Judith M. Rumsey

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Neuropsychological findings in high-functioning men with infantile autism, residual state.

Ten men (ages 18-39) with clear histories of Infantile autism and approximately average verbal and nonverbal intelligence were studied with a comprehensive battery of neuropsychological tests. Comparisons with 10 matched normal controls showed no significant differences in many visuoperceptual or memory skills or in sensory-perceptual or motor skills or their lateralization. Differences seen on language measures were small, but statistically significant. In contrast to this, the autistic group demonstrated dramatic deficits on simple and complex, verbal and nonverbal problem-solving tasks, such as the Wisconsin Card Sorting Test, selected tasks from the Stanford-Binet, and the Trail Making Test. A left-hemisphere hypothesis of autism was not supported, nor was there compelling evidence of any posterior cortical deficit. Results are compatible with frontal-system dysfunction or with more widespread pathology.

A QUANTITATIVE MRI STUDY OF THE CORPUS CALLOSUM IN CHILDREN AND ADOLESCENTS

Total midsagittal area and seven subdivisions of the corpus callosum were measured on magnetic resonance images of 114 healthy boys and girls, aged 4 to 18. Striking variability of size was noted for all measures. Total midsagittal corpus callosum area increased in a robust and linear fashion from ages 4 to 18 (slope = 13.1 mm2/year, P = 0.0001 and slope = 11.1 mm2/year, P = 0.0001 for females and males, respectively). Posterior and mid regions demonstrated greater age-related changes than anterior regions with the rostrum and genu (anterior regions) having reached adult sizes in the youngest of our subjects. There were no significant effects of sex for any measures. These findings support anatomical studies indicating ongoing myelination of higher association areas throughout adolescence, but raise intriguing questions about anterior-posterior gradients of interhemispheric myelination.

Autistic Children as Adults: Psychiatric, Social, and Behavioral Outcomes

The psychiatric, social, and behavioral outcomes of 14 men (X age = 28 years, S.D. = 6.8), with well-documented histories of infantile autism, 9 of whom were unusually high functioning, were studied in the longest term, systematic follow-up on autism to date. Residual social impairments and varied residual psychiatric and behavioral symptoms were seen in all subjects and are described. Especially frequent were stereotyped movements and concrete thinking. No subject showed positive schizophrenic symptoms or qualified for any DSM-III adult diagnosis other than autism or autism, residual state.

The NIH MRI study of normal brain development: Performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery

The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study in which structural and metabolic brain development and behavior are followed longitudinally from birth to young adulthood in a population-based sample of healthy children. The neuropsychological assessment protocol for children aged 6 to 18 years is described and normative data are presented for participants in that age range (N = 385). For many measures, raw score performance improved steeply from 6 to 10 years, decelerating during adolescence. Sex differences were documented for Block Design (male advantage), CVLT, Pegboard and Coding (female advantage). Household income predicted IQ and achievement, as well as externalizing problems and social competence, but not the other cognitive or behavioral measures. Performance of this healthy sample was generally better than published norms. This linked imaging-clinical/behavioral database will be an invaluable public resource for researchers for many years to come.

Preliminary evidence of widespread morphological variations of the brain in dyslexia.

The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia.

Conceptual problem-solving in highly verbal, nonretarded autistic men.

Nine highly verbal, nonretarded men, ages 18 to 39, with clearly documented childhood diagnoses of infantle autism were studied with the Wisconsin Card Sorting Test, a measure of conceptual problem solving sensitive to frontal system dysfunction, and with a measure of socialadaptive functioning. Their performances were compared with 10 controls matched for age, sex, education, and IQ, as well as with published norms for various groups of braindamaged patients. Significant deficits in the formulation of rules and significant perseverative tendencies were documented in the autistic sample. No significant correlation between these deficits and socialadaptive deficits was seen. These findings were discussed with respect to the heterogeneity of the autistic disorder and Damasios hypothesis concerning frontalsubcortical dysfunction in autism.

Neuropsychological divergence of high-level autism and severe dyslexia

The relationship between cognitive deficits in high-level autism and those in learning disabilities has received little attention. To determine whether high-functioning autistic patients and individuals with severe dyslexia display different cognitive characteristics, 10 nonretarded men (mean age 26 years) with infantile autism, residual state, were compared with 15 severely dyslexic men (mean age 22 years) and 25 matched controls on a neuropsychological test battery. The two clinical groups were dissociated by a reduced digit span seen in the dyslexics and by impaired problem-solving skills (Wisconsin Card Sort and selected subtests from the Binet) seen in the autistic group. These results suggest different localization of brain dysfunction and different educational/habilitative needs.

Dysfunctional attention in autistic savants

A dysfunctional attention hypothesis of the basis of savant skills was tested with a series of computerized tasks that assessed the ability to divide, shift, direct, and sustain attention. Ten healthy men with pervasive developmental disorders and unusual calendar-calculating skill, and 10 age- and sex-matched controls were tested. There were four general findings. First, the savants and controls did not differ on a measure of visual sustained attention. Second, the savants failed to detect rare auditory targets significantly more than did the controls. Third, the savants were unable to efficiently divide their attention when required to detect both visual and auditory targets simultaneously. Finally, deficient orienting or a deficit in shifting selective attention from one stimulus location to another was evidenced in overall slower reaction times for the savants across tasks requiring shifts and redirecting of attention. This deficit was attributed to an inability to disengage attention as a result of deficient orienting and overselectivity.

Corpus callosum morphology, as measured with MRI, in dyslexic men

To test the hypothesis of anomalous anatomy in posterior brain regions associated with language and reading, the corpus callosum was imaged in the midsagittal plane with magnetic resonance. The areas of the anterior, middle, and posterior segments were measured in 21 dyslexic men (mean age 27 yrs, SD 6) and in 19 matched controls. As predicted, the area of the posterior third of the corpus callosum, roughly equivalent to the isthmus and splenium, was larger in dyslexic men than in controls. No differences were seen in the anterior or middle corpus callosum. The increased area of the posterior corpus callosum may reflect anatomical variation associated with deficient lateralization of function in posterior language regions of the cortex and their right-sided homologues, hypothesized to differ in patients with dyslexia.