Daniel P. Buxhoeveden

Minicolumnar pathology in autism

ObjectiveTo determine whether differences exist in the configuration of minicolumns between the brains of autistic and control patients. Background Autism is a severe and pervasive developmental disturbance of childhood characterized by disturbances in both social interactions and communication, as well as stereotyped patterns of interests, activities, and behaviors. Postmortem neuropathologic studies remain inconclusive. MethodsThe authors used a computerized imaging program to measure details of cell column morphologic features in area 9 of the prefrontal cortex and areas 21 and posterior 22 (Tpt) within the temporal lobe of nine brains of autistic patients and controls. ResultsThe authors found significant differences between brains of autistic patients and controls in the number of minicolumns, in the horizontal spacing that separates cell columns, and in their internal structure, that is, relative dispersion of cells. Specifically, cell columns in brains of autistic patients were more numerous, smaller, and less compact in their cellular configuration with reduced neuropil space in the periphery. ConclusionsIn autism, there are minicolumnar abnormalities in the frontal and temporal lobes of the brain.

Disruption in the Inhibitory Architecture of the Cell Minicolumn: Implications for Autisim

The modular arrangement of the neocortex is based on the cell minicolumn: a self-contained ecosystem of neurons and their afferent, efferent, and interneuronal connections. The authors’ preliminary studies indicate that minicolumns in the brains of autistic patients are narrower, with an altered internal organization. More specifically, their minicolumns reveal less peripheral neuropil space and increased spacing among their constituent cells. The peripheral neuropil space of the minicolumn is the conduit, among other things, for inhibitory local circuit projections. A defect in these GABAergic fibers may correlate with the increased prevalence of seizures among autistic patients. This article expands on our initial findings by arguing for the specificity of GABAergic inhibition in the neocortex as being focused around its mini- and macrocolumnar organization. The authors conclude that GABAergic interneurons are vital to proper minicolumnar differentiation and signal processing (e.g., filtering capacity of the neocortex), thus providing a putative correlate to autistic symptomatology.

Clinical and Macroscopic Correlates of Minicolumnar Pathology in Autism

All subcortical arrangements are primarily nuclear in type. The cortex has been the first part of the brain to evolve a radial and laminar arrangement of cells. The resultant modular arrangement is based on the cell minicolumn: a self-contained ecosystem of connectivity linking afferent, efferent, and inerneuronal connections. Recently, the cell minicolumn has been found to be abnormal in patients with autism. This article relates different aspects of the cell minicolumn and larger-scale neuronal assemblies to potential research techniques and their application to clinical practice. (J Child Neurol 2002;17:692-695).

Lateralization of Minicolumns in Human Planum temporale Is Absent in Nonhuman Primate Cortex

Gross analyses of large brain areas, as in MRI studies of macroanatomical structures, average subtle alterations in small regions, inadvertently missing significant anomalies. We developed a computerized imaging program to microscopically examine minicolumns and used it to study Nissl-stained slides of normal human, chimpanzee, and rhesus monkey brains in a region of the planum temporale. With this method, we measured the width of cell columns, the peripheral neuropil space, the spacing density of neurons within columns, and the Gray Level index per minicolumn. Only human brain tissue revealed robust asymmetry in two aspects of minicolumn morphology: wider columns and more neuropil space on the left side. This asymmetry was absent in chimpanzee and rhesus monkey brains.

Neuronal Density and Architecture (Gray Level Index) in the Brains of Autistic Patients

Although neuropathologic studies have centered on small samples, it is accepted that brains of autistic individuals tend to be large, on average. Knowledge regarding the cause of this macrocephaly is limited. Postmortem studies reveal little in terms of cortical dysplasia. Some of these studies suggest increased cell-packing density in subcortical structures. These neuronomorphometric studies have been subjective or based their conclusions on measures of neuronal density. Our study sought the possible presence of increased cell-packing density by using the Gray Level Index. The Gray Level Index is defined as the ratio of the area covered by Nissl-stained elements to unstained area in postmortem samples. Analyzed images included Brodmanns cortical areas 9, 21, and 22 of 9 autistic patients (7 males, 2 females; mean age of 12 years, with a range of 5 to 28 years) and 11 normal controls (7 males, 4 females; mean age of 14 years, with a range of 3 to 25 years). The overall multivariate test revealed significant differences both between autistic patients and controls (P = .001) and between hemispheres (P = .025). Follow-up univariate tests showed significant diagnosis-dependent effects in feature distance (P = .005), the standard deviation in distance (P = .016), and feature amplitude (P = .001). The overall mean Gray Level Index was 19.4% in controls and 18.7% in autism (P = .724). In autism, an increased number of minicolumns, combined with fewer cells per column (or their greater dispersion), results in no global difference in neuronal density. (J Child Neurol 2002;17:515-521).

Reduced minicolumns in the frontal cortex of patients with autism

Cell minicolumns were shown to be narrower in frontal regions in brains of autistic patients compared with controls. This was not found in primary visual cortex. Within the frontal cortex, dorsal and orbital regions displayed the greatest differences while the mesial region showed the least change. We also found that minicolumns in the brain of a 3‐year‐old autistic child were indistinguishable from those of the autistic adult in two of three frontal regions, in contrast to the control brains. This may have been due to the small size of the columns in the adult autistic brain rather than to an accelerated development. The presence of narrower minicolumns supports the theory that there is an abnormal increase in the number of ontogenetic column units produced in some regions of the autistic brain during corticoneurogenesis.

The minicolumn and evolution of the brain

The minicolumn is generally considered an elementary unit of the neocortex in all mammalian brains. This essential building block has been affected by changes in the circuitry of the cortex during evolution. Researchers believe that enlargement of the cortical surface occurs through the addition of minicolumns rather than of single neurons. Therefore, minicolumns integrate cortical encephalization with organization. Despite these insights, few studies have analyzed the morphometry of the minicolumn to detect subtle but important differences among the brains of diverse mammals. The notion that minicolumns are essentially unchanged across species is challenged by strong evidence to the contrary. Because they are subject to species-specific variation, they can be used as a way to study evolutionary changes. Unfortunately, comparative studies are marred by a lack of standardized techniques, tissue preparation, cortical regions, or anatomical feature studied. However, recent advances in methodology enable standardized, quantified comparisons of minicolumn morphology.

Asperger's Syndrome and Cortical Neuropathology

Aspergers disorder or syndrome is characterized by impaired social interaction, normal intelligence, and adequate language skills in the areas of grammar and vocabulary. The symptoms are pervasive in nature and usually manifested in childhood. Despite the gravity and chronicity of the condition, the medical literature remains sparse and offers no information about possible neuropathologic underpinnings. The present study is a case report on two patients with Aspergers syndrome. Neuropathologic examination revealed no degenerative changes or gliosis. A more detailed assessment with computerized image analysis indicated abnormalities in the minicolumnar organization of the three areas examined (9, 21, 22) (P = .032). Specifically, minicolumns were smaller, and their component cells were more dispersed than normal. A similar neuropathology has recently been reported for autism and disputes the uniqueness of these findings. The minicolumnar changes provide a possible link to receptive field abnormalities and a useful clinicopathologic correlate to Aspergers syndrome. (J Child Neurol 2002;17:142-145).

A comparative quantitative analysis of cytoarchitecture and minicolumnar organization in Broca's area in humans and great apes

Brocas area was identified in the inferior frontal gyrus of chimpanzee, bonobo, gorilla, and orangutan brains through direct cytoarchitectonic comparison with human brains. Across species, Brocas area comprises Brodmanns areas 44 and 45. We found that these areas exhibited similar cytoarchitectonic characteristics in all species examined. We analyzed the minicolumnar organization of cells in layer III of Brocas area in 11 human and 9 great ape specimens. A semiautomated method was used to analyze digitized images of histological sections stained for Nissl substance. Horizontal spacing distance and gray level index (GLI; or the area fraction occupied by cells) were quantified in all images. In contrast to area Tpt, the only cortical area for which comparative minicolumnar data have been published previously for humans and one of the great apes, we found no population‐level asymmetry, for either horizontal spacing distance or GLI. Only human females exhibited a leftward asymmetry in GLI. GLI was lower in humans than in great apes (P < 0.001), allowing more space for connectivity in layer III. In humans, horizontal spacing distance was greater than in great apes but smaller relative to brain size. J. Comp. Neurol. 510:117–128, 2008.

Minicolumnar pathology in dyslexia.

The minicolumn is an anatomical and functional unit of the brain whose genesis accrues from germinal cell divisions in the ventricular zone of the brain. Disturbances in the morphometry of minicolumns have been demonstrated recently for both autism and Downs syndrome. We report minicolumnar abnormalities in the brain of a dyslexic patient. The corresponding developmental disturbance (ie, large minicolumns) could account for the perceptual errors observed in dyslexia.