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Consecutive anodal transcranial direct current stimulation enhances synaptic plasticity, dendritic morphology and working memory in a diabetic rat model
Abstracts / Brain Stimulation 10 (2017) 346e540
Methods: To develop the protocol, n¼26 individuals with MS were trained in tDCS application, using a caregiver proxy for participants with higher levels of neurologic impairment. Equipment was customized for use by those with limited manual dexterity and all procedures with streamlined for simplicity. After an initial baseline training session, nine additional sessions were administered remotely in real-time through videoconferencing. tDCS (1.5 mA x 20 minutes) was paired with cognitive training. These participants were compared to a control group that completed cognitive training only using the same remotely-supervised procedures. Next, using the RS-tDCS protocol, n¼20 individuals with MS were randomized to 20 sessions of active (2.0 mA) or sham tDCS. The primary outcomes included changes in mood, cognitive processing measures, and fatigue ratings. Results: A total of n¼56 individuals with MS have self-administered tDCS using our RS-tDCS protocol for a total of over 650 sessions. Compliance has been higher than reported from studies requiring clinic visits with safety and tolerability at or better than reports. Initial benefit has been found for aspects of cognitive processing speed (complex attention, intra-individual variability in response time), mood, and fatigue. Discussion: Our RS-tDCS protocol is feasible for clinical study of benefits in MS and is can be adapted for use in individuals with a wide range of neurologic disability. Initial efficacy has been observed in cognition, mood and fatigue. Keywords: tDCS, telerehabilitation, multiple sclerosis, clinical trial methodology [0366] TRANSCRANIAL DIRECT CURRENT STIMULATION FOR DEPRESSION IN ALZHEIMER'S DISEASE PATIENT e PRELIMINARY DATA FROM THE ONGOING RANDOMIZED CONTROLLED TRIAL Y. Yokoi*1, Z. Narita 1, T. Inagawa 1, T. Otsuka 2, M. Shibaoka 1, N. Miyagawa 1, K. Nakagome 1. 1 National Center of Neurology and Psychiatry, Japan; 2 Hiagari Hospital, Japan Introduction: Behavioural and psychiatric symptoms of dementia are often as problematic as or more severe than cognitive decline in Alzheimer’s disease. Among symptoms, depression in Alzheimer’s disease (dAD) has the second most prevalence (former research suggests 36.7 to 47.8 %) behind agitation, and unfortunately randomized controlled trials failed to show significant effectiveness of antidepressants for dAD. While research on physiological background dAD is accumulating that suggests dysfunction in neurotransmitters and brain metabolism, such as decreased blood glucose metabolism in frontal cortex (dorsolateral prefrontal cortex, superior frontal gyrus and anterior cingulate gyrus) and loss of serotonin receptors in hippocampus. Therefore we planned and started a randomized controlled trial of transcranial direct current stimulation (tDCS) for dAD. Methods: Eligible participants are aged between 65 and 90, meet criteria of probable Alzheimer’s disease defined by NINCDS-ADRDA and dAD defined by NIMH criteria. Their psychotropic medication is maintained on stable dose throughout the trial. Participants without informative caregiver, at risk of suicide or hospitalization due to depression, with severe dementia, are excluded. 15 sessions of tDCS with 2 mA, 35 cm2 of sponge pads on F3(anode) and Fp1(cathode), 30-minute duration, is implemented as often as 5 sessions a week. Half of participants are randomly allocated to sham-tDCS without actual stimulation during procedure and both rater and participant are blind to allocattion. The primary endpoint is attrition rate due to any adverse event and secondary outcomes are dAD by Cornell Scale for Depression in Dementia, Geriatric Depression Scale, Neuropsychiatric Inventory for behavioural psychiatric symptoms, Zarit Burden Interview for caregiver burden, Starkstein Apathy Scale for apathy, and Clinical Global Impression of Improvement. Results and discussion: So far four out of twenty participants finished full evaluation. Current fixed data suggests tDCS is safe and tolerable. Accruing number is needed to decide its clinical effectiveness. ClinicalTrials.gov ID: NCT02351388 Keywords: Alzheimer's disease, Depression, Dementia, Neuropsychiatric symptoms
423
[0368] CONSECUTIVE ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION ENHANCES SYNAPTIC PLASTICITY, DENDRITIC MORPHOLOGY AND WORKING MEMORY IN A DIABETIC RAT MODEL Y.J. Wu*, C.C. Lin, K.S. Hsu. National Cheng Kung University, Taiwan Background and objective: Transcranial direct current stimulation (tDCS) has been reported to facilitate working memory (WM) in healthy participants and patients with diabetes mellitus. In this study, we investigated the synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR) expression and dendritic spine morphology changes after tDCS to explore the neurophysiological mechanisms of tDCS in facilitating WM. Methods: Anodal tDCS (200mA / 3.14 mm2, 30 minutes) or sham (200mA / 3.14 mm2, 30 seconds) was applied on the medial prefrontal cortex (PFC) in a streptozotocin (STZ)-induced diabetic rat model for consecutive 8 days. Delayed nonmatch-to-place T maze (DNMT) immediately after tDCS or sham was used to evaluate the spatial WM of the STZ rats. After the DNMT task brain slices were obtained to study the synaptic plasticity by field excitatory postsynaptic potential, NMDAR expression by RT-PCR and Western blotting, and the morphological changes by Golgi stain after tDCS. C-Fos immunofluorescence stain was adopted to explore the regions activated by tDCS. Results: Our results showed that (1) STZ-induced diabetic rats presented impaired WM, decreased NMDAR expressions and long term potentiation (LTP) when compared with the healthy control rats; (2) consecutive anodal-PFC-tDCS restored the impaired PFC-LTP of STZ rats to the level similar to that of healthy rats, enhanced the protein and mRNA expressions of NMDAR, and increased the dendritic spine numbers along with improvement of WM in STZ rats when compared with the sham treated STZ rats. The target region being stimulated by tDCS (PFC) and the functional connected remote area (ventral hippocampus) were both activated with increased C-Fos expressions. Conclusion: Our findings suggest that the neurophysiological mechanism of anodal tDCS to improve working memory is through facilitating synaptic plasticity by up regulating the NMDAR expressions and enhancing the dendritic morphology with increased spine numbers as shown in an in vivo disease animal model. These findings provide a direct proof of concept for the working mechanism of tDCS and the potential therapeutic significance of tDCS for people with cognitive disorders. Keywords: transcranial direct current stimulation, synaptic plasticity, Nmethyl-D-aspartate receptor (NMDAR), working memory [0369] PRACTICAL CONSIDERATIONS STIMULATION IN THE OLD-OLD
FOR
TRANSCRANIAL
MAGNETIC
P. Fernandes*. Creighton University School of Medicine, USA Introduction: Studies in the medical literature have reported the successful use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression across various age groups. Treatments have included elderly subjects, usually up to the age of 75, highlighting neurophysiological considerations like cortical atrophy in this age group. The purpose of this report is to describe unique and specific treatment issues encountered in the administration of rTMS to a woman age 87, who would fall into the ‘old-old’ life stage subgroup. Methods: A case report of a woman, age 87 with a diagnosis of major depressive disorder-recurrent, with treatment resistance, referred for rTMS treatment, is described. Psychiatric evaluation revealed presence of a severe depressive episode, not responding to multiple antidepressant trials and electroconvulsive therapy. There was no evidence of cognitive impairment or psychotic features. The patient was fully independent, highly educated and very motivated to proceed with the treatment. Results: Motor threshold determination was done and a course of acute transcranial magnetic stimulation of the left dorsolateral prefrontal cortex was initiated. Several issues arose during the treatment, which have practical and clinical implications.
Methods: To develop the protocol, n¼26 individuals with MS were trained in tDCS application, using a caregiver proxy for participants with higher levels of neurologic impairment. Equipment was customized for use by those with limited manual dexterity and all procedures with streamlined for simplicity. After an initial baseline training session, nine additional sessions were administered remotely in real-time through videoconferencing. tDCS (1.5 mA x 20 minutes) was paired with cognitive training. These participants were compared to a control group that completed cognitive training only using the same remotely-supervised procedures. Next, using the RS-tDCS protocol, n¼20 individuals with MS were randomized to 20 sessions of active (2.0 mA) or sham tDCS. The primary outcomes included changes in mood, cognitive processing measures, and fatigue ratings. Results: A total of n¼56 individuals with MS have self-administered tDCS using our RS-tDCS protocol for a total of over 650 sessions. Compliance has been higher than reported from studies requiring clinic visits with safety and tolerability at or better than reports. Initial benefit has been found for aspects of cognitive processing speed (complex attention, intra-individual variability in response time), mood, and fatigue. Discussion: Our RS-tDCS protocol is feasible for clinical study of benefits in MS and is can be adapted for use in individuals with a wide range of neurologic disability. Initial efficacy has been observed in cognition, mood and fatigue. Keywords: tDCS, telerehabilitation, multiple sclerosis, clinical trial methodology [0366] TRANSCRANIAL DIRECT CURRENT STIMULATION FOR DEPRESSION IN ALZHEIMER'S DISEASE PATIENT e PRELIMINARY DATA FROM THE ONGOING RANDOMIZED CONTROLLED TRIAL Y. Yokoi*1, Z. Narita 1, T. Inagawa 1, T. Otsuka 2, M. Shibaoka 1, N. Miyagawa 1, K. Nakagome 1. 1 National Center of Neurology and Psychiatry, Japan; 2 Hiagari Hospital, Japan Introduction: Behavioural and psychiatric symptoms of dementia are often as problematic as or more severe than cognitive decline in Alzheimer’s disease. Among symptoms, depression in Alzheimer’s disease (dAD) has the second most prevalence (former research suggests 36.7 to 47.8 %) behind agitation, and unfortunately randomized controlled trials failed to show significant effectiveness of antidepressants for dAD. While research on physiological background dAD is accumulating that suggests dysfunction in neurotransmitters and brain metabolism, such as decreased blood glucose metabolism in frontal cortex (dorsolateral prefrontal cortex, superior frontal gyrus and anterior cingulate gyrus) and loss of serotonin receptors in hippocampus. Therefore we planned and started a randomized controlled trial of transcranial direct current stimulation (tDCS) for dAD. Methods: Eligible participants are aged between 65 and 90, meet criteria of probable Alzheimer’s disease defined by NINCDS-ADRDA and dAD defined by NIMH criteria. Their psychotropic medication is maintained on stable dose throughout the trial. Participants without informative caregiver, at risk of suicide or hospitalization due to depression, with severe dementia, are excluded. 15 sessions of tDCS with 2 mA, 35 cm2 of sponge pads on F3(anode) and Fp1(cathode), 30-minute duration, is implemented as often as 5 sessions a week. Half of participants are randomly allocated to sham-tDCS without actual stimulation during procedure and both rater and participant are blind to allocattion. The primary endpoint is attrition rate due to any adverse event and secondary outcomes are dAD by Cornell Scale for Depression in Dementia, Geriatric Depression Scale, Neuropsychiatric Inventory for behavioural psychiatric symptoms, Zarit Burden Interview for caregiver burden, Starkstein Apathy Scale for apathy, and Clinical Global Impression of Improvement. Results and discussion: So far four out of twenty participants finished full evaluation. Current fixed data suggests tDCS is safe and tolerable. Accruing number is needed to decide its clinical effectiveness. ClinicalTrials.gov ID: NCT02351388 Keywords: Alzheimer's disease, Depression, Dementia, Neuropsychiatric symptoms
423
[0368] CONSECUTIVE ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION ENHANCES SYNAPTIC PLASTICITY, DENDRITIC MORPHOLOGY AND WORKING MEMORY IN A DIABETIC RAT MODEL Y.J. Wu*, C.C. Lin, K.S. Hsu. National Cheng Kung University, Taiwan Background and objective: Transcranial direct current stimulation (tDCS) has been reported to facilitate working memory (WM) in healthy participants and patients with diabetes mellitus. In this study, we investigated the synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR) expression and dendritic spine morphology changes after tDCS to explore the neurophysiological mechanisms of tDCS in facilitating WM. Methods: Anodal tDCS (200mA / 3.14 mm2, 30 minutes) or sham (200mA / 3.14 mm2, 30 seconds) was applied on the medial prefrontal cortex (PFC) in a streptozotocin (STZ)-induced diabetic rat model for consecutive 8 days. Delayed nonmatch-to-place T maze (DNMT) immediately after tDCS or sham was used to evaluate the spatial WM of the STZ rats. After the DNMT task brain slices were obtained to study the synaptic plasticity by field excitatory postsynaptic potential, NMDAR expression by RT-PCR and Western blotting, and the morphological changes by Golgi stain after tDCS. C-Fos immunofluorescence stain was adopted to explore the regions activated by tDCS. Results: Our results showed that (1) STZ-induced diabetic rats presented impaired WM, decreased NMDAR expressions and long term potentiation (LTP) when compared with the healthy control rats; (2) consecutive anodal-PFC-tDCS restored the impaired PFC-LTP of STZ rats to the level similar to that of healthy rats, enhanced the protein and mRNA expressions of NMDAR, and increased the dendritic spine numbers along with improvement of WM in STZ rats when compared with the sham treated STZ rats. The target region being stimulated by tDCS (PFC) and the functional connected remote area (ventral hippocampus) were both activated with increased C-Fos expressions. Conclusion: Our findings suggest that the neurophysiological mechanism of anodal tDCS to improve working memory is through facilitating synaptic plasticity by up regulating the NMDAR expressions and enhancing the dendritic morphology with increased spine numbers as shown in an in vivo disease animal model. These findings provide a direct proof of concept for the working mechanism of tDCS and the potential therapeutic significance of tDCS for people with cognitive disorders. Keywords: transcranial direct current stimulation, synaptic plasticity, Nmethyl-D-aspartate receptor (NMDAR), working memory [0369] PRACTICAL CONSIDERATIONS STIMULATION IN THE OLD-OLD
FOR
TRANSCRANIAL
MAGNETIC
P. Fernandes*. Creighton University School of Medicine, USA Introduction: Studies in the medical literature have reported the successful use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression across various age groups. Treatments have included elderly subjects, usually up to the age of 75, highlighting neurophysiological considerations like cortical atrophy in this age group. The purpose of this report is to describe unique and specific treatment issues encountered in the administration of rTMS to a woman age 87, who would fall into the ‘old-old’ life stage subgroup. Methods: A case report of a woman, age 87 with a diagnosis of major depressive disorder-recurrent, with treatment resistance, referred for rTMS treatment, is described. Psychiatric evaluation revealed presence of a severe depressive episode, not responding to multiple antidepressant trials and electroconvulsive therapy. There was no evidence of cognitive impairment or psychotic features. The patient was fully independent, highly educated and very motivated to proceed with the treatment. Results: Motor threshold determination was done and a course of acute transcranial magnetic stimulation of the left dorsolateral prefrontal cortex was initiated. Several issues arose during the treatment, which have practical and clinical implications.