T J Crow

Anomalies of cerebral asymmetry in schizophrenia interact with gender and age of onset: a post-mortem study

In a post-mortem study of cerebral asymmetry in schizophrenia it was found that asymmetry of the length from the frontal pole to the central sulcus measured dorsally over the external surface of the brain on both hemispheres, showed a gender x diagnosis interaction (p = 0.002). Female controls had a left-greater-than-right asymmetry, and the male controls had a right-greater-than-left asymmetry. This pattern was reversed in schizophrenia. The converse effect was observed on a similar measure of the occipito-parietal lobes (p = 0.028). Significant changes were not seen in measures taken around the lateral surface of the hemispheres. Further, within the patient group, the frontal lobe asymmetry was related to age of onset such that leftward asymmetrical brains were associated with a later age of onset than rightward asymmetrical brains (p = 0.0463 for the females; p = 0.0162 for the males). The occipito-parietal asymmetry was not related to age of onset. We conclude that the asymmetry of the relative distribution of tissue between frontal and posterior regions of the hemispheres is altered in schizophrenia. The findings also suggest that there is an interaction between gender and cerebral asymmetry that is critical in determining age of onset.

Minicolumnar structure in Heschl’s gyrus and planum temporale: Asymmetries in relation to sex and callosal fiber number

AIMnTo investigate the cytoarchitectural basis of asymmetries in human auditory cortex. Minicolumn spacing and number, and regional cortical volume and surface area were measured in the primary auditory region (Heschls gyrus, HG) and posterior auditory association region (planum temporale, PT) in 17 neurologically normal adults (10 female, seven male). PT surface area, minicolumn spacing and minicolumn number were greater in the left hemisphere. HG surface area was larger in the left hemisphere. Asymmetries of minicolumn number in primary and association auditory regions correlated with axonal fiber numbers in the subregions of the corpus callosum through which they project. PT minicolumn number was more asymmetrical in men than women but total number was similar in the two sexes. We conclude that asymmetry of the surface area of the PT is a function of minicolumn spacing. Fewer callosal projections between the plana are found when the minicolumn spacing is more asymmetrical.

Callosal misconnectivity and the sex difference in psychosis

The sex difference in age of onset in schizophrenia is paradoxical in the sense that the brain is developing faster in females but onsets are earlier in males. Therefore if schizophrenia, as widely believed, is a disorder of development, the difference is in the wrong direction. Here we attempt to resolve the paradox with the hypothesis that psychosis is an anomaly of development of cerebral asymmetry and the following assumptions: (1) asymmetry (the torque) confers directionality on the ‘language circuit’ - failure to develop asymmetry leads to the risk of reverse transmission, a putative mechanism of psychotic symptoms; (2) the corpus callosum goes on developing in an antero-posterior direction into the third and fourth decades of life; (3) a sex difference in structure and development of the corpus callosum (with some anterior components greater in males and posterior components greater in females) reflects stronger, faster lateralization in females; (4) because of the inverse relationship between asymmetry and interhemispheric connections, females, by developing faster, avoid the misconnectivity phenomena in the frontal lobes that males, developing more slowly, may encounter at a younger age with particular risk of negative symptoms.

Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia

Reduced density of calbindin-containing interneurons in the prefrontal cortex in schizophrenia has been reported (Beasley et al 2002; Biol Psych 52:708-715). Calbindin is a calcium-binding protein (CBP) present in a subpopulation of GABAergic neurons restricted mainly to layer II of the cortex. A paraffin-embedded, 10-mum-thick section from the planum temporale (PT) of each hemisphere was prepared from 12 patients with schizophrenia and 12 controls. Calbindin-containing cells were stained using an antibody (D-28K). Counting frames were superimposed to sample within layer II of the PT. A bilateral reduction (20%) in calbindin cell density was found in patients (controlling for fixation time). Furthermore, mean calbindin cell cross-sectional area was increased in female patients and reduced in male patients. Reduced CBP expression (reducing the excitability of interneurons) or reduced number of CBP-containing cells may cause disinhibition of pyramidal cells. The majority of calbindin-containing cells in the mature brain are double-bouquet cells with vertically oriented dendrites and axon bundles. By exercising inhibitory modulation of pyramidal cells in a columnar arrangement, they make possible cohesive vertical inhibition of minicolumns. Loss of columnar inhibition may result in reduced minicolumnar segregation and altered cell size may reflect altered minicolumn size.

A theory of the origin of cerebral asymmetry: Epigenetic variation superimposed on a fixed right-shift

A theory of the genetic basis of cerebral asymmetry is outlined according to which (1) a single right-shift factor in all human individuals interacts with (2) epigenetic variation that is apparently random, transmissible between parent and child, but with a half-life extending over a small number of generations. The right-shift factor arose late (150 to 200 thousand years ago [KYA]) in hominid evolution as a mutation in the X copy of a gene pair (Protocadherin11XY) in a region of homology between the X and Y chromosomes created by a duplication 6MYA at the chimpanzee hominid separation. The epigenetic imprint originates in the process now known as “meiotic suppression of unpaired chromosomes” (MSUC); it reflects random pairing of partly homologous X and Y chromosome regions in male meiosis, and confers species-specific diversity of cerebral structure on the human population.

The cytoarchitecture of sulcal folding in Heschl's sulcus and the temporal cortex in the normal brain and schizophrenia: lamina thickness and cell density.

Developmental and psychiatric disorders, including schizophrenia, may be associated with altered cortical thickness and folding. Two studies were performed: (1) to assess cortical layering around a sulcus; cortical thickness, relative thickness of the supragranular (I-III):infragranular (IV-VI) layers, and cell density were assessed at anatomically defined points around Heschls sulcus in tissue from 10 controls and 10 schizophrenia patients. (2) To sample sulci of contrasting prominence; sulcal depth, width, lamina thickness, and cell density from laminae II-VI were taken from various sulci within the temporal lobes from another group of 6 controls and 10 patients. Reduced cell density was found in the fundi of sulci in schizophrenia. Independent of diagnosis; increased sulcal prominence in temporal cortex accompanies reduced lamina thickness (particularly layers V and VI), deep layers show negative relationships between cell density and layer thickness, and total cortex width in Heschls sulcus reduces by half at the bottom compared to the top. Furthermore, compared to the supragranular layers, the infragranular division is relatively thicker at the top of a gyrus, equal in the wall of the sulcus and relatively thinner at the bottom. Many effects of sulcal folding on laminar proportions in controls are similar in schizophrenia. However, cell density is less at the bottom of some sulci in the temporal lobe in schizophrenia. Sampling methods should consider that cortical folding affects cell and lamina distribution in the sampled region in a highly localised manner.

Where and what is the right shift factor or cerebral dominance gene? A critique of Francks et al. (2007)

Francks et al. (2007, p. 1129) claim to have identified “The first potential genetic influence on human handedness … and the first putative genetic effect on variability in human brain asymmetry” and a gene “that underlies much of human cognition, behaviour and emotion” (p. 1129). We criticise this claim on the basis that the authors have made unjustified assumptions concerning mode of transmission both of psychosis and relative hand skill, that they have failed to establish a parent of origin effect, and have overlooked previous findings concerning the genetic basis of handedness and asymmetry. We suggest that some of these errors relate to the application of linkage disequilibrium to detect variation that is common in the population and relates to the characteristic that defines the species. While we agree (and indeed first proposed) that the variation underlying psychosis is intrinsically related to the cerebral torque, which we take to be the anatomical basis of language, we are unconvinced by the data for LRRTM1 presented by Francks et al. We consider that a stronger case can be mounted for the Protocadherin11X/Y gene pair located in the hominid specific Xq21.3/Yp11.2 region of homology that was generated by a duplication from the X between 6 and 5 million years ago and that has been subject to a number of chromosomal and sequence changes. This gene pair can account for relationships between relative hand skill and verbal and non-verbal ability that are sex dependent, and morphological changes in the brain in psychosis that reflect interactions between sex and laterality, which are already established in the literature.

Temporal-lobe length is reduced, and gyral folding is increased in schizophrenia: a post-mortem study.

This post-mortem study of the brains of 29 controls and 25 patients with schizophrenia investigated the length and gyral folding of the temporal lobes, and the asymmetries and inter-relationships of these two measures. The degree of gyral folding was significantly increased in schizophrenia (p = 0.002), but the orientation of the sulci was not changed (p = 0.420). Neither gender nor side affected any of the measures of gyral anatomy, nor were there any significant interactions of these variables with diagnosis. The temporal lobes were significantly shortened in schizophrenia, on two different measures (p = 0.009, and p = 0.001), and on one of these, females had shorter temporal lobes than males (p < 0.0005). No diagnosis x side interactions were found. The temporal-lobe shortening remained after controlling for brain weight and was not statistically related to gyral folding. These two structural changes may reflect an alteration of the cortico-cortical connectivity of the brain in schizophrenia.

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functional-connectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functional-connectivity involving the inferior frontal gyri (Brocas area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Brocas area, and these changes were correlated with delusions/blunted affect. For chronic patients, functional-connectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative, and general symptoms, respectively. Thalamic changes became prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.

Protocadherin 11X/Y a Human-Specific Gene Pair: an Immunohistochemical Survey of Fetal and Adult Brains

Protocadherins 11X and 11Y are cell adhesion molecules of the δ1-protocadherin family. Pcdh11X is present throughout the mammalian radiation; however, 6 million years ago (MYA), a reduplicative translocation of the Xq21.3 block onto what is now human Yp11 created the Homo sapiens-specific PCDH11Y. Therefore, modern human females express PCDH11X whereas males express both PCDH11X and PCDH11Y. PCDH11X/Y has been subject to accelerated evolution resulting in human-specific changes to both proteins, most notably 2 cysteine substitutions in the PCDH11X ectodomain that may alter binding characteristics. The PCDH11X/Y gene pair is postulated to be critical to aspects of human brain evolution related to the neural correlates of language. Therefore, we raised antibodies to investigate the temporal and spatial expression of PCDH11X/Y in cortical and sub-cortical areas of the human fetal brain between 12 and 34 postconceptional weeks. We then used the antibodies to determine if this expression was consistent in a series of adult brains. PCDH11X/Y immunoreactivity was detectable at all developmental stages. Strong expression was detected in the fetal neocortex, ganglionic eminences, cerebellum, and inferior olive. In the adult brain, the cerebral cortex, hippocampal formation, and cerebellum were strongly immunoreactive, with expression also detectable in the brainstem.