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Increased severity of neurological soft signs (NSS) in schizophrenia have been associated with abnormal brain morphology in cerebello-thalamo-cortical structures, but it is unclear whether similar structures underlie NSS prior to the onset of psychosis. The present study investigated the relationship between severity of NSS and grey matter volume (GMV) in individuals at ultra-high risk for psychosis (UHR) stratified for later conversion to psychosis. Structural T1-weighted MRI scans were obtained from 56 antipsychotic-naïve UHR individuals and 35 healthy controls (HC). The UHR individuals had follow-up data (mean follow-up: 5.2 years) to ascertain clinical outcome. Using whole-brain voxel-based morphometry, the relationship between NSS and GMV at baseline was assessed in UHR, HC, as well as individuals who later transitioned (UHR-P, n = 25) and did not transition (UHR-NP, n = 31) to psychosis. NSS total and subscale scores except motor coordination were significantly higher in UHR compared to HC. Higher signs were also found in UHR-P, but not UHR-NP. Total NSS was not associated with GMV in the whole sample or in each group. However, in UHR-P individuals, greater deficits in sensory integration was associated with lower GMV in the left cerebellum, right insula, and right middle frontal gyrus. In conclusion, NSS are present in UHR individuals, particularly those who later transitioned to a psychotic disorder. While these signs show little overall variation with GMV, the association of sensory integration deficits with lower GMV in UHR-P suggests that certain brain areas may be implicated in the development of specific neurological abnormalities in the psychosis prodrome., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Recently, there has been growing interest in the glymphatic system (the functional waste clearance pathway for the central nervous system and its role in flushing solutes (such as amyloid ß and tau), metabolic, and other cellular waste products in the brain. Herein, we investigate a recent potential biomarker for glymphatic activity (the diffusion tensor imaging along the perivascular space [DTI-ALPS] parameter) using diffusion MRI imaging in an elderly cohort comprising 10 cognitively normal, 10 mild cognitive impairment (MCI), and 16 Alzheimer's disease (AD)., Methods: All 36 participants imaged on a Siemens 3.0T Tim Trio. Single-SE diffusion weighted Echo-planar imaging scans were acquired as well as T1 magnetization prepared rapid gradient echo, T2 axial, and susceptibility weighted imaging. Three millimeter regions of interest were drawn in the projection and association fibers adjacent to the medullary veins at the level of the lateral ventricle. The DTI-ALPS parameter was calculated in these regions and correlated with cognitive status, Mini-Mental State Examination (MMSE), and ADASCog11 measures., Results: Significant correlations were found between DTI-ALPS and MMSE and ADASCog11 in the right hemisphere adjusting for age, sex, and APoE ε4 status. Significant differences were also found in the right DTI-ALPS indices between cognitively normal and AD groups (P < .026) and MCI groups (P < .025) in a univariate general linear model corrected for age, sex, and APoE ε4. Significant differences in apparent diffusion coefficient between cognitively normal and AD groups were found in the right projection fibers (P = .028)., Conclusion: Further work is needed to determine the utility of DTI-ALPS index in larger elderly cohorts and whether it measures glymphatic activity., (© 2021 American Society of Neuroimaging.)

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls., Method: We scanned all participants with the PET radioligand 11 C-(R)-PK-11195 and undertook structural MRI to measure gray matter volume and white matter fractional anisotropy (FA)., Results: We found increased binding of 11 C-(R)-PK-11195 in total white matter compared to controls ( p < 0.01), but not in gray matter regions, and this did not correlate with illness severity or duration. Gray matter was reduced in the thalamus ( p < 0.0001) in patients, who also showed widespread reductions in FA across the brain compared to controls ( p < 0.001). A significant correlation between 11 C-(R)-PK11195 binding and FA was shown ( p = 0.002), driven by the NPC patient group., Conclusions: Our findings suggest that neuroinflammation-particularly in white matter-may underpin some structural and degenerative changes in patients with NPC., (© 2020 American Academy of Neurology.)

Background: Australian and US guidelines recommend routine brain imaging, either computed tomography or magnetic resonance imaging, to exclude structural lesions in presentations for first-episode psychosis. The aim of this review was to examine the evidence for the appropriateness and clinical utility of this recommendation by assessing the frequency of abnormal radiological findings in computed tomography and magnetic resonance imaging scans among patients with first-episode psychosis., Methods: PubMed and Embase database were searched from inception to April 2018 using appropriate MeSH or Emtree terms. Studies were included in the review if they reported data on computed tomography or magnetic resonance imaging scan findings of individuals with first-episode psychosis. No restriction on the geographical location of the study or the age of participants was applied. We calculated the percentage of abnormal radiological findings in each study, separately by the two diagnostic methods., Results: There were 16 suitable studies published between 1988 and 2017, reporting data on an overall 2312 patients with first-episode psychosis. Most were observational studies with a retrospective design and the majority examined patients with computed tomography. While structural abnormalities were a relatively common finding, these rarely required clinical intervention (range across studies: 0-60.7%; median: 3.5%) and were very rarely the cause of the psychotic symptoms (range: 0-3.3%; median: 0%). Only 2 of the 16 studies concluded that brain imaging should be routinely ordered in first-episode psychosis., Conclusion: There is insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment. The appropriate screening procedure for structural brain lesions is conventional history-taking, mental status and neurological examination. If intracranial pathology is suspected clinically, a magnetic resonance imaging or computed tomography scan should be performed depending on the clinical signs, the acuity and the suspected pathology. National guidelines should reflect evidence-based data.

Objective: Based on the experiences of neuroimaging psychiatry registrars, we describe several reflections on improving the understanding and integration of magnetic resonance imaging in clinical psychiatry., Conclusion: Better integration of magnetic resonance imaging into clinical psychiatry can be highly productive when our investments are focused on understanding the gaps in clinical knowledge and the systemic barriers involving the patient and relevant clinicians.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.

The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

There is growing interest in the neurobiological substrate of general intelligence. Psychometric estimates of general intelligence are reduced in a range of neurological disorders, leading to practical application as sensitive, but non-specific, markers of cerebral disorder. This study examined estimates of general intelligence in neurotypical adults using diffusion tensor imaging and resting-state functional connectivity analysis. General intelligence was related to white matter organisation across multiple brain regions, confirming previous work in older healthy adults. We also found that variation in general intelligence was related to a large functional sub-network involving all cortical lobes of the brain. These findings confirm that individual variance in general intelligence is related to diffusely represented brain networks., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Alzheimer's disease (AD) is characterized by two cardinal pathologies, which have different topological distributions. The differential anatomical distributions of these pathologies raise the possibility that they exert differential effects on brain networks., Objectives: To investigate whether cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies have differential relationships with functional connectivity networks in patients with dementia of the Alzheimer's type (DAT)., Methods: Thirty-nine participants underwent CSF sampling and resting-state functional magnetic resonance imaging. Functional connectivity networks were computed for each participant. CSF biomarker levels of p-tau and amyloid-β (Aβ) were regressed onto these networks to identify subnetworks associated with each biomarker., Results: A subnetwork associated with tau-related pathology was identified with its hub in the right anterior entorhinal cortex. A separate subnetwork associated with Aβ with its hub in the right dorsal anterior cingulate cortex was identified., Conclusion: These results demonstrate the differential effects of AD biomarkers on functional connectivity networks, supporting a possible division of labour between the cardinal pathologies., (© 2015 S. Karger AG, Basel.)

Objective: To investigate partial volume correction (PVC) of 2-[F]-fluoro-2-deoxy-D-glucose positron emission tomography in Alzheimer disease in a longitudinal context., Methods: A total of 115 participants were included, including 55 controls, 53 patients with mild cognitive impairment, and 7 patients with dementia of the Alzheimer type. Imaging was performed at baseline and 24 months. Partial volume corrected vs uncorrected rates of longitudinal change were compared for mesial temporal and cortical regions of interest., Results: Partial volume correction increased apparent uptake, and this effect was greater at 24 months compared with baseline. Partial volume correction decreased the rate of decline, causing an apparent increase in uptake at 24 months compared with baseline. This effect was correlated with the structural atrophy., Conclusions: These findings suggest that applying PVC in a longitudinal context in Alzheimer disease might produce unpredictable results. Accordingly, both PVC corrected and uncorrected data should be reported to ensure that the results are physiologically plausible.

Background: Investigation of aberrant large-scale brain networks offers novel insight into the role these networks play in diverse psychiatric disorders such as schizophrenia. Although studies report altered functional brain connectivity in participants at ultra-high risk (UHR) for psychosis, it is unclear whether these alterations extend to structural brain networks., Methods: Whole-brain structural covariance patterns of 133 participants at UHR for psychosis (51 of whom subsequently developed psychosis) and 65 healthy control (HC) subjects were studied. Following data preprocessing (using VBM8 toolbox), the mean signal in seed regions relating to specific networks (visual, auditory, motor, speech, semantic, executive control, salience, and default-mode) were extracted, and voxel-wise analyses of covariance were conducted to compare the association between whole-brain signal and each seed region for UHR and HC individuals. The UHR participants who transitioned to psychosis were compared with the UHR participants who did not., Results: Significantly reduced structural covariance was observed in the UHR sample compared with the HC sample for the default-mode network, and increased covariance was observed for the motor and executive control networks. When the UHR participants who transitioned to psychosis were compared with the UHR participants who did not, aberrant structural covariance was observed in the salience, executive control, auditory, and motor networks., Conclusions: Whole-brain structural covariance analyses revealed subtle changes of connectivity of the default-mode, executive control, salience, motor, and auditory networks in UHR individuals for psychosis. Although we found significant differences, these are small changes and tend to reflect largely intact structural networks., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

It remains unclear whether brain structural abnormalities observed before the onset of psychosis are specific to schizophrenia or are common to all psychotic disorders. This study aimed to measure regional gray matter volume prior to the onset of schizophreniform and of affective psychoses. We investigated 102 subjects at ultrahigh risk (UHR) of developing psychosis recruited from the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia. Twenty-eight of these subjects developed psychosis subsequent to scanning: 19 schizophrenia, 7 affective psychoses, and 2 other psychoses. We examined regional gray matter volume using 1.5 mm thick, coronal, 1.5 Tesla magnetic resonance imaging and voxel-based morphometry methods of image analysis. Subjects were scanned at presentation and were followed up clinically for a minimum of 12 months, to detect later transition to psychosis. We found that both groups of subjects who subsequently developed psychosis (schizophrenia and affective psychosis) showed reductions in the frontal cortex relative to UHR subjects who did not develop psychosis. The subgroup that subsequently developed schizophrenia also showed smaller volumes in the parietal cortex and, at trend level, in the temporal cortex, whereas those who developed an affective psychosis had significantly smaller subgenual cingulate volumes. These preliminary findings suggest that volumetric abnormalities in UHR individuals developing schizophrenia vs affective psychoses comprise a combination of features that predate both disorders and others that may be specific to the nature of the subsequent disorder.

Niemann-Pick Type C disease (NPC) is a rare genetic disorder of lipid metabolism. A parameter related to horizontal saccadic peak velocity was one of the primary outcome measures in the clinical trial assessing miglustat as a treatment for NPC. Neuropathology is widespread in NPC, however, and could be expected to affect other saccadic parameters. We compared horizontal saccadic velocity, latency, gain, antisaccade error percentage and self-paced saccade generation in 9 adult NPC patients to data from 10 age-matched controls. These saccadic measures were correlated with appropriate MRI-derived brain structural measures (e.g., dorsolateral prefrontal cortex, frontal eye fields, supplemental eye fields, parietal eye fields, pons, midbrain and cerebellar vermis) and with measures of disease severity and duration. The best discriminators between groups were reflexive saccade gain and the two volitional saccade measures. Gain was also the strongest correlate with disease severity and duration. Most of the saccadic measures showed strongly significant correlations with neurophysiologically appropriate brain regions. While our patient sample is small, the apparent specificity of these relationships suggests that as new diagnostic methods and treatments become available for NPC, a broader range of saccadic measures may be useful tools for the assessment of disease progression and treatment efficacy.

Although historically gray matter changes have been the focus of neuropathological and neuroradiological studies in schizophrenia, in recent years an increasing body of research has implicated white matter structures and its constituent components (axons, their myelin sheaths and supporting oligodendrocytes). This article summarizes this body of literature, examining neuropathological, neurogenetic and neuroradiological evidence for white matter pathology in schizophrenia. We then look at the possible role that antipsychotic medication may play in these studies, examining both its role as a potential confounder in studies examining neuronal density and brain volume, but also the possible role that these medications may play in promoting myelination through their effects on oligodendrocytes. Finally, the role of potential novel therapies is discussed.

Context: People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent., Objective: To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites., Design: Case-control study., Setting: Multisite., Participants: A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not., Main Outcome Measures: Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry., Results: The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not., Conclusions: Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

The neuroacanthocytoses are a group of disorders characterised by peripheral blood acanthocytes, central nervous system as well as neuromuscular symptoms. These disorders uniformly result in pathology in the basal ganglia, which account for the characteristic motor symptoms such as chorea or dystonia, but may also account for the apparent elevated rates of major mental disorders in these syndromes. Elevated rates of dysexecutive syndromes, obsessive-compulsive disorder, depression and schizophrenia-like psychosis appear to occur in chorea-acanthocytosis, McLeod's syndrome, pantothenate kinase-associated neurodegeneration, and Huntington's disease-like 2. Disruptions to key frontostriatal loops secondary to pathology in the striatum and pallidum appear to predispose individuals to major neuropsychiatric syndromes; however, treatment can be instituted for a number of these manifestations, which lessens the overall burden of disease in neuroacanthocytosis patients and their families., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion-weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

In this review, we describe neuropsychological and brain imaging findings in the early stages of psychosis and schizophrenia. We focus on recent clinical high-risk studies and consider whether the evidence supports these as 'endophenotypes' of a vulnerability to the illness or as 'biomarkers' of illness onset and transition. The findings suggest that there are a number of processes at psychosis onset that may represent biomarkers of incipient illness. These neurobiological indices particularly implicate the integrity of frontal and temporal cortices, which may or may not be related to the genetics of psychosis (i.e. potential 'endophenotypes'). However, these brain regions are dynamically changing during normal maturation, meaning that any putative neurobiological markers identified at the earliest stages of illness may be relatively unstable.We suggest that, while such measures maybe readily identified as potential neurobiological markers of established illness, they are inconsistent at (or around) the time of illness onset when assessed cross-sectionally. Instead,identification of more valid risk markers may require longitudinal assessment to ascertain normal or abnormal trajectories of neurodevelopment. Accordingly, we assert that the current conceptualisations of potential biomarkers and/or 'endophenotypes' for schizophrenia may need to be reconsidered in the context of normal and abnormal brain maturational processes at the time of onset of psychotic disorders.

Background: Imaging studies of epilepsy patients with comorbid affective disturbance demonstrate morphometric changes in limbic brain regions implicated in psychiatric disease. Genetic Absence Epilepsy Rats from Strasbourg (GAERS), specifically bred for their epilepsy phenotype, also exhibit elevated anxiety-like behaviors suggesting a common causality. Here we examined whether relevant cerebral morphological alterations exist in this rat strain using volumetric measurements and large deformation high dimensional mapping (HDM-LD), a tool recently validated to produce accurate three-dimensional surface representations of the hippocampus., Methods: Volumetric MRI and the Open Field test of anxiety were performed in adult female GAERS (n=12) and Non-Epileptic Controls (NEC; n=11). The volumes of selected brain regions, including cortex, hippocampus, amygdala, thalamus, hypothalamus and lateral ventricles, were measured using Region-Of-Interest analysis from the MRI data and total volumes compared between the two strains., Results: GAERS had increased amygdala (right: p=0.003; left p<0.001), cortices (right: p=0.006; left p=0.012) and ventricular volumes (p=0.002) when compared with NEC rats. Further, HDM-LD showed GAERS to have hippocampal volume loss in two regions: the medial hippocampal surface immediately caudal to the hippocampal commissure, and the lateral hippocampal surface over the mid-portion of the septotemporal axis. GAERS exhibited increased anxiety in the Open Field compared with NEC rats: reduced distance traveled (p<0.001) and reduced time in the centre area (p=0.042)., Conclusions: Morphometric brain changes in GAERS could be relevant to their hyperanxious and epileptic phenotypes. This model may be useful in illuminating the pathogenesis of affective disorders generally, as well as modeling psychiatric comorbidities of epilepsy.

Neuroimaging studies of individuals at risk of psychosis have the potential to identify markers predictive of illness onset and features that progress with transition. To date, reduced brain volumes have shown weak predictive value for onset of psychotic illness. All published longitudinal studies of the transition to psychosis show progressive brain changes that are not seen in at-risk individuals who do not develop the disorder. Although the cause of these changes is unclear, they challenge the conventional neurodevelopmental model of schizophrenia.

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12=6.1, p=0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20=4.4, p=0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r=-0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.

Background: Grey matter changes have been described in individuals who are pre- and peri-psychotic, but it is unclear if these changes are accompanied by changes in white matter structures., Aims: To determine whether changes in white matter occur prior to and with the transition to psychosis in individuals who are pre-psychotic who had previously demonstrated grey matter reductions in frontotemporal regions., Method: We used magnetic resonance imaging (MRI) to examine regional white matter volume in 75 people with prodromal symptoms. A subset of the original group (n=21) were rescanned at 12-18 months to determine white matter volume changes. Participants were retrospectively categorised according to whether they had or had not developed psychosis at follow-up., Results: Comparison of the baseline MRI data from these two subgroups revealed that individuals who later developed psychosis had larger volumes of white matter in the frontal lobe, particularly in the left hemisphere. Longitudinal comparison of data in individuals who developed psychosis revealed a reduction in white matter volume in the region of the left fronto-occipital fasciculus. Participants who had not developed psychosis showed no reductions in white matter volume but increases in a region subjacent to the right inferior parietal lobule., Discussion: The reduction in volume of white matter near the left fronto-occipital fasciculus may reflect a change in this tract in association with the onset of frank psychosis.

Obsessive-compulsive disorder (OCD) has been linked to a dysfunction of brain corticostriatal networks, although functional imaging studies of OCD rarely apply network-sensitive analysis methods. In this study, we compared a univariate and a multivariate analysis of PET data in OCD patients and healthy subjects; the latter approach was considered more suitable for characterizing functional networks of brain activity. Although both methods suggested there was abnormal corticostriatal activity in OCD patients, the nature, extent and magnitude of this activity was clearly enhanced by the multivariate approach. Implications for the analysis of such studies are discussed.

A wide range of neuropathological abnormalities have been detected in schizophrenia sufferers, and emerging evidence points to neural substrates of connectivity as having a key role in the development of disease. This article reviews the available evidence for white matter pathology in schizophrenia, and examines its possible role as a substrate of impaired connectivity. Neuropathological data is suggestive of abnormalities in glial structure and function, and myelinated structures have also been implicated. A number of studies, particularly using gene array technology, are pointing towards significant disruption in expression of myelination genes. Magnetic resonance imaging has tended to focus on, and detect, more grey than white matter abnormalities, although non-volumetric techniques are suggestive of changes in the microstructure of white matter in schizophrenia. Myelinated structures are an attractive candidate for an anatomical substrate for disconnectivity, and may act synergistically with synaptic changes to result in functional disconnectivity although the relationship between white and grey matter changes in the illness remains unclear.

The underlying neurobiology of emerging psychotic disorders is not well understood. While there is evidence from structural imaging and other studies supporting the popular notion that schizophrenia arises as a consequence of an "early neurodevelopmental" lesion, more recent findings challenge this notion. Evidence, including our own data, suggests that dynamic brain changes occur during the earliest stages of a psychotic illness, including around the time of transition to illness. In this article we review the available longitudinal and relevant cross-sectional structural neuroimaging studies focusing on both the very early neurodevelopmental markers (pre- or perinatal origin) and the later markers (late neurodevelopmental) around the period of transition to illness. Based on our review of recent findings, we suggest that the onset of psychosis is a time of active brain changes, wherein, for a proportion of individuals, (i) an early (pre- and perinatal) neurodevelopmental lesion renders the brain vulnerable to anomalous late (particularly postpubertal) neurodevelopmental processes, as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions; and (ii) these anomalous neurodevelopmental processes interact with other causative factors associated with the onset of psychosis (e.g., substance use, stress, and dysregulation of the hypothalamic-pituitary-adrenal axis function), which together have neuroprogressive sequelae involving medial temporal and orbital prefrontal regions, as suggested by imaging studies around transition to active illness. However, the pathological processes underlying such progressive changes during "late neurodevelopment" remain unclear but may reflect anomalies of synaptic plasticity, abnormal brain maturation, the adverse effects of stress, or other environmental factors. In this context, the features of schizophrenia, including the neuropsychological deficits and behavioral manifestations, can be understood as direct effects of these multiple pathological processes at various neurodevelopmental stages, including genetic and nongenetic etiological factors.

Objective: The evidence from structural imaging studies supports the notion that schizophrenia arises from an early abnormality in brain development. In this paper we review the timing of structural changes in schizophrenia and argue that schizophrenia is a neuro-developmental disorder with limited progressive brain changes occurring during the evolution and early phase of psychosis., Method: The available cross-sectional and longitudinal studies are reviewed, along with data from our own research., Results: The current literature, including our own data, suggests that structural brain changes are apparent premorbidly, consistent with a neurodevelopmental lesion. These are prominent in frontal and cingulate regions, and appear related to premorbid neuropsychological deficits in executive function. However, there appear to be additional brain changes over the transition to illness and beyond., Conclusions: We propose first, that an early neurodevelopmental insult interacts with either normal or abnormal postpubertal brain maturation to produce further (late neurodevelopmental) brain structural and functional changes; and second, that the effect of such neurodevelopmental lesions will have different consequences for functions that normally develop early in life, such as memory, compared with functions developing later, such as executive functions. A model is presented suggesting that the structural and functional abnormalities in schizophrenia can be understood as a consequence of the neurodevelopmental stage at which brain changes occur.

Background: Psychotic disorders, such as schizophrenia, are associated with neuroanatomical abnormalities, but whether these predate the onset of symptoms or develop progressively over the course of illness is unclear. We investigated this issue with MRI to study people with prodromal symptoms who are at ultra high-risk for the development of psychosis., Methods: We did two comparisons, cross-sectional and longitudinal. For the cross-sectional comparison, 75 people with prodromal signs of psychosis were scanned with MRI. After at least 12 months of follow-up, 23 (31%) had developed psychosis and 52 (69%) had not. Baseline MRI data from these two subgroups were compared. For the longitudinal comparison, 21 of the ultra high-risk individuals were scanned again with MRI after at least 12 months. Ten of these had developed psychosis and 11 had not. MRI data from baseline and follow-up were compared within each group of people., Findings: In the cross-sectional comparison, compared with people who did not develop psychosis, those who did develop the disorder had less grey matter in the right medial temporal, lateral temporal, and inferior frontal cortex, and in the cingulate cortex bilaterally. In the longitudinal comparison, when re-scanned, individuals who had developed psychosis showed a reduction in grey matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In those who had not become psychotic, longitudinal changes were restricted to the cerebellum., Interpretation: Some of the grey-matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression.

Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) affects 2–3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry. [ABSTRACT FROM AUTHOR]

The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks. [ABSTRACT FROM AUTHOR]

Objective: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis. Methods: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years). Results: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia (p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend (p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%). Conclusion: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes. [ABSTRACT FROM AUTHOR]

Objective: The caudate nucleus (CN) is a crucial component of the ventral striatum, which is part of a prefrontal-striatal-thalamic circuit that is modulated by limbic structures to subserve emotional processing. Bipolar disorder is thought to be underpinned by dysfunctional anterior limbic networks, although MRI studies examining the CN have shown equivocal results. As gross volumetric analyses may not detect subtle regional change, we aimed to clarify the role of the CN in bipolar disorder by undertaking shape analysis to detect regional reductions.Methods: The CN was manually traced on MRI scans from 27 patients with bipolar-I disorder and 24 matched controls. A non-parametric spherical harmonic shape analysis was undertaken using the SPHARM toolkit.Results: Whilst the left CN volume was consistently larger in the sample, there was no effect of group or gender or significant interactions between these variables. Volume did not correlate with illness duration or lithium dosage, but was larger in those with a history of psychosis at trend level. However, left caudate shape differed significantly between groups, with deflation in an area along the ventromedial surface (connecting to dorsolateral prefrontal regions) in bipolar patients. Psychotic patients showed increases in the dorsal head and body at trend level overall, in regions connecting to medial and orbitofrontal regions.Conclusions: These findings suggest that subtle rather than gross structural changes occur in the CN, which may not be detectable by volumetric analysis alone, and reflect alterations in specific frontostriatal circuitry in the disorder. [ABSTRACT FROM PUBLISHER]

Background: The shape of the corpus callosum may differ in schizophrenia, although no study has compared first-episode with established illness.Aims: To investigate the size and shape of the corpus callosum in a large sample of people with first-episode and established schizophrenia.Method: Callosal size and shape were determined using high-resolution magnetic resonance imaging on 76 patients with first-episode schizophrenia-spectrum disorders, 86 patients with established schizophrenia and 55 healthy participants.Results: There were no significant differences in total area across groups. Reductions in callosal width were seen in the region of the anterior genu in first-episode disorder (P<0.005). Similar reductions were seen in the chronic schizophrenia group in the anterior genu, but also in the posterior genu and isthmus (P=0.0005).Conclusions: Reductions in anterior callosal regions connecting frontal cortex are present at the onset of schizophrenia, and in established illness are accompanied by changes in other regions of the callosum connecting cingulate, temporal and parietal cortices. [ABSTRACT FROM AUTHOR]

Background: Previous studies on substance-dependent populations have shown that age of first use and duration of use are associated with alterations in regional brain volumes. However, it is not clear whether such alterations are factors that predispose young people to use, and so are also present in recreational users, or are a consequence of chronic exposure to substances and/or comorbid psychopathology. Objective: To investigate relationships between key brain structures and parameters of alcohol and cannabis use, in otherwise healthy male recreational users. Method: High-resolution magnetic resonance imaging was used to measure hippocampal, amygdala, whole-brain and intracranial cavity (ICC) volumes in 22 young men with a history of both alcohol and cannabis use. Results: Linear regression analyses with hippocampal, amygdala and whole-brain volumes as the dependent variables and age and ICC as covariates were performed. Findings showed that use of cannabis and alcohol at an earlier age were independently predictive of larger amygdala volumes, whereas longer duration of cannabis use was predictive of smaller hippocampal volumes. Conclusions: Our findings offer preliminary support for a relationship between patterns of substance use and regional brain volumes in recreational users. It is speculative, but possible that this relationship is an evidence of a neurobiological vulnerability to drug-taking behaviour. [ABSTRACT FROM AUTHOR]

Examination of the corpus callosum provides a window to cortical brain change in brain disorders. Combining volumetric with microstructural analysis allows a greater understanding of the biology underpinning change, and examining callosal structure alongside the structure of the cortical regions it interconnects may allow us to understand the true significance of callosal change in psychiatric disorders. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 54-year-old patient with idiopathic normal pressure hydrocephalus (NPH). Aside from bipolar affective disorder, the patient reportedly have a history of urinary incontinence and short-term memory impairment. It reports results of the physical and laboratory examinations performed on the patient which include magnetic resonance imaging and computed tomography scan. It also mentions the significant improvement demonstrated by the patient following surgery.

Non-motor symptoms of Parkinson’s disease (PD) include cognitive deficits and impairment in the recognition of emotions. Recently, a number of studies have investigated theory of mind (ToM) deficits in PD. In this meta-analysis of 18 studies, the ToM performance of 487 non-demented individuals with Parkinson’s disease (PD) was compared with 459 healthy controls. Meta-regression analyses were conducted to investigate the relationship between ToM deficits and demographical and clinical features in PD, including medication, stage of the illness and neurocognition. PD was associated with significant ToM impairment ( d = 0.83) in both verbal and visual tasks. In individual task analyses, PD patients performed worse than controls in both faux pas recognition ( d = 0.55) and reading the mind from the eyes ( d = 0.67) tests. Severity of ToM impairment was significantly associated with cognitive impairment. Impairments in social cognitive abilities, including ToM, may be important contributors to the functional impairments observed in PD. [ABSTRACT FROM AUTHOR]