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Increasing evidence suggests that neural plasticity impairments, observed in schizophrenia patients, are driven by dysfunctional integration of neural signaling. However, what is less clear is whether this impairment is resultant from a general deficit in plastic induction or whether a specific plastic mechanism is affected. In the current study we aimed to assess whether schizophrenia has a selective impact on focal or non-focal plasticity induction. To pursue this goal we utilized two non-invasive stimulation techniques that differ in the mechanism of long-term potentiation (LTP)-like plasticity induction: focal paired associative stimulation (PAS) and non-focal anodal transcranial direct current stimulation (a-tDCS). 20 schizophrenia patients and 20 matched healthy controls received PAS and a-tDCS in two separate sessions. Cortical excitability and cortical plasticity were assessed by transcranial magnetic stimulation (TMS)-elicited motor evoked potentials (MEP). In both study groups, non-focal a-tDCS resulted in a significant increase of mean MEP magnitude indicating the successful induction of non-focal LTP-like plasticity. In contrast, an increase in mean MEP magnitude following PAS was only observed in the control group, suggesting impaired focal LTP-like plasticity in schizophrenia. Additionally, we observed significantly impaired short-latency intracortical inhibition (SICI) in schizophrenia. This is the first study to comparatively evaluate non-focal and focal plasticity mechanisms in schizophrenia patients. The differential patterns of LTP-like plasticity responses indicate that reduced plasticity in schizophrenia could be ascribed to impairments in spatially and temporally restricted signal integration. This impairment, coupled with an observed reduction of inhibitory circuit efficacy, might further contribute to impairments in coordinating focal signals.

Impaired neuroplastic responses following noninvasive brain stimulation have been reported repeatedly in schizophrenia patients. These findings have been associated with deficits in GABAergic, glutamatergic, and cholinergic neurotransmission. Although various neurophysiological studies have indicated a relationship between nicotine and neuroplasticity in healthy individuals, the present study is the first investigation into the impact of nicotine on LTD-like plasticity in patients with schizophrenia. Cortical excitability and cortical plasticity were explored in 30 schizophrenia patients (17 smoker, 13 nonsmoker) and 45 healthy controls (13 smoker, 32 nonsmoker) by using single-pulse transcranial magnetic stimulation (TMS) before and following cathodal transcranial direct current stimulation (tDCS) applied to the left primary motor cortex. Our analysis revealed abolished LTD-like plasticity in nonsmoking schizophrenia patients. However, these plasticity deficits were not present in smoking schizophrenia patients. In healthy controls, significant MEP reductions following cathodal tDCS were observed in nonsmoking individuals, but only trend-level reductions in smokers. In smoking schizophrenia patients, the severity of negative symptoms correlated positively with reduced neuroplasticity, whereas nonsmoking patients displayed the opposite effect. Taken together, the data of our study support the notion of an association between chronic smoking and the restitution of impaired LTD-like plasticity in schizophrenia patients. Although replication and further research are needed to better understand this relationship, our findings indicate that nicotine intake might stabilize the impaired inhibition-facilitation balance in the schizophrenic brain through a complex interaction between cortical plasticity, and GABAergic and cholinergic neurotransmission, and might explain the reduced prevalence of negative symptoms in this population.

Background Transcranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions. Objective To provide a systematic review of TMS studies (1985–2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). Methods Systematic literature-based review. Results Across disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction. Conclusions The results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. METHODS: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. RESULTS: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. CONCLUSIONS: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory intracortical interneuron-networks, cortical plasticity, and the BDNF-Val66Met-polymorphism. Further replication and validation need to be dedicated to this question to confirm this relationship. Open-Access-Publikationsfonds 2015 peerReviewed

Transcranial magnetic stimulation is an established method to probe inhibitory and facilitatory networks within the human motor cortex. Reduced motor-cortical inhibition is a common finding in schizophrenia patients. Based on neuropathological findings, the reduced cortical inhibition in schizophrenia has been linked mainly to alterations in GABAergic neurotransmission. The aim of this study was to investigate the impact of disease state on intracortical inhibitory and facilitatory networks measured by TMS in schizophrenia. Cortical excitability was investigated in a pooled cross-sectional sample of recent-onset-schizophrenia (RO-SZ), chronically-ill schizophrenia patients (CH-SZ) and healthy controls (HC) using single- and paired-pulse TMS applied to the left primary motor cortex. The sample included 41 RO-SZ, 42 CH-SZ and 59 HC. Analyses were focused on resting motor threshold (RMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP). There was a significant difference regarding the mean CSP durations across our three study groups (p=0.002). Subgroup comparisons revealed a shorter CSP in HC compared to RO-SZ (p

Introduction Neuronal plasticity is a characteristic feature of the human central nervous system. Impaired cortical plasticity has been reported to be associated with a val/met gene-polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Based on former studies, impaired cortical plasticity has been described as a common, yet not fully understood phenomenon in patients with schizophrenia. Objectives The aim of the study was to investigate the impact of the val/met-BDNF gene-polymorphism on cortical plasticity in patients with schizophrenia. Materials & Methods Cortical plasticity was investigated in a cross-sectional sample of schizophrenia patients (SZ) and healthy controls (HC) using anodal and cathodal transcranial direct current stimulation (tDCS) applied to the primary motor cortex inducing long-term potentiation (LTP) and depression (LTD). The after-effect of the applied tDCS was then probed by TMS before and after tDCS stimulation. TMS in all participants was conducted using a standard 70 mm-TMS figure-of-eight magnetic coil connected to a MagPro X 100 magnetic stimulator. Analyses were focused on resting-motor threshold (RMT), 1mV motor-evoked potential (MEP), short-interval intracortical inhibition (SICI at 3 ms), intracortical facilitation (ICF at 12 ms) and cortical silent period (CSP at 120% RMT). Results The statistical analyses included n=43 SZ and n=44 HC participants (all numbers presented under reserve of further examination) thus resulting in the largest available sample to probe cortical plasticity parameters in BDNF-genotyped schizophrenia patients. Further results will be presented at the conference. Conclusion The findings will give new insights into the influence of plasticity-associated gene polymorphisms and the pathophysiology of schizophrenia.

Introduction Since many years, transcranial magnetic stimulation (TMS) has been used to probe cortical physiology in awake humans. In particular, single-and paired-pulse TMS-protocols applied to the human motor cortex allowed the exploration of various intracortical inhibitory and facilitatory networks. In psychiatry, TMS offers the possibility to access motor-cortical excitability and to link the findings to possible neurotransmitter alterations with regard to the investigated disorder. However, little is known about general patterns of cortical excitability across psychiatric disorders. Objectives We aimed to review the evidence for impaired cortical excitability in psychiatric disorders using TMS. Methods A systematically literature research for this review was conducted via the internet database PubMed (1985–2012) using predefined search-algorithms. This search offered 684 publications in total. After screening of the abstracts and careful review of the content by two independent researchers with regard to the objectives of this review, a number of 82 publications was considered to be suitable. Results Most studies (n = 20) investigated the effects of TMS in patients with schizophrenia. Remarkably, all major psychiatric disorders were investigated by TMS: dementia (n = 19), attention deficit hyperactivity disorder (n = 13), Tourette syndrome (n = 6), cocaine dependence (n = 5), depression (n = 4), alcohol dependence (n = 3), cannabis-dependence (n = 3), nicotine dependence (n = 2), obsessive compulsive disorder (n = 2), borderline personality disorder (n = 1), bipolar disorder (n = 1), posttraumatic stress disorder (n = 1), altered personality traits (n = 1) and subjects at risk to develop psychosis (n = 1). In general, psychiatric illness can be linked to reduced cortical inhibition and in parts to enhanced cortical facilitation, resulting in a motor-cortex hyperexcitability. Detailed descriptions and exceptions will be presented and discussed at the conference. Conclusion Our results show that motor-cortex TMS is currently not suitable as a general diagnostic tool for psychiatric disorders. The disease state, different phenotypes of the same diseases and the influence of neuroactive medication can be discussed as major confounding factors. While it seems to be possible to hypothetically transmit results from motor-cortex TMS to other cortical and subcortical structures, further investigations are needed to understand the meaning of alterations in motor-cortex excitability in psychiatric disorders.

Introduction Transcranial magnetic stimulation (TMS) has been established as a method to probe inhibitory and facilitatory networks in the motor cortex. Reduced motor-cortical inhibition is a common, finding in patients with schizophrenia. Based on neuropathological findings, the reduced cortical inhibition in schizophrenia has been linked to alterations in GABAergic networks. Objectives The aim of the present study was to investigate the impact of disease state and antipsychotic medications on cortical inhibition. Materials & Methods Cortical inhibition was investigated in a pooled cross-sectional sample of first-episode (FE-SZ) and chronically ill (CH-SZ) schizophrenia patients and healthy controls (HC) using TMS to the left primary motor cortex. Analyses were focused on resting-motor threshold (RMT), short-interval intracortical inhibition (SICI at 3 ms), intracortical facilitation (ICF at 12 and 15 ms) and cortical silent period (CSP at 120% RMT). Results There was a significant difference concerning the mean CSP durations between HC and FE-SZ (MW-U: p=0.001). An overall comparison between HC and all patients further showed significant differences in SICI, presenting in a shorter mean SICI of HC than of SZ patients (MW-U: p=0.031). Conclusion This is the largest homogenous sample presenting various parameters of cortical excitability in schizophrenia patients. Thus, the findings allow to reduce the variance of different smaller samples and confirm the complex pattern of impaired cortical inhibition and excitability in patients with schizophrenia. The findings further indicate an impact of an early disease state on GABAB network performance.

Introduction Transcranial magnetic stimulation (TMS) has been established as a method to probe inhibitory and facilitatory networks in the motor cortex. Reduced motor-cortical inhibition is a common, yet not fully understood finding in patients with schizophrenia. Based on neuropathological findings, the reduced cortical inhibition in schizophrenia has been linked to alterations in GABAergic networks. Antipsychotic treatment and the course of the disease have been discussed to influence inhibitory cortical networks. Objectives The aim of the present study was to investigate the impact of disease state and antipsychotic medications on cortical inhibition. Materials and methods Cortical inhibition was investigated in a pooled cross-sectional sample of first-episode-schizophrenia patients (FE-SZ), chronically ill schizophrenia patients (CH-SZ) and healthy controls (HC) using single-and paired-pulse TMS to the left primary motor cortex. TMS in all participants was conducted using a standard 70 mm-TMS figure-of-eight magnetic coil connected to a MagPro X 100 magnetic stimulator. Analyses were focused on resting-motor threshold (RMT), short-interval intracortical inhibition (SICI at 3 ms), intracortical facilitation (ICF at 12 and 15 ms) and cortical silent period (CSP at 120% RMT). Results Our pooled analyses included n = 36 FE-SZ, n = 67 CH-SZ and n = 61 HC participants (all numbers presented under reserve of further examination). Cortical inhibition was in general reduced in all schizophrenia patients compared to healthy control. Further results (FE-SZ vs. CH-SZ vs. HC; medication effects) will be presented at the conference. Conclusion This is the largest homogenous sample presenting various parameters of cortical excitability in schizophrenia patients. The findings allow to reduce the variance of different smaller samples and give new insights into the influence of antipsychotics and disease state on cortical excitability.