Neurogenetics DOI 10.1007/s10048-014-0393-1

REVIEW ARTICLE

Brain-derived neurotrophic factor: its impact upon neuroplasticity and neuroplasticity inducing transcranial brain stimulation protocols L. Chaieb & A. Antal & G. G. Ambrus & W. Paulus

Received: 7 January 2014 / Accepted: 7 February 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Val66Met (rs6265) is a gene variation, a single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene that codes for the protein BDNF. The substitution of Met for Val occurs at position 66 in the pro-region of the BDNF gene and is responsible for altered activity-dependent release and recruitment of BDNF in neurons. This is believed to manifest itself in an altered ability in neuroplasticity induction and an increased predisposition toward a number of neurological disorders. Many studies using neuroplasticity-inducing protocols have investigated the impact of the BDNF polymorphism on cortical modulation and plasticity; however, the results are partly contradictory and dependent on the paradigm used in a given study. The aim of this review is to summarize recent knowledge on the relationship of this BDNF SNP and neuroplasticity.

during adulthood [1–3]. Many studies have confirmed the role of BDNF in regulating synaptic consolidation in adults and neural plasticity (e.g., [4–8]). The BDNF gene, coding for the BDNF protein, is located on chromosome 11 at the boundary of 11p13 and 11p14 in the human [9] and has been investigated in a wide range of neuroplasticity-related areas, including differences in gross brain morphology, learning, and memory, interactions with plasticity-inducing brain stimulation protocols, and recovery after brain insult [10–13] and has been linked to a wide diversity of neurological disorders, including, e.g., depression, ADHD, and schizophrenia [14–17].

BDNF gene expression Keywords BDNF . Single nucleotide polymorphism . Synaptic plasticity . Neuroplasticity . Brain stimulation

Introduction Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family of signaling proteins which includes nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). It has been shown to have a number of important roles in the regulation of neuronal cell proliferation and survival, not only during development but also

All of the authors contributed equally. L. Chaieb : A. Antal (*) : G. G. Ambrus : W. Paulus Clinic for Clinical Neurophysiology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany e-mail: [email protected]

Studies examining the structural organization and regulation of the BDNF gene highlight its complexity. The rodent genome is comprised of nine exons each with its own promoter responsible for producing 24 different transcripts [18]. The human genome possesses 11 exons with nine different functional promoters generating 17 transcripts which all encode the same protein [19]. This indicates not only an organized regulation of gene expression but also ensures accurate control of BDNF production. In vivo studies show that BDNF promoters are differentially dispersed throughout different cell types and across brain regions, even being expressed in different parts of the neuron: rodent studies have shown that exon III promoters are detectable in the soma of neurons while exon IV transcripts are located in both the soma and dendrites of visual cortex neurons [20]. These transcripts are regulated by a number of factors, which also modulate neuronal activity such as physical exertion, seizure activity, oxygen deprivation, and drug administration as well as externally administered electrical activity.

Neurogenetics

BDNF synthesis, localization, and secretion in the CNS BDNF is initially synthesized as a precursor (proBDNF) and cleaved to generate mature (m)BDNF. proBDNF interacts preferentially with the pan-neurotrophin receptor p75 (p75NTR), whereas mBDNF selectively binds and activates the receptor tyrosine kinase TrkB [21]. Evidence supports the “yin-yang” hypothesis, in which pro and mBDNF elicit opposite biological effects by activating two distinct receptor systems. proBDNF promotes long-term depression (LTD) through the activation of p75NTR in the hippocampus, while mBDNF-TrkB signaling is essential for the early phase of long-term potentiation (LTP) [6, 22, 23]. BDNF-TrkB and BDNF-p75NTR signaling pathways follow those of other kinase-related signaling cascades: activation of each receptor causes autophosphorylation, which then causes activation of three main signaling pathways, the phospholipase Cy (PLCy), phosphatidylinositol 3-kinase (PI3K), and extracellular signal-related kinases (ERK). This then leads to the activation of CREB, a transcription factor which is responsible for the regulation of genes related to neuronal differentiation and survival [24]. As a result, intracellular levels of calcium (Ca2+) rise which cause the downstream activation of the calcium calmodulin dependent kinase (CaMKII) complex, which when phosphorylated, activates CREB and causes gene transcription. As a result, BDNF is able to activate its own gene expression due to levels of intracellular Ca2+ and CaMKII autophosphorylation and can be released in an activity dependent way [25, 26]. Although BDNF protein can be found in almost every area of the cortex, it is not ubiquitously expressed throughout cortical matter. BDNF messenger RNA (mRNA) expression is most abundant in pyramidal cells in the hippocampus and neocortex (for a review, see [27]). However, the striatum is almost completely devoid of BDNF mRNA. BDNF has also been shown to be somatodendritically localized in hippocampal and pyramidal neurons and to be trafficked to proximal dendrites or neurons after being exposed to short bursts of depolarizing currents [28]. Studies examining anterograde BDNF transport and somatodendritic BDNF localization used an antibody-specific approach to detect BDNF within cellular compartments and have shown that BDNF is mainly located in the nucleus or cytoplasm of cells, which in turn suggests axonal and dendritic targeting of endogenous BDNF in CNS neurons [29–31]. Pre and postsynaptic storage of endogenous BDNF in vesicles has also been found in dendrites and dendritic spines [32], and a postsynaptic localization of BDNF at glutamatergic synapses was observed in rodent cortical synapses using electron microscopy [29, 33]. BDNF secretion from neurons can occur as a result of electrical activity or more generally as an activity-dependent response. Wetmore and colleagues [34] demonstrated that BDNF was trafficked from cellular structures to the

extracellular neuropil of pyramidal cells in the hippocampus after kainite-induced depolarization [29, 34]. Since then, many studies have gone on to show that BDNF secretion can occur at the axon as well as at dendrites and is dependent upon action potential generation and not steady-state depolarization [35].

The relationship between BDNF and neuroplasticity BDNF has been shown to play an important role in the mechanisms of neuroplasticity induction giving rise to cellular events resulting in LTP and LTD (e.g., [36, 37]). These processes and their neural correlates underlie theories of learning and memory and so BDNF may be crucial to the formation of memories and learned behavior. The role of the BDNF gene within the human population may also have an important impact upon the processes of long-term memory induction as well as in the rehabilitation and treatment of neurological disorders (e.g., [38, 39]). Indeed, it was observed that exposure to BDNF leads to axonal branching, dendritic growth, and activity-dependent alterations of synapses (e.g., [40]). BDNF and synaptic modulation The impact of BDNF has mainly been characterized in the hippocampus in CA3-CA1 synapses (e.g., [41, 42]). The BDNF-TrkB receptor complex is localized along with the sites of synthesis and distribution of BDNF at glutamate synapses. This results in a largely synthesis-dependent consolidation of synaptic modulation at the glutamatergic synapse through the activation of NMDA receptors and also implies a role for BDNF in the strengthening of synaptic transmission and a role for BDNF in neuroplasticity-inducing processes [43]. BDNF regulates protein synthesis at the synapse and therefore transcriptional and posttranscriptional processes. Secretion and release can be upregulated by stimulation protocols that target the glutamatergic synapse, for example, theta burst stimulation (TBS) in slice preparation as well as in the intact cortex [44]. Pre and postsynaptic effects of BDNF LTP through BDNF secretion and activation can be both pre and postsynaptic. Two models of presynaptic BDNF neuroplasticity induction exist: BDNF is released after highfrequency stimulation (HFS) which induces a persistent presynaptic modification. This in turn results in enhanced neurotransmitter release. The second scenario suggests that BDNF has only transient presynaptic effects which are maintained by the longer-lasting secretion of more BDNF from the glutamatergic synapse—the focus here is on activity-dependent modulation of the glutamatergic synapse. Glutamate release

Neurogenetics

results in the maintenance phase of LTP being associated with an increase in potassium-evoked glutamate release from synaptosomes [45]. The presynaptic locus for BDNF can regulate synaptic fatigue [46, 47]. This is mostly confined to CA3-CA1 fibers [48]. Synaptic fatigue is believed to cause a reduction in EPSP amplitude, hence LTD induction [47]. At the postsynaptic site LTP induction is influenced by downstream changes in Arc expression. This results in alterations in dendritic protein synthesis [3]. Arc is implicated in LTP maintenance and memory consolidation. Arc downstream causes mRNA to be rapidly trafficked to dendritic processes following LTP induction (for a review, see [49]).

BDNF polymorphism and brain morphology Numerous findings from different groups Egan et al. [50], Pezawas et al. [51], Bueller et al. [52], and Montag et al. [53] have found bilateral reduction of hippocampal gray matter volumes in Met BDNF carriers compared with Val/Val subjects, although later investigations have failed to reproduce this finding [54, 55] (Table 1). The reports regarding the volume of the amygdalae are still conflicting, with Sublette et al. [56] describing no difference and Montag et al. [53]

reporting a comparative reduction in the right amygdala. Sublette et al. have also described Met carriers to have smaller parahippocampal areas and a smaller thalamus compared to Val/Val subjects. Additional loci of reduced gray matter volumes were found in the frontal areas, including the lateral convexity of the frontal lobes with peak values encompassing the dorsolateral prefrontal cortex bilaterally [50, 51].

BDNF polymorphisms, learning, and memory Hippocampus-dependent declarative memory, mainly episodic memory, has been widely reported to be affected by the Val66Met polymorphism. Episodic memory performance has been reported by multiple studies to be decreased in Met carriers when compared to Val/Val homozygotes (Table 2). Hariri and colleagues have found that in addition to a lower performance in tasks involving the encoding and subsequent retrieval of novel, complex scenes Met carries have also demonstrated a diminished hippocampal engagement when compared to Val/Val homozygotes [57]. A similar comparatively diminished performance by healthy Met carriers in episodic memory performance have been reported by Dempster et al. [58], and Egan et al. [50] who used the delayed score of the logical memory subtest from the Wechsler

Table 1 The anatomical and functional effects of the BDNF Val/Met SNP Parameter

Finding

Reported by

Total cerebral volume Hippocampal volume

No difference Reduced in Met carriers

Sublette et al. [56] Egan et al. [50] Pezawas et al. [51] Bueller et al. [52] Montag et al. [53] Karnik et al. [54] Richter-Schmidinger et al. [55]

No difference between Val/Val and Met carriers Parahippocampal volume Thalamus volume Amygdalar volume Frontal and prefrontal cortex morphology Frontal and prefrontal cortex activation Activity of the amygdala Hippocampal activation

Reduced in Met carriers Reduced in Met carriers No difference Smaller right amygdala in Met carriers Reduced gray matter in several areas in Met carriers Overreaction in the DLPFC, reduced activation in the vmPFC in Met carriers in a spatial two-back task Enhanced amygdala activity in Met carriers (in extinction learning) Over activation in Met carriers (during the n-back task) Diminished engagement in Met carriers (during an episodic learning task) Reduced activation in Met carriers (during a virtual navigation task)

Montag et al. [53] Montag et al. [53] Sublette et al. [56] Montag et al. [53] Egan et al. [50] Montag et al. [53] Cerasa et al. [70] Soliman et al. [80] Egan et al. [50] Hariri et al. [57] Banner et al. [68]

Reduced encoding-related brain activity in the bilateral hippocampi and Hashimoto et al. [96] right parahippocampal gyrus in Met carriers (during an episodic learning task) Activation of the caudate nucleus Increased activation in Met carriers (during a virtual navigation task) Banner et al. [68] Differential effects are highlighted in italic

Neurogenetics Table 2 The effects of the BDNF Val/Met SNP on memory functions Parameter

Finding

Reported by

Executive functions

No difference in WCST performance

Response inhibition Working memory

Higher false alarm rate in Val/Val subjects (Go/Nogo task) Lower performance in Met carriers (Inventar zur Gedächtnisdiagnostik, IGD, [52]) No significant difference A trend towards a worse performance in Met carriers No significant difference No significant difference (Rey-Osterrieth Complex Figure task) Val/Val subjects performed better than Met carriers (WAIS Object Assembly) Met carriers had a reduced rate of adaptation during learning and long-term retention No significant difference in performance, change in strategy observed No significant difference

Nagel et al. [65] Rybakowski et al. [64] Beste et al. [63] Richter-Schmidinger et al. [55]

Spatial working memory

Visual memory Visual-motor problem-solving Visuomotor adaptation Virtual navigation task Short-term associative vocabulary learning Verbal memory

Nagel et al. [65] Cerasa et al. [70] Richter-Schmidinger et al. [55] Banner et al. [68] Tsai et al. [72] Joundi et al. [71] Banner et al. [68] Freundlieb et al. [75]

Implicit motor learning

Healthy Val homozygous had higher verbal memory scores than Met carriers. (Rey Auditory Verbal Learning Test) No significant difference

Ho et al. [97]

Artificial grammar learning Episodic memory

No significant difference Lower performance in Met carriers

Extinction learning

Weaker extinction observed in Met carriers

Witte et al. [74] Freundlieb et al. [75] Witte et al. [74] Hariri et al. [57] Egan et al. [50] Dempster et al. [58] Goldberg et al. [59] Cathomas et al. [60] Soliman et al. [80]

Temporal discrimination

No difference between Val homozygotes and Met carriers

Wiener et al. [69]

Differential effects are highlighted in italic

Memory Scale (revised version). Using a verbal recognition memory task, Goldberg et al. [59] have also found that Met carriers performed relatively weaker. Cathomas et al. [60] used a task requiring the learning and free recall of words with varying emotional content and have found that Met carriers had a comparatively weaker performance in recalling words with positive valence, while for words with neutral and negative valence no such difference could be observed. A recent meta-analysis looked at 24 studies investigating hippocampus-dependent memory functions in both healthy and clinical populations and concluded that the Val66Met polymorphism, via the structure and physiology of the hippocampus, has a significant effect on memory performance and that Met carriers are adversely affected [61]. A follow-up commentary has called into question the methodology employed by the authors, citing the selection of the voxels for effect-size analysis in the MRI studies as the primary concern [62]. That the Val/Met polymorphism has a differential impact on the emotional content of the material to be

acquired seems to be corroborated by the fact that structural and functional differences have been observed between Val/ Val homozygotes and Met carriers regarding the volume and the activation of the amygdala [53]. For example, both behavioral and activity differences have been shown in extinction learning (extinguishing a conditioned fear response), where the Met carriers have shown weaker extinction than Val/Val subjects, while their amygdalar activities have been shown to be prolonged. Also, differences in executive functions have been reported in a Go/NoGo task [63] with Met carriers performing comparatively lower, although Rybakowski et al. [64] and Nagel et al. [65] found no such difference in the performance of healthy subjects with regard to another standard instrument for assessing executive functions, the Wisconsin Card Sorting Task (WCST). It is worth mentioning that the performancemodulating effect of the Val66Met genotype on executive functions has shown to be illness specific, as Met carrier patients with bipolar disorder have performed worse on the WCST than Val homozygotes afflicted by the same condition,

Neurogenetics

while no such difference has been observed in the case of patients with schizophrenia [64, 66, 67]. In opposite to these results, no differences have been observed regarding spatial and visual memory [55, 68], and temporal discrimination [69], although a trend toward a worse performance in Met carriers has been shown by Cerasa et. al. [70] in a spatial working memory test. It is worth noting that while no significant behavioral difference was observed, Banner et al. [68] also reported differential hippocampal engagement during a visual navigation task where the activity of the hippocampus was reduced and the activity of the caudate nucleus was increased in Met carriers compared to Val/Val subjects. Met carriers show a comparatively diminished performance in visuomotor adaptation [71] and visual-motor problem solving [72]. Implicit learning does not seem to be affected by the BDNF Val/Met SNP. Implicit motor learning, as measured by the serial reaction time task [73], has been investigated in two experiments independently; Witte et al. [74] and Freundlieb et al. [75] have found that there are no substantial differences in performance between Val/Val homozygotes and Met carriers. Investigation of artificial grammar learning, also another implicit learning paradigm, failed to yield differential results [74].

Impact of BDNF on use-dependent plasticity Kleim et al. [76] have demonstrated that Met carriers exhibit less changes in the use-dependent motor cortical map than Val/Val subjects following voluntary motor practice, as they show a less pronounced change in motor map size and shift in the center of gravity. In contrast, another study [77] has found no significant differences between Val/Val and Val/Met carriers in a task involving motor learning (index finger movements in 3D space). Furthermore, it was suggested that this lack of change may be overcome, as shown by McHughen et al. [78] by a prolonged training period over multiple days. Cirillo et al. [79] used a simple ballistic motor task and a complex visuomotor tracking task in combination with transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) to measure use-dependent plasticity in connection with the Val/Met polymorphism. They have found an increase in MEP size after the execution of the simple motor task, independence of genotype, a lack of use-dependent change in MEP size in Val/Met subjects and a decrease in Met/Met carriers in the complex visuomotor task. The authors speculate that since it has been demonstrated in an animal model that BDNF expression in the motor cortex is more likely to be modified by complex, rather than simple motor tasks, the difference in task load may be able to explain the their diverging results.

BDNF and transcranial stimulation: probing synaptic plasticity in the cortex In vivo and in vitro studies, BDNF and rTMS The influence of the BDNF Val/Met SNP on the effects of a number of plasticity-inducing methods has also been investigated (Table 3). Patterned and repetitive TMS (rTMS) paradigms have revealed differential plasticity enhancement for carriers of the Met substitution in animal and human studies. Two recent rodent studies have examined the impact of rTMS on synaptic plasticity with regard to the BDNF polymorphism. BDNF-TrkB signaling and BDNF-NMDAR interaction were upregulated in the prefrontal cortex of adult rats by a daily application of 5 Hz rTMS over 5 days. BDNF binds to the TrkB receptor complex, which has been shown to mediate synaptic plasticity and processes of learning and memory [80]. The study demonstrated that consecutive applications of rTMS increased BDNF levels in the plasma of rats and humans as well as increasing BDNF-TrkB signaling in lymphocytes. rTMS did not increase levels of other NTs and so the authors reported that rTMS preferentially upregulated the efficacy of the BDNF-TrkB signaling pathway by increasing the affinity of BDNF for the TrkB receptor. The authors also found a correlation between an increase in resting motor threshold (RMT) as measured using single-pulse TMS and BDNF-TrkB signaling, but not the BDNF-NMDAR interaction. The RMT is a measure of the excitability of a central core of neurons and is an indicator of membrane excitability [81]. It was indicated that rTMS exerts its effects on BDNF-TrkB signaling on both pre and postsynaptic components as potassium depolarization and NMDA/glycine stimulation lead to an increase of activated wild type BDNF-TrkB and not its truncated form [82, 83]. The authors concluded that applications of rTMS to the cortex improves BDNF-TrkB and BDNF-NMDAR signaling in the prefrontal cortex and lymphocytes, which on a cellular level causes an upregulation of synaptic excitability as the BDNF-TrkB complex potentiates glutamatergic neurotransmission [83, 84] and NMDAR- dependent LTP [48]. In a second study, Wang and colleagues [85] sought to investigate the impact of low (0.5 Hz) and high (5 Hz) frequency rTMS on the cognitive restoration of a rat model of vascular dementia. Thirty-six male rats underwent rTMS in discrete treatment groups; the low-frequency rTMS group received 0.5 Hz rTMS for 6 weeks while the high frequency treatment group, 5 Hz rTMS for 6 weeks. Two other treatments groups were normal healthy controls and a vascular dementia control group. The test phase was conducted using the Morris water maze prior to the cortex being examined for ultrastructural changes using a transmission electron microscope. The expressions of BDNF, synaptophysin mRNA, and other LTP-related proteins were investigated using real-time

Neurogenetics Table 3 The effects of the BDNF Val/Met SNP found in experiments using plasticity-modulating protocols Parameter

Finding

Reported by

Cortical motor map of the first dorsal interosseus (FDI) following voluntary motor practice Afterefects of anodal tDCS on MEPs

Less pronounced change in motor map size and shift in the center of gravity in Met carriers More pronounced increase in excitability in the case of Met carriers No significant difference, a trend toward a more pronounced decrease in excitability in Met carriers No significant difference Plasticity could only be induced in Val/Val subjects Aftereffects reduced or absent in Met carriers Val/Val patients had greater reduction in HAMD than Met carriers Aftereffects reduced or absent in Met carriers Met carriers show a decreased response, no significant difference

Kleim et al. [76]

Afterefects of cathodal tDCS on MEPs Afterefects of tRNS on MEPs Aftereffects of iTBS on MEPs rTMS effect on depression Aftereffects of cTBS on MEPs Aftereffects of PAS on MEPs tDCS+1 Hz rTMS; reversal of the inhibitory aftereffects of cathodal tDCS by the application of rTMS Effects of cathodal tDCS on MEPs Effect of pharyngeal electrical stimulation and 1–5 Hz rTMS on pharyngeal motor cortex plasticity Effect of 5 Hz rTMS and iTBS on MEPs cTBS combined with iTBS

Met carriers show a decreased homeostatic response No difference between Val and Met carriers Electrical stimulation, Val/Val subjects showed significant increase in MEPs, Met carriers did not; rTMS, no difference between Val and Met carriers No difference between Val and Met carriers No difference between Val and Met carriers

Antal et al. [87] Antal et al. [87] Antal et al. [87] Antal et al. [87] Cheeran et al. [86] Bocchio-Chiavetto et al. [98] Cheeran et al. [86] Cheeran et al. [86] Witte et al. [74] Cheeran et al. [86] Di Lazzaro et al. [94] Jayasekeran et al. [88]

Li Voti et al. [77] Mastroeni et al. [90]

Differential effects are highlighted in bold

PCR, conducted on hippocampal CA1 slice preparation, and using immunohistochemistry assays [85]. The results of the study indicate that there was an improvement in the cognitive abilities of the vascular dementia treatment group that underwent rTMS regardless of rTMS frequency. The authors found that posttreatment, the average latency of each rat in the water maze task was reduced and their spatial exploration ability enhanced and that NMDAR1 expression in the hippocampus was strengthened [85]. They speculated that rTMS aided cognitive restoration due to synaptic plasticity effects: BDNF increases NMDAR channel potentiation and enhances NMDAR-dependent LTP through the phosphorylation of postsynaptic elements and NMDAR subunits as well as modulating calcium ion influx into cells, activating intracellular calcium-dependent enzymes also linked to NMDARdependent LTP-induction. It was also noted that rTMS may affect presynaptic plasticity as synaptophysin expression in the presynaptic region improved the efficacy of synaptic connections in the vascular dementia rTMS treatment group, which showed attenuation in cognitive deficits associated with learning and memory in rats [85]. With regard to human investigations, Cheeran and colleagues [86] used a number of plasticity probing techniques to investigate the susceptibility of synapses to neuroplastic modifications in Met carriers. They applied intermittent theta burst stimulation (iTBS), continuous theta burst stimulation (cTBS), paired associative stimulation (PAS), and a

transcranial direct current stimulation (tDCS)/rTMS metaplasticity (1 Hz rTMS) protocol. The authors used this approach to investigate excitability alterations in the motor cortex and to examine processes of synaptic plasticity induction. They reported that Met carriers showed a reduced or absent response to iTBS and cTBS and a decreased response to PAS plasticity protocols (see following subsection) compared to Val/Val individuals. Similarly, in a retrospective study, Antal and colleagues [87] reported that after applying iTBS to 15 healthy BDNF-genotyped volunteers, increases in MEP amplitude could only be observed in Val/Val individuals. No overall increase in cortical excitability was recorded from Met carriers. These results suggest that Met carriers are less likely to undergo neuroplastic changes using these protocols. When tDCS was used as a priming protocol before 1 Hz rTMS, the Met carriers showed a reduced homeostatic response (see following subsection). The authors reported that this effect arose due to tDCS and rTMS acting on different neural circuits that are differentially responsive due to the BDNF polymorphism [86]. Another study confirmed this differential response with regard to BDNF polymorphisms to neurostimulation, however, not on the amplitude but on the latency of MEPs [88]. Thirty-eight healthy participants received either pharyngeal electrical stimulation or 1 and 5 Hz rTMS. One Hz rTMS had no effect upon MEP amplitudes, but Met individuals showed shorter latencies in response to 5 Hz stimulation [88].

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Nevertheless, the effects of iTBS, as reported by Li Voti [77] or quadripulse stimulation [89], were not shown to be modulated by the BDNF Val66Met polymorphism. Similarly, a recent study has found no significant difference regarding stimulation-induced homeostatic metaplasticity between Val66Val participants and Met carriers in a three-session, repeated measures (cTBS followed by cTBS, cTBS followed by iTBS, and iTBS followed by iTBS) study [90]. The authors refer to methodological differences among studies, e.g., in the Li Voti study, poststimulation MEPs were more frequently collected; Mastroeni et al. used only male participants, the TMS waveforms (monophasic vs. biphasic) and intensities and the timing of the MEP measurements have varied across the studies. The origin of the contradictory findings is yet to be clarified. BDNF and PAS PAS is a frequently employed method for investigating motor cortex plasticity (e.g., [91]). Using PAS in a twin study, Missitzi et al. [92] have shown that externally induced motor cortex plasticity is partially (68 %) genetically determined. Similarly, to some of the TBS results, the effects of PAS have also been found to be reduced in Met carriers [86], and this result has been subsequently confirmed by Missitzi et al. [92] and Cirillo et al. [79], although it is worth to note that Witte et al. [74] have found no such differences in PASinduced aftereffects. It was proposed that while a longer exposure to stimulation may be able to induce sufficient secretion of the BDNF protein in Met carriers, a stimulation protocol of 30 min may be too long to elicit the BDNF Val/ Met SNP-related differences found to be induced using other approaches, such as in the quadripulse paradigm [89]. BDNF and tDCS: mechanisms of neuroplastic induction via membrane modulation Fritsch et al. [93] measured BDNF levels before and after anodal direct current stimulation (DCS) in rat brain slices. They found that combined DCS and low-frequency stimulation enhanced BDNF secretion and TrkB activation. They suggest that tDCS in humans and animals may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1. A recent study investigated the effect of DCS on the induction of LTP of synaptic activity at CA3-CA1 synapses in the hippocampus [42]. The authors have shown that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Expression of immediate early genes, such as c-fos and zif268 were rapidly induced following neuronal activation. Furthermore, in this study, an important role of zif268 in the induction and maintenance of LTP has been demonstrated. BDNF expression was

found to be reduced in slices that were cathodally stimulated. These studies suggest that (1) BDNF plays a role in tDCS effects and (2) by modulating BDNF secretion, the BDNF gene (and related SNP) influences tDCS effects. In the human motor cortex aftereffects of 7–10 min anodal and cathodal tDCS on MEPs tended to be more pronounced in the case of Met carriers; however, this effect was not significant. No difference at all was observable in the case of tRNS [87]. Using a longer stimulation duration (20 min), a recent study found that the BDNF genotype had no influence on tDCS aftereffects [94]. These results again raise the likelihood that a longer stimulation duration might overrule the effect of genotype. In another study, both Val homozygotes and Met carriers have shown decreased corticospinal excitability after cathodal tDCS, a change that was not significantly different between Val66Val subjects and Met carriers. However, the homeostatic reversal of the inhibitory aftereffects of the combined application of cathodal tDCS and 1 Hz rTMS did not manifest in Met carriers while in Val homozygotes an increase of MEP amplitudes was observed [86].

Summary and conclusions Most of the above mentioned studies suggest that there is firm evidence of an association between neuroplastic changes in the brain and BDNF polymorphisms. As a general conclusion, it appears that BDNF susceptibility in transcranial stimulation decreases with longer stimulation duration. Concerning clinical populations, the present results have limited generalizability [95]. Furthermore, it is very likely that additional genes and polymorphisms can influence the effect of transcranial stimulation methods. Recently, the interaction between BDNF Val/ Met and COMT Val/Met genotypes on PAS-induced plasticity was described [74]. In BDNF/Val homozygotes PAS-induced plasticity was higher if participants were also COMT/Met homozygotes, compared with BDNF/Met carriers. Therefore, it cannot be ruled out that similar interactions with SNPs might arise when applying different types of transcranial stimulation techniques.

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