Shared and distinct white matter abnormalities in adolescent-onset schizophrenia and adolescent-onset psychotic bipolar disorder.

BACKGROUND: While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. METHODS: Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. RESULTS: Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.

Comparison of Surface Area and Cortical Thickness Asymmetry in the Human and Chimpanzee Brain.

Comparative study of the structural asymmetry of the human and chimpanzee brain may shed light on the evolution of language and other cognitive abilities in humans. Here we report the results of vertex-wise and ROI-based analyses that compared surface area (SA) and cortical thickness (CT) asymmetries in 3D MR images obtained for 91 humans and 77 chimpanzees. The human brain is substantially more asymmetric than the chimpanzee brain. In particular, the human brain has 1) larger total SA in the right compared with the left cerebral hemisphere, 2) a global torque-like asymmetry pattern of widespread thicker cortex in the left compared with the right frontal and the right compared with the left temporo-parieto-occipital lobe, and 3) local asymmetries, most notably in medial occipital cortex and superior temporal gyrus, where rightward asymmetry is observed for both SA and CT. There is also 4) a prominent asymmetry specific to the chimpanzee brain, namely, rightward CT asymmetry of precentral cortex. These findings provide evidence of there being substantial differences in asymmetry between the human and chimpanzee brain. The unique asymmetries of the human brain are potential neural substrates for cognitive specializations, and the presence of significant CT asymmetry of precentral gyrus in the chimpanzee brain should be further investigated.

Measurement of Sylvian Fissure asymmetry and occipital bending in humans and Pan troglodytes.

The evolution of human-specific lateralised functions such as language has been linked to the development of structural asymmetries in the brain. Here we applied state of the art image analysis techniques to measure Sylvian Fissure (SF) asymmetry and Occipital Bending (OB) in 3D Magnetic Resonance (MR) images of the brain obtained in-vivo for 30 humans and 30 chimpanzees (Pan troglodytes). SF morphology differed between species, with the human SF terminating more superiorly in right inferior parietal lobe, an asymmetry that was on average absent in chimpanzees (F (1,52) = 5.963, p = 0.018). Irrespective of morphology, Total SF Length was, as previously reported, leftward in humans but not in chimpanzees, although the difference did not reach significance between species. However, when only brains possessing comparable bilateral SF bifurcation morphology were compared, humans showed previously reported "Typical" left-lateralised Anterior-Horizontal (AH-SF) and right-lateralised Vertical (V-SF) SF asymmetries. In contrast, chimpanzees lacked both asymmetries, and this approached being a significant difference between-species in the AH-SF segment (F (1, 34) = 3.680, p = 0.064). On average in humans the left occipital lobe crossed the midline toward the right (Rightward OB) which was significantly different from the chimpanzee cohort that showed no average OB (Independent-Samples Mann-Whitney U Test, p = 0.012). Furthermore, OB was related to SF asymmetry in humans, such that the more rightward V-SF and leftward AH-SF, the more rightward the OB. This "Default" pattern of SF and OB asymmetries was found in 41.7% of human individuals with bilateral SF bifurcation but none of the chimpanzees. To our knowledge, this is the first study highlighting that a pattern of SF and OB asymmetry distinguishes the human from the chimpanzee brain, and suggests this may be associated with a unique trajectory of brain development and functional abilities in humans.

Human torque is not present in chimpanzee brain.

We searched for positional brain surface asymmetries measured as displacements between corresponding vertex pairs in relation to a mid-sagittal plane in Magnetic Resonance (MR) images of the brains of 223 humans and 70 chimpanzees. In humans deviations from symmetry were observed: 1) a Torque pattern comprising right-frontal and left-occipital "petalia" together with downward and rightward "bending" of the occipital extremity, 2) leftward displacement of the anterior temporal lobe and the anterior and central segments of superior temporal sulcus (STS), and 3) posteriorly in the position of left occipito-temporal surface accompanied by a clockwise rotation of the left Sylvian Fissure around the left-right axis. None of these asymmetries was detected in the chimpanzee, nor was associated with a sex difference. However, 4) an area of cortex with its long axis parallel to the olfactory tract in the orbital surface of the frontal lobe was found in humans to be located higher on the left in females and higher on the right in males. In addition whereas the two hemispheres of the chimpanzee brain are equal in extent in each of the three dimensions of space, in the human brain the left hemisphere is longer (p = 3.6e-12), and of less height (p = 1.9e-3), but equal in width compared to the right. Thus the asymmetries in the human brain are potential correlates of the evolution of the faculty of language.

Patients with chronic bipolar disorder exhibit widespread increases in extracellular free water.

OBJECTIVES: Bipolar disorder (BP) is a debilitating psychiatric disease that is not well understood. Previous diffusion magnetic resonance imaging (dMRI) studies of BP patients found prominent microstructural white matter (WM) abnormalities of reduced fractional anisotropy (FA). Because FA is a nonspecific measure, relating these abnormalities to a specific pathology is difficult. Here, dMRI specificity was increased by free water (FW) imaging, which allows identification of changes in extracellular space (FW) from neuronal tissue (fractional anisotropy of tissue [FA-t]). Previous studies identified increased FW in early schizophrenia (SZ) stages which was replaced by widespread decreased FA-t in chronic stages. This is the first analysis utilizing this method to compare BP patients and controls. METHODS: 3 Tesla diffusion weighted imaging (3T DWI) data were acquired for 17 chronic BP and 28 healthy control (HC) participants at Oxford University. Tract-based spatial statistics was utilized to generate a WM skeleton. FW imaging deconstructed the diffusion signal into extracellular FW and tissue FA-t maps. These maps were projected onto the skeleton and FA, FA-t, and FW were compared between groups. RESULTS: We found significantly lower FA in BP patients when compared to HC in areas that overlapped with extensive FW increases. There were no FA-t differences. CONCLUSIONS: Our study suggests that chronic BP shows similar WM changes to early SZ, suggesting that extracellular FW increases could be a transient indication of recent psychotic episodes. Since FW increase in SZ has been suggested to be related to neuroinflammation, we theorize that neuroinflammation might be a shared pathology between chronic BP and early SZ.

The XY gene hypothesis of psychosis: origins and current status.

Sex differences in psychosis and their interaction with laterality (systematic departures from 50:50 left-right symmetry across the antero-posterior neural axis) are reviewed in the context of the X-Y gene hypothesis. Aspects of laterality (handedness/cerebral asymmetry/the torque) predict (1) verbal and non-verbal ability in childhood and across adult life and (2) anatomical, physiological, and linguistic variation relating to psychosis. Neuropsychological and MRI evidence from individuals with sex chromosome aneuploidies indicates that laterality is associated with an X-Y homologous gene pair. Within each mammalian species the complement of such X-Y gene pairs reflects their potential to account for taxon-specific sexual dimorphisms. As a consequence of the mechanism of meiotic suppression of unpaired chromosomes such X-Y gene pairs generate epigenetic variation around a species defining motif that is carried to the zygote with potential to initiate embryonic gene expression in XX or XY format. The Protocadherin11XY (PCDH11XY) gene pair in Xq21.3/Yp11.2 in probable coordination with a gene or genes within PAR2 (the second pseudo-autosomal region) is the prime candidate in relation to cerebral asymmetry and psychosis in Homo sapiens. The lately-described pattern of sequence variation associated with psychosis on the autosomes may reflect a component of the human genome's adjustment to selective pressures generated by the sexually dimorphic mate recognition system.

Neuropathology of epilepsy and psychosis: the contributions of J.A.N. Corsellis.

Professor J.A.N. Corsellis, whose life and work is recalled here, gained great insight into the meaning of morphological cerebral aberrations found in neuropsychiatric disease through exact neuropathological investigations of tissue specimens obtained from patients with distinct syndromes. He was a leading authority in the field. We have searched and compiled resources relating to J.A.N. Corsellis' life and work, including personal memories from colleagues and data from scientific publications. J.A.N. Corsellis made seminal contributions to the understanding of neuropsychiatric disease; his works substantially added to the understanding of the dementias, schizophrenia and the psychoses, and morphological sequelae of boxing. In seizure disorders, his name is linked to the first description of focal cortical dysplasia and limbic encephalitis, the pathology of status epilepticus and Ammon's horn sclerosis, and the systematic investigation of epilepsy surgery specimens in general. Both his life and work are closely linked to Runwell Hospital, Wickford, Essex and the Maudsley Hospital. During his professional life he established a large brain bank, now known as the Corsellis Collection. J.A.N. Corsellis had significant impact on neuroscience; many of his observations were groundbreaking and are still valid.

Duration of untreated illness and outcome in schizophrenia: test of predictions in relation to relapse risk.

BACKGROUND: The nature of the relationship between duration of the pre-diagnostic interval in schizophrenia and better outcomes remains unclear. AIMS: To re-examine data from one of the earliest studies suggesting an association between long pre-treatment interval and compromised outcome, assessing the relationship between symptomatic and social variables and increased relapse risk at 1 year. METHOD: Symptomatic, social and demographic data from participants in the Northwick Park Study of First Episodes who completed 12-month follow-up (n = 101) were re-analysed in the context of duration of untreated illness (DUI). RESULTS: At admission, those with long DUI were more likely to have lower scores on tension derived from the Present State Examination, exhibited more behaviour threatening to others and more bizarre behaviour, were more likely to be single, to live alone or dependently, to be unemployed and to have experienced more adverse life events prior to admission. Logistic regression showed that diminished tension, bizarre behaviour and unemployed status independently increased the risk of relapse, bizarre behaviour making the single biggest contribution. Tension did not remain significant with log-transformation of data. CONCLUSIONS: Findings are consistent with the conclusion that long DUI can reflect characteristics of the psychosis itself rather than delay in treatment.

Schizophrenia delays and alters maturation of the brain in adolescence.

Early-onset schizophrenia appears to be clinically more severe than the adult-onset form of the disease. In a previous study, we showed that anatomically related grey and white matter abnormalities found in adolescents patients were larger and more widespread than what had been reported in the literature on adult schizophrenia. Particularly, we found novel structural abnormalities in the primary sensorimotor and premotor systems. Here, we tested alternative hypotheses: either this striking sensorimotor-related pattern is an artefact due to a better sensitivity of the methods, or apparent greater structural abnormalities in the early-onset population are specifically associated with earlier disease onset. Then, if we were to find such characteristic structural pattern, we would test whether these anatomical abnormalities would remain static or, conversely, show dynamic changes in the still developing brain. To address these questions, we combined a cross-sectional study of brain structure for adolescent-onset patients (n = 25) and adult-onset patients (n = 35) and respective matched healthy subjects with a longitudinal study of adolescent-onset patients (n = 12, representative subset of the cross-sectional group) and matched healthy controls for >2 years. Looking at differences between adolescent and adult patients' grey matter volume and white matter microstructure abnormalities, we first confirmed the specificity (especially in motor-related areas) and the greater severity of structural abnormalities in the adolescent patients. Closer examination revealed, however, that such greater anomalies seemed to arise because adolescent patients fail to follow the same developmental time course as the healthy control group. Longitudinal analysis of a representative subset of the adolescent patient and matched healthy populations corroborated the delayed and altered maturation in both grey and white matters. Structural abnormalities specific to adolescent-onset schizophrenia in the sensori-motor cortices and corticospinal tract were less marked or even disappeared within the longitudinal period of observation, grey matter abnormalities in adolescent patients evolving towards the adult-onset pattern as defined by recent meta-analyses of adult schizophrenia. Combining cross-sectional adolescent and adult datasets with longitudinal adolescent dataset allowed us to find a unique, abnormal trajectory of grey matter maturation regardless of the age at onset of symptoms and of disease duration, with a lower and later peak than for healthy subjects. Taken together, these results suggest common aetiological mechanisms for adolescent- and adult-onset schizophrenia with an altered neurodevelopmental time course in the schizophrenic patients that is particularly salient in adolescence.

Paracingulate sulcus asymmetry; sex difference, correlation with semantic fluency and change over time in adolescent onset psychosis.

The left paracingulate sulcus (PCS) is longer than the right and the adjacent cortex is activated by the generation of words. In adult patients with chronic schizophrenia the anatomical asymmetry is reduced. In 35 controls and 38 adolescents with schizophrenia or schizoaffective disorder (mean age = 16 years) we found that semantic verbal fluency correlated with leftward PCS asymmetry in controls but not in patients. At intake, PCS length did not differ between patients and controls, but at follow-up (13 controls, 10 patients, mean age = 18 years) PCS asymmetry (comprising both increasing left and decreasing right length) increased significantly, the increase was greater in males than in females, and there was a trend for a diagnosis * sex * side * time interaction such that in controls leftward PCS asymmetry increased, while in patients of both sexes there was convergence toward symmetry. Thus sulcal anatomy develops differentially in the two sexes during adolescence, and the pattern of asymmetric sex-dependent change over time may distinguish patients with psychosis from controls. Greater change in asymmetry during adolescence may explain earlier age of onset in males and greater deficits in verbal fluency.

Auditory cortex asymmetry, altered minicolumn spacing and absence of ageing effects in schizophrenia.

The superior temporal gyrus, which contains the auditory cortex, including the planum temporale, is the most consistently altered neocortical structure in schizophrenia (Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1-52). Auditory hallucinations are associated with abnormalities in this region and activation in Heschl's gyrus. Our review of 34 MRI and 5 post-mortem studies of planum temporale reveals that half of those measuring region size reported a change in schizophrenia, usually consistent with a reduction in the left hemisphere and a relative increase in the right hemisphere. Furthermore, female subjects are under-represented in the literature and insight from sex differences may be lost. Here we present evidence from post-mortem brain (N = 21 patients, compared with 17 previously reported controls) that normal age-associated changes in planum temporale are not found in schizophrenia. These age-associated differences are reported in an adult population (age range 29-90 years) and were not found in the primary auditory cortex of Heschl's gyrus, indicating that they are selective to the more plastic regions of association cortex involved in cognition. Areas and volumes of Heschl's gyrus and planum temporale and the separation of the minicolumns that are held to be the structural units of the cerebral cortex were assessed in patients. Minicolumn distribution in planum temporale and Heschl's gyrus was assessed on Nissl-stained sections by semi-automated microscope image analysis. The cortical surface area of planum temporale in the left hemisphere (usually asymmetrically larger) was positively correlated with its constituent minicolumn spacing in patients and controls. Surface area asymmetry of planum temporale was reduced in patients with schizophrenia by a reduction in the left hemisphere (F = 7.7, df 1,32, P < 0.01). The relationship between cortical asymmetry and the connecting, interhemispheric callosal white matter was also investigated; minicolumn asymmetry of both Heschl's gyrus and planum temporale was correlated with axon number in the wrong subregions of the corpus callosum in patients. The spacing of minicolumns was altered in a sex-dependent manner due to the absence of age-related minicolumn thinning in schizophrenia. This is interpreted as a failure of adult neuroplasticity that maintains neuropil space. The arrested capacity to absorb anomalous events and cognitive demands may confer vulnerability to schizophrenic symptoms when adult neuroplastic demands are not met.

Bilateral generic working memory circuit requires left-lateralized addition for verbal processing.

According to the Baddeley-Hitch model, phonological and visuospatial representations are separable components of working memory (WM) linked by a central executive. The traditional view that the separation reflects the relative contribution of the 2 hemispheres (verbal WM--left; spatial WM--right) has been challenged by the position that a common bilateral frontoparietal network subserves both domains. Here, we test the hypothesis that there is a generic WM circuit that recruits additional specialized regions for verbal and spatial processing. We designed a functional magnetic resonance imaging paradigm to elicit activation in the WM circuit for verbal and spatial information using identical stimuli and applied this in 33 healthy controls. We detected left-lateralized quantitative differences in the left frontal and temporal lobe for verbal > spatial WM but no areas of activation for spatial > verbal WM. We speculate that spatial WM is analogous to a "generic" bilateral frontoparietal WM circuit we inherited from our great ape ancestors that evolved, by recruitment of additional left-lateralized frontal and temporal regions, to accommodate language.

The influence of sex chromosome aneuploidy on brain asymmetry.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X-Y homologous gene [Crow (1993); Lancet 342:594-598]. In particular, females with Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's syndrome (KS) who possess a supernumerary X-chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crow's prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal-occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero-posterior axis.

The 'big bang' theory of the origin of psychosis and the faculty of language.

OBJECTIVE: To achieve a unified concept of the aetiology of psychosis. BACKGROUND: The nuclear symptoms of "schizophrenia" occur with approximately the same age- and sex-specific incidence in all human populations. No substantive environmental precipitant has been identified, and yet these "illnesses" are associated with deviations in brain structure that are uniform across populations, are established late in development and relate to the capacity for language. No genes have been identified by linkage or association strategies. ARGUMENT: It is postulated that the variation 1. relates precisely to the genetic mechanism that distinguishes the species Homo sapiens from its precursor. 2. constitutes a class of epigenetic diversity intrinsic to the genetic control of the species characteristic (the "specific mate recognition system" according to the theory of HEH Paterson). 3. reflects the role of the cerebral torque in the neuro-developmental re-organization that enabled the faculty of language. A genetic mechanism involving both the X and the Y chromosomes is suggested by 1) evidence for anomalies of asymmetry of brain structure and function in the sex chromosome aneuploidies, 2) a same sex concordance effect for handedness, 3) sex differences in lateralization, and verbal and spatial ability, and their inter-relationships. These three facts direct attention to the Xq21.3/Yp11.2 homology block that was established by an X to Y duplication 6 million years ago, ie at the time of origin of the hominid lineage. Within this block a gene pair (Protocadherin11X and Y) expressed as two cell surface adhesion molecules at axo-dendritic synapses has been subject to change (16 amino-acid substitutions in the Y, and critically 5 in the X sequence) in the hominid lineage. The X to Y duplication and its subsequent modification (4 deletions and a paracentric inversion) on the Y may have played a central role in hominid speciation with the most recent change (at around 160,000 years) representing the transition to language and modern Homo sapiens (the 'big bang'). The expression of genes within the homologous region is influenced by the extent to which the X and Y chromosomes pair in male meiosis (referred to as MSUC "meiotic suppression of unpaired chromosomes"). This mechanism generates epigenetic diversity relating to the species capacity for language; it is proposed as the basis of the genetic predisposition to psychosis. CONCLUSION: Language and psychosis have a common origin in the genetic event (the 'big bang') that defined the species.

Axon bundle spacing in the anterior cingulate cortex of the human brain.

The anterior cingulate cortex (ACC) is implicated in neuropsychiatric disorders. Post-mortem axon bundle data will be important to complement novel MRI methods for analysing cortical diffusion data. [Jespersen SN, Kroenke CD, Ostergaard L, et al. Modeling dendrite density from magnetic resonance diffusion measurements. Neuroimage. 2007;34:1473-86] Therefore we aimed to assess perimeter, area, density and spacing of axon bundles in BA24 not previously measured in the human ACC using image analysis of 10 microm-thick tangential sections of layer IV in 4 normal patients. Axon bundle mean perimeter was 53.8 microm, mean area was 197.1 microm(2), mean density was 226.3/mm(2), and mean spacing was 73.8 microm. Thus, axon bundles were widely spaced relative to cell body minicolumns and other prelimbic areas. A review of the literature suggests that there is hierarchical regional variation of bundle and column spacing.

How and why genetic linkage has not solved the problem of psychosis: review and hypothesis.

OBJECTIVE: The author examined the chromosomal linkage method as an approach to the genetic basis of schizophrenia and bipolar disorder. METHOD: Comparisons were conducted of recent meta-analyses of genome scans of schizophrenia and bipolar disorder and of the three largest (N>300) sibling pair studies of schizophrenia and schizoaffective disorder and a comparable study of bipolar illness. RESULTS: Recent meta-analyses have not identified consistent sites of linkage. The three largest studies of schizophrenia fail to agree on a single locus, no commonality with bipolar illness has been demonstrated, and there is no replicable support for any of the current candidate genes. DISCUSSION: An alternative to the concept that DNA sequence variation lies in "multiple genes of small effect" is the hypothesis that the variation is epigenetic but related to the genetic transition ("the speciation event") that separated Homo sapiens from a prior hominid species. This hypothesis draws attention to the chromosomal rearrangement (the Xq21.3/Yp translocation) that occurred some 6 million years ago in the hominid lineage and subsequent rearrangements, including a paracentric inversion, that have taken place within the translocated segment. Here it is argued that the most recent of these events is relevant to specifically human characteristics, including language. The gene pair protocadherin X and Y within this region is under new selective pressure and is in a novel (epigenetic) situation with respect to X inactivation. CONCLUSIONS: Epigenetic variation associated with chromosomal rearrangements that occurred in the hominid lineage and that relates to the evolution of language could account for predisposition to schizophrenia and schizoaffective and bipolar disorder and failure to detect such variation by standard linkage approaches.

Schneider's first rank symptoms and continuous performance disturbance as indices of dysconnectivity of left- and right-hemispheric components of language in schizophrenia.

BACKGROUND: Here we investigate pathophysiological dimensions (language disturbance, negative symptoms, lateralisation and the continuous performance test) in relation to ICD-10 and DSM-IV concepts of diagnosis. METHODS: A total of 32 consecutive psychotic patients with at least one Schneider's first rank symptom (SFRS), 15 depressed patients without SFRS and 17 normal volunteers were assessed with the Clinical Language Disorder Rating Scale (CLANG), SFRS, "pure defect" Huber's basic symptoms (HBS), handedness (Annett's pegboard task), and the A-X Continuous Performance Test (AX-CPT). RESULTS: CLANG total score (an index of severity of language disorder) was correlated with the severity of SFRS, a higher leftward shift of handedness, and poorer performance on AX-CPT. Receiver operating characteristic (ROC) analysis showed that only CLANG and AX-CPT variables had adequate predictive validity in separating cases of ICD-10 schizophrenia from other diagnoses. The logistic regression model predicting the presence of ICD-10 schizophrenia was statistically significant using CLANG and AX-CPT variables, but not SFRS or other variables. HBS did not correlate with other variables and did not predict ICD-10 diagnosis. CONCLUSIONS: A cross-sectional diagnosis based on language disturbance and CPT performance yields a diagnostic construct largely overlapping with the ICD-10 definition of schizophrenia. We suggest that Schneider's first rank symptoms (that play a large role in the DSM-IV concept) can be considered an index of left hemisphere dysconnectivity for language whereas CPT dysfunction reflects dysconnectivity of the right hemisphere for those remoter ("spatial") associations that are closer to Bleuler's core defect and to the chronicity implicit in the ICD definition. Thus the dimensions of language disturbance in psychosis can be traced to specific cortico-cortical dysconnectivities.

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 (Broca's area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's 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.

March 27, 1827 and what happened later--the impact of psychiatry on evolutionary theory.

In the interaction between Psychiatry and evolutionary theory the force of the impact has not always been in one direction. The Brownes, father and son, had an influence on the development of Darwin's theory at different points in the nineteenth century. The crystallization by Miskolczy in 1933 of the concept that schizophrenia is a disorder that is specific to Homo sapiens is another example. In 1964 the formulation of the central paradox of psychosis by Huxley, Mayr and co-authors and the subsequent critique by Kuttner et al. of the solution Huxley et al. had offered opened up evolutionary approaches to aetiology. Here it is argued that a resolution of this paradox requires identification of the speciation event for modern H. sapiens and elucidation of its neuroanatomical and physiological consequences. It necessitates a saltational account of species transitions and the recognition of species-specific genetic variation. Pursuit of these objectives leads to the hypothesis that speciation events occur selectively on the heterogametic chromosome (the Y in mammals) and are followed by a phase of sexual selection to establish a new specific mate recognition system. In H. sapiens the core component of this system is the capacity for language; the nuclear symptoms of schizophrenia are necessary clues to its neural structure.

Macroscopic brain asymmetry is changed along the antero-posterior axis in schizophrenia.

BACKGROUND: Anatomical asymmetry may be altered in schizophrenia, but the changes are subtle and in some studies undetected perhaps due to methodological limitations. METHODS: In a postmortem MRI study (23 patients, 20 controls), we used a geometric mesh technique to define the cortical surface and to separate two components of brain asymmetry: hemisphere shift, conceived as the position of an entire hemisphere relative to the other (which may be reversed in situs inversus), and the distribution of tissue within the hemisphere along the antero-posterior axis ("volume torque"). RESULTS: Only volume torque was changed in schizophrenia-in comparison subjects, the coronal section of maximal left hemisphere volume was more anteriorly placed than on the right [and correlated with left superior temporal gyrus (STG) volume], and, in patients, it was more posterior (showing a reversed correlation with left STG volume). CONCLUSIONS: The findings validate a new approach to cerebral asymmetry. Assessments of cerebral asymmetry in psychosis should account for, or exclude, hemisphere shift, which is not changed, and focus on the second component, A-P volume distribution; the findings point to an anomaly of relative hemispheric development that may have pathophysiological significance.