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.

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.

Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up.

Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.

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.

Asymmetry of lexico-semantic processing in schizophrenia changes with disease progression.

BACKGROUND: Are anomalies of cerebral asymmetry integral to the disease process? Here, we examined the influence of age, chronicity and age of onset of illness in 34 patients with early onset schizophrenia and 20 controls in relation to structural asymmetries of the temporal lobe and performance asymmetries on a semantic language lexical decision task. METHODS: Volumetric MRI and a novel divided visual field probe of lateralised lexico-semantic language were assessed in patients with early onset schizophrenia (EOS) and controls. Novel ratios of age-illness overlap and directional asymmetry were developed in order to examine the association of chronicity factors to asymmetry. RESULTS: Loss of laterality on the lexical decision task and discordant structural asymmetry were correlated with duration of illness but were not seen in younger, less chronic patients. Reduced lateral processing speed, and discordant structural asymmetry were associated with greater proportion of lifetime schizophrenia. CONCLUSION: Although the conclusions are limited by the cross sectional nature of the study, anomalies of cerebral asymmetry in early onset patients may be an index of disease progression, and reflect directly on the disease process.

The relationship between callosal axons and cortical neurons in the planum temporale: alterations in schizophrenia.

The relationship between "connectivity" measures such as DTI and the cellular alterations in the cortex that give rise to those connections remains unclear. Cytoarchitectural changes in the planum temporale (PT) suggest impaired layer III feedforward projection neurons in schizophrenia. Altered hemispheric asymmetry of the PT has been reported in patients, along with altered white matter density in the corpus callosum, and there is anomalous activation of the PT during auditory hallucinations. We measured layer III cell density and pyramidal neuron size in PT of both hemispheres of post-mortem brains from patients with schizophrenia (n=16) and control subjects (n=16). We found reduced cell density and the loss of a correlation between magnopyramidal neuron density and axon number in the isthmus of the corpus callosum in schizophrenia. The normal asymmetry indicated that magnopyramidal neurons tend towards being larger and denser in the left PT but this asymmetry is significantly reduced in schizophrenia. The findings offer cytoarchitectural insight into the relationship between PT cortex and callosal white matter abnormalities in schizophrenia.

Proteomic analysis of short- and intermediate-term memory in Hermissenda.

Changes in cellular and synaptic plasticity related to learning and memory are accompanied by both upregulation and downregulation of the expression levels of proteins. Both de novo protein synthesis and post-translational modification of existing proteins have been proposed to support the induction and maintenance of memory underlying learning. However, little is known regarding the identity of proteins regulated by learning that are associated with the early stages supporting the formation of memory over time. In this study we have examined changes in protein abundance at two different times following one-trial in vitro conditioning of Hermissenda using two-dimensional difference gel electrophoresis (2D-DIGE), quantification of differences in protein abundance between conditioned and unpaired controls, and protein identification with tandem mass spectrometry. Significant regulation of protein abundance following one-trial in vitro conditioning was detected 30 min and 3 h post-conditioning. Proteins were identified that exhibited statistically significant increased or decreased abundance at both 30 min and 3 h post-conditioning. Proteins were also identified that exhibited a significant increase in abundance only at 30 min, or only at 3 h post-conditioning. A few proteins were identified that expressed a significant decrease in abundance detected at both 30 min and 3 h post-conditioning, or a significant decrease in abundance only at 3 h post-conditioning. The proteomic analysis indicates that proteins involved in diverse cellular functions such as translational regulation, cell signaling, cytoskeletal regulation, metabolic activity, and protein degradation contribute to the formation of memory produced by one-trial in vitro conditioning. These findings support the view that changes in protein abundance over time following one-trial in vitro conditioning involve dynamic and complex interactions of the proteome.

'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.

Proteomic analysis of post-translational modifications in conditioned Hermissenda.

Post-translational modifications of proteins are a major determinant of biological function. Phosphorylation of proteins involved in signal transduction contributes to the induction and maintenance of several examples of cellular and synaptic plasticity. In this study we have identified phosphoproteins regulated by Pavlovian conditioning in lysates of Hermissenda nervous systems using two-dimensional electrophoresis (2DE) in conjunction with (32)P labeling, fluorescence based phosphoprotein in-gel staining, and mass spectrometry. Modification of protein phosphorylation regulated by conditioning was first assessed by densitometric analysis of (32)P labeled proteins resolved by 2DE from lysates of conditioned and pseudorandom control nervous systems. An independent assessment of phosphorylation regulated by conditioning was obtained from an examination of 2D gels stained with Pro-Q Diamond phosphoprotein dye. Mass spectrometric analysis of protein digests from phosphoprotein stained analytical gels or Coomassie Blue stained preparative gels provided for the identification of phosphoproteins that exhibited statistically significant increased phosphorylation in conditioned groups as compared to pseudorandom controls. A previously identified cytoskeletal related protein, Csp24 (24 kDa conditioned stimulus pathway phosphoprotein), involved in intermediate-term memory exhibited significantly increased phosphorylation detected 24 h post-conditioning. Our results show that proteins involved in diverse cellular functions such as transcriptional regulation, cell signaling, cytoskeletal regulation, metabolic activity, and protein degradation contribute to long-term post-translational modifications associated with Pavlovian conditioning.

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.

Beyond symptom dimensions: schizophrenia risk factors for patient groups derived by latent class analysis.

INTRODUCTION: Patients grouped by latent class analysis of symptoms show some consensus between studies, and may be less etiologically heterogeneous than current diagnoses. If so, the effect size of 'neurodevelopmental' risk factors may be greater than in equivalent DSMIV diagnostic groups. METHOD: Two hundred fifty six individuals with neurodevelopmental risk factors recorded in the National Child Development Study (1958) UK birth cohort were grouped by data-driven illness subtypes, derived previously in over 1000 individuals. The effect sizes of these risks were compared between data-derived and DSMIV schizophrenia (295.x) groups. RESULTS: Compared to DSMIV schizophrenia, the data-driven subtype broadly characterized by the presence of psychotic symptoms in the absence of affective symptoms showed significantly greater effect sizes in eight out of thirteen continuously-rated risk factors: birth weight, cognition, childhood behavioural problems, and neurological softsigns including handedness. CONCLUSION: A data-driven subgroup of schizophrenia patients, characterized as lacking co-morbid depressive symptoms, is less heterogeneous with respect to neurodevelopmental etiology.

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.

The emperors of the schizophrenia polygene have no clothes.

A substantial body of research literature, identified by nine out of ten papers on genetics in the recent ISI research front on schizophrenia, claims to have established associations between aspects of the disease and sequence variation in specific candidate genes. These candidatures have proven unreplicated in large sibling pair linkage surveys and a targeted association study. Even if the case for an association be regarded as a lucky guess (assuming one gene in 30 000 was guessed right) the large linkage and association studies provide no evidence of sequence variation relating to psychosis at any of these gene loci. Thus this body of work must be regarded as an indicator of the extent to which the 'eye of faith' is able to discern meaning in complex data when none is present.

One-trial in vitro conditioning regulates an association between the beta-thymosin repeat protein Csp24 and actin.

One-trial conditioning in Hermissenda results in enhanced intrinsic cellular excitability of sensory neurons in the conditioned stimulus pathway, and the phosphorylation of several proteins. Previous results demonstrated that the development of enhanced intrinsic excitability was dependent on the expression of conditioned stimulus pathway phosphoprotein-24 (Csp24), an intracellular protein containing four repeated beta-thymosin homology domains. Consistent with this, antisense oligonucleotide-mediated inhibition of Csp24 expression prevents the reduction in amplitude of the A-type transient K+ current (I(A)) and the depolarized shift in the steady-state activation curve normally produced by one-trial in vitro conditioning of isolated photoreceptors. One-trial conditioning also regulates Csp24 phosphorylation. We now show that purified recombinant Csp24 sequesters G-actin in vitro with an approximate K(d) value of 2.8 microM. We also observed a significant increase in the coprecipitation of actin with Csp24 after one-trial in vitro conditioning using antibodies directed toward either Csp24 or phospho-Csp24. Preincubation with protein kinase C (PKC) selective inhibitors attenuated the increase in Csp24 phosphorylation and coprecipitated actin observed after one-trial conditioning. Our findings indicate that the PKC signaling pathway contributes to the phosphorylation of Csp24 after one-trial conditioning, and that PKC activity modulates an association between Csp24 and actin. These data suggest Csp24 may influence intrinsic excitability by regulating cytoskeletal dynamics.

Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2.

In order to investigate the replication timing properties of PCDH11X and PCDH11Y, a pair of protocadherin genes located in the hominid-specific non-pseudoautosomal homologous region Xq21.3/Yp11.2, we conducted a FISH-based comparative study in different human and non-human primate (Gorilla gorilla) cell types. The replication profiles of three genes from different regions of chromosome X (ZFX, XIST and ATRX) were used as terms of reference. Particular emphasis was given to the evaluation of allelic replication asynchrony in relation to the inactivation status of each gene. The human cell types analysed include neuronal cells and ICF syndrome cells, considered to be a model system for the study of X inactivation. PCDH11 appeared to be generally characterized by replication asynchrony in both male and female cells, and no significant differences were observed between human and gorilla, in which this gene lacks X-Y homologous status. However, in differentiated human neuroblastoma and cerebral cortical cells PCDH11X replication profile showed a significant shift towards allelic synchrony. Our data are relevant to the complex relationship between X-inactivation, as a chromosome-wide phenomenon, and asynchrony of replication and expression status of single genes on chromosome X.

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.