Modelling impairment of evoked gamma range oscillations in schizophrenia

© 2015 Metzner et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Abnormal oscillatory activity in schizophrenia has been found in a wide range of experimental paradigms [1]. For example, schizophrenic patients show reduced evoked gamma activity, which has been associated with negative symptoms, and increased spontaneous gamma activity, which has been associated with positive symptoms [2]. However, the underlying mechanisms remain elusive. Here we investigated the impact of circuit abnormalities on oscillatory activity in the gamma range (> 30 Hz) by simulating auditory entrainment in an established computational model of the primary auditory cortex [3]. Auditory click entrainment experiments showed that for schizophrenic patients EEG/MEG power decreased at 40 Hz and increased at 20 Hz in response to 40 Hz drive but no differences between were visible in response to 30 Hz drive [4, 5]. Here we used the primary auditory cortex model from Beeman [3] and simulated click train stimulation at 40 Hz, to investigate gamma entrainment deficits, and at 30 Hz as a control condition. Without alterations the model entrained at the driving frequency of 30 and 40 Hz, respectively. Similar to previous approaches [6], however, focusing on evoked rather than spontaneous activity, we next explored the effects of (1) connectivity disturbances (reduced (a) recurrent excitation, (b) pyramidal cell input and (c) total connectivity), (2) prolonged GABAergic decay time constant, and (3) reduced inhibitory output. All three interventions in connectivity (1a-c) led to an increase in 40 Hz power for 40 Hz drive, contrary to human EEG/MEG experiments. A prolonged GABAergic decay time constant produced a reduction of power at 40 Hz and an increase in power at 20 Hz, for the 40 Hz drive, which concurs with [4, 5]. Furthermore, for the 30 Hz drive, no differences to the standard model were observed. Reduction of inhibitory output led to decreases in power at 40 Hz for 40 Hz drive but no increases at 20 Hz. In the 30 Hz drive condition, a decrease was visible, in contrast to experimental data [4, 5]. In conclusion, only prolonged GABAergic decay time constants (2), but not interventions (1) and (3) led to changes in entrainment comparable to experimental evidence in agreement with previous modeling approaches [5]. Our simulations suggest that prolonged time constants at GABAergic synapses might play a key role in abnormal evoked gamma rhythms in schizophrenia. However, since we only investigated one intervention at a time, further studies are needed to investigate the complex interactions of these circuit abnormalities. Furthermore, it remains unclear if the same mechanism also underlies increased spontaneous gamma activity in schizophrenia.Peer reviewe

Center-surround interactions in a network model of layer 4Cα of primary visual cortex

© 2013 Metzner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedContext integration is an ubiquitious principle in cortical processing underlying many perceptual and cognitive functions. Several neuropsychiatric disorders have been associated with an impairment of integration of context information, particularly schizophrenia. One way to investigate the mechanisms underlying context processing and its impairments, is to look at context integration in the well-understood visual system. Center-surround interactions (CSI), i.e. the mutual influencing of stimuli presented in the center and in the surround of the visual or receptive field, respectively, are well established, both in animal neurophysiology and human psychophysical and neuroimaging studiesPeer reviewe

Spike-timing dependent plasticity facilitates excitatory/inhibitory disbalances in early phases of tinnitus manifestation

© 2012 Metzner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedThe majority of tinnitus cases are related to cochlear dysfunction, leading to altered peripheral input to the central auditory system. These alterations are believed to diminish the difference in activation during on- and off-conditions of sound. As a compensatory means the affected region of primary auditory cortex tries to maximize the difference between basic level activity and sound-induced activity by changing the excitatory /inhibitory balance. In a previous model comprising ~3000 multi-compartment Hodgkin-Huxley-type neurons, we have shown that solely an increase of excitatory influences may be sufficient to achieve these maximization. This previous Hodgkin-Huxley-type model did not take into account synaptic plasticity, howeverPeer reviewedFinal Published versio

Computational multifactoriality in a detailed neural network model resembling centre-surround suppression deficits in schizophrenia

© 2014 Metzner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedPeer reviewe

Context integration in visual processing: a computational model of center-surround suppression in the visual system

[Poster presentation]. A dysfunction of GABAergic neurotransmission is hypothesized to be an important factor in the pathophysiology of schizophrenia [1], depression and anxiety disorders. Findings of decreased center-surround suppression (CSS, i.e. the mutual inhibition of a focal visual stimulus and its surrounding) have been interpreted in terms of GABAergic dysfunction [2]. Consistently, strongly decreased CSS is reported in schizophrenic patients [3]. However, the underlying mechanisms of this decrease remain unclearPeer reviewe

Early signs of tinnitus in a simulation of the mammalian primary auditory cortex

© 2011 Metzner et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited[Poster presentation] The majority of tinnitus cases are related to cochlear dysfunction, leading to altered peripheral input to the central auditory system. These alterations are believed to increase the basic level of neural activity during off-conditions of sound and to diminish the increase in neural activity when sound is presented. As a compensatory means the affected region of primary auditory cortex tries to maximize the difference between basic level activity and sound-induced activity by adapting inhibitory and excitatory influences towards less GABAergic inhibition. This adaptation in turn triggers unmasking of dormant synapses and creation of new connections through axonal sprouting and finally results in a reorganization of tonotopic receptive fields and the manifestation of tinnitusPeer reviewe

Multifactorial modeling of impairment of evoked gamma range oscillations in schizophrenia

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.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.Peer reviewedFinal Published versio

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)