Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit/hyperactivity disorder (ADHD) have been limited by use of callosal rather than sulcal/gyral landmarks in defining cerebral lobes and functionally relevant sublobar regions (e.g., prefrontal cortex). We present an investigation of cerebral volumes in ADHD using a Talairach-based approach that uses cortical landmarks to define functionally relevant regions. METHODS: Volumes were compared between groups of 12 boys with ADHD and 12 age- and gender-matched control subjects, using a series of multiple analyses of variance. RESULTS: Boys with ADHD had (on average) 8.3% smaller total cerebral volumes. Significant reductions in lobar volumes were seen only for the frontal lobes. Within the frontal lobes, a reduction was seen in both gray and white matter volumes, with some evidence suggesting lateralization of these findings: reduction in frontal white matter volume was specific to the left hemisphere; there was a bilateral reduction in frontal gray matter volume but more so in the right hemisphere. Subparcellation of the frontal lobe revealed smaller prefrontal, premotor, and deep white matter volumes. CONCLUSIONS: Findings suggest that ADHD is associated with decreased frontal lobe gray and white matter volumes. More than one subdivision of the frontal lobes appears to be reduced in volume, suggesting that the clinical picture of ADHD encompasses dysfunctions attributable to anomalous development of both premotor and prefrontal cortices.     

The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder.

BACKGROUND: The reported neuropsychological effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) are inconsistent. The assumed relationships between these neuropsychological effects and clinical efficacy have not been substantiated. We therefore investigated the effects of chronic MPH administration on neuropsychological functioning. METHODS: We conducted a 12-week, placebo-controlled, double-blinded, randomized, crossover trial (MPH .3 and .6 mg/kg/dose and placebo). Participants were 75 boys aged 7-15 years with ADHD. Neuropsychological performance was assessed with tests taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery and a GoNoGo task. RESULTS: Chronic MPH improved performance (p < .001) on aspects of the GoNoGo task (p < .02) and on three CANTAB tasks which together contributed to a "recognition memory" component identified through principal components analysis (delayed matching to sample [DMtS], pattern and spatial recognition). There were no effects on other, high or low "executive demand" tasks (p > .05). GoNoGo performance improvements were the only neuropsychopharmacological changes associated with clinical response. Poor performance on the DMtS task was the sole baseline neuropsychological predictor of clinical response. CONCLUSIONS: Chronic MPH predominantly enhanced neuropsychological functioning on "recognition memory" component tasks with modest "executive" demands. Neuropsychological measures offer only modest contributions to the prediction of clinical responses to MPH in ADHD.     

Visuospatial working memory underlies choice-impulsivity in boys with attention-deficit/hyperactivity disorder

The present study examined the directional relationship between choice-impulsivity and separate indices of phonological and visuospatial working memory performance in boys (aged 8–12 years) with (n = 16) and without ADHD (n = 19). Results indicated that high ratings of overall ADHD, inattention, and hyperactivity were significantly associated with increased impulsivity and poorer phonological and visuospatial working memory performance. Further, results from bias-corrected bootstrapped mediation analyses revealed a significant indirect effect of visuospatial working memory performance, through choice-impulsivity, on overall ADHD, inattention, and hyperactivity/impulsivity. Collectively, the findings suggest that deficits of visuospatial working memory underlie choice-impulsivity, which in turn contributes to the ADHD phenotype. Moreover, these findings are consistent with a growing body of literature that identifies working memory as a central neurocognitive deficit of ADHD.     

The 4-year course of tic disorders in boys with attention-deficit/hyperactivity disorder

BACKGROUND: Despite long-standing clinical concerns, relatively little is known about the comorbidity between attention-deficit/hyperactivity disorder (ADHD) and tic disorders. Therefore, we examined tic disorders in an ongoing prospective follow-up study of male subjects with ADHD, a sample unselected for any comorbid disorder. METHODS: One hundred twenty-eight male children and adolescents with ADHD and 110 male controls were comprehensively evaluated at baseline and 4 years later. We characterized tic disorders along with a wide range of neuropsychiatric correlates, including other comorbid disorders and indices of psychosocial function in multiple domains (school, cognitive, social, and family). RESULTS: Compared with controls, subjects with ADHD showed more tic disorders at baseline and more new onsets were reported at follow-up. Attention-deficit/hyperactivity disorder and tic disorders appeared to be independent in course: in contrast to low rates of ADHD remission, tic disorders mostly remitted. The age-adjusted rate of ADHD remission was 20% and that of tic remission, 65%. Tic disorders had little effect on the psychosocial functioning of subjects with ADHD. CONCLUSIONS: These findings suggest that comorbidity with a tic disorder has a limited effect on ADHD outcome. However, because of the relatively small sample of subjects with tic disorders, our conclusions should be considered preliminary until confirmed in larger studies of medicated and unmedicated children with ADHD with and without tic disorders.     

Methylphenidate treatment of attention-deficit hyperactivity disorder in boys with Tourette's syndrome

The effects of methylphenidate on four boys diagnosed as attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome (TS) were examined under single-blind, placebo-controlled conditions. Clinical ratings and playroom observations showed improvement in ADHD symptoms with methylphenidate. Results also indicated that methylphenidate had no untoward effects on the frequency of tic occurrence. In all four children, the highest dose resulted in improved classroom ratings of tics compared with initial placebo treatment. In three cases, mild tic exacerbation was reported for a lower dose. Because variability of tic status was observed in the experimental conditions, the findings suggest the possibility that tic response was independent of clinical doses of methylphenidate. The findings were also consistent with the theory that methylphenidate, a dopamine agonist, might effect tic status by altering dopamine receptor sensitivity. Further investigation of these effects is indicated, given the efficacy of methylphenidate in treating ADHD symptoms of TS patients.     

The neuropsychopharmacology of attention-deficit/hyperactivity disorder.

More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.     

Altered response control and anterior cingulate function in attention-deficit/hyperactivity disorder boys.

OBJECTIVE: To investigate mechanisms and structures underlying prefrontal response control and inhibition in boys suffering from attention-deficit/hyperactivity disorder (ADHD). METHOD: Sixteen boys with ADHD and 19 healthy controls were investigated electrophysiologically during performance of a visual Go-Nogo task (Continuous Performance Test, CPT). An electrophysiological source localization method was employed to further analyze the data. RESULTS: The ADHD boys showed a significantly diminished central Nogo-P3, due to a lack of Nogo-related frontalization of the positive brain electrical field in this group. This two-dimensional effect was associated with a significantly reduced activation of the anterior cingulate cortex (ACC) in the ADHD boys in the Nogo condition of the CPT. Both groups did not significantly differ regarding the amplitude of the Nogo-N2. CONCLUSIONS: The results indicate deficits in prefrontal response control in unmedicated ADHD boys that do not seem to be specifically inhibitory in nature. A supposed dysfunction of the ACC in ADHD was confirmed.     

A family study of psychiatric comorbidity in girls and boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Because attention-deficit/hyperactivity disorder (ADHD) is relatively infrequent among girls, little is known about the nature and causes of psychiatric comorbidity in girls and the reason for gender differences in the prevalence of these comorbidities. METHODS: Using blinded, structured psychiatric interviews, we studied two groups of boys: 140 ADHD probands and 120 non-ADHD comparisons. These groups had 454 and 368 first-degree biological relatives, respectively. We also studied two groups of girls: 140 ADHD probands and 122 non-ADHD comparisons. These groups had 417 and 369 first-degree biological relatives, respectively. RESULTS: The co-occurrence of ADHD and comorbid psychopathology in families was the same for families ascertained through boy and girl probands. CONCLUSIONS: Our results suggest that boys and girls do not differ in the familial risk factors that mediate comorbid psychopathology and the familial aggregation of comorbid disorders in ADHD families. Although this is consistent with prior work suggesting more similarities than differences in the nature of psychiatric comorbidity in ADHD boys and girls, we cannot make strong conclusions, owing to the possibility of cohort effects.     

Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence of methylphenidate

Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.     

Comprehensive examination of frontal regions in boys and girls with attention-deficit/hyperactivity disorder

The current study examined regional frontal lobe volumes based on functionally relevant subdivisions in contemporaneously recruited samples of boys and girls with and without attention-deficit/hyperactivity disorder (ADHD). Forty-four boys (21 ADHD, 23 control) and 42 girls (21 ADHD, 21 control), ages 8-13 years, participated. Sulcal-gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor regions [supplementary motor complex (SMC), frontal eye field, lateral premotor cortex (LPM)], and prefrontal cortex (PFC) regions [medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC), and medial OFC]. Compared to sex-matched controls, boys and girls with ADHD showed reduced volumes (gray and white matter) in the left SMC. Conversely, girls (but not boys) with ADHD showed reduced gray matter volume in left LPM; while boys (but not girls) with ADHD showed reduced white matter volume in left medial PFC. Reduced left SMC gray matter volumes predicted increased go/no-go commission rate in children with ADHD. Reduced left LPM gray matter volumes predicted increased go/no-go variability, but only among girls with ADHD. Results highlight different patterns of anomalous frontal lobe development among boys and girls with ADHD beyond that detected by measuring whole lobar volumes.     

Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings

OBJECTIVE: To study the influence of increased familial risk for attention-deficit/hyperactivity disorder (ADHD) on brain morphology. METHOD: Volumetric cerebral measures based on whole brain magnetic resonance imaging scans from 30 boys with ADHD, 30 of their unaffected siblings, and 30 matched controls were compared. RESULTS: Both subjects with ADHD and their unaffected siblings displayed reductions in right prefrontal gray matter and left occipital gray and white matter of up to 9.1% (p < 0.05). Right cerebellar volume was reduced by 4.9% in subjects with ADHD (p = 0.026) but not in their unaffected siblings (p = 0.308). A 4.0% reduction in intracranial volume was found in subjects with ADHD (p = 0.031), while a trend was observed in their unaffected siblings (p = 0.068). CONCLUSIONS: The volumetric reductions in cortical gray and white matter in subjects with ADHD are also present in their unaffected siblings, suggesting that they are related to an increased familial risk for the disorder. In contrast, the cerebellum is unaffected in siblings, suggesting that the reduction in volume observed in subjects with ADHD may be more directly related to the pathophysiology of this disorder.     

The dopamine transporter and attention-deficit/hyperactivity disorder.

The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.     

EEG activity in girls with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study investigated the EEG of girls with Attention-deficit/hyperactivity disorder (ADHD). METHODS: Subjects consisted of 100 girls with ADHD between the ages of 8 and 12 years and 40 age- and gender-matched controls. EEG was recorded from 21 sites during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and relative power in the delta, theta, alpha and beta bands. Factor analysis was used to group sites into 3 regions, covering frontal, central and posterior regions. The total ADHD group was compared to the control group as well as the data being subjected to cluster analysis. RESULTS: The ADHD subjects had greater total power, more relative theta, and less relative delta, alpha and beta than controls. Cluster analysis indicated the presence of two distinct EEG clusters of girls with ADHD. These were (a) a large subgroup characterized by increased total power, more relative theta, and less relative delta and beta than control subjects; and (b) a small subgroup with a substantially-increased amount of high amplitude theta activity, with deficiencies in all other bands. CONCLUSIONS: These results indicate that girls with ADHD exhibit abnormalities in their EEGs, but there is far less variance in their EEG profiles than is found in boys with the disorder. The results also suggest that there may be distinct groups of girls with ADHD who are not being referred for clinical treatment. Recommendations are made for further research in this population. This study is significant in that it is the first major study to separately investigate the EEG of girls with ADHD.     

College students with attention-deficit/hyperactivity disorder

As more students with attention-deficit/hyperactivity disorder attend college, studies are emerging that reveal problems in psychosocial and academic functioning. Substance use may magnify deficits in self-regulation. Recommendations are made for comprehensive assessment; however, the usual diagnostic categories may not be developmentally relevant. Students who are identified benefit from medication and nonmedication interventions, strategy support, and accommodations.