High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats

Your doctor will need to determine what can be changed in your recovery protocols even though this was just tested in rats. You do want the kitchen sink thrown at your recovery, don't you? So ask your fucking doctor what interventions that are not yet clinically proven in humans s/he is testing on you.
http://www.mdpi.com/1422-0067/18/2/455/htm
Rats

Jing Luo ^1,†, Haiqing Zheng ^1,†, Liying Zhang ^1,†, Qingjie Zhang ¹, Lili Li ¹, Zhong Pei ² and Xiquan Hu ^1,*

¹

Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China

²

Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China

*

Correspondence; Tel.: +86-20-8217-9022; Fax: +86-20-8525-2753

^†

These authors contributed equally to this work.

Academic Editor: Irmgard Tegeder

Received: 16 November 2016 / Accepted: 10 February 2017 / Published: 20 February 2017

Abstract:

Repetitive transcranial magnetic stimulation (rTMS) has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS) on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO), following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX), NeuN and glial fibrillary acidic protein (GFAP), and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.

Keywords:

rTMS; neurological function; neural stem cells; BDNF; TrkB; MCAO

1. Introduction

Stroke is a major cause of neurological disability that leads to serious clinical consequences. It has been estimated that 90% of stroke survivors suffer permanent neurological deficits [1]. At present, rehabilitation therapy is the best approach for treating neurological deficits after stroke [2]. However, it is not ideal because most stroke survivors remain neurologically impaired after rehabilitation. Thus, there is an urgent need for the development of novel approaches to stroke rehabilitation. One promising strategy for stroke rehabilitation is to enhance endogenous pathways that support restoration after brain damage [3]. Neural stem cell (NSC) plays a key role in endogenous restoration following stroke [4]. NSC persists in the rostral subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) throughout life in mammals [5]. More importantly, NSC can proliferate and migrate into damaged brain regions following ischemic stroke [3,4,6]. Therefore, the promotion of endogenous neurogenesis is an attractive strategy for stroke rehabilitation.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulatory technique which affects brain physiology through magnetic pulses. Different rTMS techniques have been applied to stroke rehabilitation [7], and, interestingly, they can produce different modulatory effects. For example, high-frequency rTMS (>5 Hz) stimulates cortical excitability and generates long-term potentiation (LTP)-like effects. In contrast, low-frequency rTMS (<1 Hz) reduces cortical excitability and produces long-term depression (LTD) [8]. Intermittent theta burst stimulation (iTBS) is a novel form of high-frequency rTMS [9]. Conventional high-frequency rTMS procedures last between 20 and 45 min, as compared to TBS paradigms that require 1 to 3 min of stimulation [10]. Recently, some studies have suggested that iTBS applied to the ipsilateral side of human or animals has similar or better efficacy in treating stroke compared to conventional rTMS [11,12]. Whether iTBS is better than conventional high-frequency rTMS on improvement of functional recovery in ischemic rats is still unknown. Moreover, it is reported that high-frequency rTMS enhances neurogenesis in ischemic rats [13]. However, the underlying mechanism remains elusive.

One possible mechanism might be an increase in the expression of brain-derived neurotrophic factor (BDNF) after high-frequency rTMS [14]. BDNF is a member of the neurotrophin family, which has recently been shown to play a role both in protection and in recovery of function after stroke [15]. BDNF promotes NSC migration and proliferation via its receptor, tropomyosin-related kinase B (TrkB) [16,17]. Therefore, this study aimed to investigate whether the beneficial effect of rTMS on functional recovery is mediated via enhanced neurogenesis and activation of the BDNF-TrkB signaling pathway and to compare the effect of conventional 20 Hz rTMS and iTBS on neurogenesis in ischemic rats