Bridge-building between communities: Imagining the future of biomedical autism research.

A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.

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 were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: (1) the standard white flash, (2) the standard 30 Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30 mg of arbaclofen (STX209, GABAB agonist) in a randomized, double-blind, crossover 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 a 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 using an 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 the central processing of sensory information, which may be upstream of more complex autistic phenotypes.

Editorial Perspective: Bridging the translational neuroscience gap in autism - development of the 'shiftability' paradigm.

Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our 'shiftability' paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.

Development of neonatal brain functional centrality and alterations associated with preterm birth.

Formation of the functional connectome in early life underpins future learning and behavior. However, our understanding of how the functional organization of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterized voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and a decrease within the motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

The 'PSILAUT' protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.

BACKGROUND: The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. METHODS: The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. RESULTS: This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. CONCLUSIONS: This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. TRIAL REGISTRATION: NCT05651126.

Immunogenetics of autism spectrum disorder: A systematic literature review.

The aetiology of autism spectrum disorder (ASD) is complex and, partly, accounted by genetic factors. Nonetheless, the genetic underpinnings of ASD are poorly defined. The presence of immune dysregulations in autistic individuals, and their families, supports a role of the immune system and its genetic regulators. Albeit immune responses belong either to the innate or adaptive arms, the overall immune system genetics is broad, and encompasses a multitude of functionally heterogenous pathways which may have different influences on ASD. Hence, to gain insights on the immunogenetic underpinnings of ASD, we conducted a systematic literature review of previous immune genetic and transcription studies in ASD. We defined a list of immune genes relevant to ASD and explored their neuro-immune function. Our review confirms the presence of immunogenetic variability in ASD, accounted by inherited variations of innate and adaptive immune system genes and genetic expression changes in the blood and post-mortem brain of autistic individuals. Besides their immune function, the identified genes control neurodevelopment processes (neuronal and synaptic plasticity) and are highly expressed in pre/peri-natal periods. Hence, our synthesis bolsters the hypothesis that perturbation in immune genes may contribute to ASD by derailing the typical trajectory of neurodevelopment. Our review also helped identifying some of the limitations of prior immunogenetic research in ASD. Thus, alongside clarifying the neurodevelopment role of immune genes, we outline key considerations for future work into the aetiology of ASD and possible novel intervention targets.

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies.

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells.

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/µl) or interleukin (IL)-1ß (10 ng/µl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1ß-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1ß impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1ß receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1ß than IFNγ; and c) the genes differentially regulated in SZ lines - in the face of a cytokine challenge - are primarily associated with mitochondrial, "loss-of-function", pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.

T1-Weighted/T2-Weighted Ratio Mapping at 5 Months Captures Individual Differences in Behavioral Development and Differentiates Infants at Familial Risk for Autism from Controls.

Identifying structural measures that capture early brain development and are sensitive to individual differences in behavior is a priority in developmental neuroscience, with potential implications for our understanding of both typical and atypical populations. T1-weighted/T2-weighted (T1w/T2w) ratio mapping, which previously has been linked to myelination, represents an interesting candidate measure in this respect, as an accessible measure from standard magnetic resonance imaging (MRI) sequences. Yet, its value as an early infancy measure remains largely unexplored. Here, we compared T1w/T2w ratio in 5-month-old infants at familial risk (n = 27) for autism spectrum disorder (ASD) to those without elevated autism risk (n = 16). We found lower T1w/T2w ratio in infants at high risk for ASD within widely distributed regions, spanning both white and gray matter. In regions differing between groups, higher T1w/T2w ratio was robustly associated with higher age at scan (range: ~ 4-6.5 months), implying sensitivity to maturation at short developmental timescales. Further, higher T1w/T2w ratio within these regions was associated with higher scores on measures of concurrent developmental level. These findings suggest that T1w/T2w ratio is a developmentally sensitive measure that should be explored further in future studies of both typical and atypical infant populations.

Phenotyping the Preterm Brain: Characterizing Individual Deviations From Normative Volumetric Development in Two Large Infant Cohorts.

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterizing brain volumetric development in 274 term-born infants, modeling for age at scan and sex. We then compared 89 preterm infants scanned at term-equivalent age with these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalizability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, nonuniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguises a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterization of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

Simultaneous quantification of GABA, Glx and GSH in the neonatal human brain using magnetic resonance spectroscopy.

Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Preterm birth alters the development of cortical microstructure and morphology at term-equivalent age.

INTRODUCTION: The dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. METHODS: We sought to first map typical cortical micro- and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n = 259). Then we offer a comprehensive characterization of the cortical consequences of preterm birth in 76 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. RESULTS: In the term-born neonatal brain, we observed heterogeneous and regionally specific associations between age at scan and measures of cortical morphology and microstructure, including rapid surface expansion, greater cortical thickness, lower cortical anisotropy and higher neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. CONCLUSION: We showed that preterm birth alters cortical micro- and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants.

Neurometabolite mapping highlights elevated myo-inositol profiles within the developing brain in down syndrome.

The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimer's disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (mIns). The NA+/mIns co-transporter is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain mIns was previously associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain mIns is increased earlier in development. The aim of this study was to estimate mIns concentration levels and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr)] in the developing brain in DS and aged-matched controls. We used in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n = 12) and age-matched controls (n = 26) scanned just after birth (36-45 weeks postmenstrual age). Moreover, we used Mass Spectrometry in early (10-20 weeks post conception) ex vivo fetal brain tissue samples from DS (n = 14) and control (n = 30) cases. Relative to [Cho] and [Cr], we report elevated ratios of [mIns] in vivo in the basal ganglia/thalamus, in neonates with DS, when compared to age-matched typically developing controls. Glycine concentration ratios [Gly]/[Cr] and [Cho]/[Cr] also appear elevated. We observed elevated [mIns] in the ex vivo fetal cortical brain tissue in DS compared with controls. In conclusion, a higher level of brain mIns was evident as early as 10 weeks post conception and was measurable in vivo from 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.

Heterogeneity in Brain Microstructural Development Following Preterm Birth.

Preterm-born children are at increased risk of lifelong neurodevelopmental difficulties. Group-wise analyses of magnetic resonance imaging show many differences between preterm- and term-born infants but do not reliably predict neurocognitive prognosis for individual infants. This might be due to the unrecognized heterogeneity of cerebral injury within the preterm group. This study aimed to determine whether atypical brain microstructural development following preterm birth is significantly variable between infants. Using Gaussian process regression, a technique that allows a single-individual inference, we characterized typical variation of brain microstructure using maps of fractional anisotropy and mean diffusivity in a sample of 270 term-born neonates. Then, we compared 82 preterm infants to these normative values to identify brain regions with atypical microstructure and relate observed deviations to degree of prematurity and neurocognition at 18 months. Preterm infants showed strikingly heterogeneous deviations from typical development, with little spatial overlap between infants. Greater and more extensive deviations, captured by a whole brain atypicality index, were associated with more extreme prematurity and predicted poorer cognitive and language abilities at 18 months. Brain microstructural development after preterm birth is highly variable between individual infants. This poorly understood heterogeneity likely relates to both the etiology and prognosis of brain injury.

Development of Microstructural and Morphological Cortical Profiles in the Neonatal Brain.

Interruptions to neurodevelopment during the perinatal period may have long-lasting consequences. However, to be able to investigate deviations in the foundation of proper connectivity and functional circuits, we need a measure of how this architecture evolves in the typically developing brain. To this end, in a cohort of 241 term-born infants, we used magnetic resonance imaging to estimate cortical profiles based on morphometry and microstructure over the perinatal period (37-44 weeks postmenstrual age, PMA). Using the covariance of these profiles as a measure of inter-areal network similarity (morphometric similarity networks; MSN), we clustered these networks into distinct modules. The resulting modules were consistent and symmetric, and corresponded to known functional distinctions, including sensory-motor, limbic, and association regions, and were spatially mapped onto known cytoarchitectonic tissue classes. Posterior regions became more morphometrically similar with increasing age, while peri-cingulate and medial temporal regions became more dissimilar. Network strength was associated with age: Within-network similarity increased over age suggesting emerging network distinction. These changes in cortical network architecture over an 8-week period are consistent with, and likely underpin, the highly dynamic processes occurring during this critical period. The resulting cortical profiles might provide normative reference to investigate atypical early brain development.

Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions.

BACKGROUND: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. METHODS: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). RESULTS: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10(-7); OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). CONCLUSIONS: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Women With Schizophrenia: A Randomized Controlled Trial.

OBJECTIVES: An herbal preparation called peony-glycyrrhiza decoction (PGD) may have the potential in reducing antipsychotic-related hyperprolactinemia (hyperPRL). This double-blind, randomized placebo-controlled study aimed to reevaluate the efficacy of PGD against antipsychotic-related hyperPRL. METHODS: Ninety-nine schizophrenic women who were under antipsychotic therapy and had symptomatic hyperPRL were randomly assigned to additional treatment with placebo (n = 50) or PGD (n = 49, 45 g/d) for 16 weeks. The severity of hyperPRL, psychosis, and abnormal involuntary movements was assessed at baseline and weeks 8 and 16 using standard instruments including the Prolactin Related Adverse Event Questionnaire. Blood levels of prolactin (PRL) and related pituitary and sex hormones were measured at the same time points. RESULTS: Peony-glycyrrhiza decoction treatment produced a significantly greater reduction of the Prolactin Related Adverse Event Questionnaire score at weeks 8 and 16 and a greater improvement on abnormal involuntary movements at end point compared with placebo, without altering the severity of psychosis. The group treated with PGD showed significantly higher proportion of having overall improvement on hyperPRL symptoms (χ = 4.010, P = 0.045) and menstrual resumption (χ = 4.549, P = 0.033) at week 8 than placebo. Serum PRL levels were similar in the 2 groups. CONCLUSIONS: Peony-glycyrrhiza decoction is effective in reducing antipsychotic-related hyperPRL and abnormal involuntary movement symptoms, but no reduction in blood PRL concentrations was observed. The underlying mechanisms of PGD's effects need further investigation (trial registration of NCT01852331 at www.clinicaltrials.gov).

Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice.

Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more 'sensitive' to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits.

The default mode network is disrupted in Parkinson's disease with visual hallucinations.

BACKGROUND: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinson's disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. METHODS: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. RESULTS: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. CONCLUSION: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher "connectivity" is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to "positive" symptom generation in PD.

MRI predicts remission at 1 year in first-episode schizophrenia in females with larger striato-thalamic volumes.

BACKGROUND/AIMS: The Remission in Schizophrenia Working Group has defined remission as 'a low-mild symptom intensity level, maintained for a minimum of 6 months, where such symptoms do not affect an individual's behaviour' [Andreasen et al.: Am J Psychiatry 2005;162:441-449]. Since brain morphology relates to symptomatology, treatment and illness progression, MRI may assist in predicting remission. METHODS: Thirty-nine patients newly diagnosed with DSM-IV schizophrenia underwent MRI brain scan prior to antipsychotic exposure. The Global Assessment of Functioning (GAF) score was entered into a voxel-based analysis to evaluate its relationship with cerebral grey matter volume from the baseline MRI. We entered age, total intracranial volume and intake GAF score as co-variates. Males and females were analysed separately because gender is a potent determinant of outcome. RESULTS: Males had lower GAF scores than females, both at intake and at 1 year. Males comprised only 40% (12 out of 39) of the early remission group. For females only, early remission was strongly and positively correlated with bilateral lentiform and striatal volumes. For males, there was no such relationship. CONCLUSION: Larger striato-thalamic volume correlated with early remission in females only. These baseline MRI findings were unlikely to be confounded by antipsychotic treatment and chronicity. These brain morphological markers show gender dimorphism and may assist in the prediction of early remission in newly diagnosed schizophrenia.