Robert F. Asarnow

The Neural Correlates of Motor Skill Automaticity

Acquisition of a new skill is generally associated with a decrease in the need for effortful control over performance, leading to the development of automaticity. Automaticity by definition has been achieved when performance of a primary task is minimally affected by other ongoing tasks. The neural basis of automaticity was examined by testing subjects in a serial reaction time (SRT) task under both single-task and dual-task conditions. The diminishing cost of dual-task performance was used as an index for automaticity. Subjects performed the SRT task during two functional magnetic imaging sessions separated by 3 h of behavioral training over multiple days. Behavioral data showed that, by the end of testing, subjects had automated performance of the SRT task. Before behavioral training, performance of the SRT task concurrently with the secondary task elicited activation in a wide network of frontal and striatal regions, as well as parietal lobe. After extensive behavioral training, dual-task performance showed comparatively less activity in bilateral ventral premotor regions, right middle frontal gyrus, and right caudate body; activity in other prefrontal and striatal regions decreased equally for single-task and dual-task conditions. These data suggest that lateral and dorsolateral prefrontal regions, and their corresponding striatal targets, subserve the executive processes involved in novice dual-task performance. The results also showed that supplementary motor area and putamen/globus pallidus regions showed training-related decreases for sequence conditions but not for random conditions, confirming the role of these regions in the representation of learned motor sequences.

A clinical and demographic profile of a sample of adults with attention deficit hyperactivity disorder, residual state.

It is becoming increasingly recognized that one third to one half of children diagnosed as having attention deficit/hyperactivity disorder (ADHD) continue to exhibit symptoms of the disorder into adulthood. The nature of the clinical picture is not well understood by a substantial number of clinicians. The purpose of this study is to report on the demographic and clinical profile of 56 adults, age 19 to 65 years (48 men, eight women) who present with adult ADHD and meet DSM-III-R criteria for the disorder. Patients underwent a diagnostic work-up consisting of medical and psychiatric evaluation, a structured interview Schedule for Affective Disorders and Schizophrenia-Lifetime Version [SADS-L]), the Symptoms Checklist Revised (SCL-9OR), Conners Attention Deficit Disorder With Hyperactivity (ADDH) scale, structured interview of ADDH, the Global Assessment of Functioning Scale (GAF), and, when available, information from parents was obtained. Ninety-one percent of our sample met the Utah Criteria for adult ADHD. The majority of the sample had additional DSM-III-R diagnoses and only seven had ADHD diagnosis alone. Fifty-three percent of the sample met the criteria for generalized anxiety disorder, 34% alcohol abuse or dependence, 30% drug abuse, 25% dysthymic disorder, and 25% cyclothymic disorder. These findings were similar to those reported in the literature.

Neurocognitive Outcomes and Recovery After Pediatric TBI: Meta-Analytic Review of the Literature

Traumatic Brain Injury (TBI) continues to be one of the leading causes of death and disability in the pediatric population. Although the literature on neurocognitive outcomes is relatively rich, studies vary significantly in the methods used to group subjects on several moderating variables, including age at injury, injury severity, and time since injury, making it difficult to combine and summarize the data for comparison. Further complicating this effort is the wide range of measures used to document functional outcomes in key neurocognitive domains. In this meta-analytic review, 28 publications (1988 to 2007) that met inclusion criteria were summarized based on three distinct injury severity and time post injury groups for 14 key neurocognitive domains. Effect sizes were calculated to reflect the extent to which the above groups differed in case-control and case-case studies, as well as address recovery based on longitudinal studies. To the best of our knowledge, this is the first published quantitative summary of the literature on neurocognitive outcomes after pediatric TBI. Limitations of the current state of the literature as well as recommendations for future studies are discussed.

Cerebral hemispherectomy Hospital course, seizure, developmental, language, and motor outcomes

Objective: To compare hemispherectomy patients with different pathologic substrates for hospital course, seizure, developmental, language, and motor outcomes. Methods: The authors compared hemispherectomy patients (n = 115) with hemimegalencephaly (HME; n = 16), hemispheric cortical dysplasia (hemi CD; n = 39), Rasmussen encephalitis (RE; n = 21), infarct/ischemia (n = 27), and other/miscellaneous (n = 12) for differences in operative management, postsurgery seizure control, and antiepilepsy drug (AED) usage. In addition, Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ), language, and motor assessments were performed pre- or postsurgery, or both. Results: Surgically, HME patients had the greatest perioperative blood loss, and the longest surgery time. Fewer HME patients were seizure free or not taking AEDs 1 to 5 years postsurgery, but the differences between pathologic groups were not significant. Postsurgery, 66% of HME patients had little or no language and worse motor scores in the paretic limbs. By contrast, 40 to 50% of hemi CD children showed near normal language and motor assessments, similar to RE and infarct/ischemia cases. VABS DQ scores showed +5 points or more improvement postsurgery in 57% of patients, and hemi CD (+12.7) and HME (+9.1) children showed the most progress compared with RE (+4.6) and infarct/ischemia (−0.6) cases. Postsurgery VABS DQ scores correlated with seizure duration, seizure control, and presurgery DQ scores. Conclusions: The pathologic substrate predicted pre- and postsurgery differences in outcomes, with hemimegalencephaly (but not hemispheric cortical dysplasia) patients doing worse in several domains. Furthermore, shorter seizure durations, seizure control, and greater presurgery developmental quotients predicted better postsurgery developmental quotients in all patients, irrespective of pathology.

A unique adolescent response to reward prediction errors

Previous work has shown that human adolescents may be hypersensitive to rewards, but it is not known which aspect of reward processing is responsible for this. We separated decision value and prediction error signals and found that neural prediction error signals in the striatum peaked in adolescence, whereas neural decision value signals varied depending on how value was modeled. This suggests that heightened dopaminergic prediction error responsivity contributes to adolescent reward seeking.

Neurocognitive predictors of work outcome in recent-onset schizophrenia.

While the role of neurocognitive impairment in predicting functional outcome in chronic schizophrenia is now widely accepted, the results that have examined this relationship in the early phase of psychosis are surprisingly rather mixed. The predictive role of cognitive impairment early in the illness is of particular interest because interventions during this initial period may help to prevent the development of chronic disability. In a University of California, Los Angeles (UCLA) longitudinal study, we assessed schizophrenia patients with a recent first episode of psychosis using a neurocognitive battery at an initial clinically stabilized outpatient point and then followed them during continuous treatment over the next 9 months. Three orthogonal cognitive factors were derived through principal components analysis: working memory, attention and early perceptual processing, and verbal memory and processing speed. All patients were provided a combination of maintenance antipsychotic medication, case management, group skills training, and family education in a UCLA research clinic. A modified version of the Social Adjustment Scale was used to assess work outcome. Multiple regression analyses indicate that the combination of the 3 neurocognitive factors predicts 52% of the variance in return to work or school by 9 months after outpatient clinical stabilization. These data strongly support the critical role of neurocognitive factors in recovery of work functioning after an onset of schizophrenia. Cognitive remediation and other interventions targeting these early cognitive deficits are of major importance to attempts to prevent chronic disability.

Working memory in childhood-onset schizophrenia and attention-deficit/hyperactivity disorder.

We investigated verbal and spatial working memory in participants with childhood-onset schizophrenia (N=13), attention-deficit/hyperactivity disorder (ADHD; N=31) and age-matched normal children (N=27). The ages of the participants ranged from 9 to 20 years, with an average age of approx. 14 in all groups. Diagnoses were based on structured interviews (Kiddie-Schedule for Affective Disorders and Schizophrenia) with the children and their parents and made using DSM-III-R criteria. Verbal working memory was assessed by the highest number of digits recalled in forward and backward order on the Digit Span subtest of the Wechsler Intelligence Scale. Results showed that normal children recalled more digits than schizophrenic and ADHD children, who did not differ. Spatial working memory was assessed with the Dot Test of Visuospatial Working Memory: The children were presented with a dot on a page for 5 s and asked to mark its location on a blank page immediately after presentation or 30 s later. A distracter task was used during the delay to prevent verbal rehearsal. The average distance between the target dot and the childs mark in the 30-s condition was shorter for normal than for schizophrenic and ADHD children, who did not differ. Thus, both schizophrenic and ADHD children showed deficits in verbal and spatial working memory. These results suggest that in both disorders, the capacity of the sensory buffers may be diminished, and/or the availability and allocation of resources to the central executive may be limited.

Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms.

Two‐year postsurgical developmental outcomes were assessed in 24 children with infantile spasms who underwent resective surgery. The mean age of onset of infantile spasms was 12.0 weeks and the mean age at surgery was 20.8 months. Developmental outcomes were assessed using the Vineland Adaptive Behavior Scales (VABS). There was a significant increase in developmental level at 2 years postsurgery compared with presurgical levels. At 2 years postsurgery only one of the children in this series was severely retarded. The developmental outcomes of patients in the series were better than those in prior studies of symptomatic patients receiving medical treatment for infantile spasms. It is surprising that the children in the UCLA series frequently had developmental outcomes equal to and sometimes superior to other groups of children with infantile spasms, since all the UCLA patients were symptomatic, had neurologic deficits and had failed to respond to adrenocorticotropic hormone (ACTH) and antiepileptic drugs. The 2‐year postsurgery developmental outcomes were best for the children who received surgery, when they were relatively young and who had the highest level of developmental attainments presurgically.

Surgery for symptomatic infant-onset epileptic encephalopathy with and without infantile spasms

Children undergoing surgery with infant-onset epilepsy were classified into those with medically refractory infantile spasms (IS), successfully treated IS, and no IS history, and the groups were compared for pre- and postsurgery clinical and Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ). Children without an IS history were older at surgery and had longer epilepsy durations than those with IS despite similar substrates, surgeries, and seizure frequencies. In all groups, better postsurgery VABS-DQ scores were associated with early surgical intervention indicating that infant-onset epilepsy patients with or without IS are at risk for seizure-induced encephalopathy.

Leptin Replacement Improves Cognitive Development

Background Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown. Objective To evaluate the effect of leptin on neurocognitive development. Methodology A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children. Principal Findings Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia. Conclusions We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system. Trial Registration ClinicalTrials.gov NCT00659828