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).To demonstrate that reductions in neuritic processes can produce excessive priming in patients with schizophrenia.Associative memory was simulated using a computer-based neural network system consisting of two interactive neural groups, one coding for individual memories and the other for the category to which each memory belonged.Variation of a single parameter determining the density of local connections within the two neuronal groups gave a close approximation to levels of memory access and semantic priming previously reported in normal subjects and in patients with schizophrenia.This study suggests that schizophrenia arises from excessive pruning of local connections in association cortex. Its findings shed light on the mechanisms underlying cognitive priming more generally, and how it might emerge developmentally.

Priming (agriculture)

Synaptic Pruning

Association (psychology)

Temporal cortex

10.1192/bjp.180.4.345

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Citations (36)

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

Neural Computation (2017)

Peter J. Siekmeier

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.g., rodent) or in vitro test systems, relatively little attention has been paid to the potential of computational, or in silico, methodologies. Here we describe such a methodology, using as an example a biophysically detailed computational model of hippocampus that is made to generate putative schizophrenia biomarkers by the inclusion of a number of neuropathological changes that have been associated with the illness (NMDA system deficit, decreased neural connectivity, hyperdopaminergia). We use the specific inability to attune to gamma band (40 Hz) auditory stimulus as our illness biomarker. We expose this system to a large number of virtual medications, defined by systematic variation of model parameters corresponding to five cellular-level effects. The potential efficacy of virtual medications is determined by a wellness metric (WM) that we have developed. We identify a number of virtual agents that consist of combinations of mechanisms, which are not simply reversals of the causative lesions. The manner in which this methodology could be extended to other neuropsychiatric conditions, such as Alzheimer's disease, autism, and fragile X syndrome, is discussed.

Fragile X Syndrome

10.1162/neco_a_00944

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Citations (2)

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

Schizophrenia Research (2006)

Peter J. Siekmeier Michael E. Hasselmo Marc W. Howard Joseph T. Coyle

Psychotomimetic

10.1016/j.schres.2006.08.007

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Citations (39)

Patterns of Spontaneous Magnetoencephalographic Activity in Patients With Schizophrenia

Journal of Clinical Neurophysiology (2010)

Peter J. Siekmeier Steven M. Stufflebeam

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. Although the variety of measures used by different research groups makes a quantitative meta-analysis difficult, it appears that magnetoencephalography activity in patients may exhibit identifiable patterns, defined by topographic organization and frequency band. Specifically, 11 of the 12 studies showed increased theta (4–8 Hz) and delta (1–4 Hz) band oscillations in the temporal lobes of patients; of the 10 studies that examined the relationship between oscillatory activity and symptomatology, 8 found a positive correlation between temporal lobe theta activity and positive schizophrenic symptoms. Abnormally high frontal delta activity was not seen. These findings are analyzed in comparison with the electroencephalogram literature on schizophrenics, and possible confounds (e.g., medication effects) are discussed. In the future, magnetoencephalography might be used to assist in diagnosis or might be fruitfully used in conjunction with new neuroscience research approaches such as computational modeling, which may be able to link oscillatory activity and cellular-level pathology.

Magnetoencephalography

Frontal lobe

10.1097/wnp.0b013e3181e0b20a

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Citations (50)

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

PLoS ONE (2013)

Peter J. Siekmeier David P. vanMaanen

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. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete "clusters" of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.

Neuropathology

Calretinin

10.1371/journal.pone.0058607

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Citations (24)

JAMA Psychiatry

JAMA Psychiatry (2013)

Phil Fontanarosa Annette Flanagin Paula Glitman Brenda Gregoline Tracy Frey

10.1001/jamapsychiatry.2013.2019

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Citations (0)

The Japanese employment system and the evolution of the firm