Sexually dimorphic white matter geometry abnormalities in adolescent onset schizophrenia.

The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.

Schizophrenia as variation in the sapiens-specific epigenetic instruction to the embryo.

The psychoses (schizophrenia and bipolar disorder) occur in all populations with approximately uniform incidence and sex-dependent age of onset. Core symptoms involve aspects of language; brain structural deviations are sex and hemisphere-related. Genetic predisposition is unaccounted for by linkage or association. The hypothesis is proposed that the 'missing heritability' is epigenetic in form and generated in meiosis on a species-specific XY chromosomal template. A duplication from Xq21.3 to Yp11.2 that occurred 6 million years ago is proposed as critical to hominin evolution. Within this block of homology the Protocadherin11XY gene pair is expressed as a cell surface adhesion factor in both X and Y forms; it has undergone a series of coding changes (16 in the Y sequence and 5 in the X including two to cysteines) in the hominin lineage. According to the hypothesis these sequence changes, together with one or more deletions and a paracentric inversion in the Y block, were successively selected; late events in this series established cerebral asymmetry (the 'torque') as the defining characteristic of the human brain. Built around this reference frame, an epigenetic message channels early development of the embryo in a sapiens-specific format. Diversity in meiotic pairing is postulated as the basis for species-specific deviations in development associated with psychosis.

'The missing genes: what happened to the heritability of psychiatric disorders?'.

Less than 2% of the 80-90% heritability of major psychiatric disease, for example, schizophrenia and manic-depressive illness is attributable to genes identified by linkage and association. Where is the missing heritability? The recently described PRDM9 gene imposes epigenetic stability on the XY body in male meiosis including Sapiens-specific variation relating to a gene pair (Protocadherin11XY) created by X to Y duplication at 6MYA. Thus sexually dimorphic variation that distinguishes the species may be transmitted between generations in epigenetic form that evades detection by linkage and association.

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 (Protocadherin 11XY) 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.

Associative behavioral modification in hermissenda: cellular correlates.

Three days of training consisting of trials of light paired with rotation produces a long-term modification of photopositive behavior in Hermissenda crassicornis. The behavioral modification depends on the temporal association of light and rotation. For animals that received light paired with rotation, significant increases in the spontaneous activity of type B photoreceptors were correlated with changes in photopositive behavior after training. A persistent tonic depolarization of type B photoreceptors can explain the cellular changes correlated with the long-term behavioral modification produced by the temporal association of light and rotation.

Retention of an associative behavioral change in Hermissenda.

The nudibranch mollusk Hermissenda crassicornis is normally attracted to a test light. Three days of training consisting of 50 trials per day of light paired with a rotational stimulus led to a significant increase, lasting for days, in the animal's response latency to enter a test light. The group that received light associated with rotation was significantly different from groups subjected to nonassociative control procedures. Modifications of well-known sensory networks may be related to a behavioral change that shares several operational features with associative learning.

Lack of coincidence between neural and behavioral manifestations of cortical spreading depression.

The presence of cortical spreading depression is typically inferred from the presence of hypesthesia. The electrocorticogram and slow-potential change were recorded during cortical spreading depression and it was found that hypesthesia remained long after the cortex recovered from neural depression. Hypesthesia, therefore, is an unreliable indicant of cortical spreading depression; if cortical spreading depression is used as a research tool, neural activity must be monitored. These data offer a special problem for memory transfer studies.

Impaired learning and decreased cortical norepinephrine after bilateral locus coeruleus lesions.

Bilateral lesions of the nucleus locus coeruleus in rats deplete the cerebral cortex of norepinephrine and significantly diminish the rate of increase of running for food reward in a simple L-shaped runway. As assessed in this situation, learning was absent in those rats with the most complete ablations of the locus coeruleus, although these rats showed normal weight gain and normal motor and exploratory activity.

Neuropeptide Y distribution in the rat brain.

A massive neuronal system was detected by immunocytochemistry and radioimmunoassay with antibodies to neuropeptide Y, the recently isolated peptide of the pancreatic polypeptide family. Immunoreactive cell bodies and fibers were most prevalent in cortical, limbic, and hypothalamic regions. Neuropeptide Y was extracted in concentrations higher than those of any other peptide hitherto discovered in the mammalian brain. Column chromatography of brain extracts and double immunostaining experiments indicate that neuropeptide Y is the endogenous brain peptide responsible for immunostaining of pancreatic polypeptide-like immunoreactivity in the mammalian brain.

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.

Craddock & Owen vs Kraepelin: 85 years late, mesmerised by "polygenes".

The case for replacing the binary Kraepelinian system with a continuum concept originated with Kraepelin [Kraepelin, E. (1920) Die Erscheinungsformen des Irreseins (translated by H Marshall as: Patterns of mental disorder. In: Themes and Variations in European Psychiatry. Eds S.R. Hirsch & M. Shepherd. Wright, Bristol, pp7-30, l974). Zeitschrift Gesamte Neurologie Psychiatrie, vol. 62, 1-29.], and is based upon studies of familial aggregation and phenomenology. Craddock and Owen's [Craddock, N.J., Owen, M.J. (2007) Rethinking psychosis: the disadvantages of a dichotomous classification now outweigh the advantages. World Psychiatry 6: 20-27.] claim for the "beginning of the end for the Kraepelinian dichotomy" on the basis of linkage and association is undermined by un-replicability of findings across studies (Crow, T.J. (2007) How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. American Journal of Psychiatry, 164, 13-21). Absence of evidence of linkage is consistent with the concept that the variation is epigenetic in form rather than DNA sequence-based. But what are the dimensions that underly the continuum? The BBC Internet survey (Peters, M., Reimers, S., Manning, J.T. (2006) Hand preference for writing and associations with selected demographic and behavioral variables in 255,100 subjects: the BBC internet study. Brain and Cognition 62, 177-189), reinforces the concept that lateralisation is a major and sex-dependent dimension of human variation in verbal and spatial ability: twin studies indicate that inter-individual variation in dominance for language is epigenetic and the paternal age effect can be similarly explained. Thus an epigenetic imprint, arising in relation to the sapiens specific torque and persisting over one or two generations is a better fit to the genetics of the psychotic continuum than Craddock and Owen's elusive "polygenic" variations.

Schizophrenia as failure of hemispheric dominance for language.

Schizophrenic illnesses occur with approximately the same incidence in all human populations with a characteristic distribution (slightly earlier in males) of ages of onset. Given that the predisposition (which presumably is genetic) is associated with a procreative disadvantage why do such illnesses persist? Here it is suggested that these conditions are a manifestation of genetic diversity in the evolution of the specifically human characteristic of language, an innovation that has occurred by a process of progressive hemispheric specialization-the establishment of dominance for some critical component of language in one or the other hemisphere. Individuals who develop schizophrenic symptoms show lesser anatomical and functional asymmetries than the population as a whole; such symptoms may reflect 'dominance failure' for language.

PCDH11 is X/Y homologous in Homo sapiens but not in Gorilla gorilla and Pan troglodytes.

Protocadherin X (PCDHX) and Protocadherin Y (PCDHY) are cell-surface adhesion molecules expressed predominantly in brain. The human PCDH11X/Y gene pair is located in the non-pseudoautosomal X-Y homologous region (Xq21.3/Yp11.2). The possible existence of PCDH11 gene dosage differences between human and non-human primates is of evolutionary significance with respect to species differences and escape from X inactivation, and has been repeatedly debated. Previous investigations on the X/Y homologous status of PCDH11 and adjacent sequences in non-human primates have highlighted the complexity of the molecular pattern and evolutionary history of this genomic region. This paper provides for the first time direct evidence for the absence of the PCDH11 genefrom the Y chromosome of chimpanzee (Pan troglodytes) as well as gorilla (Gorilla gorilla). By confirmingthe suspected lack of X-Y homologous status for PCDH11 in non-human primates, our results reinforce the hypothesis of a hominid-specific role for this gene in brain development.

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

AIM: To 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 (Heschl's 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.

Multiple markers of cortical morphology reveal evidence of supragranular thinning in schizophrenia.

In vivo structural neuroimaging can reliably identify changes to cortical morphology and its regional variation but cannot yet relate these changes to specific cortical layers. We propose, however, that by synthesizing principles of cortical organization, including relative contributions of different layers to sulcal and gyral thickness, regional patterns of variation in thickness of different layers across the cortical sheet and profiles of layer variation across functional hierarchies, it is possible to develop indirect morphological measures as markers of more specific cytoarchitectural changes. We developed four indirect measures sensitive to changes specifically occurring in supragranular cortical layers, and applied these to test the hypothesis that supragranular layers are disproportionately affected in schizophrenia. Our findings from the four different measures converge to indicate a predominance of supragranular thinning in schizophrenia, independent of medication and illness duration. We propose that these indirect measures offer novel ways of identifying layer-specific cortical changes, offering complementary in vivo observations to existing post-mortem studies.

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.

The third biannual winter workshop on schizophrenia. Schladming, Austria, Jan 26-31, 1986.

The following general principles seem to summarize the emphasis that was evident from the several days of multiple presentations and discussions. The need exists to continue to develop improvements in the tools applicable to research in psychiatry, both clinical and biological "instruments" that are both sensitive and specific to the questions asked. New molecular genetic technology has already been used to explore genetic susceptibility hypotheses, as well as novel viral associations. Imaging of brain receptor kinetics in vivo is in progress. Improvements in structured clinical rating scales for quantifying changes in biologically important clusters of symptoms (eg, negative vs positive symptoms) or the defining of prodromal symptoms that lead to relapse are critical to progress in etiological and treatment research. A genetic factor or factors for schizophrenia exist, although whether a "familial" type defines only a subgroup of schizophrenia is controversial. The relative importance of genetic vs environmental variables, and whether there is genetic and environmental heterogeneity, continue to be debated. The most important epidemiological data, the seasonality of birth, and the controversial question of geographical variation in prevalence can be clues to the etiology of schizophrenia and are presently being clarified. The pursuit of new treatments and modifications of present conventional treatments to increase the percentage of patients recovering from psychotic illnesses or lead to more complete recovery states is always of prime importance. An emphasis on clarifying the dopamine hypothesis of schizophrenia with PET continues to be at the forefront of psychiatric research. A focus on patients in a first episode of schizophrenia can clarify major issues.(ABSTRACT TRUNCATED AT 250 WORDS)

Tritiated LSD binding in frontal cortex in schizophrenia.

It has been reported that the binding of tritiated LSD (at 2 or 4 nm) to frontal cortex is reduced in schizophrenia, a finding that has been interpreted as a reduction in the number of serotonin receptors. The present study, however, reveals in a Scatchard analysis of tritiated LSD binding in frontal cortex in the brains of 13 schizophrenic patients that there was no decrease in binding by comparison with eight control brains. Quantities of neuroleptic remaining in the brain after death cannot be readily washed out and could have led to the previous report of reduced LSD binding. A decrease in affinity of LSD binding sites consistent with this possibility has been demonstrated in chlorpromazine-treated rats. In the brains of five patients who had probably been neuroleptic-free for the year before death, tritiated LSD binding was significantly increased. This result needs to be replicated in larger samples.

Schizophrenia, genetic retrenchment, and epidemiologic renaissance. The Sixth Biennial Winter Workshop on Schizophrenia, Badgastein, Austria, January 26-February 1, 1992.

A distinctive feature of these workshops, in addition to those noted in the introductory overview, is the selection of a relatively isolated location for a 1-week period. This, together with a rich and varied program and an ethos of informality, encourages participants to discuss not only the work presented but also their unpublished work and their intuitions based on preliminary data and analyses. Such an interchange is of inestimable value to the schizophrenia research community. In scientific terms, a panel of concluding discussants (Drs Kendell, Torrey, and Waddington) were in some measure of agreement that genetics, particularly molecular genetics, appears to be experiencing a period of retrenchment, while epidemiology is experiencing something of a renaissance. Maternal influenza was a prominent theme, although the data were far from consistent. It was argued by Dr Wessely that risk for schizophrenia putatively attributable to maternal influenza might be 5% to 10% of all cases, indicating a modest effect. Eclectically, Dr Kendell believed the effect to be "real" but slight and fragile, it being sought against large aggregates that almost inevitably result in differing findings from differing countries or from different data bases within a given country. Gender differences were also among the more prominent themes, not just in an epidemiologic context but also in a variety of other studies. This points anew to disturbances in schizophrenia of factors that regulate, or are intimately associated with, sexual dimorphism in brain development. Abnormalities in cerebral asymmetry continue to pervade a variety of research findings and point further to neurodevelopmental anomalies.(ABSTRACT TRUNCATED AT 250 WORDS)

Anterior pituitary hormone secretion in chronic schizophrenics.

Venous samples were obtained serially from 18 chronic schizophrenics and nine controls before and after the intravenous administration of protirelin and gonadorelin (gonadotropin releasing hormone [GnRH] ) and by venipuncture from 38 controls. Significant reductions in basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were found in the schizophrenic group associated with a reduction in the fluctuation of LH in serial samples. The FSH and prolactin responses to the administration of protirelin and gonadorelin were reduced in the schizophrenic group and abnormal increments of growth hormone secretion were noted in a number of patients, particularly those with reduced basal and stimulated hormone secretion. This pattern of hypothalamic-pituitary dysfunction, which is distinct from that seen in other psychiatric and endocrinological conditions, suggests a reduction in spontaneous GnRH release from the hypothalamus in schizophrenia and may be of potential pathophysiological significance.