Right-left asymmetrics in the brain.

Structural asymmetries between the hemispheres are found in the human brain. Asymmetries in the auditory regions and in the Sylvian fissures are present even in the fetus. The Sylvian asymmetries may have existed in Neanderthal man and are found consistently in some apes. They may relate to right-left differences infunction. Thus, the striking auditory asymmetries could underlie language lateralization. The asymmetries in the frontal and occipital lobes and the lateral ventricles are correlated with hand preference. Anatomical asymmetries may help to explain the range of human talents, recovery from acquired disorders of language function, certain childhood learning disabilities, some dementing illnesses of middle life, and the evidence for behavioral lateralization in nonhuman primates.

The return of Phineas Gage: clues about the brain from the skull of a famous patient.

When the landmark patient Phineas Gage died in 1861, no autopsy was performed, but his skull was later recovered. The brain lesion that caused the profound personality changes for which his case became famous has been presumed to have involved the left frontal region, but questions have been raised about the involvement of other regions and about the exact placement of the lesion within the vast frontal territory. Measurements from Gage's skull and modern neuroimaging techniques were used to reconstitute the accident and determine the probable location of the lesion. The damage involved both left and right prefrontal cortices in a pattern that, as confirmed by Gage's modern counterparts, causes a defect in rational decision making and the processing of emotion.

Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat.

Embryonic knockdown of candidate dyslexia susceptibility gene (CDSG) homologs in cerebral cortical progenitor cells in the rat results in acute disturbances of neocortical migration. In the current report we investigated the effects of embryonic knockdown and overexpression of the homolog of DCDC2, one of the CDSGs, on the postnatal organization of the cerebral cortex. Using a within-litter design, we transfected cells in rat embryo neocortical ventricular zone around embryonic day (E) 15 with either 1) small hairpin RNA (shRNA) vectors targeting Dcdc2, 2) a DCDC2 overexpression construct, 3) Dcdc2 shRNA along with DCDC2 overexpression construct, 4) an overexpression construct composed of the C terminal domain of DCDC2, or 5) an overexpression construct composed of the DCX terminal domain of DCDC2. RNAi of Dcdc2 resulted in pockets of heterotopic neurons in the periventricular region. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Dcdc2 shRNA-transfected neurons migrated in a bimodal pattern, with approximately 7% of the neurons migrating a short distance from the ventricular zone, and another 30% migrating past their expected lamina. Rats transfected with Dcdc2 shRNA along with the DCDC2 overexpression construct rescued the periventricular heterotopia phenotype, but did not affect the percentage of transfected neurons that migrate past their expected laminar location. There were no malformations associated with any of the overexpression constructs, nor was there a significant laminar disruption of migration. These results support the claim that knockdown of Dcdc2 expression results in neuronal migration disorders similar to those seen in the brains of dyslexics.

Early cortical damage in rat somatosensory cortex alters acoustic feature representation in primary auditory cortex.

Early postnatal freeze-lesions to the cortical plate result in malformations resembling human microgyria. Microgyria in primary somatosensory cortex (S1) of rats are associated with a reduced behavioral detection of rapid auditory transitions and the loss of large cells in the thalamic nucleus projecting to primary auditory cortex (A1). Detection of slow transitions in sound is intact in animals with S1 microgyria, suggesting dissociation between responding to slow versus rapid transitions and a possible dissociation between levels of auditory processing affected. We hypothesized that neuronal responses in primary auditory cortex (A1) would be differentially reduced for rapid sound repetitions but not for slow sound sequences in animals with S1 microgyria. We assessed layer IV cortical responses in primary auditory cortex (A1) to single pure-tones and periodic noise bursts (PNB) in rats with and without S1 microgyria. We found that responses to both types of acoustic stimuli were reduced in magnitude in animals with microgyria. Furthermore, spectral resolution was degraded in animals with microgyria. The cortical selectivity and temporal precision were then measured with conventional methods for PNB and tone-stimuli, but no significant changes were observed between microgyric and control animals. Surprisingly, the observed spike rate reduction was similar for rapid and slow temporal modulations of PNB stimuli. These results suggest that acoustic processing in A1 is indeed altered with early perturbations of neighboring cortex. However, the type of deficit does not affect the temporal dynamics of the cortical output. Instead, acoustic processing is altered via a systematic reduction in the driven spike rate output and spectral integration resolution in A1. This study suggests a novel form of plasticity, whereas early postnatal lesions of one sensory cortex can have a functional impact on processing in neighboring sensory cortex.

Neurology of developmental dyslexia.

Developmental dyslexia was until recently considered to belong solely in the domain of educational psychology. With the advent of better theories on language and reading, and better methods for assessing the structure and function of living human brains and for determining genetic transmission, dyslexia is now poised to become a focal concern of cognitive neuroscience, neurology, and genetic research. Still unresolved are questions relating to how much a reading disability represents a normal variation or a separate pathological entity, and whether the cognitive disorder is primarily cognitive, or secondary to a disorder in early perception. Recent findings from neuroanatomy, neurophysiology, neuropsychology, and genetics research are reviewed. (This review is an updated version of a review first published in Current Opinion In Neurology and Neurosurgery 1992, 5:71-76.)

Histometric changes and cell death in the thalamus after neonatal neocortical injury in the rat.

Freezing injury to the developing cortical plate results in a neocortical malformation resembling four-layered microgyria. Previous work has demonstrated that following freezing injury to the somatosensory cortex, males (but not females) have more small and fewer large cells in the medial geniculate nucleus. In the first experiment, we examined the effects of induced microgyria to the somatosensory cortex on neuronal numbers, neuronal size, and nuclear volume of three sensory nuclei: ventrobasal complex, dorsal lateral geniculate nucleus, and medial geniculate nucleus. We found that there was a decrease in neuronal number and nuclear volume in ventrobasal complex of microgyric rats when compared with shams, whereas there were no differences in these variables in the dorsal lateral geniculate nucleus or medial geniculate nucleus. We also found that there were more small and fewer large neurons in both ventrobasal complex and medial geniculate nucleus. In experiment 2, we attempted to determine the role of cell death in the thalamus on these histometric measures. We found that cell death peaked within 24 h of the freezing injury and was concentrated mostly in ventrobasal complex. In addition, there was evidence of greater cell death in males at this age. Taken together, these results support the notion that males are more severely affected by early injury to the cerebral cortex than females.

DYX1C1 functions in neuronal migration in developing neocortex.

Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1's function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.

Biological substrates of anatomic asymmetry.

Asymmetric cortical areas differ in volume and in the number of neurons. There are also differences between asymmetric and symmetric areas. As asymmetry increases, the total area of the region decreases, suggesting that when a brain is symmetric, it is the result of two large sides rather than two small sides. Also, these volume differences are caused by changes in the number of cells, not changes in cell-packing density. The ontogenetic basis for this difference in cell numbers likely relates to events that occur quite early in corticogenesis before final mitosis of proliferative units, but definitive proof is lacking. Finally, the pattern and degree of callosal connections differ between symmetric and asymmetric brains, with differential axonal pruning being implicated as the likely mechanism.

Freezing lesions of the developing rat brain: a model for cerebrocortical microgyria.

Cerebrocortical microgyri were induced by placing a freezing probe on the skull of P0 and P1 rat pups. Freezing lesions resulted in laminar necrosis of the infragranular layers and the subsequent migration of supragranular neurons through the region of damage. The result was most often a region of four-layered microgyric cortex consisting of a molecular layer, a thickened layer ii, a lamina dissecans (corresponding to the necrotized layers IV, V, and VIa), and a neuronal layer iv which corresponded to layer VIb of the intact cortex. Immunocytochemical investigation of the microgyric cortex with antibodies to neurofilament, glial fibrillary acidic protein and glutamate showed more widespread disruption of neocortical architecture than could be seen from Nissl preparations. In contrast, vasoactive intestinal peptide-containing neuronal bodies appeared to be distributed normally in the microgyric region although their processes were sometimes distorted. These results are considered in the light of previous research on induced microgyria, and possible implications for the behavioral consequences of focal, developmental neuropathologic lesions are discussed.

The development of induced cerebrocortical microgyria in the rat.

Placement of a freezing probe on the skull of neonatal rats produces four-layered microgyria, complete with a lamina dissecans and microsulcus. We studied the developmental course of this induced microgyria under light microscopy by examining changes in neurons, glia, and macrophages following a focal freezing insult on the day of birth (postnatal day [P]0). The destruction of neurons and glia induced by the freezing probe extends through the cortical plate and occasionally through the subplate, but the pial membrane appears undamaged and radial glial cells, while damaged, are not eliminated. Reactive astrocytes and macrophages arrive in the damaged area within 24 hours of the injury, and repair of the damaged tissue peaks within the first week. Damaged radial glial fibers regrow, and supragranular neurons migrate through this damaged area, also within the first week. The newly formed supragranular layer overlies the cell-free area. The damaged cortex begins to assume its adult-like microgyric appearance from P5 to P10. On P15 and P32, long glial fibers, resembling radial glia, are present and are immunoreactive for glial fibrillary acidic protein and radial glial fiber antibodies (vimentin and Rat-401). No such fibers appear at this age in the non-microgyric areas or in normal brains. We conclude that microgyria formation may be the consequence of brain repair mechanisms occurring during neuronal migration to the neocortex, and that it appears to preserve primitive features characteristic of the developing cortex.

Progressive multifocal neurologic deficit with disseminated subpial demyelination.

A sixty-six year-old man developed visual and gait difficulties, a deficit in recent memory and hearing, and acute urinary retention. He subsequently became blind, deaf, and quadriparetic. Terminally, weakness deepended and he lapsed into semi-coma. The cerebrospinal fluid contained increased amounts of protein with a normal electrophoretic pattern, and a moderate mononuclear pleocytosis. Gross examination of the brain revealed normal vessels and meninges. Coronal sections showed irregular areas of subpial discoloration in forebrain and brainstem. Stains for myelin revealed scattered foci of pallor in the intracortical myelinated fibers; demyelination throughout the brainstem, most severe in subpial areas; and a focus of central pontine myelin loss. The subependymal myelin was intact throughout the neuraxis. Histological examination showed axonal preservation in areas of extreme myelin loss. Demyelination was accompanied by astrocytic gliosis showing different degrees of activity, and occasional perivascular cuffing with mononuclear cells in cerebral and meningeal vessels. Electron microscopy revealed filamentous structures in cell nuclei. These were 180-220 A in diameter, had a hollow core, and, in some tangential sections, showed cross striations. The unusual clinical picture and correspondingly striking pattern of demyelination suggest that this case might represent a distinct clinical entity.

The intrinsic architectonic and connectional organization of the superior temporal region of the rhesus monkey.

The superior temporal region (STR) in the rhesus monkey includes the circular sulcus (Cis), the supratemporal plane (STP), and the superior temporal gyrus (STG). Rostrally the STR is continuous with the periallocortices of the prepyriform and anterior insular regions; caudally it borders the isocortices of the inferior parietal lobule and the superior temporal sulcus. The STR contains 12 cytoarchitectonic areas: four fields on the Cis, four on the STP, and four on the STG. The sulcal fields (root fields) are adjacent to the insula and resemble it in the possession of a relatively strong layer V; the STP fields (core fields) are characterized by well-developed layer IV; and the STG fields (belt fields) exhibit strong differentiation of layer III. In each line of fields the more rostral ones show relative prominence of the deeper layers, with increasing prominence of the superficial layers occurring caudad in a stepwise fashion. Analysis of the connectional organization of the fields within the STR suggests an assembly of four rostrocaudal stages, each composed of one field from each line--a root, a core, and a belt field. There is a specific arrangement of connections among the fields of a given stage and between fields in adjacent stages. Projections directed caudally from one field to another field in the adjacent stage arise in layers V and VI and terminate in the superficial layers (mainly layer I). Projections directed to a field in a rostrally adjacent stage arise from layer III neurons and terminate in layers III and IV, usually in columns. There is also a laminar specificity between fields lying within a given stage.

Changes in efferent and afferent connectivity in rats with induced cerebrocortical microgyria.

Freezing injury to the cortical plate at postnatal day (P) 1 initiates a cascade of events that ultimately result in a focal neocortical malformation resembling human 4-layered microgyria. This malformation has been associated with widespread changes in neocortical and thalamic architecture and physiology. It was hypothesized that at least some of these alterations could result from connectional reorganization following early injury. The current experiment was designed to delineate the efferent and afferent connections between the cerebral hemispheres and between the cortex and thalamus of rats with induced cerebrocortical microgyria. Microgyria were induced in the parietal cortex of rats by freezing injury on postnatal day 1. In adulthood, injections of biotinylated dextran amine were made either in the microgyric cortex, in homologous regions of the opposite hemisphere, or in ipsilateral ventrobasal complex of the thalamus. Appropriately directed connections to homotopic areas were seen in some but not all microgyric rats. In addition, heterotopic projections to frontal and secondary sensorimotor cortices were noted. Projections from homotopic regions in the hemisphere opposite to the malformation terminated most often in the medial portions of the microgyrus or avoided it entirely. There were almost no thalamocortical or corticothalamic projections between the ventrobasal complex and the microgyrus itself, although a dense plexus of thalamocortical fibers was often noted at the border between the malformed and normal cortex. These connectional changes may help explain disturbances in architecture, physiology, and behavior associated with these focal malformations.

The insular formations of the dolphin brain: quantitative cytoarchitectonic studies of the insular component of the limbic lobe.

The large insula of the bottlenose dolphin consists of radial gyri arising, in fanlike fashion, from the transverse insular gyrus, and is covered completely by the frontal, parietal, and temporal opercula . On cytoarchitectonic grounds, the dolphin insula is divided into anterior, middle, and posterior sectors that may be the equivalent of the three similar sectors present in the primate insula. Rostrocaudally, these sectors become increasingly more homogeneous and less laminated. Within each sector progressive differentiation occurs in the direction of the circular sulcus. A transitional cortex, the peripaleocortex in the transverse insular gyrus, is interposed between the prepiriform and the periamygdalar cortex and the proisocortex of the insula proper. This peripaleocortex consists of outer and inner cellular strata separated by a hypocellular lamina dissecans. The outer cell stratum is continuous with layers II and III of the insular proisocortex ; the more prominent inner stratum is continuous with proisocortical layers V and VI; the intervening lamina dissecans becomes partially filled, mostly with modified pyramidal cells of medium size that may constitute an incipient layer IV. A band of myelinated fibers corresponding to the external band of Baillarger is found within the lamina dissecans. The anterior insular sector is characterized by distinct lamination and a well-defined, ribbonlike layer Va. In the middle sector, the cortex is internodense and lamination is less clear. The posterior sector is even less laminated and tends to be externodense . Within each sector, lamination becomes clearer in the direction of the circular sulcus. Furthermore, the rostrocaudal architectonic changes suggest a possible transition from a motor-type to a sensory-type cortex. Beyond the insula, the architecture of the opercular cortices reflect, in turn, the influences of the insular sectors.

Symmetry and asymmetry in the human posterior thalamus. I. Cytoarchitectonic analysis in normal persons.

We parceled the posterior thalami of nine normal human brains according to cytoarchitectonic criteria, measured relevant nuclear volumes, and sought left-right asymmetries. We found that thalamic zones with multiple projections to the cerebral cortex, using the centromedian-parafascicular nucleus as a prototype, were mostly symmetric. This group includes the medial, lateral, and inferior pulvinar nuclei. Thalamic zones that project discretely to a few, clearly defined cortical receptor fields (using the medial geniculate nucleus [MG] as a prototype) closely reflected the asymmetry of the cortical fields to which they project. Hence, the MG showed a slight right-sided bias, and the lateralis posterior nucleus (related to the grossly asymmetric inferior parietal lobule) showed a significant leftsided bias in eight of the nine brains measured. This asymmetry may partially explain the apparent language specialization of the dominant thalamus.

Inferior parietal lobule. Divergent architectonic asymmetries in the human brain.

Architectonic parcellation of the parietal lobes of eight human brains, with special attention paid to the inferior parietal lobule, resulted in a map that bore a close relationship to previous maps and took into consideration modern data on physiology and connections. Two general parietal zones were distinguished, one above and the other below the intraparietal sulcus, similar to the dorsal-ventral distinction suggested for the frontal lobe. Five areas were recognized in the inferior parietal lobule, of which areas parietal areas EG (PEG), G (PG), and occipitoparietal G (OPG) were in the angular gyrus. A lateralization toward the right was found for area PEG, an area structurally similar to the visually related cortices of the posterior superior parietal region. A lateralization toward the left was found for area PG, but only in brains with a larger left planum temporale. The asymmetry in area PG seemed to be linked to other asymmetries present in language areas, whereas the right-sided area PEG preponderance showed no relation to the language asymmetries.

Symmetry and asymmetry in the human posterior thalamus. II. Thalamic lesions in a case of developmental dyslexia.

The cytoarchitecture of the brain of a patient with developmental dyslexia was analyzed. The cortical abnormalities, consisting of micropolygyria encompassing most of posterior temporoparietal area and ectopic cell collections elsewhere have been described previously. In this study, the posterior thalamus was likewise analyzed, and a bilateral disruption of cytoarchitecture was noted in the medial geniculate nucleus and the lateralis posterior nucleus, a nuclear group of probable relevance to language found to be asymmetric.

Human brain. Cytoarchitectonic left-right asymmetries in the temporal speech region.

The auditory regions in four normal brains were mapped and the full extent of the cytoarchitectonic subdivisions was measured for the presence of right-left asymmetries. It was found that asymmetries similar to those found in the planum temporale (left commonly larger than right) are also seen in auditory cytoarchitectonic area Tpt, and area of probable importance for language function. There is a strong positive correlation between the planum asymmetry and the asymmetry of Tpt. It is concluded that the previously described planum asymmetries probably reflect asymmetries in an auditory cytoarchitectonic area and therefore may represent, at least in part, the anatomic substrate for language lateralization.

The neurology of depression. Cognitive and behavioral deficits with focal findings in depression and resolution after electroconvulsive therapy.

Deficits in cognition and behavior have frequently been described in severely depressed patients. Recent reports have drawn attention to focal left-sided neurologic findings occurring in depression. We describe a depressed patient with marked cognitive and behavioral impairment and focal left-sided signs. The depression, mental status deficits, and physical findings all resolved after electroconvulsive therapy.

Dorsal forebrain anomaly in Williams syndrome.

BACKGROUND: Williams syndrome (WMS) is a rare neurogenetic condition with a behavioral phenotype that suggests a dorsal and/or ventral developmental dissociation, with deficits in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus has been observed in autopsy specimens. OBJECTIVE: To compare gross anatomical features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in brain magnetic resonance images from a sample of subjects with WMS and age- and sex-matched control subjects. SUBJECTS: Twenty-one subjects having clinically and genetically diagnosed WMS (mean +/- SD age, 28.9 +/- 7.9 years) were compared with 21 age- and sex-matched typically developing controls (mean +/- SD age, 28.8 +/- 7.9 years). DESIGN: High-resolution structural magnetic resonance images were acquired. The extent of the central sulcus was qualitatively assessed via surface projections of the cerebral cortex. RESULTS: The dorsal central sulcus is less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both left (P< .001, chi(2) = 15.79) and right (P< .001, chi(2) = 12.95) hemispheres. No differences between the groups were found in the ventral extent of the central sulcus. CONCLUSIONS: Anomalies in the dorsal region in patients with WMS are indicative of early neurodevelopmental problems affecting the development of the dorsal forebrain and are most likely related to the deficits in visuospatial ability and behavioral timing often observed in this condition.