Publications by authors named "Tsung-Hsun Hsieh"

54 Publications

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury.

Redox Biol 2021 Oct 17;46:102067. Epub 2021 Jul 17.

Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address:

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.
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http://dx.doi.org/10.1016/j.redox.2021.102067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327355PMC
October 2021

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Nano Lett 2021 07 15;21(14):5967-5976. Epub 2021 Jul 15.

Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 106319, Taiwan.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.
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http://dx.doi.org/10.1021/acs.nanolett.1c00886DOI Listing
July 2021

Cortical Electrical Stimulation Ameliorates Traumatic Brain Injury-Induced Sensorimotor and Cognitive Deficits in Rats.

Front Neural Circuits 2021 14;15:693073. Epub 2021 Jun 14.

School of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan.

: Individuals with different severities of traumatic brain injury (TBI) often suffer long-lasting motor, sensory, neurological, or cognitive disturbances. To date, no neuromodulation-based therapies have been used to manage the functional deficits associated with TBI. Cortical electrical stimulation (CES) has been increasingly developed for modulating brain plasticity and is considered to have therapeutic potential in TBI. However, the therapeutic value of such a technique for TBI is still unclear. Accordingly, an animal model of this disease would be helpful for mechanistic insight into using CES as a novel treatment approach in TBI. The current study aims to apply a novel CES scheme with a theta-burst stimulation (TBS) protocol to identify the therapeutic potential of CES in a weight drop-induced rat model of TBI. : TBI rats were divided into the sham CES treatment group and CES treatment group. Following early and long-term CES intervention (starting 24 h after TBI, 1 session/day, 5 days/week) in awake TBI animals for a total of 4 weeks, the effects of CES on the modified neurological severity score (mNSS), sensorimotor and cognitive behaviors and neuroinflammatory changes were identified. : We found that the 4-week CES intervention significantly alleviated the TBI-induced neurological, sensorimotor, and cognitive deficits in locomotor activity, sensory and recognition memory. Immunohistochemically, we found that CES mitigated the glial fibrillary acidic protein (GFAP) activation in the hippocampus. : These findings suggest that CES has significant benefits in alleviating TBI-related symptoms and represents a promising treatment for TBI.
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http://dx.doi.org/10.3389/fncir.2021.693073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236591PMC
June 2021

Neuromodulatory effects of repetitive transcranial magnetic stimulation on neural plasticity and motor functions in rats with an incomplete spinal cord injury: A preliminary study.

PLoS One 2021 4;16(6):e0252965. Epub 2021 Jun 4.

Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.

We investigated the effects of intermittent theta-burst stimulation (iTBS) on locomotor function, motor plasticity, and axonal regeneration in an animal model of incomplete spinal cord injury (SCI). Aneurysm clips with different compression forces were applied extradurally around the spinal cord at T10. Motor plasticity was evaluated by examining the motor evoked potentials (MEPs). Long-term iTBS treatment was given at the post-SCI 5th week and continued for 2 weeks (5 consecutive days/week). Time-course changes in locomotor function and the axonal regeneration level were measured by the Basso Beattie Bresnahan (BBB) scale, and growth-associated protein (GAP)-43 expression was detected in brain and spinal cord tissues. iTBS-induced potentiation was reduced at post-1-week SCI lesion and had recovered by 4 weeks post-SCI lesion, except in the severe group. Multiple sessions of iTBS treatment enhanced the motor plasticity in all SCI rats. The locomotor function revealed no significant changes between pre- and post-iTBS treatment in SCI rats. The GAP-43 expression level in the spinal cord increased following 2 weeks of iTBS treatment compared to the sham-treatment group. This preclinical model may provide a translational platform to further investigate therapeutic mechanisms of transcranial magnetic stimulation and enhance the possibility of the potential use of TMS with the iTBS scheme for treating SCIs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252965PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177618PMC
June 2021

Subsequent Acupuncture Reverses the Aftereffects of Intermittent Theta-Burst Stimulation.

Front Neural Circuits 2021 28;15:675365. Epub 2021 Apr 28.

School of Physical Therapy, Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan.

Objective: This study explored whether acupuncture affects the maintenance of long-term potentiation (LTP)-like plasticity induced by transcranial magnetic stimulation (TMS) and the acquisition of motor skills following repetitive sequential visual isometric pinch task (SVIPT) training.

Methods: Thirty-six participants were recruited. The changes in the aftereffects induced by intermittent theta-burst stimulation (iTBS) and followed acupuncture were tested by the amplitude motor evoked potential (MEP) at pre-and-post-iTBS for 30 min and at acupuncture-in and -off for 30 min. Secondly, the effects of acupuncture on SVIPT movement in inducing error rate and learning skill index were tested.

Results: Following one session of iTBS, the MEP amplitude was increased and maintained at a high level for 30 min. The facilitation of MEP was gradually decreased to the baseline level during acupuncture-in and did not return to a high level after needle extraction. The SVIPT-acupuncture group had a lower learning skill index than those in the SVIPT group, indicating that acupuncture intervention after SVIPT training may restrain the acquisition ability of one's learning skills.

Conclusion: Acupuncture could reverse the LTP-like plasticity of the contralateral motor cortex induced by iTBS. Subsequent acupuncture may negatively affect the efficacy of the acquisition of learned skills in repetitive exercise training.
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http://dx.doi.org/10.3389/fncir.2021.675365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115810PMC
April 2021

The voiding efficiency in rat models with dopaminergic brain lesions induced through unilateral and bilateral intrastriatal injections.

PLoS One 2020 3;15(12):e0243452. Epub 2020 Dec 3.

School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.

Bladder dysfunction is a common phenomenon in Parkinson's disease (PD) patients. A research attempt was made to analyze the voiding efficiency (VE) and bladder functions in rats with PD induced by unilateral or bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. PD rats were divided into unilateral- and bilateral-injected groups and subjected to rotation and beam walking tests. Further, the experimental rats underwent cystometric measurements for analyses of bladder dysfunction and VE. Immunohistochemical analysis was performed to analyze the dopaminergic neuron depletion on the target area. Outcomes of the rotation and beam walking tests revealed the extent of parkinsonism in the experimental rats. Urodynamic observations denoted that rats with unilateral PD exhibited a significantly decreased VE (from 68.3±3.5% to 32.7±5.8%), while rats with bilateral PD displayed a much-reduced and substantially lower level of VE of 18.3±5.1% compared to the control value and to that of rats with unilateral PD. Rats with bilateral PD showed more-extensive behavioral deficits and urodynamic changes than did rats with unilateral PD. These significant changes in motor, behavioral, bladder function and VE were due to an extensive degeneration of dopaminergic neurons in the substantia nigra region on both sides of the brain. The obtained results were substantiated with appropriate immunohistochemical results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243452PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714362PMC
January 2021

Efficacy of Deep Brain Stimulation on the Improvement of the Bladder Functions in Traumatic Brain Injured Rats.

Brain Sci 2020 Nov 12;10(11). Epub 2020 Nov 12.

School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.

Objective: Traumatic brain injuries (TBIs) are a prime public health challenge with a high incidence of mortality, and also reflect severe economic impacts. One of their severe symptoms is bladder dysfunction. Conventional therapeutic methods are not effective in managing bladder dysfunction. Henceforth, a research endeavor was attempted to explore a new therapeutic approach for bladder dysfunction through deep brain stimulation (DBS) procedures in a TBI animal model.

Methods: TBI in this animal model was induced by the weight-drop method. All rats with an induced TBI were housed for 4 weeks to allow severe bladder dysfunction to develop. Subsequently, an initial urodynamic measurement, the simultaneous recording of cystometric (CMG) and external urethral sphincter electromyography (EUS-EMG) activity was conducted to evaluate bladder function. Further, standard DBS procedures with varying electrical stimulation parameters were executed in the target area of the pedunculopontine tegmental nucleus (PPTg). Simultaneously, urodynamic measurements were re-established to compare the effects of DBS interventions on bladder functions.

Results: From the variable combinations of electrical stimulation, DBS at 50 Hz and 2.0 V, significantly reverted the voiding efficiency from 39% to 69% in TBI rats. Furthermore, MRI studies revealed the precise localization of the DBS electrode in the target area.

Conclusions: The results we obtained showed an insightful understanding of PPTg-DBS and its therapeutic applications in alleviating bladder dysfunction in rats with a TBI. Hence, the present study suggests that PPTg-DBS is an effective therapeutic strategy for treating bladder dysfunction.
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http://dx.doi.org/10.3390/brainsci10110850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698168PMC
November 2020

Astaxanthin attenuates joint inflammation induced by monosodium urate crystals.

FASEB J 2020 08 10;34(8):11215-11226. Epub 2020 Jul 10.

Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Gouty arthritis is the one of the most painful arthritis and is caused by an inflammatory reaction. This study investigated whether astaxanthin (AXT), which has documented anti-inflammatory and antioxidant properties, exhibits protective effects against monosodium urate (MSU) crystal-induced inflammation. Cell viability of J774A.1 murine macrophages was assessed by AXT dose-dependent incubation by MTT assays, and expression levels of iNOS and COX-2 proteins as well as secretion of IL-1β were also analyzed under MSU crystals stimulation with or without AXT treatment. The production of inflammatory mediators was found to significantly decrease with AXT treatment, and the formation of the inflammasome complex was also attenuated when cells were co-stimulated with MSU crystals and AXT. Furthermore, we found that expression of the MAPK pathway was downregulated in J774A.1 cells. AXT also inhibited the induction of COX-2 and IL-6 in human chondrocytes and synovial fibroblasts by western blots. Finally, an MSU crystal intra-articular injection rat model for gouty arthritis was utilized in which treatment groups received 5-daily intraperitoneal injections of AXT prior to MSU crystal stimulation, or once intra-articular injections of AXT following MSU crystal stimulation for 6 hours. Results of synovitis score analysis revealed that inflammation was significantly attenuated in the group which received intraperitoneal AXT injection prior to MSU crystal stimulation compared to the group which received MSU only. These results indicate that AXT attenuates the effects of MSU crystal-induced inflammation by suppressing the production of pro-inflammatory cytokines and inflammatory mediators. Our findings that the anti-inflammatory activities of AXT may be beneficial in the treatment of MSU crystal-induced arthritis.
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http://dx.doi.org/10.1096/fj.202000558RRDOI Listing
August 2020

A preliminary study of Parkinson's gene therapy via sono-magnetic sensing gene vector for conquering extra/intracellular barriers in mice.

Brain Stimul 2020 May - Jun;13(3):786-799. Epub 2020 Feb 24.

Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Background: Non-virus genetic treatment for Parkinson's disease (PD) via plasmid glial cell-line derived neurotrophic factor (pGDNF) has shown potential for repairing damaged dopaminergic neurons. However, development of this gene therapy is largely hampered by the insufficient transfection efficiency as a result of the cell membrane, lysosome, and cytoskeleton meshwork.

Methods: In this study, we propose the use of polyethylenimine (PEI)-superparamagnetic iron oxide-plasmid DNA (pDNA)-loaded microbubbles (PSp-MBs) in conjunction with focused ultrasound (FUS) and two-step magnetic navigation to provide cavitation, proton sponge effect and magnetic effects to increase the efficiency of gene delivery.

Results: The gene transfection rate in the proposed system was 2.2-fold higher than that of the commercial agent (TransIT®-LT1). The transfection rate could be boosted ∼11%, ∼10%, and 6% by cavitation-magnetic hybrid enhanced cell membrane permeabilization, proton sponge effect, and magnetic-assisted cytoskeleton-reorganization, respectively. In vivo data suggested that effective gene delivery with this system results in a 3.2-fold increase in recovery of dopaminergic neurons and a 3.9-fold improvement in the motor behavior when compared to untreated genetic PD mice.

Conclusions: We proposed that this novel FUS-magnetic hybrid gene delivery platform could be integrated with a variety of therapeutic genes for treating neurodegenerative diseases in the future.
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http://dx.doi.org/10.1016/j.brs.2020.02.024DOI Listing
November 2020

Early transcranial direct current stimulation treatment exerts neuroprotective effects on 6-OHDA-induced Parkinsonism in rats.

Brain Stimul 2020 May - Jun;13(3):655-663. Epub 2020 Feb 6.

School of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background: Transcranial direct current stimulation (tDCS) has been proven to be able to modulate motor cortical plasticity might have potential as an alternative, adjunctive therapy for Parkinson's disease (PD). However, the efficacy of tDCS in PD is still uncertain. A disease animal model may be useful to clarify the existence of a treatment effect and to explore an effective therapeutic strategy using tDCS protocols.

Objective: The current study was designed to identify the comprehensive therapeutic effects of tDCS in 6-hydroxydopamine (6-OHDA)-lesioned PD rats.

Methods: Following early and long-term tDCS application (starting 24 h after PD lesion, 300 μA anodal tDCS, 20 min/day, 5 days/week) in awake PD animals for a total of 4 weeks, the effects of tDCS on motor and non-motor behaviors as well as dopaminergic neuron degeneration levels, were identified.

Results: We found that the 4-week tDCS intervention significantly alleviated 6-OHDA-induced motor deficits in locomotor activity, akinesia, gait pattern and anxiety-like behavior, but not in apomorphine-induced rotations, recognition memory and depression-like behavior. Immunohistochemically, tyrosine hydroxylase (TH)-positive neurons in the substantia nigra were significantly preserved in the tDCS intervention group.

Conclusions: These results suggest that early and long-term tDCS could exert neuroprotective effects and reduce the aggravation of motor dysfunctions in a 6-OHDA-induced PD rat model. Furthermore, this preclinical model may enhance the promising possibility of the potential use of tDCS and serve as a translational platform to further identify the therapeutic mechanism of tDCS for PD or other neurological disorders.
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http://dx.doi.org/10.1016/j.brs.2020.02.002DOI Listing
November 2020

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson's Disease.

Brain Sci 2020 Apr 1;10(4). Epub 2020 Apr 1.

Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

Parkinson's disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.
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http://dx.doi.org/10.3390/brainsci10040206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226147PMC
April 2020

Neuromodulatory Effects of Transcranial Direct Current Stimulation on Motor Excitability in Rats.

Neural Plast 2019 17;2019:4252943. Epub 2019 Dec 17.

School of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan.

Transcranial direct current stimulation (tDCS) is a noninvasive technique for modulating neural plasticity and is considered to have therapeutic potential in neurological disorders. For the purpose of translational neuroscience research, a suitable animal model can be ideal for providing a stable condition for identifying mechanisms that can help to explore therapeutic strategies. Here, we developed a tDCS protocol for modulating motor excitability in anesthetized rats. To examine the responses of tDCS-elicited plasticity, the motor evoked potential (MEP) and MEP input-output (IO) curve elicited by epidural motor cortical electrical stimulus were evaluated at baseline and after 30 min of anodal tDCS or cathodal tDCS. Furthermore, a paired-pulse cortical electrical stimulus was applied to assess changes in the inhibitory network by measuring long-interval intracortical inhibition (LICI) before and after tDCS. In the results, analogous to those observed in humans, the present study demonstrates long-term potentiation- (LTP-) and long-term depression- (LTD-) like plasticity can be induced by tDCS protocol in anesthetized rats. We found that the MEPs were significantly enhanced immediately after anodal tDCS at 0.1 mA and 0.8 mA and remained enhanced for 30 min. Similarly, MEPs were suppressed immediately after cathodal tDCS at 0.8 mA and lasted for 30 min. No effect was noted on the MEP magnitude under sham tDCS stimulation. Furthermore, the IO curve slope was elevated following anodal tDCS and presented a trend toward diminished slope after cathodal tDCS. No significant differences in the LICI ratio of pre- to post-tDCS were observed. These results indicated that developed tDCS schemes can produce consistent, rapid, and controllable electrophysiological changes in corticomotor excitability in rats. This newly developed tDCS animal model could be useful to further explore mechanical insights and may serve as a translational platform bridging human and animal studies, establishing new therapeutic strategies for neurological disorders.
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http://dx.doi.org/10.1155/2019/4252943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942908PMC
September 2020

Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus Renders Neuroprotection through the Suppression of Hippocampal Apoptosis: An Experimental Animal Study.

Brain Sci 2020 Jan 2;10(1). Epub 2020 Jan 2.

School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.

The core objective of this study was to determine the neuroprotective properties of deep brain stimulation of the pedunculopontine tegmental nucleus on the apoptosis of the hippocampus. The pedunculopontine tegmental nucleus is a prime target for Parkinson's disease and is a crucial component in a feedback loop connected with the hippocampus. Deep brain stimulation was employed as a potential tool to evaluate the neuroprotective properties of hippocampal apoptosis. Deep brain stimulation was applied to the experimental animals for an hour. Henceforth, the activity of Caspase-3, myelin basic protein, Bcl-2, BAX level, lipid peroxidation, interleukin-6 levels, and brain-derived neurotrophic factor levels were evaluated at hours 1, 3 and 6 and compared with the sham group of animals. Herein, decreased levels of caspases activity and elevated levels of Bcl-2 expressions and inhibited BAX expressions were observed in experimental animals at the aforementioned time intervals. Furthermore, the ratio of Bcl-2/BAX was increased, and interleukin -6, lipid peroxidation levels were not affected by deep brain stimulation in the experimental animals. These affirmative results have explained the neuroprotection rendered by hippocampus apoptosis as a result of deep brain stimulation. Deep brain stimulation is widely used to manage neuro-motor disorders. Nevertheless, this novel study will be a revelation for a better understanding of neuromodulatory management and encourage further research with new dimensions in the field of neuroscience.
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http://dx.doi.org/10.3390/brainsci10010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016688PMC
January 2020

Long-Term Voluntary Physical Exercise Exerts Neuroprotective Effects and Motor Disturbance Alleviation in a Rat Model of Parkinson's Disease.

Behav Neurol 2019 5;2019:4829572. Epub 2019 Dec 5.

Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder affecting 7-10 million individuals. The pathologic hallmark of PD is nigrostriatal dopaminergic neuron loss, leading to several motor and nonmotor disturbances, such as akinesia, gait disturbance, depression, and anxiety. Recent animal studies have demonstrated that physical exercise improves behavioral and neuropathological deficits in PD. However, the exact underlying mechanism underlying this effect remains unclear. In this study, we investigated whether long-term exercise has neuroprotective effects on dopaminergic nigrostriatal neurons and whether it further alleviates impairment of the gait pattern, locomotor activity, akinesia, and anxiety-like behavior in PD rats.

Methods: A hemiparkinsonian rat model, generated by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to evaluate neuroprotective effects and motor behaviors. Comprehensive spatiotemporal gait analysis, open-field locomotor activity, akinesia, apomorphine-induced rotational analysis, and dopaminergic neuron degeneration level were assessed every week and up to 8 weeks after daily voluntary running wheel exercise.

Results: Compared with the sham-treated group, we found that 10 weeks of voluntary exercise (i.e., 2-week exercise before PD lesion and 8-week exercise post-PD lesion) significantly reduced 6-OHDA-induced motor deficits in the gait pattern, akinesia, and rotational behavior in the exercise group. Immunohistochemically, a tyrosine hydroxylase-positive neuron in the substantia nigra was significantly preserved in the exercise group.

Conclusions: Our results demonstrated that long-term exercise training is effective for neuroprotection and further attenuates motor declines induced by 6-OHDA in an experimental model of PD. Our data further highlighted potential therapeutic effects of long-term physical exercise relevant to clinical effects for further potential application on human PD subjects.
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http://dx.doi.org/10.1155/2019/4829572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915149PMC
May 2020

Cystometric Measurements in Rats with an Experimentally Induced Traumatic Brain Injury and Voiding Dysfunction: A Time-Course Study.

Brain Sci 2019 Nov 14;9(11). Epub 2019 Nov 14.

School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei-11031, Taiwan.

Traumatic brain injuries (TBIs) are a serious public health issue worldwide with increased mortality as well as severe disabilities and injuries caused by falls and road accidents. Unfortunately, there is no approved therapy for TBIs, and bladder dysfunction is a striking symptom. Accordingly, we attempted to analyze bladder dysfunction and voiding efficiency in rats with a TBI at different time-course intervals. Time-dependent analyses were scheduled from the next day until four weeks after a TBI. Experimental animals were grouped and analyzed under the above conditions. Cystometric measurements were used for this analysis and were further elaborated as external urethral sphincter electromyographic (EUS-EMG) activity and cystometrogram (CMG) measurements. Moreover, magnetic resonance imaging (MRI) studies were conducted to investigate secondary injury progression in TBI rats, and results were compared to normal control (NC) rats. Results of EUS-EMG revealed that the burst period, active period, and silent period in TBI rats were drastically reduced compared to NC rats, but they increased later and reached a stagnant phase. Likewise, in CMG measurements, bladder function, the voided volume, and voiding efficiency decreased immediately after the TBI, and other parameters like the volume threshold, inter-contraction interval, and residual volume drastically increased. Later, those levels changed, and all observed results were compared to NC rats. MRI results revealed the prevalence of cerebral edema and the progression of secondary injury. All of the above-stated results of the experiments were extensively substantiated. Thus, these innovative findings of our study model will surely pave the way for new therapeutic interventions for TBI treatment and prominently highlight their applications in the field of neuroscience in the future.
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http://dx.doi.org/10.3390/brainsci9110325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895874PMC
November 2019

Transcranial focused ultrasound pulsation suppresses pentylenetetrazol induced epilepsy in vivo.

Brain Stimul 2020 Jan - Feb;13(1):35-46. Epub 2019 Sep 24.

Department of Electrical Engineering, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. Electronic address:

Background: Epilepsy is a neurological disorder characterized by abnormal neuron discharge, and one-third of epilepsy patients suffer from drug-resistant epilepsy (DRE). The current management for DRE includes epileptogenic lesion resection, disconnection, and neuromodulation. Neuromodulation is achieved through invasive electrical stimulus including deep brain stimulation, vagus nerve stimulation, or responsive neurostimulation (RNS). As an alternative therapy, transcranial focused ultrasound (FUS) can transcranially and non-invasively modulate neuron activity.

Objective: This study seeks to verify the use of FUS pulsations to suppress spikes in an acute epileptic small-animal model, and to investigate possible biological mechanisms by which FUS pulsations interfere with epileptic neuronal activity.

Methods: The study used a total of 76 Sprague-Dawley rats. For the epilepsy model, rats were administered pentylenetetrazol (PTZ) to induce acute epileptic-like abnormal neuron discharges, followed by FUS exposure. Various ultrasound parameters were set to test the epilepsy-suppressing effect, while concurrently monitoring and analyzing electroencephalogram (EEG) signals. Animal behavior was monitored and histological examinations were conducted to evaluate the hazard posed by ultrasound exposure and the expression of neuronal activity markers. Western blotting was used to evaluate the correlation between FUS-induced epileptic suppression and the PI3K-mTOR signaling pathway.

Results: We observed that FUS pulsations effectively suppressed epileptic activity and observed EEG spectrum oscillations; the spike-suppressing effect depended on the selection of ultrasound parameters and highly correlated with FUS exposure level. Expression level changes of c-Fos and GAD65 were confirmed in the cortex and hippocampus, indicating that FUS pulsations deactivated excitatory cells and activated GABAergic terminals. No tissue damage, inflammatory response, or behavioral abnormalities were observed in rats treated with FUS under these exposure parameters. We also found that the FUS pulsations down-regulated the S6 phosphorylation and decreased pAKT expression.

Conclusion: Our results suggest that pulsed FUS exposure effectively suppresses epileptic spikes in an acute epilepsy animal model, and finds that ultrasound pulsation interferes with neuronal activity and affects the PTZ-induced PI3K-Akt-mTOR pathway, which might help explain the mechanism underlying ultrasound-related epileptic spike control.
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http://dx.doi.org/10.1016/j.brs.2019.09.011DOI Listing
June 2020

Voluntary exercise delays progressive deterioration of markers of metabolism and behavior in a mouse model of Parkinson's disease.

Brain Res 2019 10 18;1720:146301. Epub 2019 Jun 18.

Core Laboratory of Neuroscience, Office of R&D, Taipei Medical University, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address:

Although a good deal is known about the genetics and pathophysiology of Parkinson's disease (PD), and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained capacity to prevent or attenuate the ongoing neurodegenerative processes. However, there is accumulating clinical results to suggest that physical exercise is such a treatment, and studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD further support this hypothesis. Exercise is a non-pharmacological, economically practical, and sustainable intervention with little or no risk and with significant additional health benefits. In this study, we investigated the long-term effects of voluntary exercise on motor behavior and brain biochemistry in the transgenic MitoPark mouse PD model with progressive degeneration of the DA systems caused by DAT-driven deletion of the mitochondrial transcription factor TFAM in DA neurons. We found that voluntary exercise markedly improved behavioral function, including overall motor activity, narrow beam walking, and rotarod performance. There was also improvement of biochemical markers of nigrostriatal DA input. This was manifested by increased levels of DA measured by HPLC, and of the DA membrane transporter measured by PET. Moreover, exercise increased oxygen consumption and, by inference, ATP production via oxidative phosphorylation. Thus, exercise augmented aerobic mitochondrial oxidative metabolism vs glycolysis in the nigrostriatal system. We conclude that there are clear-cut physiological mechanisms for beneficial effects of exercise in PD.
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http://dx.doi.org/10.1016/j.brainres.2019.146301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702069PMC
October 2019

Designing and Implementing a Novel Transcranial Electrostimulation System for Neuroplastic Applications: A Preliminary Study.

IEEE Trans Neural Syst Rehabil Eng 2019 05 2;27(5):805-813. Epub 2019 Apr 2.

Recently, a specific repetitive transcranial magnetic stimulation (rTMS) waveform, namely, the theta burst stimulation (TBS) protocol, has been proposed for more efficiently inducing neuroplasticity for various clinic rehabilitation purposes. However, few studies have explored the feasibility of using the TBS combined with direct current (dc) waveform for brain neuromodulation; this waveform is transcranially delivered using electrical current power rather than magnetic power. This study implemented a prototype of a novel transcranial electrostimulation device that can flexibly output a waveform that combined dc and the TBS-like protocol and assessed the effects of the novel combinational waveform on neuroplasticity. An in vivo experiment was conducted first to validate the accuracy of the stimulator's current output at various impedance loads. Using this transcranial stimulator, a series of transcranial stimulation experiments was conducted on the brain cortex of rats, in which electrode-tissue impedance and motor evoked potentials (MEPs) were measured. These experiments were designed to assess the feasibility and efficacy of the new combinational waveforms for brain neuroplasticity. Our results indicated that the transcranial electrostimulation system exhibited satisfactory performance, as evidenced by the error percentage of less than 5% for current output. In the animal experiment, the dc combined with intermittent TBS-like protocol exerted a stronger neuroplastic effect than the conventional dc protocol. These results demonstrated that the combination of electrical dc and TBS-like protocols in our system can produce a new feasible therapeutic waveform for transcranially inducing a promising neuromodulatory effect on various diseases of the central nervous system.
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http://dx.doi.org/10.1109/TNSRE.2019.2908674DOI Listing
May 2019

Release parameters during progressive degeneration of dopamine neurons in a mouse model reveal earlier impairment of spontaneous than forced behaviors.

J Neurochem 2019 07 9;150(1):56-73. Epub 2019 May 9.

Graduate Program on Neuroregeneration, Taipei Medical University, Taipei, Taiwan, R.O.C.

To determine the role of reduced dopaminergic transmission for declines of forced versus spontaneous behavior, we used a model of Parkinson's disease with progressive degeneration of dopamine (DA) neurons, the MitoPark mouse. Mice were subjected to rotarod tests of motor coordination, and open field and cylinder tests for spontaneous locomotor activity and postural axial support. To measure DA release in dorsal striatum and the shell of Nucleus Accumbens (NAc), we used ex vivo fast-scan cyclic voltammetry in 6- to 24-week-old mice. To determine decline of DA transporter function, we used 18FE-PE2I positron emission tomography. We show here that fast-scan cyclic voltammetry is a sensitive tool to detect evoked DA release dysfunction in MitoPark mice and that electrically evoked DA release is affected earlier in nigrostriatal than mesolimbic DA systems. DA reuptake was also affected more slowly in NAc shell. Positron emission tomography data showed DA uptake to be barely above detection levels in 16- and 20-week-old MitoPark mice. Rotarod performance was not impaired until mice were 16 weeks old, when evoked DA release in striatum had decreased to ≈ 40% of wild-type levels. In contrast, impairment of open field locomotion and rearing began at 10 weeks, in parallel with the initial modest decline of evoked DA release. We conclude that forced behaviors, such as motivation not to fall, can be partially maintained even when DA release is severely compromised, whereas spontaneous behaviors are much more sensitive to impaired DA release, and that presumed secondary non-dopaminergic system alterations do not markedly counteract or aggravate effects of severe impairment of DA release. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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http://dx.doi.org/10.1111/jnc.14702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592720PMC
July 2019

Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model.

Cereb Cortex 2019 12;29(11):4506-4518

Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Neuromodulation Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.
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http://dx.doi.org/10.1093/cercor/bhy328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150617PMC
December 2019

Improved voiding function by deep brain stimulation in traumatic brain-injured animals with bladder dysfunctions.

Int Urol Nephrol 2019 Jan 24;51(1):41-52. Epub 2018 Nov 24.

School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.

Objective: Traumatic brain injury (TBI) is a global scenario with high mortality and disability, which does not have an effectual and approved therapy till now. Bladder dysfunction is a major symptom after TBI, and this study deals with the alleviation of bladder function in TBI rats, with the aid of deep brain stimulations (DBS).

Methods: TBI was induced by weight drop model (WDM) and standardized with the experimental subjects with variable heights for weight dropping. The rats survived after TBI were considered for bladder dysfunction observations. DBS with variable stimulation parameters like cystometric analysis and MRI studies were also performed.

Results: After experimental studies, TBI 2-m-height crash was determined as suitable parameter due to minimal mortality rate and significant reduction in the voiding efficiency from 67 to 28%, whereas DBS significantly reversed the value of voiding efficiency to 65-84%. MRI studies revealed the severity of TBI impact and DBS localization.

Conclusion: The results showed profound therapeutic effect of PnO-DBS on voiding functions and bladder control on TBI rats.
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http://dx.doi.org/10.1007/s11255-018-2028-1DOI Listing
January 2019

Modulation of motor excitability by cortical optogenetic theta burst stimulation.

PLoS One 2018 30;13(8):e0203333. Epub 2018 Aug 30.

Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

Intermittent theta burst stimulation (iTBS) and continuous theta burst stimulation (cTBS) are protocols used in repetitive transcranial magnetic stimulation (rTMS) or cortical electrical stimulation (CES) to facilitate or suppress corticospinal excitability. However, rTMS and CES excite all types of neuron in the target cortex probed by the coil or electrode, making it difficult to differentiate the effect of TBS on specific neural circuits involved in motor plasticity. In this study, TBS protocols were converted into an optogenetic model to achieve focalized and cell-type-specific cortical modulation. Light-sensitive channelrhodopsin-2 (ChR2) was expressed in the glutamatergic neuron in the primary motor cortex (M1) driven by the CaMKIIα promoter. A custom-made optrode comprising an optical fiber and a metal cannula electrode was fabricated to achieve optogenetic stimulation and simultaneous local field potential (LFP) recording. Single-pulse CES was delivered into M1 to elicit motor-evoked potential (MEP), which served as an indicator of motor excitability, before and after TBS intervention. Results show that both CES-iTBS and optogenetic iTBS (Opto-iTBS) can potentiate MEP activity. However, CES-cTBS suppressed MEP activity whereas Opto-cTBS enhanced it. This discrepancy may have resulted from the different neural networks targeted by the two TBS modalities, with CES-cTBS exciting all types of neuron and Opto-cTBS targeting excitatory neuron specifically. The results support the idea that intra-cortical networks determine the variation of TBS-induced neuroplasticity. This study shows that focalized and cell-type-specific brain stimulation using the optogenetic approach is viable and can be extended for further exploration of neuroplasticity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117070PMC
February 2019

Differences in Nicotine Encoding Dopamine Release between the Striatum and Shell Portion of the Nucleus Accumbens.

Cell Transplant 2019 03 28;28(3):248-261. Epub 2018 May 28.

5 Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague-Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared. In both structures, tonic release was suppressed by inhibition of the nicotine receptor (via Mec) and the α4β2 receptor (via DHβe). Paired-pulse ratio (PPR) was facilitated in both structures after nicotine and Mec infusion, and this facilitation was suppressed by increasing the stimulation interval. After variable frequency stimulation (simulating phasic burst), nicotine infusion induced significant augmentation of DA release in the striatum that was not seen in the absence of nicotine. In contrast, nicotine reduced phasic DA release in NAc, although frequency augmentation was seen both with and without nicotine. Evaluation of DA release evoked by various trains (high-frequency stimulation (HFS) 100 Hz) of high-frequency stimulation revealed significant enhancement after a train of three or more pulses in the striatum and NAc. The concentration differences between tonic and phasic release related to nicotine desensitization were more pronounced in the NAc shell. Nicotine desensitization is associated with suppression of tonic release of DA in both the striatum and NAc shell that may occur via the α4β2 subtype of nAChR, whereas phasic frequency-dependent augmentation and HFS-related gating release is more pronounced in the striatum than in the NAc shell. Differences between phasic and tonic release associated with nicotine desensitization may underlie processing of reward signals in the NAc shell, and this may have major implications for addictive behavior.
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http://dx.doi.org/10.1177/0963689718775382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425113PMC
March 2019

Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats.

Int J Mol Sci 2018 Apr 11;19(4). Epub 2018 Apr 11.

The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP) was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA) hemi-parkinsonian (PD) rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c.) using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB). The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA) lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development.
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http://dx.doi.org/10.3390/ijms19041153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979480PMC
April 2018

Exercise Ameliorates Motor Deficits and Improves Dopaminergic Functions in the Rat Hemi-Parkinson's Model.

Sci Rep 2018 03 5;8(1):3973. Epub 2018 Mar 5.

Graduate Program on Neuroregeneration, Taipei Medical University, Taipei, Taiwan.

To determine the influences of exercise on motor deficits and dopaminergic transmission in a hemiparkinson animal model, we measured the effects of exercise on the ambulatory system by estimating spatio-temporal parameters during walking, striatal dopamine (DA) release and reuptake and synaptic plasticity in the corticostriatal pathway after unilateral 6-OHDA lesions. 6-OHDA lesioned hemiparkinsonian rats were exercised on a fixed speed treadmill for 30 minutes per day. Controls received the same lesion but no exercise. Animals were subsequently analyzed for behavior including gait analysis, rotarod performance and apomorphine induced rotation. Subsequently, in vitro striatal dopamine release was analyzed by using FSCV and activity-dependent plasticity in the corticostriatal pathway was measured in each group. Our data indicated that exercise could improve motor walking speed and increase the apomorphine-induced rotation threshold. Exercise also ameliorated spatiotemporal impairments in gait in PD animals. Exercise increased the parameters of synaptic plasticity formation in the corticostriatal pathway of PD animals as well as the dynamics of dopamine transmission in PD animals. Fixed speed treadmill training 30 minutes per day could ameliorate spatial-temporal gait impairment, improve walking speed, dopamine transmission as well as corticostriatal synaptic plasticity in the unilateral 6-OHDA lesioned rat model.
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http://dx.doi.org/10.1038/s41598-018-22462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838260PMC
March 2018

Voluntary Physical Exercise Improves Subsequent Motor and Cognitive Impairments in a Rat Model of Parkinson's Disease.

Int J Mol Sci 2018 Feb 8;19(2). Epub 2018 Feb 8.

The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Background: Parkinson's disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease.

Methods: In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD.

Results: We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA-induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group.

Conclusions: We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model.
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http://dx.doi.org/10.3390/ijms19020508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855730PMC
February 2018

Feasibility of deep brain stimulation for controlling the lower urinary tract functions: An animal study.

Clin Neurophysiol 2017 12 30;128(12):2438-2449. Epub 2017 Sep 30.

Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan; School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address:

Objective: To evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg).

Methods: A bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings.

Results: PAG DBS at 2-2.5 V, PnO DBS at 2-2.5 V, and PPTg DBS at 1.75-2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5-5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions.

Conclusion: PPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions.

Significance: DBS could be a potential approach to manage bladder function under various conditions.
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http://dx.doi.org/10.1016/j.clinph.2017.09.102DOI Listing
December 2017

Relationship of mechanical impact magnitude to neurologic dysfunction severity in a rat traumatic brain injury model.

PLoS One 2017 26;12(5):e0178186. Epub 2017 May 26.

Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan.

Objective: Traumatic brain injury (TBI) is a major brain injury type commonly caused by traffic accidents, falls, violence, or sports injuries. To obtain mechanistic insights about TBI, experimental animal models such as weight-drop-induced TBI in rats have been developed to mimic closed-head injury in humans. However, the relationship between the mechanical impact level and neurological severity following weight-drop-induced TBI remains uncertain. In this study, we comprehensively investigated the relationship between physical impact and graded severity at various weight-drop heights.

Approach: The acceleration, impact force, and displacement during the impact were accurately measured using an accelerometer, a pressure sensor, and a high-speed camera, respectively. In addition, the longitudinal changes in neurological deficits and balance function were investigated at 1, 4, and 7 days post TBI lesion. The inflammatory expression markers tested by Western blot analysis, including glial fibrillary acidic protein, beta-amyloid precursor protein, and bone marrow tyrosine kinase gene in chromosome X, in the frontal cortex, hippocampus, and corpus callosum were investigated at 1 and 7 days post-lesion.

Results: Gradations in impact pressure produced progressive degrees of injury severity in the neurological score and balance function. Western blot analysis demonstrated that all inflammatory expression markers were increased at 1 and 7 days post-impact injury when compared to the sham control rats. The severity of neurologic dysfunction and induction in inflammatory markers strongly correlated with the graded mechanical impact levels.

Conclusions: We conclude that the weight-drop-induced TBI model can produce graded brain injury and induction of neurobehavioral deficits and may have translational relevance to developing therapeutic strategies for TBI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446124PMC
September 2017

Trajectory of Parvalbumin Cell Impairment and Loss of Cortical Inhibition in Traumatic Brain Injury.

Cereb Cortex 2017 12;27(12):5509-5524

Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Many neuropsychiatric symptoms that follow traumatic brain injury (TBI), including mood disorders, sleep disturbance, chronic pain, and posttraumatic epilepsy (PTE) are attributable to compromised cortical inhibition. However, the temporal trajectory of cortical inhibition loss and its underlying mechanisms are not known. Using paired-pulse transcranial magnetic stimulation (ppTMS) and immunohistochemistry, we tracked functional and cellular changes of cortical inhibitory network elements after fluid-percussion injury (FPI) in rats. ppTMS revealed a progressive loss of cortical inhibition as early as 2 weeks after FPI. This profile paralleled the increasing levels of cortical oxidative stress, which was accompanied by a gradual loss of parvalbumin (PV) immunoreactivity in perilesional cortex. Preceding the PV loss, we identified a degradation of the perineuronal net (PNN)-a specialized extracellular structure enwrapping cortical PV-positive (PV+) inhibitory interneurons which binds the PV+ cell maintenance factor, Otx2. The trajectory of these impairments underlies the reduced inhibitory tone, which can contribute to posttraumatic neurological conditions, such as PTE. Taken together, our results highlight the use of ppTMS as a biomarker to track the course of cortical inhibitory dysfunction post-TBI. Moreover, the neuroprotective role of PNNs on PV+ cell function suggests antioxidant treatment or Otx2 enhancement as a promising prophylaxis for post-TBI symptoms.
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http://dx.doi.org/10.1093/cercor/bhw318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075565PMC
December 2017
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