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.

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.

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.

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.

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.

Laterality interacts with sex across the schizophrenia/bipolarity continuum: an interpretation of meta-analyses of structural MRI.

Review of the first comprehensive meta-analysis of VBM (voxel-based morphometry) studies in schizophrenia indicates asymmetrical reductions of anterior cingulate gyrus to the right, and medial temporal lobe (including the uncus) and para-hippocampal gyrus to the left. In subsequent meta-analyses of schizophrenia and bipolar disorder change in these limbic structures is systematically related to change in the insula. Deficits in insula (and para-hippocampal gyrus) to the left, and dorsal anterior cingulate gyrus to the right are greater in schizophrenic psychoses whereas deficits in anterior cingulate to the left and insula to the right are greater in bipolar illness. Thus (1) brain structures implicated in schizophrenia include those implicated in bipolar disorder, (2) the variation that separates the prototypical psychoses may be a subset of that relating to the structural asymmetry (the "torque") characteristic of the human brain, and (3) the meta-analysis of Bora et al. (2012) indicates that laterality of involvement of the insula and cingulate gyrus across the spectrum of bipolar and schizophrenic psychoses is critically dependent upon the sex ratio. Thus structural change underlying the continuum of psychosis relates to the interaction of laterality and sex.

The protocadherin 11X/Y (PCDH11X/Y) gene pair as determinant of cerebral asymmetry in modern Homo sapiens.

Annett's right-shift theory proposes that human cerebral dominance (the functional and anatomical asymmetry or torque along the antero-posterior axis) and handedness are determined by a single "right-shift" gene. Familial transmission of handedness and specific deviations of cerebral dominance in sex chromosome aneuploidies implicate a locus within an X-Y homologous region of the sex chromosomes. The Xq21.3/Yp11.2 human-specific region of homology includes the protocadherin 11X/Y (PCDH11X/Y) gene pair, which encode cell adhesion molecules subject to accelerated evolution following the separation of the human and chimpanzee lineages six million years ago. PCDH11X and PCDH11Y, differentially regulated by retinoic acid, are highly expressed in the ventricular zone, subplate, and cortical plate of the developing cerebral cortex. Both proteins interact with ß-catenin, a protein that plays a role in determining axis formation and regulating cortical size. In this way, the PCDH11X/Y gene pair determines cerebral asymmetry by initiating the right shift in Homo sapiens.

Hemispheric asymmetry in the fusiform gyrus distinguishes Homo sapiens from chimpanzees.

While the neural basis for linguistic communication has been linked to brain structural asymmetries found only in humans (wider connective spacing is found between the minicolumns of neurons in the left hemisphere language areas), it is unknown if the opposite microanatomical asymmetry exists in the fusiform gyrus which typically supports a right hemisphere bias for face processing. Unlike language, face processing is an ability shared with chimpanzees and, as Darwin observed, the widespread use of facial expressions in animal communication suggests a biological basis. We tested the principle that minicolumn asymmetry follows typical functional dominance in humans, and tested its evolutionary continuity, by measuring minicolumn width, neuronal size and density in the mid-fusiform cortex in 14 humans and 14 chimpanzees. We found that microanatomical asymmetry distinguishes humans from chimpanzees although the direction of asymmetry is the same as in language areas-the right hemisphere contained narrower minicolumns and smaller pyramidal neurons, as in auditory language areas. Uniformly narrow minicolumns in chimpanzees and in the human right hemisphere are consistent with mechanistic predictions supporting the apparent bias towards holistic face processing. Wider minicolumns and larger neurons in the human left hemisphere may be consistent with a language function such as word-form processing. Microanatomical asymmetry in the neocortex therefore provides a correlate of hemispheric specialisation.

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.

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.

Asymmetry loss is local rather than global in adolescent onset schizophrenia.

Meta-analyses in adult-onset schizophrenia report loss of normal planum temporale (PT) asymmetry, posited to relate to language and symptoms, but are inconclusive regarding global "cerebral torque". PT asymmetry has been reported unchanged in childhood onset schizophrenia. Here the discrepancy is examined in adolescence. Unbiased PT asymmetry and torque measures were obtained on 35 adolescents with schizophrenia or schizoaffective disorder and 31 adolescent controls. Patients had less PT asymmetry than controls, but torque was unchanged. Taken with previous reports, these results in adolescent onset psychosis suggest that local disturbance of cerebral asymmetry increases with patient age; it could indicate that differential rate of change at the cortical surface in the two hemispheres is the mechanism of symptom generation.

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.

Attenuated asymmetry of functional connectivity in schizophrenia: a high-resolution EEG study.

The interhemispheric asymmetries that originate from connectivity-related structuring of the cortex are compromised in schizophrenia (SZ). Under the assumption that such abnormalities affect functional connectivity, we analyzed its correlate-EEG synchronization-in SZ patients and matched controls. We applied multivariate synchronization measures based on Laplacian EEG and tuned to various spatial scales. Compared to the controls who had rightward asymmetry at a local level (EEG power), rightward anterior and leftward posterior asymmetries at an intraregional level (1st and 2nd order S-estimator), and rightward global asymmetry (hemispheric S-estimator), SZ patients showed generally attenuated asymmetry, the effect being strongest for intraregional synchronization in the alpha and beta bands. The abnormalities of asymmetry increased with the duration of the disease and correlated with the negative symptoms. We discuss the tentative links between these findings and gross anatomical asymmetries, including the cerebral torque and gyrification pattern, in normal subjects and SZ patients.

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).