AimsWe wanted to discover the time delay between the initial assessment of service users referred to a Community Mental Health Team (CMHT) and suspicion that they had an Autistic Spectrum Disorder (ASD). We wanted to know whether early use of a screening questionnaire could significantly reduce this delay.BackgroundAbout 1% of the UK population have ASD and the rate is higher among service users within CMHTs. Although CMHT staff are trained to recognize service users with ASD, often the diagnosis is only suspected when service users do not make progress with standard treatment. Early recognition of ASD informs a treatment pathway individualised for people with ASD. Brief screening instruments for ASD can help clinicians decide whether to refer someone for a full diagnostic assessment. The fifty question Autism Questionnaire (AQ50) and ten question Autism Questionnaire (AQ10) both perform well as a screen for ASD.MethodAll referrals from two adult CMHTs to a specialist Wiltshire Autism Diagnostic service (WADS) over a 2.5 year period were ascertained from a referral database. 24 service users referred from the CMHTs were identified. We determined from their records: (A) overall time between initial CMHT appointment and referral to WADS, (B) time between initial CMHT appointment and screening test (when used), (C) time between screening test and referral to WADS.ResultFor all 24 cases, the average time between initial CMHT appointment and referral to WADS was 186 days. 18 of the 24 service users completed a screening questionnaire prior to WADS referral (AQ10 or AQ50 or both); 16 of these had positive screening tests. The average time between initial CMHT appointment and use of screening test was 164 days. The average time between screening test use and referral to WADS was 32 days.ConclusionOur results demonstrated the average time taken from CMHT staff first seeing a patient to suspecting ASD and referring to a specialist diagnostic team was about 6 months. However, after a screening questionnaire had taken place, the time to referral was only around one month. We propose that screening is considered at an earlier opportunity; ideally during (or prior to) the first appointment with the CMHT in order to reduce the time before a referral to a specialist diagnostic team is made. This would enable treatment in a care pathway which incorporates the diagnosis of ASD at an earlier stage.

Functional magnetic resonance imaging (fMRI) has increasingly been employed to establish whether there is a specific brain neural network dedicated to maternal responsiveness. We undertook systematic review and meta-analysis of all studies in which healthy new mothers were exposed to visual stimuli of own versus other infants to determine the quality of evidence for a dedicated maternal neural network. Systematic literature review revealed a pattern of specific neural responses commonly induced by visual infant paradigms. Brain areas consistently reported as activated in mothers in response to own versus unknown infant included the left thalamus, bilateral pre-central gyrus, left limbic lobe, uncus, amygdala and left caudate. These regions are implicated in reward, attention, emotion processing and other core social cognitive skills. Meta-analysis, however, revealed a more limited subset of brain areas activated in mothers specifically in response to their own versus unknown infant and suggested considerable inter-study variability. Further work is needed if functional imaging is to become an objective tool for the assessment of neural pathways associated with distinct patterns of maternal care behaviour. Such a tool would be invaluable in developing biomarkers of neural activity associated with healthy maternal care and for monitoring treatment/intervention effects of costly parenting interventions.

Functional magnetic resonance imaging (fMRI) has increasingly been employed to establish whether there is a specific brain neural network dedicated to maternal responsiveness. We undertook systematic review and meta-analysis of all studies in which healthy new mothers were exposed to visual stimuli of own versus other infants to determine the quality of evidence for a dedicated maternal neural network. Systematic literature review revealed a pattern of specific neural responses commonly induced by visual infant paradigms. Brain areas consistently reported as activated in mothers in response to own versus unknown infant included the left thalamus, bilateral pre-central gyrus, left limbic lobe, uncus, amygdala and left caudate. These regions are implicated in reward, attention, emotion processing and other core social cognitive skills. Meta-analysis, however, revealed a more limited subset of brain areas activated in mothers specifically in response to their own versus unknown infant and suggested considerable inter-study variability. Further work is needed if functional imaging is to become an objective tool for the assessment of neural pathways associated with distinct patterns of maternal care behaviour. Such a tool would be invaluable in developing biomarkers of neural activity associated with healthy maternal care and for monitoring treatment/intervention effects of costly parenting interventions.

Background It is unclear to what extent the traditional distinction between neurological and psychiatric disorders reflects biological differences. Aims To examine neuroimaging evidence for the distinction between neurological and psychiatric disorders. Method We performed an activation likelihood estimation meta-analysis on voxel-based morphometry studies reporting decreased grey matter in 14 neurological and 10 psychiatric disorders, and compared the regional and network-level alterations for these two classes of disease. In addition, we estimated neuroanatomical heterogeneity within and between the two classes. Results Basal ganglia, insula, sensorimotor and temporal cortex showed greater impairment in neurological disorders; whereas cingulate, medial frontal, superior frontal and occipital cortex showed greater impairment in psychiatric disorders. The two classes of disorders affected distinct functional networks. Similarity within classes was higher than between classes; furthermore, similarity within class was higher for neurological than psychiatric disorders. Conclusions From a neuroimaging perspective, neurological and psychiatric disorders represent two distinct classes of disorders.

Ian Ellison-Wright (ian.ew@inbox.com) Pradeep J Nathan (pn254@cam.ac.uk) Edward T Bullmore (etb23@cam.ac.uk) Rashid Zaman (rz218@cam.ac.uk) Robert Dudas (rbd21@cam.ac.uk) Mark Agius (ma393@cam.ac.uk) Emilio Fernandez-Egea (Emilio.Fernandez@cpft.nhs.uk) Ulrich Müller (um207@cam.ac.uk) Chris M Dodds (Chris.M.Dodds@gsk.com) Natalie J Forde (plugkicker@gmail.com) Cathy Scanlon (cathy.scanlon@nuigalway.ie) Alexander Leemans (Alexander@isi.uu.nl) Colm McDonald (colm.mcdonald@nuigalway.ie) Dara M Cannon (dara.cannon@nuigalway.ie)

Many studies have shown widespread but subtle pathological changes in gray matter in patients with schizophrenia. Some of these studies have related specific alterations to the genesis of auditory hallucinations, particularly in the left superior temporal gyrus, but none has analysed the relationship between morphometric data and a specific scale for auditory hallucinations. The present study aims to define the presence and characteristics of structural abnormalities in relation with the intensity and phenomenology of auditory hallucinations by means of magnetic resonance voxel-based morphometry (MR-VBM) method applied on a highly homogeneous group of 18 persistent hallucinatory patients meeting DSM-IV criteria for schizophrenia compared to 19 healthy matched controls. Patients were evaluated using the PSYRATS scale for auditory hallucinations. Reductions of gray matter concentration in patients to controls were observed in bilateral insula, bilateral superior temporal gyri and left amygdala. In addition, specific relationships between left inferior frontal and right postcentral gyri reductions and the severity of auditory hallucinations were observed. All these areas might be implicated in the genesis and/or persistence of auditory hallucinations through specific mechanisms. Precise morphological abnormalities may help to define reliable MR-VBM biomarkers for the genesis and persistence of auditory hallucinations.

Background Gray and white matter brain changes have been found in schizophrenia but the anatomical organizing process underlying these changes remains unknown. We aimed to identify gray and white matter volumetric changes in a group of patients with schizophrenia and to quantify the distribution of white matter tract changes using a novel approach which applied three complementary analyses to diffusion imaging data. Methods 21 patients with schizophrenia and 21 matched control subjects underwent brain magnetic resonance imaging. Gray and white matter volume differences were investigated using Voxel-based Morphometry (VBM). White matter diffusion changes were located using Tract Based Spatial Statistics (TBSS) and quantified within a standard atlas. Tracts where significant regional differences were located were examined using fiber tractography. Results No significant differences in gray or white matter volumetry were found between the two groups. Using TBSS the schizophrenia group showed significantly lower fractional anisotropy (FA) compared to the controls in regions (false discovery rate <0.05) including the genu, body and splenium of the corpus callosum and the left anterior limb of the internal capsule (ALIC). Using fiber tractography, FA was significantly lower in schizophrenia in the corpus callosum genu ( p = 0.003). Conclusions In schizophrenia, white matter diffusion deficits are prominent in medial frontal regions. These changes are consistent with the results of previous studies which have detected white matter changes in these areas. The pathology of schizophrenia may preferentially affect the prefrontal-thalamic white matter circuits traversing these regions.

Background: The authors sought to compare gray matter changes in First Episode Schizophrenia (FES) compared with Fronto-Temporal Lobar Degeneration (FTLD) using meta-analytic methods applied to neuro-imaging studies.Methods: A systematic search was conducted for published, structural voxel-based morphometric MRI studies in patients with FES or FTLD. Data were combined using anatomical likelihood estimation (ALE) to determine the extent of gray matter decreases and analysed to ascertain the degree of overlap in the spatial distribution of brain changes in both diseases.Results: Data were extracted from 18 FES studies (including a total of 555 patients and 621 comparison subjects) and 20 studies of FTLD or related disorders (including a total of 311 patients and 431 comparison subjects). The similarity in spatial overlap of brain changes in the two disorders was significant (p = 0.001). Gray matter deficits common to both disorders included bilateral caudate, left insula and bilateral uncus regions.Conclusions: There is a significant overlap in the distribution of structural brain changes in First Episode Schizophrenia and Fronto-Temporal Lobar Degeneration. This may reflect overlapping aetiologies, or a common vulnerability of these regions to the distinct aetio-pathological processes in the two disorders.

Los resultados de los estudios genéticos recientes han indicado que las dos formas principales de psicosis clásicamente diferenciadas, la esquizofrenia y el trastorno bipolar, pueden compartir factores causales. No obstante, no está claro hasta qué punto pueden tener también perfiles similares de anomalías cerebrales. Utilizamos técnicas metaanalíticas para generar y comparar mapas de anomalías estructurales cerebrales en muestras extensas de pacientes con ambos procesos estudiados utilizando resonancia magnética. Se efectuó una búsqueda sistemática de estudios sobre morfometría basada en vóxeles que examinaron la sustancia gris de pacientes con esquizofrenia o trastorno bipolar. La distribución anatómica de las coordenadas de las diferencias de sustancia gris se metaanalizó utilizando la estimación de probabilidad anatómica (anatomical likelihood estimation). Se compararon 42 estudios sobre esquizofrenia, que incluyeron a 2.058 pacientes con la enfermedad y a 2.131 individuos de control, con 14 estudios sobre trastorno bipolar, que incluyeron a 366 pacientes con el trastorno y a 497 individuos de cotrol. En la esquizofrenia hubo extensos déficit de sustancia gris en la corteza frontal, temporal, cingular e insular y el tálamo, y un aumento de la sustancia gris en los ganglios basales. En el trastorno bipolar se apreciaron reducciones de la sustancia gris en la corteza cingular anterior y la ínsula bilateral. Se superpusieron sustancialmente con las áreas de reducción de la sustancia gris en la esquizofrenia, excepto para una región de la corteza cingular anterior, donde la reducción de la sustancia gris fue específica del trastorno bipolar. En los estudios sobre trastorno bipolar hubo reducciones homogéneas de la sustancia gris regional en las regiones paralímbicas (corteza cingular anterior e ínsula) implicadas en el procesamiento de las emociones. En los estudios sobre esquizofrenia, las reducciones de la sustancia gris fueron más extensas y afectaron a las estructuras límbicas y neocorticales, al igual que a las regiones paralímbicas afectadas en el trastorno bipolar. Recent genetic results have indicated that the two major, classically distinct forms of psychosis — schizophrenia and bipolar disorder — may share causative factors in common. However it is not clear to what extent they may also have similar profiles of brain abnormality. We used meta-analytic techniques to generate and compare maps of brain structural abnormality in the large samples of patients with both disorders that have been studied using magnetic resonance imaging. A systematic search was conducted for voxel-based morphometry studies examining gray matter in patients with schizophrenia or bipolar disorder. The anatomical distribution of the co-ordinates of gray matter differences was meta-analysed using Anatomical Likelihood Estimation. Forty-two schizophrenia studies including 2058 patients with schizophrenia and 2131 comparison subjects were compared with fourteen bipolar studies including 366 patients with bipolar disorder and 497 comparison subjects. In schizophrenia, there were extensive gray matter deficits in frontal, temporal, cingulate and insular cortex and thalamus, and increased gray matter in the basal ganglia. In bipolar disorder, gray matter reductions were present in the anterior cingulate and bilateral insula. These substantially overlapped with areas of gray matter reduction in schizophrenia, except for a region of anterior cingulate where gray matter reduction was specific to bipolar disorder. In bipolar disorder studies there were consistent regional gray matter reductions in paralimbic regions (anterior cingulate and insula) implicated in emotional processing. Gray matter reductions in schizophrenia studies were more extensive and involved limbic and neocortical structures as well as the paralimbic regions affected in bipolar disorder.

The human cerebral cortex is a complex network of functionally specialized regions interconnected by axonal fibers, but the organizational principles underlying cortical connectivity remain unknown. Here, we report evidence that one such principle for functional cortical networks involves finding a balance between maximizing communication efficiency and minimizing connection cost, referred to as optimization of network cost-efficiency. We measured spontaneous fluctuations of the blood oxygenation level-dependent signal using functional magnetic resonance imaging in healthy monozygotic (16 pairs) and dizygotic (13 pairs) twins and characterized cost-efficient properties of brain network functional connectivity between 1041 distinct cortical regions. At the global network level, 60% of the interindividual variance in cost-efficiency of cortical functional networks was attributable to additive genetic effects. Regionally, significant genetic effects were observed throughout the cortex in a largely bilateral pattern, including bilateral posterior cingulate and medial prefrontal cortices, dorsolateral prefrontal and superior parietal cortices, and lateral temporal and inferomedial occipital regions. Genetic effects were stronger for cost-efficiency than for other metrics considered, and were more clearly significant in functional networks operating in the 0.09-0.18 Hz frequency interval than at higher or lower frequencies. These findings are consistent with the hypothesis that brain networks evolved to satisfy competitive selection criteria of maximizing efficiency and minimizing cost, and that optimization of network cost-efficiency represents an important principle for the brain's functional organization.

BACKGROUND:Recent genetic results have indicated that the two major, classically distinct forms of psychosis - schizophrenia and bipolar disorder - may share causative factors in common. However it is not clear to what extent they may also have similar profiles of brain abnormality. We used meta-analytic techniques to generate and compare maps of brain structural abnormality in the large samples of patients with both disorders that have been studied using magnetic resonance imaging. METHOD:A systematic search was conducted for voxel-based morphometry studies examining gray matter in patients with schizophrenia or bipolar disorder. The anatomical distribution of the co-ordinates of gray matter differences was meta-analysed using Anatomical Likelihood Estimation. RESULTS:Forty-two schizophrenia studies including 2058 patients with schizophrenia and 2131 comparison subjects were compared with fourteen bipolar studies including 366 patients with bipolar disorder and 497 comparison subjects. In schizophrenia, there were extensive gray matter deficits in frontal, temporal, cingulate and insular cortex and thalamus, and increased gray matter in the basal ganglia. In bipolar disorder, gray matter reductions were present in the anterior cingulate and bilateral insula. These substantially overlapped with areas of gray matter reduction in schizophrenia, except for a region of anterior cingulate where gray matter reduction was specific to bipolar disorder. IMPLICATIONS:In bipolar disorder studies there were consistent regional gray matter reductions in paralimbic regions (anterior cingulate and insula) implicated in emotional processing. Gray matter reductions in schizophrenia studies were more extensive and involved limbic and neocortical structures as well as the paralimbic regions affected in bipolar disorder.

Background: It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial.Methods: A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis.Results: Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were -.07% for whole brain volume, -.59% for whole brain gray matter, -.32% for frontal white matter, -.32% for parietal white matter, -.39% for temporal white matter, and -.36% for bilateral lateral ventricles.Conclusions: These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation.

BACKGROUND:Although structural neuroimaging methods have been widely used to study brain morphology in schizophrenia, synthesizing this literature has been difficult. With the increasing popularity of voxel-based morphometric (VBM) methods in which group differences are reported in standardized coordinates, it is possible to apply powerful meta-analytic techniques initially designed for functional neuroimaging. In this study, we performed a voxelwise, coordinate-based meta-analysis to better conceptualize the neuroanatomic correlates of schizophrenia. METHODS:Thirty-one peer-reviewed articles, with a total of 1195 patients with schizophrenia contrasted with 1262 healthy volunteers, were included in the meta-analysis. Coordinates from each article were used to create a statistical map that estimated the likelihood of between-group gray matter density differences at every brain voxel. These results were subsequently entered into a network analysis. RESULTS:Patients had reduced gray matter density relative to control subjects in a distributed network of regions, including bilateral insular cortex, anterior cingulate, left parahippocampal gyrus, left middle frontal gyrus, postcentral gyrus, and thalamus. Network analysis grouped these regions into four distinct networks that potentially represent different pathologic processes. Patients had increased gray matter density in striatal regions. CONCLUSIONS:This study expands on previous meta-analyses of the neuroanatomy of schizophrenia by elucidating a series of brain networks disrupted by the illness. Because it is possible that these networks are influenced by independent etiologic factors, this work should foster more detailed neural models of the illness and focus research designed to discover the mechanisms of gray matter reduction in schizophrenia.

Background The authors sought to map gray matter changes in Attention Deficit Hyperactivity Disorder (ADHD) using a novel technique incorporating neuro-imaging and genetic meta-analysis methods. Methods A systematic search was conducted for voxel-based structural magnetic resonance imaging studies of patients with ADHD (or with related disorders) in relation to comparison groups. The authors carried out meta-analyses of the co-ordinates of gray matter differences. For the meta-analyses they hybridised the standard method of Activation Likelihood Estimation (ALE) with the rank approach used in Genome Scan Meta-Analysis (GSMA). This system detects three-dimensional conjunctions of co-ordinates from multiple studies and permits the weighting of studies in relation to sample size. Results For gray matter decreases, there were 7 studies including a total of 114 patients with ADHD (or related disorders) and 143 comparison subjects. Meta-analysis of these studies identified a significant regional gray matter reduction in ADHD in the right putamen/globus pallidus region. Four studies reported gray matter increases in ADHD but no regional increase was identified by meta-analysis. Conclusion In ADHD there is gray matter reduction in the right putamen/globus pallidus region. This may be an anatomical marker for dysfunction in frontostriatal circuits mediating cognitive control. Right putamen lesions have been specifically associated with ADHD symptoms after closed head injuries in children.

OBJECTIVE The authors sought to map gray matter changes in first-episode schizophrenia and to compare these with the changes in chronic schizophrenia. They postulated that the data would show a progression of changes from hippocampal deficits in first-episode schizophrenia to include volume reductions in the amygdala and cortical gray matter in chronic schizophrenia. METHOD A systematic search was conducted for voxel-based structural MRI studies of patients with first-episode schizophrenia and chronic schizophrenia in relation to comparison groups. Meta-analyses of the coordinates of gray matter differences were carried out using anatomical likelihood estimation. Maps of gray matter changes were constructed, and subtraction meta-analysis was used to compare them. RESULTS A total of 27 articles were identified for inclusion in the meta-analyses. A marked correspondence was observed in regions affected by both first-episode schizophrenia and chronic schizophrenia, including gray matter decreases in the thalamus, the left uncus/amygdala region, the insula bilaterally, and the anterior cingulate. In the comparison of first-episode schizophrenia and chronic schizophrenia, decreases in gray matter volume were detected in first-episode schizophrenia but not in chronic schizophrenia in the caudate head bilaterally; decreases were more widespread in cortical regions in chronic schizophrenia. CONCLUSIONS Anatomical changes in first-episode schizophrenia broadly coincide with a basal ganglia-thalamocortical circuit. These changes include bilateral reductions in caudate head gray matter, which are absent in chronic schizophrenia. Comparing first-episode schizophrenia and chronic schizophrenia, the authors did not find evidence for the temporolimbic progression of pathology from hippocampus to amygdala, but there was evidence for progression of cortical changes.

Summary Functional magnetic resonance imaging (FMRI) measures the physiological response of the human brain to experimentally controlled stimulation. In a periodically designed experiment it is of interest to test for a difference in the timing (phase shift) of the response between two anatomically distinct brain regions. We suggest two tests for an interregional difference in phase shift: one based on asymptotic theory and one based on bootstrapping. Whilst the two procedures differ in some of their assumptions, both tests rely on employing the large number of voxels (three-dimensional pixels) in non-activated brain regions to take account of spatial autocorrelation between voxelwise phase shift observations within the activated regions of interest. As an example we apply both tests, and their counterparts assuming spatial independence, to FMRI phase shift data that were acquired from a normal young woman during performance of a periodically designed covert verbal fluency task. We conclude that it is necessary to take account of spatial autocovariance between voxelwise FMRI time series parameter estimates such as the phase shift, and that the most promising way of achieving this is by modelling the spatial autocorrelation structure from a suitably defined base region of the image slice.

Recent progress in developmental neurobiology and neuroimaging can be drawn together to provide new insight into the links between genetically specified processes of embryonic brain development and adult human brain structure and function. We used magnetic resonance imaging (MRI) to show that individuals with aniridia and deficits in executive and social cognition, due to heterozygous mutation of the neurodevelopmental control gene PAX6, have structural abnormalities of grey matter in anterior cingulate cortex, cerebellum and medial temporal lobe, as well as white matter deficits in corpus callosum. Functional MRI demonstrated reduced activation of fronto‐striato‐thalamic systems during performance of overt verbal fluency and nonsense sentence completion; the most consistent abnormality of verbal executive activation was located in the thalamus. These results provide the first evidence for brain functional differences in humans with PAX6 mutation that are compatible both with anatomical abnormalities in the same subjects and, more circumstantially, with the known roles of murine Pax6 in regional differentiation, axonal guidance and other aspects of early forebrain development. Highly conserved homeobox genes may be critical for normal ontogenesis of large‐scale neurocognitive networks supporting phylogenetically advanced mental functions.