Neurobiological mechanisms of hallucinations in schizophrenia

All perception is a construct of the brain. Yet occasionally, sensory constructions emerge without origin in the physical world and are experienced as hallucinations. Hallucinations occur transdiagnostically, cross-culturally, and in all sensory modalities. They are common in people with schizophrenia, presenting in 60-80% of patients. Despite over 20 years of active neuroimaging research on hallucinations, the neural systems supporting these anomalous perceptual experiences remain disputed. This dissertation investigates the neurobiology of hallucinations, integrating research across structural and functional magnetic resonance imaging (MRI) to elucidate how hallucinations, chiefly in the context of schizophrenia, are supported by the brain, drawing on MRI indices of neurodevelopment. I introduce the phenomenon of hallucinations and motivate the utility of MRI for studying hallucinations. Considering their prevalence in other medical conditions, I conduct a meta-analysis and systematic review of the structural brain basis of hallucinations across diagnoses, primarily schizophrenia spectrum disorders and Parkinson’s disease. This illustrated distinct neuroanatomical organizations of grey matter associated with hallucinations that occur in neurodevelopmental compared to neurodegenerative disorders, which I hypothesise constitute at least two distinct mechanisms. Focussing on the neurodevelopmental mechanism characterized by fronto-temporal and insular grey matter reductions, I turn to the contribution of cortical sulcation, a product of second and third trimester neurodevelopmental processes, which has been robustly implicated in schizophrenia pathology, and, more recently, in hallucinations. Sulcal patterns derived from structural MRI provide a proxy in adulthood for early brain development. I studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MRI from the United Kingdom and Shanghai, China, stratified into those with and without hallucinations, and healthy controls from Shanghai. I first replicate the finding that left hemisphere paracingulate sulcus (PCS) length is reduced in patients who experience hallucinations, then demonstrate similar associations for superior temporal sulcus depth. Length and depth alterations occurred with focal deviations in sulcal geometry. The interindividual and interhemispheric variability of the PCS necessitated the development of semi-automated methods to characterize its morphology and validation to a manual protocol. I used structural covariance networks of the local gyrification index to investigate how specific sulcal deviations relate to global neurodevelopmental coordination, demonstrating that hallucinations correspond to increased covariance within and between salience and auditory networks. Hypothesizing structure-function relationships, I analyse resting-state functional MRI data from the same datasets described, finding significant interactions between PCS length and hallucinations status, but no main effects. There were no effects of hallucination status on salience and auditory network connectivity or in graph theoretical measures of connectivity, suggesting that resting-state connectivity is not a trait marker for hallucinations. Together, the discovery of neurodevelopmental alterations contributing to hallucinations provides mechanistic insight into the pathological consequences of prenatal origins. The interaction of sulcal alterations and hallucination status are associated with connectivity, which may have a role in the pathophysiology of hallucinations. I provide clear predictions and recommendations for future research.Gates Cambridge Scholarshi

Abnormal surface morphology of the central sulcus in children with attention-deficit/hyperactivity disorder

The central sulcus (CS) divides the primary motor and somatosensory areas, and its three-dimensional (3D) anatomy reveals the structural changes of the sensorimotor regions. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is associated with sensorimotor and executive function deficits. However, it is largely unknown whether the morphology of the CS alters due to inappropriate development in the ADHD brain. Here, we employed the sulcus-based morphometry approach to investigate the 3D morphology of the CS in 42 children whose ages spanned from 8.8 to 13.5 years (21 with ADHD and 21 controls). After automatic labeling of each CS, we computed 7 regional shape metrics for each CS, including the global average length, average depth, maximum depth, average span, surface area, average cortical thickness and local sulcal profile. We found that the average depth and maximum depth of the left CS as well as the average cortical thickness of bilateral CS in the ADHD group were significantly larger than those in the healthy children. Moreover, significant between-group differences in the sulcal profile had been found in middle sections of the CSs bilaterally, and these changes were positively correlated with the hyperactivity-impulsivity scores in the children with ADHD. Altogether, our results provide evidence for the abnormity of the CS anatomical morphology in children with ADHD due to the structural changes in the motor cortex, which significantly contribute to the clinical symptomatology of the disorder

Evidence in cortical folding patterns for prenatal predispositions to hallucinations in schizophrenia.

All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a diverse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. Sulcal patterns derived from structural magnetic resonance (MR) images can provide a proxy in adulthood for early brain development. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MR imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK; n = 22 Shanghai) and without (n = 43 UK; n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS), which have previously been associated with hallucinations in schizophrenia, and constructed cortical folding covariance matrices organized by large-scale functional networks. In both ethnic groups, we demonstrated a significantly shorter left PCS in patients with hallucinations compared to those without, and to healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins

Towards Deciphering the Fetal Foundation of Normal Cognition and Cognitive Symptoms From Sulcation of the Cortex.

Growing evidence supports that prenatal processes play an important role for cognitive ability in normal and clinical conditions. In this context, several neuroimaging studies searched for features in postnatal life that could serve as a proxy for earlier developmental events. A very interesting candidate is the sulcal, or sulco-gyral, patterns, macroscopic features of the cortex anatomy related to the fold topology-e.g., continuous vs. interrupted/broken fold, present vs. absent fold-or their spatial organization. Indeed, as opposed to quantitative features of the cortical sheet (e.g., thickness, surface area or curvature) taking decades to reach the levels measured in adult, the qualitative sulcal patterns are mainly determined before birth and stable across the lifespan. The sulcal patterns therefore offer a window on the fetal constraints on specific brain areas on cognitive abilities and clinical symptoms that manifest later in life. After a global review of the cerebral cortex sulcation, its mechanisms, its ontogenesis along with methodological issues on how to measure the sulcal patterns, we present a selection of studies illustrating that analysis of the sulcal patterns can provide information on prenatal dispositions to cognition (with a focus on cognitive control and academic abilities) and cognitive symptoms (with a focus on schizophrenia and bipolar disorders). Finally, perspectives of sulcal studies are discussed

The Brains of Babies: A Surface Based Approach To Study Cortical Development in Term and Preterm Human Infants

Half a million infants are born before term gestation each year in the United States. Although advances in newborn medicine have increased survival rates of very preterm infants to almost 90%, surviving preterm infants are at increased risk for developing lasting neurologic impairments. In order to develop a plausible neuroprotective strategy it is imperative that we improve our understanding of normal cortical development and develop tools to evaluate injury. Using a surface based approach we have characterized normal cortical development in healthy term infants and analyzed abnormalities associated with preterm birth. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants and 12 low-risk preterm infants at term equivalent postmenstrual age were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Data from the 12 term infants were used to establish the first population average surface based atlas of human cerebral cortex at term gestation. Comparing this atlas to a previously established atlas of adult cortex revealed that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, suggesting that that several features of cortical shape are minimally reliant on the postnatal environment. Surprisingly, the pattern of postnatal expansion in surface area is strikingly non-uniform; regions of lateral temporal, parietal, and frontal cortex expand nearly twice as much as other regions in insular and medial occipital cortex. Differential expansion may point to differential sensitivity of cortical circuits to normal or aberrant childhood experiences. The pattern of human postnatal expansion parallels the pattern of evolutionary cortical expansion revealed by comparison between the human and the macaque monkey. Finally, in comparing term and preterm infants, region-specific alterations in cortical folding in the preterm population were found. The most striking shape differences were present in the orbitofrontal and inferior occipital regions with reductions in folding in the insular, lateral temporal, lateral parietal, and lateral frontal cortex. Overall these findings improve our understanding of normal cortical development and help elucidate the potential pathways for cortical injury in preterm infants

Structural brain complexity and cognitive decline in late life : A longitudinal study in the Aberdeen 1936 Birth Cohort

Copyright © 2014 Elsevier Inc. All rights reserved.Peer reviewedPostprin

Atypical sulcal anatomy in young children with autism spectrum disorder

AbstractAutism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology

Gyrification brain abnormalities as predictors of outcome in anorexia nervosa.

Gyrification brain abnormalities are considered a marker of early deviations from normal developmental trajectories and a putative predictor of poor outcome in psychiatric disorders. The aim of this study was to explore cortical folding morphology in patients with anorexia nervosa (AN). A MRI brain study was conducted on 38 patients with AN, 20 fully recovered patients, and 38 healthy women. Local gyrification was measured with procedures implemented in FreeSurfer. Vertex-wise comparisons were carried out to compare: (1) AN patients and healthy women; (2) patients with a full remission at a 3-year longitudinal follow-up assessment and patients who did not recover. AN patients exhibited significantly lower gyrification when compared with healthy controls. Patients with a poor 3-year outcome had significantly lower baseline gyrification when compared to both healthy women and patients with full recovery at follow-up, even after controlling for the effects of duration of illness and gray matter volume. No significant correlation has been found between gyrification, body mass index, amount of weight loss, onset age, and duration of illness. Brain gyrification significantly predicted outcome at follow-up even after controlling for the effects of duration of illness and other clinical prognostic factors. Although the role of starvation in determining our findings cannot be excluded, our study showed that brain gyrification might be a predictor of outcome in AN. Further studies are needed to understand if brain gyrification abnormalities are indices of early neurodevelopmental alterations, the consequence of starvation, or the interaction between both factors

Automated Sulcal Depth Measurement on Cortical Surface Reflecting Geometrical Properties of Sulci

Sulcal depth that is one of the quantitative measures of cerebral cortex has been widely used as an important marker for brain morphological studies. Several studies have employed Euclidean (EUD) or geodesic (GED) algorithms to measure sulcal depth, which have limitations that ignore sulcal geometry in highly convoluted regions and result in under or overestimated depth. In this study, we proposed an automated measurement for sulcal depth on cortical surface reflecting geometrical properties of sulci, which named the adaptive distance transform (ADT). We first defined the volume region of cerebrospinal fluid between the 3D convex hull and the cortical surface, and constructed local coordinates for that restricted region. Dijkstra’s algorithm was then used to compute the shortest paths from the convex hull to the vertices of the cortical surface based on the local coordinates, which may be the most proper approach for defining sulcal depth. We applied our algorithm to both a clinical dataset including patients with mild Alzheimer’s disease (AD) and 25 normal controls and a simulated dataset whose shape was similar to a single sulcus. The mean sulcal depth in the mild AD group was significantly lower than controls (p = 0.007, normal [mean±SD]: 7.29±0.23 mm, AD: 7.11±0.29) and the area under the receiver operating characteristic curve was relatively high, showing the value of 0.818. Results from clinical dataset that were consistent with former studies using EUD or GED demonstrated that ADT was sensitive to cortical atrophy. The robustness against inter-individual variability of ADT was highlighted through simulation dataset. ADT showed a low and constant normalized difference between the depth of the simulated data and the calculated depth, whereas EUD and GED had high and variable differences. We suggest that ADT is more robust than EUD or GED and might be a useful alternative algorithm for measuring sulcal depth