.03); these associations did not vary with age (all p > 0.1). Neuroanatomic associations of cognition varied by task but centered on prefrontal, lateral parietal and temporal cortical regions, the thalamus and putamen. The neuroanatomic correlates of ADHD symptoms overlapped significantly with those of working memory (Dice's overlap coefficient: spatial, p = 0.003; verbal, p = 0.001) and information processing (p = 0.02). Psychostimulant medication history was associated with neither cognitive skills nor with a brain-cognition relationships.ConclusionsDiagnostic differences in the cognitive profile of ADHD does not vary significantly with age; nor were cognitive differences associated with psychostimulant medication history. The neuroanatomic substrates of working memory and information overlapped with those for symptoms within these extended families, consistent with a pathophysiological role for these cognitive skills in familial ADHD.
| S-EPMC6252155 | biostudies-literature
Project description:ImportanceChildhood suicidality (ie, suicidal ideation or attempts) rates are increasing, and attention-deficit/hyperactivity disorder (ADHD) and externalizing symptoms are common risk factors associated with suicidality. More data are needed to describe associations of ADHD pharmacotherapy with childhood suicidality.ObjectiveTo investigate the associations of ADHD pharmacotherapy with externalizing symptoms and childhood suicidality.Design, setting, and participantsIn this cohort study, cross-sectional and 1-year-longitudinal associations were examined using data (collected during 2016-2019) from the Adolescent Brain Cognitive Development (ABCD) Study, a large, diverse US sample of children aged 9 to 11 years. Data analysis was performed from November to December 2020.ExposuresMain and interaction associations of externalizing symptoms (hyperactivity ADHD symptoms, oppositional defiant, and conduct disorder symptoms) and ADHD medication treatment (methylphenidate and amphetamine derivatives, α-2-agonists, and atomoxetine) at baseline assessment.Main outcomes and measuresChild-reported suicidality (past and present at baseline; current at longitudinal assessment). Covariates were age, sex, race/ethnicity, parents' education, marital status, and concomitant child psychiatric pharmacotherapy (antidepressants and antipsychotics).ResultsAmong 11 878 children at baseline assessment (mean [SD] age, 9.9 [0.6] years; 6196 boys [52.2%]; 8805 White [74.1%]), 1006 (8.5%) were treated with ADHD medication and 1040 (8.8%) reported past or current suicidality. Externalizing symptoms (median [range], 1 [0-29] symptom count) were associated with suicidality (for a change of 1 SD in symptoms, odds ratio [OR], 1.34; 95% CI, 1.26-1.42; P < .001), as was ADHD medication treatment (OR, 1.32; 95% CI, 1.06-1.64; P = .01). ADHD medication use was associated with less suicidality in children with more externalizing symptoms (significant symptom-by-medication interaction, B = -0.250; SE = 0.086; P = .004), such that for children who were not receiving ADHD medications, there was an association between more externalizing symptoms and suicidality (for a change of 1 SD in symptoms, OR, 1.42; 95% CI, 1.33-1.52; P < .001); however, for children who were receiving ADHD medication, there was no such association (OR, 1.15; 95% CI, 0.97-1.35; P = .10). The association with medication remained even when covarying for multiple confounders, including risk and protective factors for suicidality in ABCD, and was replicated in 1-year longitudinal follow-up. Sensitivity analyses matching participants with high numbers of externalizing symptoms taking and not taking ADHD medication treatment confirmed its association with less suicidality.Conclusions and relevanceThese findings suggest that ADHD medication treatment is associated with less suicidality in children with substantial externalizing symptoms and may be used to inform childhood suicide prevention strategies.
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