Jeffrey S. Bedwell

Childhood-onset schizophrenia: progressive brain changes during adolescence

BACKGROUND Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. METHODS Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. RESULTS Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. CONCLUSIONS These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development 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.

Shifting the paradigm of music instruction: implications of embodiment stemming from an augmented reality guitar learning system.

Musical instruction often includes materials that can act as a barrier to learning. New technologies using augmented reality may aid in reducing the initial difficulties involved in learning music by lowering these barriers characteristic of traditional instructional materials. Therefore, this set of studies examined a novel augmented reality guitar learning system (i.e., the Fretlight® guitar) in regards to current theories of embodied music cognition. Specifically, we examined the effects of using this system in comparison to a standard instructional material (i.e., diagrams). First, we review major theories related to musical embodiment and specify a niche within this research space we call embodied music technology for learning. Following, we explicate two parallel experiments that were conducted to address the learning effects of this system. Experiment 1 examined short-term learning effects within one experimental session, while Experiment 2 examined both short-term and long-term effects across two sessions spaced at a 2-week interval. Analyses demonstrated that, for many of our dependent variables, all participants increased in performance across time. Further, the Fretlight® condition consistently led to significantly better outcomes via interactive effects, including significantly better long term retention for the learned information across a 2 week time interval. These results are discussed in the context of embodied cognition theory as it relates to music. Potential limitations and avenues for future research are described.

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.

Lessons from childhood-onset schizophrenia

Childhood-onset schizophrenia (with an onset of psychosis by age 12) is a rare and severe form of the disorder which is clinically and neurobiologically continuous with the adult-onset disorder. Very early onset diseases provide an opportunity to look for more salient or striking risk or etiologic factors in a possibly more homogenous patient population. For the 47 patients with very early onset schizophrenia studied to date, there were more severe premorbid neurodevelopmental abnormalities, more cytogenetic anomalies, and potentially greater family histories of schizophrenia and associated spectrum disorders than later onset cases. There was no evidence for relatively increased obstetrical complications or environmental stress. These data, while preliminary, suggest a very early age of onset of schizophrenia may be secondary to greater genetic vulnerability. It is anticipated that future genetic studies of these patients may provide important etiologic information.

An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations.

Patients with childhood-onset obsessive-compulsive disorder (OCD) with symptom exacerbations following streptococcal infections benefit from treatment with plasma exchange. In this study, 5 patients with treatment-refractory OCD without a history of streptococcus-related exacerbations underwent an open 2-week course of therapeutic plasma exchange. Behavioral ratings, completed at baseline and 4 weeks after the initial treatment, included the Clinical Global Impressions Scale and the Yale-Brown Obsessive Compulsive Scale. All 5 patients completed the trial with few side effects, but none showed significant improvement. Plasma exchange does not benefit children and adolescents with OCD who do not have streptococcus-related exacerbations.

Brief Report: Association of Sex Chromosome Anomalies With Childhood-Onset Psychotic Disorders

ABSTRACT Objective An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DSM-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI). Method From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine. Results Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, X 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed. Conclusions These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine. J. Am. Acad. Child Adolesc. Psychiatry, 1998, 37(3):292–296.

Schizotypal personality disorder or prodromal symptoms of schizophrenia

Schizotypal personality disorder shares some attenuated phenotypic features with schizophrenia, but represents an independent syndrome. In contrast, prodromal symptoms of schizophrenia represent early warning signs of the impending onset of schizophrenia. Although these constructs are intended to reflect independent syndromes, self-report instruments measuring these constructs assess similar symptoms. It does not appear that existing research has examined the relative discriminant validity of screening instruments for these syndromes. A sample of 998 young adults (68% female; 73% Caucasian), within the age of risk for schizophrenia (ages 18-34; mean 20.4+/-2.2), met validity criteria after completing online versions of the Abbreviated Schizotypal Personality Questionnaire (SPQ-B) and the 24-item Abbreviated Youth Psychosis at Risk Questionnaire (Y-PARQ-B). Based on clinical cut-off scores used in previous research, 5.2% were [only] considered at heightened risk for psychosis (potentially prodromal), 3.4% had [only] schizotypal personality features, and 2.9% met criteria for both constructs (75% of individuals meeting cutoff for one measure did not meet criteria for the other). Males and younger participants scored significantly higher on both measures. The total scores from the SPQ-B and Y-PARQ-B showed a significant positive correlation (r(s)=.66, p<.001, R2=.43); however, 57% of the variance was not shared between the measures. Of the three SPQ-B subscales, Cognitive-Perceptual showed the strongest correlation with Y-PARQ-B. Results suggest that the SPQ-B and Y-PARQ-B have moderate discriminate validity between the overlapping, yet distinct, constructs of schizotypal personality and heightened risk of developing psychosis (potentially prodromal).

FUNCTIONAL NEUROANATOMY OF SUBCOMPONENT COGNITIVE PROCESSES INVOLVED IN VERBAL WORKING MEMORY

Recent research has used functional magnetic resonance imaging (fMRI) to examine brain regions related to specific subcomponent cognitive processes of verbal working memory, which include initial encoding of material, maintenance of the information over a brief delay interval, and later retrieval of the information. The present study examined each of these subcomponents in 14 healthy adults using a Sternberg verbal working memory task and fMRI. Group analysis revealed several brain regions active during all subcomponent processes, which included dorsolateral and ventrolateral prefrontal, parietal, hippocampal, and premotor cortex. Several other brain regions showed activation limited to specific subcomponent processes.

Heart rate variability and vagal tone in schizophrenia: A review

Recent heart rate variability (HRV) research has identified diminished levels of parasympathetic activity among schizophrenia patients. Over two dozen empirically-based studies have been published on this topic; primarily over the last decade. However, no theoretical review appears to have been published on this work. Further, only one empirical study has evaluated HRV research findings in the context of documented hypothalamic-pituitary-adrenal axis hyperactivity in schizophrenia. HRV research indicates that no abnormalities exist in the initial sympathetic stress response of schizophrenia patients. However, evidence has consistently demonstrated that patients exhibit a diminished capacity to recover from a stress response as a result of deficits in parasympathetic activity. Moreover, this diminished parasympathetic nervous system (PNS) response, also known as decreased vagal tone, has been found to relate to increased symptom severity. Although these findings may cause speculation that the observed vagal tone disruption merely results from anxiety produced by the presence of positive symptomology, additional studies have identified similar parasympathetic dysfunction among nonpsychotic relatives of individuals with schizophrenia. We posit that the resulting sympathovagal imbalance leads to an overall sympathetic dominance despite the fact that sympathetic nervous system activity is not abnormally elevated among patients. Implications are discussed within the context of the diathesis-stress/vulnerability-stress model, including the potential for identifying a mechanism of action by which environmental stressors may contribute to triggering first-episode psychosis.