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系統識別號 U0026-1704201715144200
論文名稱(中文) 經顱直流電刺激促進空間工作記憶與神經突觸可塑性: 從健康受試者、糖尿病多發性神經病變患者到糖尿病大鼠模式
論文名稱(英文) Transcranial direct current stimulation facilitates spatial working memory and synaptic plasticity: From healthy subjects, patients with diabetic polyneuropathy to diabetic rats
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 105
學期 2
出版年 106
研究生(中文) 吳怡真
研究生(英文) Yi-Jen Wu
學號 S98011067
學位類別 博士
語文別 英文
論文頁數 94頁
口試委員 指導教授-林宙晴
指導教授-許桂森
召集委員-阮啟弘
口試委員-黃英儒
口試委員-曾祥非
口試委員-蔡坤哲
中文關鍵字 經顱直流電刺激  空間工作記憶  背外側前額葉皮質  糖尿病  認知功能障礙  神經突觸可塑性 
英文關鍵字 Brain-derived neurotrophic factor  Diabetes Mellitus  Diabetic polyneuropathy  Dorsolateral prefrontal cortex  N-methyl-D-aspartate receptor  Spatial working memory  Streptozotocin-induced diabetic rat  Synaptic plasticity  Transcranial direct current stimulation 
學科別分類
中文摘要 經顱直流電刺激(tDCS)藉由提供一個具極性的直流電場來調節腦功能,近年來逐漸廣泛使用在神經科學研究與臨床運用,但其作用的機轉仍未清楚。我們首先運用tDCS於正常受試者來探討右背外側前額葉皮質在空間工作記憶上的功能與利用tDCS促進空間工作記憶所需要的實驗條件;再來延伸tDCS實驗探討其是否能提升糖尿病同時合併周邊神經病變及輕度認知功能障礙病患的空間工作記憶,最後利用糖尿病大鼠模式來探討tDCS用以改善認知功能的神經生理機制。
運用tDCS於正常受試者在一個刺激/偽刺激對照個體內比較(sham-controlled within-subject comparison study)的實驗方式來探討右背外側前額葉皮質於空間工作記憶中調節干擾作用的功能。利用順向及逆向回憶的Corsi Block Tapping task (CBT)作業加上手部干擾動作來評估空間工作記憶廣度及反應時間。實驗結果發現動作干擾降低了空間工作記憶的正確性以及延長作業反應時間,施予右背外側前額葉皮質陽極tDCS可以縮短空間工作記憶在有干擾情境下的反應時間,並顯著的提升受試者在有干擾情境下逆向回憶空間工作記憶的正確性。此研究結果顯示(1) 右背外側前額葉皮質在空間工作記憶中對於調節跨域動作干擾作用(cross-domain motor interference)具重要角色 (2) 施予右背外側前額葉皮質的tDCS特別能提升空間工作記憶尤其是在其需要高等複雜的心智運作能力介入時,例如在干擾的情況下逆向回憶空間工作記憶,這可能與tDCS促進背外側前額葉皮質在中央執行系統上(central executive system)調控高等注意力控制的功能 (top-down attentional control)有關。
延伸tDCS實驗至糖尿病同時患有周邊神經病變及輕度認知功能障礙的病患,首先我們發現糖尿病患者即使患有嚴重的糖尿病周邊神經病變(Dyck’s grade 2a or 2b)他們的一般智力在衛氏智力全量表上(WAIS-IV)的表現仍與年紀與教育程度匹配的健康受試者相當,然而他們卻在蒙特利爾認知評估量表(Montreal Cognitive Assessment)呈現輕度認知功能障礙及在記憶廣度量表(digit-span test on WAIS-IV)呈現工作記憶缺陷。這些病人的周邊神經病變程度(周邊神經速度傳導)也與其空間工作記憶廣度(干擾下逆向回憶CBT作業)成正向關係,亦即周邊神經病變愈嚴重者其空間工作記憶越差。利用前後比對刺激/偽刺激控制(pre-post sham-controlled study)的實驗設計,我們發現施予右背外側前額葉皮質陽極tDCS可以提升病患的此項空間工作記憶,改變這項認知功能缺陷與周邊神經病變的正相關性。此實驗結果顯示 (1)輕度認知障礙與重度的周邊神經病變可共同存在糖尿病患者身上兩者表現不同的臨床嚴重度 (2)空間工作記憶廣度與周邊神經速度傳導的正相關性提供了一個糖尿病中樞與周邊神經病變的功能性連結 (3)施予右背外側前額葉皮質陽極tDCS可以提升糖尿病周邊神經病變患者的空間工作記憶,特別是對於原本空間工作記憶較差的病人。
最後利用streptozotocin誘發糖尿病大鼠活體模式來探討在內側前額葉(medial prefrontal cortex)重複施予tDCS是否會藉由改變調控神經可塑性相關的分子表現來改善前額葉神經突觸可塑性(synaptic plasticity)進而促進其空間工作記憶。實驗結果發現(1)糖尿病大鼠具有前額葉長期增益效果(long-term potentiation)及空間工作記憶表現的缺陷,重複施予內側前額葉tDCS可以改善上述長期增益效果缺陷並顯著提升糖尿病大鼠的空間工作記憶表現。(2) 重複施予tDCS的糖尿病大鼠內側前額葉相較於偽刺激組有較高的brain-derived neurotrophic factor (BDNF)轉譯及較高的N-Methyl-D-aspartate receptor (NMDAR)轉譯和轉錄表現。(3)重複陽極 tDCS顯著增加了內側前額葉椎體細胞的樹突脊數目密度,而神經樹突複雜性並未被改變。此實驗結果顯示重複性陽極tDCS可以有效提升糖尿病大鼠的空間工作記憶表現,其可能藉由促進NMDAR與BDNF這些調控神經突觸可塑性重要分子的轉錄與轉譯表現、增加神經樹突脊的數目密度,透過改善神經結構可塑性與突觸可塑性進一步改善認知功能。
本論文首先運用tDCS作用於右背外側前額葉皮質發現tDCS促進此腦區在空間工作記憶中調節干擾作用的效果而提升健康受試者的空間工作記憶表現,再進一步使用tDCS提升了糖尿病合併周邊神經病變與輕度認知功能障礙患者的空間工作記憶廣度,最後利用糖尿病大鼠活體模式證明tDCS改善疾病相關的認知功能障礙之神經生理機轉。本論文結合tDCS的臨床運用與基礎研究探討tDCS的認知功能效益與細胞生理機制,並且回答了這個領域重要卻尚未清楚的問題:tDCS如何改善認知功能的作用機轉。糖尿病目前已知為失智症的顯著危險因子之一,我們的研究結果支持tDCS對糖尿病患者具有認知功能的治療潛能,並以疾病動物模式指出重複性給予陽極tDCS可以藉由改善神經突觸可塑性來達到促進認知功能的效果,藉由對tDCS作用機轉的深入了解我們可望最佳化tDCS的臨床運用以造福患有認知功能障礙的病人。
英文摘要 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.
論文目次 Chapter 1. Introduction, p3
1.1 Transcranial Direct Current Stimulation (tDCS), p3
1.2 Spatial Working Memory, p4
1.3 Cognitive Impairment in Patients with Diabetes Mellitus, p6
1.4 TDCS-induced Neuroplasticity, p7
1.5 Thesis Aims and Research Paradigm, p9

Chapter 2. Transcranial direct current stimulation over the right dorsolateral prefrontal cortex modulates the interference effect on spatial working memory in healthy subjects, p11
2.1 Backgrounds and Aims, p11
2.2 Material and Methods, p12
2.3 Results, p16
2.4 Discussion, p22

Chapter 3. Transcranial direct current stimulation facilitates spatial working memory in patients with diabetic polyneuropathy, p28
3.1 Backgrounds and Aims, p28
3.2 Material and Methods, p29
3.3 Results, p33
3.4 Discussion, p41

Chapter 4. Repeated transcranial direct current stimulation improves cognitive dysfunction and restores synaptic plasticity deficit in the streptozotocin-induced diabetic rats, p47
4.1 Backgrounds and Aims, p47
4.2 Material and Methods, p49
4.3 Results, p61
4.4 Discussion, p75

Chapter 5. Conclusions and Prospects , p79
5.1 Conclusions, p79
5.2 Prospects, p82

References, p84

Publication, p92

Funding, p94
參考文獻 Alrefaie, Z., and Alhayani, A. (2015). Vitamin D(3) improves decline in cognitive function and cholinergic transmission in prefrontal cortex of streptozotocin-induced diabetic rats. Behav Brain Res 287, 156-162. doi: 10.1016/j.bbr.2015.03.050.
Andrews, S.C., Hoy, K.E., Enticott, P.G., Daskalakis, Z.J., and Fitzgerald, P.B. (2011). Improving working memory: the effect of combining cognitive activity and anodal transcranial direct current stimulation to the left dorsolateral prefrontal cortex. Brain Stimul 4(2), 84-89. doi: 10.1016/j.brs.2010.06.004.
Arvanitakis, Z., Wilson, R.S., Bienias, J.L., Evans, D.A., and Bennett, D.A. (2004). Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61(5), 661-666. doi: 10.1001/archneur.61.5.661.
Baddeley, A.D. (2001). Is working memory still working? Am Psychol 56(11), 851-864.
Berryhill, M.E., Wencil, E.B., Branch Coslett, H., and Olson, I.R. (2010). A selective working memory impairment after transcranial direct current stimulation to the right parietal lobe. Neurosci Lett 479(3), 312-316. doi: 10.1016/j.neulet.2010.05.087.
Biessels, G.J., Kamal, A., Urban, I.J., Spruijt, B.M., Erkelens, D.W., and Gispen, W.H. (1998). Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 800(1), 125-135.
Bimonte-Nelson, H.A., Hunter, C.L., Nelson, M.E., and Granholm, A.C. (2003). Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav Brain Res 139(1-2), 47-57.
Boggio, P.S., Ferrucci, R., Rigonatti, S.P., Covre, P., Nitsche, M., Pascual-Leone, A., et al. (2006). Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease. J Neurol Sci 249(1), 31-38. doi: 10.1016/j.jns.2006.05.062.
Boggio, P.S., Khoury, L.P., Martins, D.C., Martins, O.E., de Macedo, E.C., and Fregni, F. (2009). Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J Neurol Neurosurg Psychiatry 80(4), 444-447. doi: 10.1136/jnnp.2007.141853.
Boggio, P.S., Nunes, A., Rigonatti, S.P., Nitsche, M.A., Pascual-Leone, A., and Fregni, F. (2007). Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci 25(2), 123-129.
Caldeira, M.V., Melo, C.V., Pereira, D.B., Carvalho, R.F., Carvalho, A.L., and Duarte, C.B. (2007). BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol Cell Neurosci 35(2), 208-219. doi: 10.1016/j.mcn.2007.02.019.
Callaghan, B.C., Cheng, H.T., Stables, C.L., Smith, A.L., and Feldman, E.L. (2012). Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 11(6), 521-534. doi: 10.1016/S1474-4422(12)70065-0.
Cheng, G., Huang, C., Deng, H., and Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 42(5), 484-491. doi: 10.1111/j.1445-5994.2012.02758.x.
Cui, Y., Jin, J., Zhang, X., Xu, H., Yang, L., Du, D., et al. (2011). Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice. PLoS One 6(5), e20312. doi: 10.1371/journal.pone.0020312.
Curtis, C.E. (2006). Prefrontal and parietal contributions to spatial working memory. Neuroscience 139(1), 173-180. doi: 10.1016/j.neuroscience.2005.04.070.
de Fockert, J.W., Rees, G., Frith, C.D., and Lavie, N. (2001). The role of working memory in visual selective attention. Science 291(5509), 1803-1806. doi: 10.1126/science.1056496.
Deeds, M.C., Anderson, J.M., Armstrong, A.S., Gastineau, D.A., Hiddinga, H.J., Jahangir, A., et al. (2011). Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim 45(3), 131-140. doi: 10.1258/la.2010.010090.
Delibas, N., Altuntas, I., Sutcu, R., Yonden, Z., and Koylu, H. (2004). Effects of dietary long chain PUFAs on hippocampal lipid peroxidation and NMDA receptor subunits A and B concentration in streptozotocin-diabetic rats. Int J Neurosci 114(10), 1353-1364. doi: 10.1080/00207450490476147.
Di Luca, M., Ruts, L., Gardoni, F., Cattabeni, F., Biessels, G.J., and Gispen, W.H. (1999). NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats. Diabetologia 42(6), 693-701. doi: 10.1007/s001250051217.
Dudchenko, P.A. (2004). An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev 28(7), 699-709. doi: 10.1016/j.neubiorev.2004.09.002.
Dyck, P.J., Albers, J.W., Andersen, H., Arezzo, J.C., Biessels, G.J., Bril, V., et al. (2011). Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev 27(7), 620-628. doi: 10.1002/dmrr.1226.
Elmer, S., Burkard, M., Renz, B., Meyer, M., and Jancke, L. (2009). Direct current induced short-term modulation of the left dorsolateral prefrontal cortex while learning auditory presented nouns. Behav Brain Funct 5, 29. doi: 10.1186/1744-9081-5-29.
Exalto, L.G., Whitmer, R.A., Kappele, L.J., and Biessels, G.J. (2012). An update on type 2 diabetes, vascular dementia and Alzheimer's disease. Exp Gerontol 47(11), 858-864. doi: 10.1016/j.exger.2012.07.014.
Ferrucci, R., Mameli, F., Guidi, I., Mrakic-Sposta, S., Vergari, M., Marceglia, S., et al. (2008a). Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology 71(7), 493-498. doi: 10.1212/01.wnl.0000317060.43722.a3.
Ferrucci, R., Marceglia, S., Vergari, M., Cogiamanian, F., Mrakic-Sposta, S., Mameli, F., et al. (2008b). Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory. J Cogn Neurosci 20(9), 1687-1697. doi: 10.1162/jocn.2008.20112.
Fertonani, A., and Miniussi, C. (2016). Transcranial Electrical Stimulation: What We Know and Do Not Know About Mechanisms. Neuroscientist. doi: 10.1177/1073858416631966.
Fischer, M.H. (2001). Probing spatial working memory with the Corsi Blocks task. Brain Cogn 45(2), 143-154. doi: 10.1006/brcg.2000.1221.
Floel, A. (2014). tDCS-enhanced motor and cognitive function in neurological diseases. Neuroimage 85 Pt 3, 934-947. doi: 10.1016/j.neuroimage.2013.05.098.
Fregni, F., Boggio, P.S., Nitsche, M., Bermpohl, F., Antal, A., Feredoes, E., et al. (2005). Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res 166(1), 23-30. doi: 10.1007/s00221-005-2334-6.
Fregni, F., Boggio, P.S., Nitsche, M.A., Rigonatti, S.P., and Pascual-Leone, A. (2006). Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depress Anxiety 23(8), 482-484. doi: 10.1002/da.20201.
Fritsch, B., Reis, J., Martinowich, K., Schambra, H.M., Ji, Y., Cohen, L.G., et al. (2010). Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66(2), 198-204. doi: 10.1016/j.neuron.2010.03.035.
Garcia-Casares, N., Berthier, M.L., Jorge, R.E., Gonzalez-Alegre, P., Gutierrez Cardo, A., Rioja Villodres, J., et al. (2014a). Structural and functional brain changes in middle-aged type 2 diabetic patients: a cross-sectional study. J Alzheimers Dis 40(2), 375-386. doi: 10.3233/JAD-131736.
Garcia-Casares, N., Jorge, R.E., Garcia-Arnes, J.A., Acion, L., Berthier, M.L., Gonzalez-Alegre, P., et al. (2014b). Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study. J Alzheimers Dis 42(4), 1337-1346. doi: 10.3233/JAD-140702.
Gardoni, F., Kamal, A., Bellone, C., Biessels, G.J., Ramakers, G.M., Cattabeni, F., et al. (2002). Effects of streptozotocin-diabetes on the hippocampal NMDA receptor complex in rats. J Neurochem 80(3), 438-447.
Goder, R., Baier, P.C., Beith, B., Baecker, C., Seeck-Hirschner, M., Junghanns, K., et al. (2013). Effects of transcranial direct current stimulation during sleep on memory performance in patients with schizophrenia. Schizophr Res 144(1-3), 153-154. doi: 10.1016/j.schres.2012.12.014.
Grzeda, E., Wisniewska, R.J., and Wisniewski, K. (2007). Effect of an NMDA receptor agonist on T-maze and passive avoidance test in 12-week streptozotocin-induced diabetic rats. Pharmacol Rep 59(6), 656-663.
Hoogenboom, W.S., Marder, T.J., Flores, V.L., Huisman, S., Eaton, H.P., Schneiderman, J.S., et al. (2014). Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes. Diabetes 63(2), 728-738. doi: 10.2337/db13-1219.
Hoy, K.E., Emonson, M.R., Arnold, S.L., Thomson, R.H., Daskalakis, Z.J., and Fitzgerald, P.B. (2013). Testing the limits: Investigating the effect of tDCS dose on working memory enhancement in healthy controls. Neuropsychologia 51(9), 1777-1784. doi: 10.1016/j.neuropsychologia.2013.05.018.
Hsu, T.Y., Tseng, L.Y., Yu, J.X., Kuo, W.J., Hung, D.L., Tzeng, O.J., et al. (2011). Modulating inhibitory control with direct current stimulation of the superior medial frontal cortex. Neuroimage 56(4), 2249-2257. doi: 10.1016/j.neuroimage.2011.03.059.
Huang, C.C., and Hsu, K.S. (2010). Activation of muscarinic acetylcholine receptors induces a nitric oxide-dependent long-term depression in rat medial prefrontal cortex. Cereb Cortex 20(4), 982-996. doi: 10.1093/cercor/bhp161.
Huang, Y.Y., Simpson, E., Kellendonk, C., and Kandel, E.R. (2004). Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci U S A 101(9), 3236-3241. doi: 10.1073/pnas.0308280101.
Jay, T.M., Burette, F., and Laroche, S. (1995). NMDA receptor-dependent long-term potentiation in the hippocampal afferent fibre system to the prefrontal cortex in the rat. Eur J Neurosci 7(2), 247-250.
Jiang, T., Xu, R.X., Zhang, A.W., Di, W., Xiao, Z.J., Miao, J.Y., et al. (2012). Effects of transcranial direct current stimulation on hemichannel pannexin-1 and neural plasticity in rat model of cerebral infarction. Neuroscience 226, 421-426. doi: 10.1016/j.neuroscience.2012.09.035.
Jo, J.M., Kim, Y.H., Ko, M.H., Ohn, S.H., Joen, B., and Lee, K.H. (2009). Enhancing the working memory of stroke patients using tDCS. Am J Phys Med Rehabil 88(5), 404-409. doi: 10.1097/PHM.0b013e3181a0e4cb.
Kamal, A., Biessels, G.J., Urban, I.J., and Gispen, W.H. (1999). Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression. Neuroscience 90(3), 737-745.
Keeser, D., Meindl, T., Bor, J., Palm, U., Pogarell, O., Mulert, C., et al. (2011). Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI. J Neurosci 31(43), 15284-15293. doi: 10.1523/JNEUROSCI.0542-11.2011.
Kim, B., and Feldman, E.L. (2012). Insulin resistance in the nervous system. Trends Endocrinol Metab 23(3), 133-141. doi: 10.1016/j.tem.2011.12.004.
Kim, J.H., Roberts, D.S., Hu, Y., Lau, G.C., Brooks-Kayal, A.R., Farb, D.H., et al. (2012). Brain-derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons. J Neurochem 120(2), 210-219. doi: 10.1111/j.1471-4159.2011.07555.x.
Koppes, A.N., Seggio, A.M., and Thompson, D.M. (2011). Neurite outgrowth is significantly increased by the simultaneous presentation of Schwann cells and moderate exogenous electric fields. J Neural Eng 8(4), 046023. doi: 10.1088/1741-2560/8/4/046023.
Kumar, A., Haroon, E., Darwin, C., Pham, D., Ajilore, O., Rodriguez, G., et al. (2008). Gray matter prefrontal changes in type 2 diabetes detected using MRI. J Magn Reson Imaging 27(1), 14-19. doi: 10.1002/jmri.21224.
Lange, E.B., and Oberauer, K. (2005). Overwriting of phonemic features in serial recall. Memory 13(3-4), 333-339.
Lavie, N., Hirst, A., de Fockert, J.W., and Viding, E. (2004). Load theory of selective attention and cognitive control. J Exp Psychol Gen 133(3), 339-354. doi: 10.1037/0096-3445.133.3.339.
Liebetanz, D., Nitsche, M.A., Tergau, F., and Paulus, W. (2002). Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain 125(Pt 10), 2238-2247.
Manschot, S.M., Biessels, G.J., Rutten, G.E., Kessels, R.P., Gispen, W.H., Kappelle, L.J., et al. (2008). Peripheral and central neurologic complications in type 2 diabetes mellitus: no association in individual patients. J Neurol Sci 264(1-2), 157-162. doi: 10.1016/j.jns.2007.08.011.
Martin, S.J., Grimwood, P.D., and Morris, R.G. (2000). Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23, 649-711. doi: 10.1146/annurev.neuro.23.1.649.
McAfoose, J., and Baune, B.T. (2009). Exploring visual-spatial working memory: a critical review of concepts and models. Neuropsychol Rev 19(1), 130-142. doi: 10.1007/s11065-008-9063-0.
McCrimmon, R.J., Ryan, C.M., and Frier, B.M. (2012). Diabetes and cognitive dysfunction. Lancet 379(9833), 2291-2299. doi: 10.1016/S0140-6736(12)60360-2.
McNab, F., and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nat Neurosci 11(1), 103-107. doi: 10.1038/nn2024.
McNab, F., Zeidman, P., Rutledge, R.B., Smittenaar, P., Brown, H.R., Adams, R.A., et al. (2015). Age-related changes in working memory and the ability to ignore distraction. Proc Natl Acad Sci U S A 112(20), 6515-6518. doi: 10.1073/pnas.1504162112.
McQuail, J.A., Beas, B.S., Kelly, K.B., Simpson, K.L., Frazier, C.J., Setlow, B., et al. (2016). NR2A-Containing NMDARs in the Prefrontal Cortex Are Required for Working Memory and Associated with Age-Related Cognitive Decline. J Neurosci 36(50), 12537-12548. doi: 10.1523/JNEUROSCI.2332-16.2016.
Moran, C., Phan, T.G., Chen, J., Blizzard, L., Beare, R., Venn, A., et al. (2013). Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36(12), 4036-4042. doi: 10.2337/dc13-0143.
Mulquiney, P.G., Hoy, K.E., Daskalakis, Z.J., and Fitzgerald, P.B. (2011). Improving working memory: exploring the effect of transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal cortex. Clin Neurophysiol 122(12), 2384-2389. doi: 10.1016/j.clinph.2011.05.009.
Nasreddine, Z.S., Phillips, N.A., Bedirian, V., Charbonneau, S., Whitehead, V., Collin, I., et al. (2005). The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4), 695-699. doi: 10.1111/j.1532-5415.2005.53221.x.
Ninomiya, T. (2014). Diabetes mellitus and dementia. Curr Diab Rep 14(5), 487. doi: 10.1007/s11892-014-0487-z.
Nitsche, M.A., and Paulus, W. (2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57(10), 1899-1901.
Nitta, A., Murai, R., Suzuki, N., Ito, H., Nomoto, H., Katoh, G., et al. (2002). Diabetic neuropathies in brain are induced by deficiency of BDNF. Neurotoxicol Teratol 24(5), 695-701.
Ohara, T., Doi, Y., Ninomiya, T., Hirakawa, Y., Hata, J., Iwaki, T., et al. (2011). Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 77(12), 1126-1134. doi: 10.1212/WNL.0b013e31822f0435.
Ohn, S.H., Park, C.I., Yoo, W.K., Ko, M.H., Choi, K.P., Kim, G.M., et al. (2008). Time-dependent effect of transcranial direct current stimulation on the enhancement of working memory. Neuroreport 19(1), 43-47. doi: 10.1097/WNR.0b013e3282f2adfd.
Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A., and Breteler, M.M. (1999). Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53(9), 1937-1942.
Parra, M.A., Abrahams, S., Logie, R.H., Mendez, L.G., Lopera, F., and Della Sala, S. (2010). Visual short-term memory binding deficits in familial Alzheimer's disease. Brain 133(9), 2702-2713. doi: 10.1093/brain/awq148.
Pearce, K.L., Noakes, M., Wilson, C., and Clifton, P.M. (2012). Continuous glucose monitoring and cognitive performance in type 2 diabetes. Diabetes Technol Ther 14(12), 1126-1133. doi: 10.1089/dia.2012.0143.
Peila, R., Rodriguez, B.L., Launer, L.J., and Honolulu-Asia Aging, S. (2002). Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51(4), 1256-1262.
Pelletier, R., Higgins, J., and Bourbonnais, D. (2015). Addressing Neuroplastic Changes in Distributed Areas of the Nervous System Associated With Chronic Musculoskeletal Disorders. Phys Ther 95(11), 1582-1591. doi: 10.2522/ptj.20140575.
Podda, M.V., Cocco, S., Mastrodonato, A., Fusco, S., Leone, L., Barbati, S.A., et al. (2016). Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression. Sci Rep 6, 22180. doi: 10.1038/srep22180.
Polania, R., Paulus, W., Antal, A., and Nitsche, M.A. (2011). Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study. Neuroimage 54(3), 2287-2296. doi: 10.1016/j.neuroimage.2010.09.085.
Sakai, K., Rowe, J.B., and Passingham, R.E. (2002). Active maintenance in prefrontal area 46 creates distractor-resistant memory. Nat Neurosci 5(5), 479-484. doi: 10.1038/nn846.
Sala, C., and Segal, M. (2014). Dendritic spines: the locus of structural and functional plasticity. Physiol Rev 94(1), 141-188. doi: 10.1152/physrev.00012.2013.
Sauseng, P., Klimesch, W., Heise, K.F., Gruber, W.R., Holz, E., Karim, A.A., et al. (2009). Brain oscillatory substrates of visual short-term memory capacity. Curr Biol 19(21), 1846-1852. doi: 10.1016/j.cub.2009.08.062.
Schratt, G.M., Nigh, E.A., Chen, W.G., Hu, L., and Greenberg, M.E. (2004). BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24(33), 7366-7377. doi: 10.1523/JNEUROSCI.1739-04.2004.
Semaming, Y., Kumfu, S., Pannangpetch, P., Chattipakorn, S.C., and Chattipakorn, N. (2014). Protocatechuic acid exerts a cardioprotective effect in type 1 diabetic rats. J Endocrinol 223(1), 13-23. doi: 10.1530/JOE-14-0273.
Stewart, R., and Liolitsa, D. (1999). Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 16(2), 93-112.
Sui, L., Wang, Y., Ju, L.H., and Chen, M. (2012). Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex. Neurobiol Learn Mem 97(4), 425-440. doi: 10.1016/j.nlm.2012.03.007.
Tesfaye, S., Boulton, A.J., Dyck, P.J., Freeman, R., Horowitz, M., Kempler, P., et al. (2010). Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33(10), 2285-2293. doi: 10.2337/dc10-1303.
Tesfaye, S., Vileikyte, L., Rayman, G., Sindrup, S.H., Perkins, B.A., Baconja, M., et al. (2011). Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev 27(7), 629-638. doi: 10.1002/dmrr.1225.
Thierry, A.M., Gioanni, Y., Degenetais, E., and Glowinski, J. (2000). Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus 10(4), 411-419. doi: 10.1002/1098-1063(2000)10:4<411::AID-HIPO7>3.0.CO;2-A.
Toepper, M., Gebhardt, H., Beblo, T., Thomas, C., Driessen, M., Bischoff, M., et al. (2010). Functional correlates of distractor suppression during spatial working memory encoding. Neuroscience 165(4), 1244-1253. doi: 10.1016/j.neuroscience.2009.11.019.
Tseng, P., and Bridgeman, B. (2011). Improved change detection with nearby hands. Exp Brain Res 209(2), 257-269. doi: 10.1007/s00221-011-2544-z.
Tseng, P., Hsu, T.Y., Chang, C.F., Tzeng, O.J., Hung, D.L., Muggleton, N.G., et al. (2012). Unleashing potential: transcranial direct current stimulation over the right posterior parietal cortex improves change detection in low-performing individuals. J Neurosci 32(31), 10554-10561. doi: 10.1523/jneurosci.0362-12.2012.
Umegaki, H. (2014). Type 2 diabetes as a risk factor for cognitive impairment: current insights. Clin Interv Aging 9, 1011-1019. doi: 10.2147/CIA.S48926.
Ungerleider, L.G., Courtney, S.M., and Haxby, J.V. (1998). A neural system for human visual working memory. Proc Natl Acad Sci U S A 95(3), 883-890.
van den Berg, E., Reijmer, Y.D., de Bresser, J., Kessels, R.P., Kappelle, L.J., Biessels, G.J., et al. (2010). A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia 53(1), 58-65. doi: 10.1007/s00125-009-1571-9.
van Elderen, S.G., de Roos, A., de Craen, A.J., Westendorp, R.G., Blauw, G.J., Jukema, J.W., et al. (2010). Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 75(11), 997-1002. doi: 10.1212/WNL.0b013e3181f25f06.
Vincent, A.M., Callaghan, B.C., Smith, A.L., and Feldman, E.L. (2011). Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7(10), 573-583. doi: 10.1038/nrneurol.2011.137.
Wang, M., Yang, Y., Wang, C.J., Gamo, N.J., Jin, L.E., Mazer, J.A., et al. (2013). NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77(4), 736-749. doi: 10.1016/j.neuron.2012.12.032.
Wood, M.D., and Willits, R.K. (2009). Applied electric field enhances DRG neurite growth: influence of stimulation media, surface coating and growth supplements. J Neural Eng 6(4), 046003. doi: 10.1088/1741-2560/6/4/046003.
Wu, Y.J., Tseng, P., Chang, C.F., Pai, M.C., Hsu, K.S., Lin, C.C., et al. (2014). Modulating the interference effect on spatial working memory by applying transcranial direct current stimulation over the right dorsolateral prefrontal cortex. Brain Cogn 91, 87-94. doi: 10.1016/j.bandc.2014.09.002.
Wu, Y.J., Tseng, P., Huang, H.W., Hu, J.F., Juan, C.H., Hsu, K.S., et al. (2016). The Facilitative Effect of Transcranial Direct Current Stimulation on Visuospatial Working Memory in Patients with Diabetic Polyneuropathy: A Pre-post Sham-Controlled Study. Front Hum Neurosci 10, 479. doi: 10.3389/fnhum.2016.00479.
Yeh, C.M., Huang, C.C., and Hsu, K.S. (2012). Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF. J Physiol 590(4), 991-1010. doi: 10.1113/jphysiol.2011.222042.
Yoon, T., Okada, J., Jung, M.W., and Kim, J.J. (2008). Prefrontal cortex and hippocampus subserve different components of working memory in rats. Learn Mem 15(3), 97-105. doi: 10.1101/lm.850808.
Yu, J., Tseng, P., Hung, D.L., Wu, S.W., and Juan, C.H. (2015). Brain stimulation improves cognitive control by modulating medial-frontal activity and preSMA-vmPFC functional connectivity. Hum Brain Mapp 36(10), 4004-4015. doi: 10.1002/hbm.22893.
Zaehle, T., Sandmann, P., Thorne, J.D., Jancke, L., and Herrmann, C.S. (2011). Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence. BMC Neurosci 12, 2. doi: 10.1186/1471-2202-12-2.
Zochodne, D.W. (2008). Diabetic polyneuropathy: an update. Curr Opin Neurol 21(5), 527-533. doi: 10.1097/WCO.0b013e32830b84cb.
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