Sanjiv Kumra

Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study

BACKGROUND The purpose of this study was to explore whether there are white matter (WM) abnormalities in children with attention-deficit/hyperactivity disorder (ADHD) using diffusion tensor imaging. Based upon the literature, we predicted decreased fractional anisotropy (FA) findings in the frontal and cerebellar regions. METHODS Eighteen patients with ADHD and 15 age- and gender-matched healthy volunteers received DTI assessments. Fractional anisotropy maps of WM were compared between groups with a voxelwise analysis after intersubject registration to Talairach space. RESULTS Children with ADHD had decreased FA in areas that have been implicated in the pathophysiology of ADHD: right premotor, right striatal, right cerebral peduncle, left middle cerebellar peduncle, left cerebellum, and left parieto-occipital areas. CONCLUSIONS These preliminary data support the hypothesis that alterations in brain WM integrity in frontal and cerebellar regions occur in ADHD. The pattern of decreased FA might implicate the corticopontocerebellar circuit in the pathophysiology of ADHD.

White matter development during late adolescence in healthy males: a cross-sectional diffusion tensor imaging study.

BACKGROUND Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (lambda( perpendicular)) and axial (lambda(||)) diffusivity. METHODS Twenty-four healthy adolescent males (mean age=16.6, SD=2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis. RESULTS At a threshold of p<0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and lambda(||) of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory. CONCLUSIONS These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and lambda(||) with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence.

A preliminary study of functional connectivity in comorbid adolescent depression

Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD (n=12) and healthy adolescents (n=14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD.

Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D2 receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and “high-dose” olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study.

BACKGROUND Research suggests that brain frontal white matter (WM) might be qualitatively altered in adolescents with early onset schizophrenia (EOS). Diffusion tensor imaging provides a relatively new approach for quantifying possible connectivity of WM in vivo. METHODS Diffusion tensor imaging was used to examine the WM integrity of frontal regions at seven levels from 25 mm above to 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. Three other regions were examined: the occipital region at the AC-PC plane and the genu and splenium of the corpus callosum. Fractional anisotropy was compared between 12 adolescents (nine male, 3 female) with EOS (onset of psychotic symptoms by age 18 years) and nine age-similar healthy comparison subjects (six male, 3 female). RESULTS Adolescents with EOS had significantly reduced fractional anisotropy in the frontal WM at the AC-PC plane in both hemispheres and in the occipital WM at the AC-PC plane in the right hemisphere. CONCLUSIONS These preliminary data support a hypothesis that alterations in brain WM integrity occur in adolescents with EOS. Abnormalities found in this study were similar to those reported in adults with chronic schizophrenia. Additional studies are needed to assess whether there is progression of WM abnormalities in schizophrenia.

Childhood‐Onset Schizophrenia: An Open‐Label Study of Olanzapine in Adolescents

ABSTRACT Objective Olanzapine, a potent 5-HT 2a/2c , dopamine D 1 D 2 D 4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting. Method Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective ( n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement. Results For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to “ideal” admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment ( p = .03). Conclusion These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics. J. Am. Acad. Child Adolesc Psychiatry , 1998, 37(4): 377–385.

Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use

BACKGROUND There is growing evidence that adolescence is a key period for neuronal maturation. Despite the high prevalence of marijuana use among adolescents and young adults in the United States and internationally, very little is known about its impact on the developing brain. Based on neuroimaging literature on normal brain developmental during adolescence, we hypothesized that individuals with heavy cannabis use (HCU) would have brain structure abnormalities in similar brain regions that undergo development during late adolescence, particularly the fronto-temporal connection. METHOD Fourteen young adult males in residential treatment for cannabis dependence and 14 age-matched healthy male control subjects were recruited. Patients had a history of HCU throughout adolescence; 5 had concurrent alcohol abuse. Subjects underwent structural and diffusion tensor magnetic resonance imaging. White matter integrity was compared between subject groups using voxelwise and fiber tractography analysis. RESULTS Voxelwise and tractography analyses revealed that adolescents with HCU had reduced fractional anisotropy, increased radial diffusivity, and increased trace in the homologous areas known to be involved in ongoing development during late adolescence, particularly in the fronto-temporal connection via arcuate fasciculus. CONCLUSIONS Our results support the hypothesis that heavy cannabis use during adolescence may affect the trajectory of normal brain maturation. Due to concurrent alcohol consumption in five HCU subjects, conclusions from this study should be considered preliminary, as the DTI findings reported here may be reflective of the combination of alcohol and marijuana use. Further research in larger samples, longitudinal in nature, and controlling for alcohol consumption is needed to better understand the pathophysiology of the effect of cannabis on the developing brain.

Case study: Risperidone-induced hepatotoxicity in pediatric patients

The purpose of this case study is to document hepatic adverse effects associated with long-term risperidone use in pediatric populations. Charts of all patients admitted to the National Institute of Mental Health (NIMH) from December 1993 to April 1996 who had been treated with risperidone were screened for hepatotoxicity and weight gain. From the medical records of 13 psychotic children admitted to the NIMH and treated with risperidone, 2 children (both male) who presented with obesity, liver enzyme abnormalities, and confirmatory evidence of fatty liver were identified. In each case liver damage was reversed after discontinuation of risperidone and/or associated weight loss. The observations suggest that long-term risperidone therapy is possibly associated with hepatotoxicity in male pediatric patients. It is recommended that pediatric patients treated with risperidone have baseline liver function tests, careful monitoring of weight, and periodic monitoring of liver function tests during the maintenance phase of therapy.

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified

OBJECTIVE Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Decision-making impairments in adolescents with early-onset schizophrenia

Adolescence is a time of vulnerability for risk-taking behaviors. This is particularly true of adolescents with schizophrenia who present with high rates of substance use as compared to the general population. Using the Iowa Gambling Task (IGT), the authors compared decision-making processes in adolescents with early-onset schizophrenia (onset of psychosis by age 18) to that of healthy volunteers. Fifteen adolescents with schizophrenia (aged 12-21 years) and 25 demographically similar healthy volunteers were administered the IGT. Overall, adolescents with schizophrenia performed significantly worse on the IGT than healthy adolescents as measured by a significant group by block interaction. Post-hoc testing revealed that adolescents with schizophrenia performed more poorly than healthy adolescents during the last two blocks of the task. Mathematical modeling further indicated that adolescents with schizophrenia allocated significantly more attention to monetary gains than losses encountered during the task, suggesting a hypersensitivity to rewards and relative insensitivity to future consequences. This is similar to what has been reported for adults with externalizing forms of psychopathology, such as those who abuse substances. These findings have potential implications for understanding the increased vulnerability for the development of substance abuse in adolescents with schizophrenia.