Comprehensive review:Computational modelling of Schizophrenia

Computational modelling has been used to address: (1) the variety of symptoms observed in schizophrenia using abstract models of behavior (e.g. Bayesian models - top-down descriptive models of psychopathology); (2) the causes of these symptoms using biologically realistic models involving abnormal neuromodulation and/or receptor imbalance (e.g. connectionist and neural networks - bottom-up realistic models of neural processes). These different levels of analysis have been used to answer different questions (i.e. understanding behavioral vs. neurobiological anomalies) about the nature of the disorder. As such, these computational studies have mostly supported diverging hypotheses of schizophrenia's pathophysiology, resulting in a literature that is not always expanding coherently. Some of these hypotheses are however ripe for revision using novel empirical evidence.Here we present a review that first synthesizes the literature of computational modelling for schizophrenia and psychotic symptoms into categories supporting the dopamine, glutamate, GABA, dysconnection and Bayesian inference hypotheses respectively. Secondly, we compare model predictions against the accumulated empirical evidence and finally we identify specific hypotheses that have been left relatively under-investigated

Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation

AbstractHomeostatic plasticity is thought to stabilize neural activity around a set point within a physiologically reasonable dynamic range. Over the last ten years, a wide range of non-invasive transcranial brain stimulation (NTBS) techniques have been used to probe homeostatic control of cortical plasticity in the intact human brain. Here, we review different NTBS approaches to study homeostatic plasticity on a systems level and relate the findings to both, physiological evidence from in vitro studies and to a theoretical framework of homeostatic function. We highlight differences between homeostatic and other non-homeostatic forms of plasticity and we examine the contribution of sleep in restoring synaptic homeostasis. Finally, we discuss the growing number of studies showing that abnormal homeostatic plasticity may be associated to a range of neuropsychiatric diseases

Genetic Controls Balancing Excitatory and Inhibitory Synaptogenesis in Neurodevelopmental Disorder Models

Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states

Functional neuroanatomy of action selection in schizophrenia

Schizophrenia remains an enigmatic disorder with unclear neuropathology. Recent advances in neuroimaging and genetic research suggest alterations in glutamate-dopamine interactions adversely affecting synaptic plasticity both intracortically and subcortically. Relating these changes to the manifestation of symptoms presents a great challenge, requiring a constrained framework to capture the most salient elements. Here, a biologically-grounded computational model of basal ganglia-mediated action selection was used to explore two pathological processes that hypothetically underpin schizophrenia. These were a drop in the efficiency of cortical transmission, reducing both the signal-to-noise ratio (SNR) and overall activity levels; and an excessive compensatory upregulation of subcortical dopamine release. It was proposed that reduced cortical efficiency was the primary process, which led to a secondary disinhibition of subcortical dopamine release within the striatum. This compensation was believed to partly recover lost function, but could then induce disorganised-type symptoms - summarised as selection ”Instability” - if it became too pronounced. This overcompensation was argued to be countered by antipsychotic medication. The model’s validity was tested during an fMRI (functional magnetic resonance imaging) study of 16 healthy volunteers, using a novel perceptual decision-making task, and was found to provide a good account for pallidal activation. Its account for striatum was developed and improved with a small number of principled model modifications: the inclusion of fast spiking interneurons within striatum, and their inhibition by the basal ganglia’s key regulatory nucleus, external globus pallidus. A key final addition was the explicit modelling of dopaminergic midbrain, which is dynamically regulated by both cortex and the basal ganglia. This enabled hypotheses concerning the effects of cortical inefficiency, compensatory dopamine release and medication to be directly tested. The new model was verified with a second set of 12 healthy controls. Its pathological predictions were compared to data from 12 patients with schizophrenia. Model simulations suggested that Instability went hand-in-hand with cortical inefficiency and secondary dopamine upregulation. Patients with high Instability scores showed a loss of SNR within decision-related cortex (consistent with cortical inefficiency); an exaggerated response to task demands within substantia nigra (consistent with dopaminergic upregulation); and had an improved fit to simulated data derived from increasingly cortically-inefficient models. Simulations representing the healthy state provided a good account for patients’ motor putamen, but only cortically-inefficient simulations representing the ill state provided a fit for ventral-anterior striatum. This fit improved as the simulated model became more medicated (increased D2 receptor blockade). The relative improvement of this account correlated with patients’ medication dosage. In summary, by distilling the hypothetical neuropathology of schizophrenia into two simplified umbrella processes, and using a computational model to consider their effects within action selection, this work has successfully related patients’ fMRI activation to particular symptomatology and antipsychotic medication. This approach has the potential to improve patient care by enabling a neurobiological appreciation of their current illness state, and tailoring their medication level appropriately

The Role of Glutaminase 1 in HIV-1 Associated Neurocognitive Disorders and in Brain Development

Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Glutamate is essential for proper brain functioning but at excess levels, it is neurotoxic and has a key role in the pathogenesis of various neurodegenerative diseases, including HIV-1 associated neurocognitive disorders (HAND). However, the detailed mechanism of glutamate-mediated neurotoxicity remains unclear. In part I, we identified the regulation of glutaminase 1 (GLS1) in the central nervous system (CNS) of HAND animal models including HIV-Tat transgenic (Tg) mouse and HIVE-SCID mouse, since GLS1 is the dominant isoform of glutaminase in mammalian brains. Interestingly, examinations of both animals revealed an upregulation of GLS1 in correlation with the increase of brain inflammation and cognitive impairment. As our previous data revealed an upregulation of glutaminase C (GAC) in the postmortem brain tissues of patients with HIV dementia by protein analysis, suggesting a critical role of GAC in the instigation of primary dysfunction and subsequent neuronal damage in HAND, thus in part II we hypothesize that GAC dysregulation in brain is sufficient to induce brain inflammation and dementia in relevance to HAND. Using a brain GAC overexpression mouse model (which has the overexpression of GAC confined in the brain), we found that the expressions of the marker for brain inflammation, the glial fibrillary acidic protein (GFAP), were increased in the brains of GAC-overexpression mice, suggesting increased reactive astrogliosis. To study the functional impact of GAC overexpression, we performed Morris Water Maze (MWM) test and Contextual Fear Conditioning (CFC) test to determine the learning and memory of mice. GAC-overexpression mice perfomed poorer in both tests, indicating that overexpressing GAC in mouse brain impaired the learning and memory of the animals. Moreover, pathological and physiologial examinations revealed synaptic damage and increased apoptosis in Nestin-GAC mouse brain. Together, these data suggest that dysregulated GAC has a causal relationship with prolonged inflammation and dementia relevant to HAND. In part III, we evaluated the feasibility of genetically knocking down GLS1 in CNS to treat HAND using human primary neural progenitor cell (NPC) culture. However, we have found that GLS1 is essential for the survival, proliferation and differentiation of human NPC. This suggests that more-advanced genetic methods capable of targeting GLS1 in specific cell types of CNS ought to be developed for the therapeutic purpose. In summary, we report that GLS1 is dysregulated in the brains of HAND murine models in correlation with increased brain inflammation and cognitive impairment. Moreover, overexpressed GAC in mouse brains has a causal relationship to prolonged brain inflammation and dementia of these animals, suggesting a pathologenic role of dysregulated brain GLS1 in relevance to HAND

An exploration of homeostatic plasticity in musculoskeletal pain

The brain has a remarkable capacity to reorganise itself through life. When changes occur at a cellular level between neurons, this is known as synaptic plasticity. Synaptic plasticity has been proposed to be a key mechanism underpinning the learning and memory formation that occurs following afferent input (i.e., incoming stimuli from movement and sensation). However, synaptic plasticity in the human brain follows a positive loop cycle where incoming stimuli can lead to excessive synaptic strengthening (long-term potentiation; LTP) or weakening (long-term depression; LTD). To prevent overexpression of LTP or LTD, regulatory mechanisms termed ‘homeostatic plasticity’ promote stability during synaptic plasticity. A large body of evidence suggests that short- or long-term changes to synaptic plasticity takes place following afferent input. Similarly, evidence also suggests synaptic plasticity is altered in individuals experiencing incoming stimuli that are painful. However, no study has examined homeostatic plasticity during pain. Published studies that have examined homeostatic plasticity in individuals with pathology have been conducted in neurological conditions such as writer’s cramp, and chronic migraine. These studies provide preliminary evidence that impaired homeostatic plasticity is associated with altered synaptic plasticity with patients displaying abnormally high primary motor cortex (M1) excitability, altered cortical organisation, increased pain perception, and sensorimotor dysfunction. As altered synaptic plasticity and similar clinical features have been observed in individuals with chronic musculoskeletal pain, it is possible that homeostatic plasticity is impaired during pain. Thus, the broad goal of this thesis was to explore the effect of pain, using a clinical chronic musculoskeletal pain population and an experimental pain model, on homeostatic plasticity in the M1. To address this broad goal, three primary research studies were conducted

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies