Multifactorial Modeling of Impairment of Evoked Gamma Range Oscillations in Schizophrenia

Abstract

Despite a significant increase in efforts to identify biomarkers and endophenotypic measures of psychiatric illnesses, only a very limited amount of computational models of these markers and measures has been implemented so far. Moreover, existing computational models dealing with biomarkers typically only examine one possible mechanism in isolation, disregarding the possibility that other combinations of model parameters might produce the same network behavior (what has been termed “multifactoriality”). In this study we describe a step toward a computational instantiation of an endophenotypic finding for schizophrenia, namely the impairment of evoked auditory gamma and beta oscillations in schizophrenia. We explore the multifactorial nature of this impairment using an established model of primary auditory cortex, by performing an extensive search of the parameter space. We find that single network parameters contain only little information about whether the network will show impaired gamma entrainment and that different regions in the parameter space yield similar network level oscillation abnormalities. These regions in the parameter space, however, show strong differences in the underlying network dynamics. To sum up, we present a first step toward an in silico instantiation of an important biomarker of schizophrenia, which has great potential for the identification and study of disease mechanisms and for understanding of existing treatments and development of novel ones.

The Effect of Alterations of Schizophrenia-Associated Genes on Gamma Band Oscillations

“…Changes to the GABAergic system have been proposed to explain the reduction in evoked gamma power [32] and modelling work has demonstrated that both, a reduction in GABA levels in schizophrenia patients [89,70] and an increase in decay times at GABAergic synapses [104,70], can lead to reduced ASSR gamma power. On the one hand, a decrease in inhibition due to reduced GABA levels decreases the precise inhibitory control over pyramidal cell firing necessary for a strong gamma rhythm.…”

“…Furthermore, optogenetically driving PV + interneurons was found to enhance gamma rhythms [11]. Consequently, cellular level alterations at PV + interneurons in schizophrenia have been linked to well-known auditory steady-state response (ASSR) deficits in the gamma band [104,70,71,47,86]. However, these studies have focused on changes to the strength and temporal dynamics of synaptic transmission.…”

Modules for Automated Validation and Comparison of Models of Neurophysiological and Neurocognitive Biomarkers of Psychiatric Disorders: ASSRUnit—A Case Study

“…The first model is based on a biophysically detailed model of primary auditory cortex by Beeman [3]. It has recently been used to study ASSR deficits by our group [30]. The model was implemented using the neural simulator GEN-ESIS [4,5].…”

“…We do not discuss the models in more detail here, since they have been described elsewhere [3,30,58,29]. Furthermore, our focus lies on the framework with which to use, validate and compare models not on the models themselves.…”

“…In this paper, we propose to adopt this framework for the computational psychiatry community and to collaboratively build common repositories of computational models, tests, test suites and tools. As a case in point, we have implemented a Python module (ASSRUnit) for auditory steady-state response (ASSR) deficits in schizophrenic patients, which are based on observations from several experimental studies ( [23,58,24])and we demonstrate how existing computational models ( [30,3,58,29]) can be validated against these observations and compared with each other.…”