Transcranial direct current stimulation facilitates spatial working memory and synaptic plasticity: From healthy subjects patients with diabetic polyneuropathy to diabetic rats

Abstract

Transcranial direct current stimulation (tDCS) providing a noninvasive polarity-specific constant electric field to modulate brain function has been surging in the usage of neuroscience and clinical application though the mechanism of action remains unclear We studied the effect of tDCS on spatial working memory (SWM) in healthy subjects firstly to identify the role of dorsolateral prefrontal cortex (DLPFC) and the tDCS experiment protocol for SWM then we applied the tDCS experiment to examine whether it improves the SWM in diabetic patients with concomitant diabetic polyneuropathy (DPN) and mild cognitive impairment (MCI) and finally we investigated the cellular mechanism of tDCS to improve SWM in a streptozotocin (STZ)-induced diabetic rat model Among the experiment with healthy participants we used tDCS to investigate the specific role of the right DLPFC in resolving interference in SWM by a sham-controlled within-subject comparison study A forward- and backward-recall computerized Corsi Block Tapping task (CBT) both with and without a concurrent motor interference task was used to measure SWM capacity and reaction time The results showed that motor interference impeded accuracy and prolonged reaction time in forward and backward recall for SWM Anodal tDCS over right DLPFC yielded the tendency to shorten participants’ reaction time in the conditions with interference (forward with interference and backward with interference) Importantly anodal tDCS significantly improved participants’ SWM span when cognitive demand was the highest in the backward-recall with motor interference condition The result suggest that (1) the right DLPFC plays a crucial role in dealing with the cross-domain motor interference for spatial working memory and (2) the anodal tDCS over right DLPFC improves SWM capacity particularly when task difficulty demands more complex mental manipulations that could be due to the facilitatory effect of anodal tDCS which enhanced the DLPFC function within central executive system at the top-down attentional level Extending the DLPFC-tDCS experiment to the diabetic patients who suffered from both DPN and MCI in a pre-post sham-controlled study our results revealed although patients with severe DPN (Dyck’s grade 2a or 2b) showed comparable general intelligence scores on WAIS-IV as their age- and education-matched healthy counterparts they nonetheless showed MCI on Montreal Cognitive Assessment and working memory deficit on digit-span test of WAIS-IV Furthermore patients’ peripheral nerve conduction velocity (NCV) was positively correlated with their SWM span in the most difficult CBT condition that involved backward-recall with motor interference such that patients with worse NCV also had lower SWM span Most importantly anodal tDCS over the right DLPFC was able to improve low-performing patients’ SWM span to be on par with the high-performers thereby eliminating the correlation between NCV and SWM These findings suggest (1) MCI and severe peripheral neuropathy can coexist with unequal severity in diabetic patients (2) the positive correlation of SWM and NCV suggests a link between peripheral and central neuropathies and (3) anodal tDCS over the right DLPFC can improve DPN patients’ SWM particularly for the low-performing patients Use the in vivo repeated tDCS over the medial prefrontal cortex (mFPC) in streptozotocin-induced diabetic rats we explored whether anodal tDCS may alter expression profiles of molecules importantly involved in maintaining synaptic structure and function which in turn promote synaptic and structural plasticity and result in improved performance of SWM Our findings showed that (1) repeated applications of prefrontal anodal tDCS improve SWM performance and restore the long-term potentiation impaired in the mPFC of diabetic rats (2) the mPFC of tDCS-treated diabetic rats exhibit higher levels of brain-derived neurotrophic factor (BDNF) protein and N-Methyl-D-aspartate receptor (NMDAR) subunit mRNA and protein compared to sham stimulation group and (3) anodal tDCS significantly increases dendritic spine density on the apical dendrites of mPFC layer V pyramidal cells in diabetic rats whereas the complexity of basal and apical dendritic trees is unaltered The results suggest that repeated anodal tDCS may improve SWM performance in diabetic rats through augmentation of synaptic plasticity that requires BDNF secretion and transcription/translation of NMDARs in the mPFC The experiments of the thesis elucidate the modulating effect of tDCS on DLPFC to facilitate SWM in healthy subjects reproduce the beneficial effect of tDCS on the patients with both DPN and MCI and finally determine the mechanistic basis of tDCS by a disease animal model The thesis links the cognitive effect and cellular mechanism of tDCS from clinical application to basic neuroscience and answers the fundamental questions in this field how tDCS improves cognitive function In summary since diabetes mellitus has been identified as a risk factor of dementia our studies support the therapeutic potential of tDCS on cognition in diabetic patients and suggest the repeated tDCS can improve cognitive dysfunction through the changes of enhancing synaptic plasticity With these advanced understandings of the neurophysiological basis of tDCS we can optimize the clinical application of tDCS for the patients with cognitive dysfunction

Date of Award	2017 Apr 24
Original language	English
Supervisor	Kuei-Sen Hsu (Supervisor)