Are Bipolar Disorder and Schizophrenia Neuroanatomically Distinct? An Anatomical Likelihood Meta-analysis

Objective: There is renewed debate on whether modern diagnostic classification should adopt a dichotomous or dimensional approach to schizophrenia and bipolar disorder. This study synthesizes data from voxel-based studies of schizophrenia and bipolar disorder to estimate the extent to which these conditions have a common neuroanatomical phenotype. Methods: A post-hoc meta-analytic estimation of the extent to which bipolar disorder, schizophrenia, or both conditions contribute to brain gray matter differences compared to controls was achieved using a novel application of the conventional anatomical likelihood estimation (ALE) method. 19 schizophrenia studies (651 patients and 693 controls) were matched as closely as possible to 19 bipolar studies (540 patients and 745 controls). Result: Substantial overlaps in the regions affected by schizophrenia and bipolar disorder included regions in prefrontal cortex, thalamus, left caudate, left medial temporal lobe, and right insula. Bipolar disorder and schizophrenia jointly contributed to clusters in the right hemisphere, but schizophrenia was almost exclusively associated with additional gray matter deficits (left insula and amygdala) in the left hemisphere. Limitation: The current meta-analytic method has a number of constraints. Importantly, only studies identifying differences between controls and patient groups could be included in this analysis. Conclusion: Bipolar disorder shares many of the same brain regions as schizophrenia. However, relative to neurotypical controls, lower gray matter volume in schizophrenia is more extensive and includes the amygdala. This fresh application of ALE accommodates multiple studies in a relatively unbiased comparison. Common biological mechanisms may explain the neuroanatomical overlap between these major disorders, but explaining why brain differences are more extensive in schizophrenia remains challenging

Distinct patterns of grey matter abnormality in high-functioning autism and Asperger's syndrome

Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger's syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance imaging (MRI) studies of autism are in disagreement. One possible reason is that the diagnosis of autism takes precedence over Asperger's syndrome and a distinction in language acquisition is rarely made. We therefore planned to examine a whole brain hypothesis that the patterns of grey matter differences in Asperger's syndrome and HFA can be distinguished. Methods: We used voxel-based computational morphometry to map grey matter volume differences in 33 children with either Asperger's syndrome or high-functioning autism compared to 55 typical developing control children balanced for age, IQ, gender, maternal language and ethnicity. Results: Children with HFA had significantly smaller grey matter volumes in subcortical, posterior cingulate and precuneus regions than the Asperger's group. Compared to controls, children with HFA had smaller grey matter volumes in predominantly fronto-pallidal regions, while children with Asperger's had less grey matter in mainly bilateral caudate and left thalamus. In addition we found a significant negative correlation between the size of a grey matter cluster around BA44 language area and the age of acquisition of phrase speech in the children with HFA. When the groups were combined we confirmed a mixed picture of smaller grey matter volumes in frontal, basal ganglia, temporal and parietal regions. Conclusions: Our study suggests that the underlying neurobiology in HFA and Asperger's syndrome is at least partly discrete. Future studies should therefore consider the history of language acquisition as a valuable tool to refine investigation of aetiological factors and management options in pervasive developmental disorders

Retinal GABAergic alterations in adults with autism spectrum disorder

Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina and in this study we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms (ERGs) were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: i) the standard white flash; ii) the standard 30-Hz flickering protocol; iii) the photopic negative response (PhNR) protocol. Participants were administered an oral dose of placebo, 15 or 30 mg of arbaclofen (STX209, GABABagonist) in a randomized, double-blind, cross-over order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by electroencephalogram in our prior study, and with broader autistic traits measured with the Autism Quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in central processing of sensory information, which may be upstream of more complex autistic phenotypes. Significance StatementOur current study provides the first direct in vivo experimental confirmation that autistic alterations in central GABA function extend to the retina. We show that arbaclofen was associated with reduced flash elicited a-wave amplitude in the electroretinogram (ERG) of autistic individuals but increased amplitude in non-autistic people. The retinal arbaclofen response correlated with previously reported arbaclofen effects on cortical visual and auditory responses in the same individuals. The extent of this differential GABAergic function correlated with the extent of autistic traits captured using the Autism Quotient. Thus, sensory processing differences in autism appear to be upstream of more complex autistic traits and the ERG from the retina is a potentially useful proxy for cross-domain brain GABA function and target engagement

Can Asperger syndrome be distinguished from autism? An anatomic likelihood meta-analysis of MRI studies

Background: The question of whether Asperger syndrome can be distinguished from autism has attracted much debate and may even incur delay in diagnosis and intervention. Accordingly, there has been a proposal for Asperger syndrome to be subsumed under autism in the forthcoming Diagnostic and Statistical Manual of Mental Disorders, fifth edition, in 2013. One approach to resolve this question has been to adopt the criterion of absence of clinically significant language or cognitive delay - essentially, the "absence of language delay." To our knowledge, this is the first meta-analysis of magnetic resonance imaging (MRI) studies of people with autism to compare absence with presence of language delay. It capitalizes on the voxel-based morphometry (VBM) approach to systematically explore the whole brain for anatomic correlates of delay and no delay in language acquisition in people with autism spectrum disorders. Methods: We conducted a systematic search for VBM MRI studies of grey matter volume in people with autism. Studies with a majority (at least 70%) of participants with autism diagnoses and a history of language delay were assigned to the autism group (n = 151, control n = 190). Those with a majority (at least 70%) of individuals with autism diagnoses and no language delay were assigned to the Asperger syndrome group (n = 149, control n = 214). We entered study coordinates into anatomic likelihood estimation meta-analysis software with sampling size weighting to compare grey matter summary maps driven by Asperger syndrome or autism. Results: The summary autism grey matter map showed lower volumes in the cerebellum, right uncus, dorsal hippocampus and middle temporal gyrus compared with controls; grey matter volumes were greater in the bilateral caudate, prefrontal lobe and ventral temporal lobe. The summary Asperger syndrome map indicated lower grey matter volumes in the bilateral amygdala/hippocampal gyrus and prefrontal lobe, left occipital gyrus, right cerebellum, putamen and precuneus compared with controls; grey matter volumes were greater in more limited regions, including the bilateral inferior parietal lobule and the left fusiform gyrus. Both Asperger syndrome and autism studies reported volume increase in clusters in the ventral temporal lobe of the left hemisphere. Limitations: We assigned studies to autism and Asperger syndrome groups for separate analyses of the data and did not carry out a direct statistical group comparison. In addition, studies available for analysis did not capture the entire spectrum, therefore we cannot be certain that our findings apply to a wider population than that sampled. Conclusion: Whereas grey matter differences in people with Asperger syndrome compared with controls are sparser than those reported in studies of people with autism, the distribution and direction of differences in each category are distinctive. © 2011 Canadian Medical Association.link_to_OA_fulltex

Quantitative susceptibility mapping as an indicator of subcortical and limbic iron abnormality in Parkinson's disease with dementia

Late stage Parkinson's disease (PD) patients were commonly observed with other non-motor comorbidities such as dementia and psychosis. While abnormal iron level in the substantia nigra was clinically accepted as a biomarker of PD, it was also suggested that the increased iron deposition could impair other brain regions and induce non-motor symptoms. A new Magnetic Resonance Imaging (MRI) called Quantitative Susceptibility Mapping (QSM) has been found to measure iron concentration in the grey matter reliably. In this study, we investigated iron level of different subcortical and limbic structures of Parkinson's disease (PD) patients with and without dementia by QSM.QSM and volumetric analysis by MRI were performed in 10 PD dementia (PDD) patients (73 ± 6 years), 31 PD patients (63 ± 8 years) and 27 healthy controls (62 ± 7 years). No significant differences were observed in the L-Dopa equivalent dosage for the two PD groups (p = 0.125).Putative iron content was evaluated in different subcortical and limbic structures of the three groups, as well as its relationship with cognitive performance. One-way ANCOVA with FDR adjustment at level of 0.05, adjusted for age and gender, showed significant group differences for left and right hippocampus (p = 0.015 & 0.032, respectively, BH-corrected for multiple ROIs) and right thalamus (p = 0.032, BH-corrected). Post-hoc test with Bonferroni's correction suggested higher magnetic susceptibility in PDD patients than healthy controls in the left and right hippocampus (p = 0.001 & 0.047, respectively, Bonferroni's corrected), while PD patients had higher magnetic susceptibility than the healthy controls in right hippocampus and right thalamus (p = 0.006 & 0.005, respectively, Bonferroni's corrected). PDD patients also had higher susceptibility than the non-demented PD patients in left hippocampus (p = 0.046, Bonferroni's corrected). The magnetic susceptibilities of the left and right hippocampus were negatively correlated with the Mini-Mental State Examination score (r = −0.329 & -0.386, respectively; p < 0.05).This study provides support for iron accumulation in limbic structures of PDD and PD patients and its correlation with cognitive performance, however, its putative involvement in development of non-motor cognitive dysfunction in PD pathogenesis remains to be elucidated. Keywords: Dementia, Parkinson's disease, Magnetic resonance imaging, Quantitative susceptibility mapping, Iron deposition, Hippocampus, Amygdal

Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology:Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials