BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

Abstract

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.

Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

“…In contrast, Met carriers did not exhibit this intensity-specific effect. Given that Met carriers appear to respond more readily to atDCS than Val/Val homozygotes [( Antal et al, 2010 ; Teo et al, 2014 ; Strube et al, 2015 ) and the current data] whereas the opposite appears to be the case following rTMS or iTBS [i.e., a propensity for Val/Val homozygotes to exhibit greater cortical change than Met carriers ( Antal et al, 2010 ; Lee et al, 2013 )], our current finding and Hwang’s could be seen to be complementary. Speculatively, these findings together suggest that the genotype that predisposes a greater response to a particular NBS (rTMS for Val/Val homozygotes; tDCS for Met carriers) may also prompt a greater response to higher stimulation intensity (rTMS) or longer stimulation duration (tDCS).…”

“…In a more recent study, whereby the numbers and demographics of the BDNF Val66Met polymorphism groups were matched, Teo et al (2014) reported that Met carriers exhibited greater increases in CSE in the period 30–90 min following 9 min of 1 mA atDCS than Val/Val homozygotes. Similarly, Strube et al (2015) reported trend level increases in CSE ( p = 0.072; d = 0.799) following 13 min of 1 mA atDCS in Met carriers (8 out of a sample of 20) compared with Val/Val homozygotes. However, in older adults, the role of the BDNF Val66Met polymorphism is less well defined.…”

“…Consistent with Antal’s findings, Teo et al (2014) reported greater facilitation 30–90 min following atDCS in Met carriers relative to Val/Val homozygotes. More recently, Strube et al (2015) reported trend level increases in CSE for healthy Met carriers relative to the Val/Val group following atDCS.…”

Genetic Modulation of Transcranial Direct Current Stimulation Effects on Cognition

“…After 20 min but not after 10 min of anodal stimulation Met allele carriers experienced enhanced corticospinal excitability compared to individuals homozygous for the Val allele (Puri et al, 2015). Furthermore, Strube et al (2015) demonstrated increased facilitatory effects of anodal stimulation on cortical plasticity in patients suffering from schizophrenia as well as in healthy controls for heterozygous compared to Val allele homozygous individuals. In contrast, cathodal stimulation caused reduced cortical inhibition in heterozygous schizophrenia patients but enhanced inhibitory effect in healthy heterozygotes indicating an interaction of interindividual differences.…”

Interplay of Brain-Derived Neurotrophic Factor and Cytokines in Schizophrenia

“…BDNF increases neuronal dopamine content: modulates dopamine release relevant for neuronal plasticity in the ventral tegmental area (46) and also decreases dopamine in mesolimbic dopaminergic system (47). Reduction in BDNF expression was observed in the prefrontal cortex, striatum and hippocampus in animal models and patients with schizophrenia (48)(49)(50).…”