Albert M. Galaburda

Planum temporale asymmetry, reappraisal since Geschwind and Levitsky

Abstract This study utilizes the same brains reported by Geschwind and Levitsky [Science161, 186–187, 1968] and looks for indirect evidence for the Geschwind Hypothesis [Geschwind and Bahan, Proc. natn. Acad Sci., U.S.A.79, 5097–5100, 1982; Geschwind and Galaburda, Arch. Neurol.42, 428–459, 521–552, 634–654, 1985] that testosterone slows down the development of the left hemisphere and allows for compensatory growth of the right in order to produce a graded shift away from standard cerebral asymmetry. There are graded asymmetries of the planum temporal in the population, averaging on the side of leftward asymmetry. Changes away from asymmetry, however, involve increase in the size of the smaller side, rather than decrease in the size of the larger. Thus symmetrical brains differ from asymmetrical brains by having two large plana, each planum being equivalent in area to the larger planum of the asymmetrical cases. If testosterone has an effect in modifying brain asymmetry, it does not appear to do so by slowing one side and allowing the growth of the other, but rather through its promotion of the growth of the small side. We consider some likely developmental mechanisms for this action and offer some anatomical and functional comments.

Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome

Williams syndrome (WMS) is a rare sporadic disorder that yields a distinctive profile of medical, cognitive, neurophysiological, neuroanatomical and genetic characteristics. The cognitive hallmark of WMS is a dissociation between language and face processing (relative strengths) and spatial cognition (profound impairment). Individuals with WMS also tend to be overly social, behavior that is opposite to that seen in autism. A genetic hallmark of WMS is a deletion on chromosome band 7q11.23. Williams syndrome is also associated with specific neuromorphological and neurophysiological profiles: proportional sparing of frontal, limbic and neocerebellar structures is seen using MRI; and abnormal functional organization of the neural systems that underlie both language and face processing is revealed through studies using event-related potentials. The non-uniformity in the cognitive, neuromorphological and neurophysiological domains of WMS make it a compelling model for elucidating the relationships between cognition, the brain and, ultimately, the genes.

From genes to behavior in developmental dyslexia

All four genes thus far linked to developmental dyslexia participate in brain development, and abnormalities in brain development are increasingly reported in dyslexia. Comparable abnormalities induced in young rodent brains cause auditory and cognitive deficits, underscoring the potential relevance of these brain changes to dyslexia. Our perspective on dyslexia is that some of the brain changes cause phonological processing abnormalities as well as auditory processing abnormalities; the latter, we speculate, resolve in a proportion of individuals during development, but contribute early on to the phonological disorder in dyslexia. Thus, we propose a tentative pathway between a genetic effect, developmental brain changes, and perceptual and cognitive deficits associated with dyslexia.

Abnormal Cortical Complexity and Thickness Profiles Mapped in Williams Syndrome

We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of ∼20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 × 192 × 124 volumes) of 42 subjects with genetically confirmed WS (mean ± SD, 29.2 ± 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 ± 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

An experiment of nature: brain anatomy parallels cognition and behavior in Williams syndrome.

Williams syndrome (WS) is a neurogenetic-neurodevelopmental disorder characterized by a highly variable and enigmatic profile of cognitive and behavioral features. Relative to overall intellect, affected individuals demonstrate disproportionately severe visual-spatial deficits and enhanced emotionality and face processing. In this study, high-resolution magnetic resonance imaging data were collected from 43 individuals with WS and 40 age- and gender-matched healthy controls. Given the distinct cognitive-behavioral dissociations associated with this disorder, we hypothesized that neuroanatomical integrity in WS would be diminished most in regions comprising the visual-spatial system and most “preserved” or even augmented in regions involved in emotion and face processing. Both volumetric analysis and voxel-based morphometry were used to provide convergent approaches for detecting the hypothesized WS neuroanatomical profile. After adjusting for overall brain volume, participants with WS showed reduced thalamic and occipital lobe gray matter volumes and reduced gray matter density in subcortical and cortical regions comprising the human visual-spatial system compared with controls. The WS group also showed disproportionate increases in volume and gray matter density in several areas known to participate in emotion and face processing, including the amygdala, orbital and medial prefrontal cortices, anterior cingulate, insular cortex, and superior temporal gyrus. These findings point to specific neuroanatomical correlates for the unique topography of cognitive and behavioral features associated with this disorder.

INDIVIDUAL VARIABILITY IN CORTICAL ORGANIZATION: ITS RELATIONSHIP TO BRAIN LATERALITY AND IMPLICATIONS TO FUNCTION

The human brain and the brains of most mammals studied for this purpose demonstrate hemispheric asymmetry of gross anatomical landmarks and/or architectonic cortical subdivisions. The magnitude as well as the direction of these cortical asymmetries vary among individuals, and in some species there exist significant population directional biases. The magnitude, if not the direction, of cortical asymmetry is found to predict for relative numbers of neurons comprising a given pair of hemispheric architectonic homologues such that the more asymmetric the region is, the smaller the number of neurons. Similarly, the more asymmetric a region is, the smaller the density of interhemispheric connections and (probably) the greater the density of intrahemispheric connections. Developmentally, the decrease in the number of neurons characterizing the more asymmetrical regions appears to reflect mainly increased unilateral ontogenetic cell loss, and diminished callosal connectivity might signify increased developmental axonal pruning. These relationships between cell numbers, callosal connections, and presumed intrahemispheric relationships can be entertained to explain variability in anatomo-clinical correlations for language function and aphasia between left- and right-handers and men and women.

More Is Not Always Better: Increased Fractional Anisotropy of Superior Longitudinal Fasciculus Associated with Poor Visuospatial Abilities in Williams Syndrome

We used diffusion tensor imaging to examine white matter integrity in the dorsal and ventral streams among individuals with Williams syndrome (WS) compared with two control groups (typically developing and developmentally delayed) and using three separate analysis methods (whole brain, region of interest, and fiber tractography). All analysis methods consistently showed that fractional anisotropy (FA; a measure of microstructural integrity) was higher in the right superior longitudinal fasciculus (SLF) in WS compared with both control groups. There was a significant association with deficits in visuospatial construction and higher FA in WS individuals. Comparable increases in FA across analytic methods were not observed in the left SLF or the bilateral inferior longitudinal fasciculus in WS subjects. Together, these findings suggest a specific role of right SLF abnormality in visuospatial construction deficits in WS.

A Twin MRI Study of Size Variations in the Human Brain

Although it is well known that there is considerable variation among individuals in the size of the human brain, the etiology of less extreme individual differences in brain size is largely unknown. We present here data from the first large twin sample (N=132 individuals) in which the size of brain structures has been measured. As part of an ongoing project examining the brain correlates of reading disability (RD), whole brain morphometric analyses of structural magnetic response image (MRI) scans were performed on a sample of adolescent twins. Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither member had RD. We first factor-analyzed volume data for 13 individual brain structures, comprising all of the neocortex and most of the subcortex. This analysis yielded two factors (cortical and subcortical) that accounted for 64 of the variance. We next tested whether genetic and environmental influences on brain size variations varied for these two factors or by hemisphere. We computed intraclass correlations within MZ and DZ pairs in each sample for the cortical and subcortical factor scores, for left and right neocortex, and for the total cerebral volume. All five MZ correlations were substantial (rs=.78 to .98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (rs=0.32 to 0.65) in both samples. The MZ-DZ difference was significant for 3 variables in the RD sample and for one variable in the smaller control sample. These results indicate significant genetic influences on these variables. The magnitude of genetic influence did not vary markedly either for the 2 factors or the 2 hemispheres. There was also a positive correlation between brain size and full-scale IQ, consistent with the results of earlier studies. The total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with full-scale IQ in the RD sample; there was a similar trend in the smaller control sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found between the subcortical factor and full-scale IQ, whereas the results for the cortical factor (r=.16 and .13) were smaller and not significant. In sum, these results provide evidence for the heritability of individual differences in brain size which do not vary markedly by hemisphere or for neocortex relative to subcortex. Since there are also correlations between brain size and full-scale IQ in this sample, it is possible that genetic influences on brain size partly contribute to individual differences in IQ.

3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry.

UNLABELLED Williams syndrome (WS) is a neurodevelopmental disorder associated with deletion of approximately 20 contiguous genes in chromosome band 7q11.23. Individuals with WS exhibit mild to moderate mental retardation, but are relatively more proficient in specific language and musical abilities. We used tensor-based morphometry (TBM) to visualize the complex pattern of gray/white matter reductions in WS, based on fluid registration of structural brain images. METHODS 3D T1-weighted brain MRIs of 41 WS subjects (age [mean+/-SD]: 29.2+/-9.2 years; 23F/18M) and 39 age-matched healthy controls (age: 27.5+/-7.4 years; 23F/16M) were fluidly registered to a minimum deformation target. Fine-scale volumetric differences were mapped between diagnostic groups. Local regions were identified where regional structure volumes were associated with diagnosis, and with intelligence quotient (IQ) scores. Brain asymmetry was also mapped and compared between diagnostic groups. RESULTS WS subjects exhibited widely distributed brain volume reductions (approximately 10-15% reduction; P<0.0002, permutation test). After adjusting for total brain volume, the frontal lobes, anterior cingulate, superior temporal gyrus, amygdala, fusiform gyrus and cerebellum were found to be relatively preserved in WS, but parietal and occipital lobes, thalamus and basal ganglia, and midbrain were disproportionally decreased in volume (P<0.0002). These regional volumes also correlated positively with performance IQ in adult WS subjects (age > or = 30 years, P = 0.038). CONCLUSION TBM facilitates 3D visualization of brain volume reductions in WS. Reduced parietal/occipital volumes may be associated with visuospatial deficits in WS. By contrast, frontal lobes, amygdala, and cingulate gyrus are relatively preserved or even enlarged, consistent with unusual affect regulation and language production in WS.

Down's syndrome Is there a decreased population of neurons?

Although gross abnormalities have been described in the brains of patients with Downs syndrome (DS), microscopic studies have revealed only minor and inconsistent findings. We compared two DS brains, in whole-brain serial sections, with similarly prepared age- and sex-matched normal controls. Architectonic abnormalities were noted, and cell counts revealed a significant poverty of granular cells in the DS brains, particularly in granular fields such as areas 3,17, and 41. Golgi studies demonstrated all major cell types. A striking feature of the brain morphology in DS may be the curtailment of a specific cell type, most likely the aspinous stellate.