Preserved navigation abilities and spatio-temporal memory in individuals with autism spectrum disorder.

Cerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric learning and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD.

Aberrant Subnetwork and Hub Dysconnectivity in Adult Bipolar Disorder: A Multicenter Graph Theory Analysis.

Neuroimaging evidence implicates structural network-level abnormalities in bipolar disorder (BD); however, there remain conflicting results in the current literature hampered by sample size limitations and clinical heterogeneity. Here, we set out to perform a multisite graph theory analysis to assess the extent of neuroanatomical dysconnectivity in a large representative study of individuals with BD. This cross-sectional multicenter international study assessed structural and diffusion-weighted magnetic resonance imaging data obtained from 109 subjects with BD type 1 and 103 psychiatrically healthy volunteers. Whole-brain metrics, permutation-based statistics, and connectivity of highly connected nodes were used to compare network-level connectivity patterns in individuals with BD compared with controls. The BD group displayed longer characteristic path length, a weakly connected left frontotemporal network, and increased rich-club dysconnectivity compared with healthy controls. Our multisite findings implicate emotion and reward networks dysconnectivity in bipolar illness and may guide larger scale global efforts in understanding how human brain architecture impacts mood regulation in BD.

Lithium prevents grey matter atrophy in patients with bipolar disorder: an international multicenter study.

BACKGROUND: Lithium (Li) is the gold standard treatment for bipolar disorder (BD). However, its mechanisms of action remain unknown but include neurotrophic effects. We here investigated the influence of Li on cortical and local grey matter (GM) volumes in a large international sample of patients with BD and healthy controls (HC). METHODS: We analyzed high-resolution T1-weighted structural magnetic resonance imaging scans of 271 patients with BD type I (120 undergoing Li) and 316 HC. Cortical and local GM volumes were compared using voxel-wise approaches with voxel-based morphometry and SIENAX using FSL. We used multiple linear regression models to test the influence of Li on cortical and local GM volumes, taking into account potential confounding factors such as a history of alcohol misuse. RESULTS: Patients taking Li had greater cortical GM volume than patients without. Patients undergoing Li had greater regional GM volumes in the right middle frontal gyrus, the right anterior cingulate gyrus, and the left fusiform gyrus in comparison with patients not taking Li. CONCLUSIONS: Our results in a large multicentric sample support the hypothesis that Li could exert neurotrophic and neuroprotective effects limiting pathological GM atrophy in key brain regions associated with BD.

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity.

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.

Higher in vivo Cortical Intracellular Volume Fraction Associated with Lithium Therapy in Bipolar Disorder: A Multicenter NODDI Study.

BACKGROUND: MRI studies in patients with bipolar disorder have suggested that lithium is associated with grey matter increases that may underlie its therapeutic effects. However, the relationship between grey matter volume and cellular microstructural changes is not straightforward, as modifications of different cellular compartments of grey matter may be involved. OBJECTIVES: Our aim was to test the hypothesis that dendritic density is higher in patients undergoing lithium therapy than in patients without lithium, using advanced modelling of water diffusion investigated with MRI. METHOD: We included 41 patients and 40 controls matched for age and gender from two sites. All subjects underwent 3T MRI with 3 shells of diffusion. We used neurite orientation dispersion and density imaging to compare the grey matter neurite density between patients undergoing lithium therapy or not and control subjects. RESULTS: We found a significant group effect in the left prefrontal region (p = 0.001, Bonferroni corrected): patients without lithium had a lower frontal neurite density than controls (p = 0.009), while those on lithium had a higher mean neurite density than those without (p < 0.001). Patients on lithium were not different from controls (p = 0.08). CONCLUSIONS: This is the first study to report in vivo evidence of preserved neurite density of the prefrontal cortex in humans associated with lithium intake. Changes of intracellular volume fraction are thought to reflect changes of grey matter microstructural organization. This reinforces the hypothesis of lithium having a positive effect on the neuronal compartment in humans.

Patients with autism spectrum disorders display reproducible functional connectivity alterations.

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified functional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our results showed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity was primarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located in prefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to within the identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiological phenotype was partially associated with core ASD symptoms related to communication and daily living skills and was not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts are encouraging with respect to potential application as a treatment and for patient stratification, the moderate link to clinical symptoms and the large overlap with healthy controls currently limit the usability of identified alterations as diagnostic or efficacy readout.

Decreased Cortical Thickness in the Anterior Cingulate Cortex in Adults with Autism.

Autism spectrum disorder (ASD) is a developmental disorder underdiagnosed in adults. To date, no consistent evidence of alterations in brain structure has been reported in adults with ASD and few studies were conducted at that age. We analyzed structural magnetic resonance imaging data from 167 high functioning adults with ASD and 195 controls. We ran our analyses on a discovery (n = 301) and a replication sample (n = 61). The right caudal anterior cingulate cortical thickness was significantly thinner in adults with ASD compared to controls in both the discovery and the replication sample. Our work underlines the relevance of studying the brain anatomy of an adult ASD population.

Local structural connectivity is associated with social cognition in autism spectrum disorder.

The current theory implying local, short-range overconnectivity in autism spectrum disorder, contrasting with long-range underconnectivity, is based on heterogeneous results, on limited data involving functional connectivity studies, on heterogeneous paediatric populations and non-specific methodologies. In this work, we studied short-distance structural connectivity in a homogeneous population of males with high-functioning autism spectrum disorder and used a novel methodology specifically suited for assessing U-shaped short-distance tracts, including a recently developed tractography-based atlas of the superficial white matter fibres. We acquired diffusion-weighted MRI for 58 males (27 subjects with high-functioning autism spectrum disorder and 31 control subjects) and extracted the mean generalized fractional anisotropy of 63 short-distance tracts. Neuropsychological evaluation included Wechsler Adult Intelligence Scale IV (WAIS-IV), Communication Checklist-Adult, Empathy Quotient, Social Responsiveness Scale and Behaviour Rating Inventory of Executive Function-Adult (BRIEF-A). In contradiction with the models of short-range over-connectivity in autism spectrum disorder, we found that patients with autism spectrum disorder had a significantly decreased anatomical connectivity in a component comprising 13 short tracts compared to controls. Specific short-tract atypicalities in temporal lobe and insula were significantly associated with clinical manifestations of autism spectrum disorder such as social awareness, language structure, pragmatic skills and empathy, emphasizing their importance in social dysfunction. Short-range decreased anatomical connectivity may thus be an important substrate of social deficits in autism spectrum disorder, in contrast with current models.

Neurodevelopmental subtypes of bipolar disorder are related to cortical folding patterns: An international multicenter study.

OBJECTIVES: Brain sulcation is an indirect marker of neurodevelopmental processes. Studies of the cortical sulcation in bipolar disorder have yielded mixed results, probably due to high variability in clinical phenotype. We investigated whole-brain cortical sulcation in a large sample of selected patients with high neurodevelopmental load. METHODS: A total of 263 patients with bipolar disorder I and 320 controls were included in a multicentric magnetic resonance imaging (MRI) study. All subjects underwent high-resolution T1-weighted brain MRI. Images were processed with an automatized pipeline to extract the global sulcal index (g-SI) and the local sulcal indices (l-SIs) from 12 a priori determined brain regions covering the whole brain. We compared l-SI and g-SI between patients with and without early-onset bipolar disorder and between patients with and without a positive history of psychosis, adjusting for age, gender and handedness. RESULTS: Patients with early-onset bipolar disorder had a higher l-SI in the right prefrontal dorsolateral region. Patients with psychotic bipolar disorder had a decreased l-SI in the left superior parietal cortex. No group differences in g-SI or l-SI were found between healthy subjects and the whole patient cohort. We could replicate the early-onset finding in an independent cohort. CONCLUSIONS: Our work suggests that bipolar disorder is not associated with generalized abnormalities of sulcation, but rather with localized changes of cortical folding restricted to patients with a heavy neurodevelopmental loading. These findings support the hypothesis that bipolar disorder is heterogeneous but may be disentangled using MRI, and suggest the need for investigations into neurodevelopmental deviations in the disorder.

A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Cerebellar anatomical alterations and attention to eyes in autism.

The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.

Shape analysis of the cingulum, uncinate and arcuate fasciculi in patients with bipolar disorder.

BACKGROUND: Abnormal maturation of brain connectivity is supposed to underlie the dysfunctional emotion regulation in patients with bipolar disorder (BD). To test this hypothesis, white matter integrity is usually investigated using measures of water diffusivity provided by MRI. Here we consider a more intuitive aspect of the morphometry of the white matter tracts: the shape of the fibre bundles, which is associated with neurodevelopment. We analyzed the shape of 3 tracts involved in BD: the cingulum (CG), uncinate fasciculus (UF) and arcuate fasciculus (AF). METHODS: We analyzed diffusion MRI data in patients with BD and healthy controls. The fibre bundles were reconstructed using Q-ball-based tractography and automated segmentation. Using Isomap, a manifold learning method, the differences in the shape of the reconstructed bundles were visualized and quantified. RESULTS: We included 112 patients and 82 controls in our analysis. We found the left AF of patients to be further extended toward the temporal pole, forming a tighter hook than in controls. We found no significant difference in terms of shape for the left UF, the left CG or the 3 right fasciculi. However, in patients compared with controls, the ventrolateral branch of the left UF in the orbitofrontal region had a tendency to be larger, and the left CG of patients had a tendency to be smaller in the frontal lobe and larger in the parietal lobe. LIMITATIONS: This was a cross-sectional study. CONCLUSION: Our results suggest neurodevelopmental abnormalities in the left AF in patients with BD. The statistical tendencies observed for the left UF and left CG deserve further study.

Striatal and Extrastriatal Dopamine Transporter Availability in Schizophrenia and Its Clinical Correlates: A Voxel-Based and High-Resolution PET Study.

Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia.

Childhood trauma and the limbic network: a multimodal MRI study in patients with bipolar disorder and controls.

BACKGROUND: Childhood trauma (CT) is a major risk factor for psychiatric conditions. It is hypothesized that CT effects are mediated by the limbic system. Few multimodal neuroimaging studies allow an integrated perspective of this impact. Our goal was thus to study the effects of CT on the limbic network. METHODS: We acquired multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 79 subjects (47 healthy controls and 32 patients with bipolar disorder, BD). We performed correlational analyses between Childhood Trauma Questionnaire (sub)scores (physical and emotional abuse/neglect and sexual abuse) and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, prefronto-limbic functional connectivity, uncinate fractional anisotropy). RESULTS: We found CTQ total scores to be negatively correlated with amygdala volume, prefronto-limbic functional connectivity (FC) and uncinate fractional anisotropy in our sample. Considering subscores, neglects (physical and emotional) were the only to affect neural parameters. The patients with BD drove most of the results. LIMITATIONS: Small sample size and low level of trauma in controls. CONCLUSIONS: Our multimodal approach enabled an integrated view of the long-term effects of CT on the limbic system.

Corpus callosum area in patients with bipolar disorder with and without psychotic features: an international multicentre study.

BACKGROUND: Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls. METHODS: We analyzed anatomic T1 MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features. RESULTS: We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features. LIMITATIONS: We found small to medium effect sizes, and there was no calibration technique among the sites. CONCLUSION: Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.

The promise of biological markers for treatment response in first-episode psychosis: a systematic review.

Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis. The present systematic review provides (1) trials that assessed biological markers associated with antipsychotic response or side effects in first-episode psychosis and (2) potential biomarkers associated with biological disturbances that may guide the choice of conventional treatments or the prescription of innovative treatments. Trials including first-episode psychoses are few in number. Most of the available data focused on pharmacogenetics markers with so far only preliminary results. To date, these studies yielded-beside markers for metabolism of antipsychotics-no or only a few biomarkers for response or side effects, none of which have been implemented in daily clinical practice. Other biomarkers exploring immunoinflammatory, oxidative, and hormonal disturbances emerged as biomarkers of first-episode psychoses in the last decades, and some of them have been associated with treatment response. In addition to pharmacogenetics, further efforts should focus on the association of emergent biomarkers with conventional treatments or with innovative therapies efficacy, where some preliminary data suggest promising results.

The Kraepelinian dichotomy viewed by neuroimaging.

The Kraepelinian dichotomy between schizophrenia (SZ) and bipolar disorder (BD) is being challenged by recent epidemiological and biological studies. We performed a comparative review of neuroimaging features in both conditions at several scales: whole-brain and regional volumes, brain activity, connectivity, and networks. Structural volumetric neuroimaging studies suggest a common pattern of volume decreases, but networks studies reveal a clearer distinction between BD and SZ with an altered connectivity generalized to all brain networks in SZ and restricted to limbic, paralimbic, and interhemispheric networks in BD.

A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity.

IMPORTANCE: Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES: To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS: Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES: Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS: Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE: In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Neuroimaging biomarkers in bipolar disorder.

There is an urgent need to identify objective biomarkers for the assessment of bipolar disorder, to improve diagnosis and prognostic evaluation. Neuroimaging is a particularly promising approach. We review here the structural and functional neuroimaging studies carried out on bipolar disorder. These studies have led to the development of neurobiological models of bipolar disorder assuming cortical-limbic dysregulation. Dorsal brain structures are thought to decrease in volume and activity in bipolar disorder, reducing inhibition of the ventral-limbic network and enhancing emotional responses. These models also assume abnormal prefrontal-subcortical limbic connectivity. This abnormal connectivity has been identified by both diffusion tensor imaging studies (anatomical connectivity) and functional MRI (functional connectivity). However, studies are currently limited by the heterogeneity of the patients included. Future research should include studies to validate biomarkers for the assessment of bipolar disorder and studies of large and well characterized samples of patients with bipolar disorder.