Reduced white matter integrity in attention-deficit hyperactivity disorder

We used diffusion tensor imaging to investigate fractional anisotropy (FA), a measure of fiber tract integrity, in attention-deficit hyperactivity disorder (ADHD). Using a tract-based atlasing approach on six-direction diffusion tensor imaging data, we examined FA within the cingulum, corpus callosum, corticospinal tract, fornix, optic radiations, superior longitudinal fasciculus, uncinate fasciculus, and the superior and inferior occipitofrontal fasciculi in an all-male sample of 17 children and adolescents with ADHD and 16 age-matched controls. ADHD patients had significantly lower FA in the corticospinal tract (P=0.02) and the superior longitudinal fasciculus (P=0.017) compared with controls. Results support that disruptions in motor and attentional networks may contribute toward ADHD pathophysiology. Future research may clarify how ADHD subtype and psychiatric comorbidities affect diffusion measures.     

Methylphenidate improves visual-spatial memory in children with attention-deficit/hyperactivity disorder

OBJECTIVE: To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or language problems. METHOD: A clinic-referred sample of school-age children with a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial memory, planning ability, and recognition memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. MPH effects on right-handed and left-handed motor control were also assessed. RESULTS: MPH significantly improved performance on a self-ordered, updating visual-spatial working memory task and on maintenance of visual-spatial information but had no effects on measures of visual-spatial planning ability or recognition memory. Also, MPH significantly improved left-handed motor control. CONCLUSIONS: Beneficial effects of MPH on visual-spatial processing in ADHD are selective and restricted to visual-spatial memory.     

Zinc in attention-deficit/hyperactivity disorder

OBJECTIVE: The aim of this study was to review the published evidence for a role of zinc nutrition in attention-deficit/hyperactivity disorder (ADHD). METHOD: A computer literature search was supplemented by the authors' knowledge. RESULTS: Numerous controlled studies report cross-sectional evidence of lower zinc tissue levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal controls and population norms. A few studies show correlations of zinc level with either clinical severity or a change thereof in response to stimulant or chemical challenge. Two placebo-controlled trials--one of zinc monotherapy, the other of zinc supplementation of methylphenidate--reported significant benefit. However, diagnostic procedures and sample representativeness were often not clear, and most such reports have come from countries and cultures with different diets and/or socioeconomic realities than are found in the United States (only one American sample in nine published reports). In particular, both positive clinical trials of zinc supplementation came from the Mid-East (Turkey and Iran), an area with suspected endemic zinc deficiency. The largest of these trials used zinc doses above the recommended upper tolerable limit and had a 2 in 3 dropout rate. CONCLUSION: It is not clear how well the accumulating evidence for a possible role of zinc in ADHD applies to middle-class American children. However, the evidence appears strong enough to warrant further controlled study in well-diagnosed samples representative of the socioeconomic spectrum. Hypothesis-testing clinical trials are needed of this potential treatment that, if found effective, might become a relatively safe, cheap substitute for, or adjunct to, current treatments in some patients. At present, it should remain an investigational treatment.     

Inattentiveness in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a long-term impact on functioning, productivity and quality of life of patients. This impact is largely due to the symptoms of inattentiveness. However, despite its impairing role in the lives of ADHD patients, inattentiveness has been studied relatively less frequently than have symptoms of impulsivity/hyperactivity and problems with executive function. This review therefore seeks to integrate the neuropsychological theories and current findings in the research fields of neuropsychology, neurophysiology, and neuroimaging, in an attempt to gain a more complete understanding of the role that inattentiveness plays in ADHD, as well as to suggest directions for future studies. The need for a more comprehensive understanding of inattentiveness and ADHD, which integrates findings from each of the three disciplines mentioned above, is emphasized.     

Set shifting and working memory in adults with attention-deficit/hyperactivity disorder

Compared to the high number of studies that investigated executive functions (EF) in children with attention-deficit/hyperactivity disorder (ADHD), a little is known about the EF performance of adults with ADHD. This study compared 37 adults with ADHD (ADHD_total) and 32 control participants who were equivalent in age, intelligence quotient (IQ), sex, and years of education, in two domains of EF—set shifting and working memory. Additionally, the ADHD_total group was subdivided into two subgroups: ADHD patients without comorbidity (ADHD⁻, n = 19) and patients with at least one comorbid disorder (ADHD⁺, n = 18). Participants fulfilled two measures for set shifting (i.e., the trail making test, TMT and a computerized card sorting test, CKV) and one measure for working memory (i.e., digit span test, DS). Compared to the control group the ADHD_total group displayed deficits in set shifting and working memory. The differences between the groups were of medium-to-large effect size (TMT: d = 0.48; DS: d = 0.51; CKV: d = 0.74). The subgroup comparison of the ADHD⁺ group and the ADHD⁻ group revealed a poorer performance in general information processing speed for the ADHD⁺ group. With regard to set shifting and working memory, no significant differences could be found between the two subgroups. These results suggest that the deficits of the ADHD_total group are attributable to ADHD rather than to comorbidity. An influence of comorbidity, however, could not be completely ruled out as there was a trend of a poorer performance in the ADHD⁺ group on some of the outcome measures.     

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.     

Genetic aspects in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.     

Impulsive behaviors in attention-deficit/hyperactivity disorder

The notion that difficulty in behavioral inhibition is the essential impairment of attention-deficit/hyperactivity disorder (AD/HD) has been prevailing. In this study, we assessed impulsive behaviors with regard to emotion, rule, and inattentiveness, by developing an impulsiveness scale and applying it for 103 parents of a boy with AD/HD. Exploratory factor analysis (EFA) of 18 items identified four primary factors: labeled emotion expression, social rule, rule in conversation, and inattentiveness. A covariance structural analysis was performed to extract response bias from latent constructs, and the fitness of the model was examined. In the finally adopted model on impulsive behaviors, the four factors extracted in EFA was explained by two independent second-order latent variables: labeled general impulsivity and cognitive impairment. Cognitive impairment significantly influenced on inattentiveness only, while general impulsivity on all the four factors. Furthermore, the scores of primary four factors were compared between two groups of a normal class group (n = 20) and three AD/HD subtypes:combined type (n = 37), predominantly hyperactive-impulsive type (n = 14), and predominantly inattentive type (n = 18). The results suggest differences in impulsive behaviors among the AD/HD subtypes.     

Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder

OBJECTIVE: Previous research has demonstrated that during task conditions requiring an increase in inhibitory function or working memory, children and adults with attention-deficit/hyperactivity disorder (ADHD) exhibit greater and more varied prefrontal cortical (PFC) activation compared to age-matched control participants. This pattern may reflect cortical inefficiency. We examined this hypothesis using a working memory task in a group of adolescent girls with and without ADHD. METHOD: Functional magnetic resonance imaging was used to investigate blood oxygenated level-dependent signal during a working memory task for 10 adolescents from each group, ages 11 to 17 years. We analyzed brain-behavior relationships with anatomically defined regions of interest in the PFC and primary motor cortex. RESULTS: The relationship between brain activity in the dorsolateral PFC and ventrolateral PFC and memory retrieval speed differed by group membership, whereby comparison girls had a more efficient brain-behavior relationship than girls with ADHD. There were no such group differences in brain-behavior relationships for primary motor cortex. CONCLUSIONS: These findings lend support to the idea that cognitive and behavioral deficits experienced by children and adolescents with ADHD may in part be related to relatively low efficiency of PFC function.     

Long-term prognosis in attention-deficit/hyperactivity disorder

The authors have traced the developmental course of ADHD from childhood to adulthood, showing that it is a bumpy road for many. In early and middle adolescence, relative deficits are seen in academic and social functioning, ADHD symptoms remain problematic in two thirds to three quarters of these children, and antisocial behaviors, in some cases amounting to CD, are common. Many of these same difficulties persist into the late teenage years. Deficits continue to be observed in academic and social domains (compared with controls, probands exhibit lower grades, more courses failed, worse performance on standardized tests, have fewer friends, and are rated less adequate in psychosocial adjustment). About two fifths continue to experience ADHD symptoms to a clinically significant degree. One quarter to one third have a diagnosed antisocial disorder, and two thirds of these individuals are arrested. Also, drug abuse is observed in a significant minority of these youths. Importantly, the greatest risk factor for the development of antisocial behavior and substance abuse by the late teenage years is the maintenance of ADD symptoms. When evaluated in their mid-twenties, dysfunctions are apparent in these same areas. Compared with controls, probands complete less schooling, hold lower-ranking occupations, and continue to suffer from poor self-esteem and social skills deficits. In addition, significantly more probands than controls exhibit an antisocial personality and, perhaps, a substance use disorder in adulthood. Furthermore, many do not outgrow all facets of their childhood syndrome. These relative deficits, however, do not tell the whole story of the ADHD child's adult fate. Indeed, nearly all probands were gainfully employed. Furthermore, some had achieved a higher-level education (e.g., completed Master's degree, enrolled in medical school) and occupation (e.g., accountant, stock broker). In addition, a full two thirds of these children showed no evidence of any mental disorder in adulthood. In conclusion, although ADHD children, as a group, fare poorly compared with their non-ADHD counterparts, the childhood syndrome does not preclude attaining high educational and vocational goals, and most children no longer exhibit clinically significant emotional or behavioral problems once they reach their mid-twenties.     

Cytogenetic abnormalities in attention-deficit/hyperactivity disorder

OBJECTIVE: To systematically assess the prevalence of fragile X syndrome, velocardiofacial syndrome, and other cytogenetic abnormalities in a group of children with attention-defict/hyperactivity disorder (ADHD). METHOD: Blood samples were obtained from 100 children (64 boys) with combined type ADHD and normal intelligence and analyzed for the presence of fragile X mutation expansions, the 22q11.2 microdeletion associated with velocardiofacial syndrome, and cytogenetic abnormalities that would be detected with high resolution chromosomal banding. RESULTS: One girl with ADHD had a sex chromosome aneuploidy (47,XXX). One boy had a premutation-sized allele for fragile X; no subjects showed the full mutation. Testing for 22q11.2 microdeletion was negative for all subjects with ADHD screened. None of these differences exceeded those expected by chance. CONCLUSIONS: In the absence of clinical signs or positive family history, these relatively expensive laboratory assessments are not clinically indicated for children with ADHD and normal intelligence, and are not recommended as a component of other genetic investigations of this disorder.     

Functional neuroanatomy of working memory in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in adults is an increasingly recognized psychiatric disorder, linked with impairments in numerous life domains and with neurocognitive dysfunctions. However, the neural substrate of cognitive functioning in adults with this disorder has been relatively unexamined. The objective of this study was to examine neural functioning in ADHD adults during performance on a verbal working memory task. METHODS: A sample of unmedicated adults with ADHD (n = 20) and control subjects (n = 20) performed a 2-back task of working memory, and the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) response was used as a measure of neural activity during working memory performance. RESULTS: Though working memory performance did not differ significantly between ADHD adults and control subjects, ADHD adults showed significantly decreased activity in cerebellar and occipital regions and a trend toward decreased activation in an a priori predicted region of the prefrontal cortex. CONCLUSIONS: ADHD adults showed altered patterns of neural activity despite comparable performance on a verbal working memory task. These findings suggest that the cerebellum is involved in the pathophysiology of at least some cognitive deficits associated with ADHD and emphasize the need for additional research aimed at elucidating the role of the cerebellum in ADHD symptomatology.     

A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder

OBJECTIVE: To determine the empirical evidence for deficits in working memory (WM) processes in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: Exploratory meta-analytic procedures were used to investigate whether children with ADHD exhibit WM impairments. Twenty-six empirical research studies published from 1997 to December, 2003 (subsequent to a previous review) met our inclusion criteria. WM measures were categorized according to both modality (verbal, spatial) and type of processing required (storage versus storage/manipulation). RESULTS: Children with ADHD exhibited deficits in multiple components of WM that were independent of comorbidity with language learning disorders and weaknesses in general intellectual ability. Overall effect sizes for spatial storage (effect size = 0.85, CI = 0.62 - 1.08) and spatial central executive WM (effect size = 1.06, confidence interval = 0.72-1.39) were greater than those obtained for verbal storage (effect size = 0.47, confidence interval = 0.36-0.59) and verbal central executive WM (effect size = 0.43, confidence interval = 0.24-0.62). CONCLUSION: Evidence of WM impairments in children with ADHD supports recent theoretical models implicating WM processes in ADHD. Future research is needed to more clearly delineate the nature, severity, and specificity of the impairments to ADHD.     

Gene-environment interactions in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by inattention, impulsivity, and/or hyperactivity in children and adults. Putative environmental risk factors for ADHD include toxin and prenatal smoke exposure, low socioeconomic status, and parental marital instability and discord. Genetic associations with ADHD have been found in the dopaminergic, serotonergic, and noradrenergic neurotransmitter systems, but findings are inconsistent across studies. Herein, we review studies of gene-environment interactions for ADHD to better understand how genetic and environmental risk factors may contribute to the disorder in a nonindependent fashion, which may account in part for the inconsistent findings on genetic associations. Although evidence of interactions between prenatal substance exposure and the dopamine genes DAT1 and DRD4 was found, findings across studies have been mixed. We discuss these findings and the future directions and limitations of current gene-environment research.     

Thought disorder in attention-deficit hyperactivity disorder

OBJECTIVE: This study compared thought disorder and associated cognitive variables in attention-deficit hyperactivity disorder (ADHD) and schizophrenia. METHOD: Speech samples of 115 ADHD, 88 schizophrenic, and 190 normal children, aged 8 to 15 years, were coded for thought disorder. A structured psychiatric interview, the WISC-R, the Continuous Performance Test, and the Span of Apprehension task were administered to each child. RESULTS: The ADHD and schizophrenic groups had thought disorder compared with the normal children. However, the subjects with ADHD had a narrower range of less severe thought disorder than did the schizophrenic subjects. The younger children with ADHD and schizophrenia had significantly more thought disorder than did the older children with these diagnoses. IQ, attention, and working memory were associated with thought disorder in the ADHD but not the schizophrenic group. CONCLUSIONS: Thought disorder in childhood is not specific to schizophrenia and reflects impaired development of children's communication skills.     

Sleep restores daytime deficits in procedural memory in children with attention-deficit/hyperactivity disorder

Sleep supports the consolidation of declarative and procedural memory. While prefrontal cortex (PFC) activity supports the consolidation of declarative memory during sleep, opposite effects of PFC activity are reported with respect to the consolidation of procedural memory during sleep. Patients with attention-deficit/hyperactivity disorder (ADHD) are characterised by a prefrontal hypoactivity. Therefore, we hypothesised that children with ADHD benefit from sleep with respect to procedural memory more than healthy children. Sixteen children with ADHD and 16 healthy controls (aged 9-12) participated in this study. A modification of the serial-reaction-time task was conducted. In the sleep condition, learning took place in the evening and retrieval after a night of sleep, whereas in the wake condition learning took place in the morning and retrieval in the evening without sleep. Children with ADHD showed an improvement in motor skills after sleep compared to the wake condition. Sleep-associated gain in reaction times was positively correlated with the amount of sleep stage 4 and REM-density in ADHD. As expected, sleep did not benefit motor performance in the group of healthy children. These data suggest that sleep in ADHD normalizes deficits in procedural memory observed during daytime. It is discussed whether in patients with ADHD attenuated prefrontal control enables sleep-dependent gains in motor skills by reducing the competitive interference between explicit and implicit components within a motor task.