An in Silico, Biomarker-Based Method for the Evaluation of Virtual Neuropsychiatric Drug Effects.

The recent explosion in neuroscience research has markedly increased our understanding of the neurobiological correlates of many psychiatric illnesses, but this has unfortunately not translated into more effective pharmacologic treatments for these conditions. At the same time, researchers have increasingly sought out biological markers, or biomarkers, as a way to categorize psychiatric illness, as these are felt to be closer to underlying genetic and neurobiological vulnerabilities. While biomarker-based drug discovery approaches have tended to employ in vivo (e.

Computational modeling of psychiatric illnesses via well-defined neurophysiological and neurocognitive biomarkers.

A good deal of recent research has centered on the identification of biomarkers and endophenotypic measures of psychiatric illnesses using in vivo and in vitro studies. This is understandable, as these measures-as opposed to complex clinical phenotypes-may be more closely related to neurobiological and genetic vulnerabilities. However, instantiation of such biomarkers using computational models-in silico studies-has received less attention.

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects.

Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics.

Patterns of spontaneous magnetoencephalographic activity in patients with schizophrenia.

Magnetoencephalography noninvasively measures the magnetic fields produced by the brain. Pertinent research articles from 1993 to 2009 that measured spontaneous, whole-head magnetoencephalography activity in patients with schizophrenia were reviewed. Data on localization of oscillatory activity and correlation of these findings with psychotic symptoms are summarized.

Evidence of multistability in a realistic computer simulation of hippocampus subfield CA1.

The manner in which hippocampus processes neural signals is thought to be central to the memory encoding process. A theoretically oriented literature has suggested that this is carried out via "attractors" or distinctive spatio-temporal patterns of activity. However, these ideas have not been thoroughly investigated using computational models featuring both realistic single-cell physiology and detailed cell-to-cell connectivity.

Modeling of context-dependent retrieval in hippocampal region CA1: implications for cognitive function in schizophrenia.

The symptoms of schizophrenia may be associated with reductions in NMDA receptor (NMDAR) function. This is suggested by the psychotomimetic effects of NMDA antagonists, the ameliorative effects of NMDAR indirect agonists, elevated levels of the NMDA antagonist N-acetyl-aspartyl-glutamate (NAAG) in schizophrenic brain, and findings from recent genetic studies. However, the link between reduced NMDAR function and the behavioral features of schizophrenics has not been made explicit.

Enhanced semantic priming in schizophrenia: a computer model based on excessive pruning of local connections in association cortex.

Background: Many studies have found that people with schizophrenia exhibit abnormally high levels of semantic priming. Post-mortem and neuroimaging studies of schizophrenia suggest a reduction of neuritic processes (dendrites and synapses).

Aims: To demonstrate that reductions in neuritic processes can produce excessive priming in patients with schizophrenia.