Magnetic resonance imaging study of corpus callosum abnormalities in patients with different subtypes of schizophrenia

Background. Reductions in the size of the corpus callosum (CC) have been described for schizophrenia patients, but little is known about the possible regional differences in schizophrenia subtypes (paranoid, disorganised, undifferentiated, residual).  Methods. We recruited 58 chronically schizophrenic patients with different subtypes, and 31 age-and-gender matched healthy controls. The callosum was extracted from a midsagittal slice from T1 weighted magnetic resonance images, and areas of the total CC, its five subregions, CC length and total brain volume were compared between schizophrenia subtypes and controls. Five subregions were approximately matched to fibre pathways from cortical regions.  Results. Schizophrenia patients had reduced CC total area and length when compared with controls. Disorganised and undifferentiated schizophrenics had a smaller prefrontal area, while there was no significant difference for the paranoid and residual groups. The premotor/supplementary motor area was smaller in all schizophrenia subtypes. The motor area was smaller only in the disorganised group. A smaller sensory area was found in all subtypes except the residual group. Parietal, temporal and occipital areas were smaller in the paranoid and undifferentiated groups. Total brain volume was smaller in all schizophrenia subtypes compared with controls, but did not reach statistical significance.  Conclusion. These findings suggest that the heterogeneity of symptoms may lead to the different CC morphological characteristics in schizophrenia subtypes

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified

Roles of autism gene ARID1B in murine brain development and behavior

Autism spectrum disorder (ASD) and intellectual disability (ID) are highly prevalent neurodevelopmental disorders characterized by social and communication deficits, stereotyped behaviors, cognitive dysfunction, and deficits in adaptive behaviors. The pathogenesis underlying these disorders remains unknown, and thus no pharmacologic or genetic therapies are currently available. Recent progress in the field has shown that haploinsufficiency of the AT-rich interactive domain-containing 1B (ARID1B) gene is a genetic cause of ASD and ID. Our lab recently developed an Arid1b knockout mouse model to better study its role in the pathogenesis of these disorders. One theory regarding the cause of neurodevelopmental disorders is disruption of the excitatory/inhibitory balance in the brain. We previously showed that interneuron deficits lead to an excitatory/inhibitory imbalance in Arid1b knockout mice, playing a significant role in the observed behavioral phenotypes. Interneurons are highly heterogenous cell types in the brain; however, little is known regarding how the different subtypes modulate various behaviors. In chapter 2, we dissect the individual roles of the two most populous interneurons in the cerebral cortex, parvalbumin and somatostatin subtypes, in ASD/ID behaviors seen with ARID1B haploinsufficiency. We show that parvalbumin interneurons affect social and emotional behaviors, while somatostatin interneurons primarily affect stereotyped behaviors and cognitive function. In addition to interneuron deficits, several studies have also implicated altered neurite outgrowth of cortical projection neurons in ASD and ID. Furthermore, deficits in neurotrophic signaling, a master regulator of neurite outgrowth, is also frequently observed. In chapter 3, we examine a potential role of ARID1B in regulating neurite development of excitatory neurons during corticogenesis. We show that loss of the Arid1b gene leads to disrupted neurite outgrowth and altered development of the corpus callosum. Additionally, we suggest a likely role of ARID1B in the BDNF neurotrophic signaling pathway. Together, these studies provide insight into possible roles of ARID1B during neurogenesis, shedding further insight into the pathogenesis of ASD and ID

Use of Dysmorphology for Subgroup Classification on Autism Spectrum Disorder in Chinese Children

Data from 1,261 Chinese Autistic Spectrum Disorder (ASD) patients were evaluated and categorized into dysmorphic (10.79 %) and non-dysmorphic groups (89.21 %) upon physical examination by the presence of dysmorphic features. Abnormal MRI/CT result, IQ scores and epilepsy were significantly associated with the dysmorphic group of ASD children. However, gender, EEG abnormality and family history and recurrence of ASD were not found to be significantly different between group statuses. It is suggested that results collected from the Chinese population generally resembles that found in the Caucasians with ethnical differences still present. Current study supports the result shown in Miles' study (Miles et al. in Am J Med Genet 135A:171-180, 2005), in which heterogeneity subtypes of autism of different genetic origins which could be distinguished by presence of dysmorphic features on the patients.postprin

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Brain Imaging Correlates of Developmental Coordination Disorder and Associated Impairments

Developmental Coordination Disorder (DCD) is a common developmental disorder characterised by an inability to learn age appropriate complex motor skills. The first aim of this thesis was to characterise additional cognitive impairments and their relationship with motor difficulties in school aged children with DCD. The second aim was to investigate grey and white matter neuroimaging correlates of motor and cognitive deficits identified. Thirty six children aged 8-10 years who met DSM-5 criteria for DCD and an age-matched typically developing group (N=17) underwent standardised assessments of motor, intellectual, attention, speech and language skills as well as structural and diffusion-weighted MRI scans. Grey matter correlates of impairments were identified using subcortical volumetrics and surface-based analyses of cortical morphology. White matter correlates were examined using tractography and fixel-based fibre morphology of the pyramidal tracts, corpus callosum and cerebellar peduncles. Alongside impaired motor skills, children with DCD performed poorer than controls on several domains of executive function (attention and processing speed) and speech motor control. Motor skills did not correlate with impairments in other domains. Cortical thickness was significantly reduced in the left central sulcus in children with DCD compared to controls. Poor motor skills correlated with measures in left sensorimotor circuitry, posterior cingulate cortex and anterior insula. Poor speech motor control was associated with measures in the thalamus and corticobulbar tract. Poor sustained attention was linked to measures in the right superior cerebellar peduncle. Lower processing speed was associated with reduced mean cortical surface area. Children with DCD show co-occurring impairments in attention and speech motor control. DCD is associated with sensorimotor circuits as well as regions that form part of the default mode and salience networks. Disruption of subcortical circuits may underlie additional impairments. This study provides novel evidence of the neural correlates of DCD

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

In-depth characterization of neuroradiological findings in a large sample of individuals with autism spectrum disorder and controls

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with quantitative differences in cortical and subcortical brain morphometry. Qualitative assessment of brain morphology provides complementary information on the possible underlying neurobiology. Studies of neuroradiological findings in ASD have rendered mixed results, and await robust replication in a sizable and independent sample. Methods: We systematically and comprehensively assessed neuroradiological findings in a large cohort of participants with ASD and age-matched controls (total N = 620, 348 ASD and 272 controls), including 70 participants with intellectual disability (47 ASD, 23 controls). We developed a comprehensive scoring system, augmented by standardized biometric measures. Results: There was a higher incidence of neuroradiological findings in individuals with ASD (89.4 %) compared to controls (83.8 %, p = .042). Certain findings were also more common in ASD, in particular opercular abnormalities (OR 1.9, 95 % CI 1.3–3.6) and mega cisterna magna (OR 2.4, 95 % CI 1.4–4.0) reached significance when using FDR, whereas increases in macrocephaly (OR 2.0, 95 % CI 1.2–3.2), cranial deformities (OR 2.4, 95 % CI: 1.0–5.8), calvarian / dural thickening (OR 1.5, 95 % CI 1.0–2.3), ventriculomegaly (OR 3.4, 95 % CI 1.3–9.2), and hypoplasia of the corpus callosum (OR 2.7, 95 % CI 1.1–6.3) did not survive this correction. Furthermore, neuroradiological findings were more likely to occur in isolation in controls, whereas they clustered more frequently in ASD. The incidence of neuroradiological findings was higher in individuals with mild intellectual disability (95.7 %), irrespective of ASD diagnosis. Conclusion: There was a subtly higher prevalence of neuroradiological findings in ASD, which did not appear to be specific to the condition. Individual findings or clusters of findings may point towards the neurodevelopmental mechanisms involved in individual cases. As such, clinical MRI assessments may be useful to guide further etiopathological (genetic) investigations, and are potentially valuable to fundamental ASD research

mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism

Investigating the role of the transcriptional coregulator Cited2 in regulating intermediate progenitor proliferation and modulating behavior

The mammalian neocortex develops from a thin layer of neuroepithelial cells into a robust mosaic of differentiated neurons organized into distinct layers and functional areas. This process requires a complex choreography of transcription factors and epigenetic regulators to be spatially and temporally activated in a precise manner. Disruptions in any aspect of this delicate process may lead to neurodevelopmental disorders like autism spectrum disorder, schizophrenia, or intellectual disability. One such transcriptional coregulator that is a crucial regulator of neocortical development is Cited2. Previous work demonstrated that forebrain-specific Cited2 loss-of-function causes a reduction in neocortical progenitor proliferation which leads to reduced thickness of neocortical superficial layers, reduced neocortical length, and a reduction of interhemispheric connectivity throughout the neocortex. This dissertation elucidates the molecular mechanism by which CITED2 functions in the developing neocortex. Further, I explore the effects Cited2 cKO has on early post-natal and young adult behaviors and reveal disruptions in neonatal ultrasonic vocalizations, increased rearing behavior, and increased sensitization to repeated acoustic startle. Additionally, I perform transcriptome analysis of purified intermediate progenitor cells (IPCs) from Cited2 cKO and WT neocortices to elucidate affected biological processes that underpin the disrupted neocortical development and behavior of Cited2 cKO mice. I uncover novel deficits in primary cilia function and potential premature neurogenesis. Further, we investigate the role CITED2 plays in neuronal fate decisions of Layer V projection neurons, exploring the relationship between Cited2 and a recently discovered microRNA posited to modulate Cited2 expression. Finally, I delve into maternal diet alteration and show folic acid supplementation rescues morphological phenotypes generated by Cited2 cKO. In summary, we identify the Cited2 forebrain-specific knockout as an excellent novel system to study mechanisms underpinning neurodevelopment and the etiology of neurodevelopmental disorders