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Is the contralesional hemisphere a suitable target for noninvasive brain stimulation after stroke?
Abstracts / Brain Stimulation 8 (2015) 326e342
Going forward, future trials need to focus efforts on providing a link between the intended neuromodulatory effect of their chosen treatment protocol and known mechanisms of migraine pathogenesis.
93 Deep repetitive transcranial magnetic stimulation (rTMS) to bilateral dorsomedial prefrontal cortex in autism spectrum disorder Peter G. Enticott a,b, Bernadette M. Fitzgibbon b, Melissa Kirkovski a,b, Amity Green b, David Elliot b, Abraham Zangen c, Paul B. Fitzgerald b a Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne, Australia b Monash Alfred Psychiatry Research Centre, The Alfred and Central Clinical School, Monash University, Melbourne, Australia c Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Autism spectrum disorder (ASD) is characterised by impairments in social relating, which have been linked to abnormal activation within ‘social brain’ networks that include dorsomedial prefrontal cortex (dmPFC). Despite a high prevalence (currently 1 in 68 children), at present there are no validated biomedical treatments for ASD that target core symptoms. Across two studies, we investigated whether high-frequency (5 Hz) stimulation of bilateral dmPFC, using a deep rTMS coil to achieve the necessary depth of stimulation, could induce clinical, cognitive, and neurobiological changes among ‘high-functioning’ adults with ASD. Study One involved a randomised, sham-controlled clinical trial of deep rTMS to bilateral dmPFC in 28 adults with ASD. Participants received active or sham deep rTMS each weekday for two weeks. Clinical and cognitive assessments were conducted before, after, and one-month following the treatment phase. There was a significant decrease in self-reported clinical ratings of social impairment for those in the active condition, but no change for participants allocated to sham stimulation. Study Two was an open-label study where 12 adults with ASD received 16 active treatments over 4 weeks. Participants underwent positron emission tomography (PET) to assess brain glucose metabolism before and after the treatment course, while clinical and cognitive assessments were conducted before, after, 1-month, 3-months, and 6-months following treatment. Preliminary findings indicate a number of clinical and cognitive improvements, and associated changes in neural activity. These data provide preliminary support for the safety and efficacy of deep rTMS to dmPFC in ASD, and suggest effects on neural networks that support the integration and understanding of social information.
94 Age influence on the quadri-pulse stimulation (QPS) induced LTP like effect R. Hanajima a,b, N. Tanaka b, R. Tsutsumi a, H. Enomoto c, M. Abe c, K. Nakamura c, S. Kobayashi c, M. Hamada b, T. Shimizu b, Y. Terao b, Y. Ugawa c a Department of Neurology Kitasato University School of Medicine, Kanagawa b Department of Neurology, The University of Tokyo, Tokyo c Department of Neurology, Fukushima Medical University, Fukushima Introduction: The inter-individual variability is one of topics in the human neuro-plasticity induced by non-invasive brain stimulation (NIBS). Almost half participants did not show expected plasticity after the theater burst stimulation (TBS) or paired associative stimulation (PAS) (“non-responder”). In this paper, we studied the
335
inter-individual variability of QPS, especially focusing the subject’s age effect on the variability of QPS. Methods: The subjects were 92 healthy volunteers (Grop1: 16 participants around 35 years of age, Group2: 23 round 45yrs and Group3: 53 around 65yrs.) We gave repeated bursts of four monophasic TMS pulses separated by inter-pulse intervals of 5ms every 5sec for 30minutes (QPS-5). We measured 10 MEPs before and at 6 time points after QPS up to 30minuts. We evaluated all the subjects as a responder or non-responder following a previous paper’s criteria. “Non-responder” was defined as the ones whose average MEP ratio (5-30 minutes) was equal or less than 1. We also compared the degree of MEP enhancement between the above three groups. Results: Among all participants, the rate of responders was 68% (non-responders 32%). The rate of responders was 88% (nonresponder 12%) for Group 1, 74% (non-responder 26%) for group 2 and 58% (non-responder 42%) for group 3. The average size ratio (5-30 minutes) was 1.54, 1.74and 1.25 for group 1, 2, 3, respectively. The older the subjects were, the smaller was the size ratio. Conclusion: The age of the subject considerably affected the long term potentiation (LTP) like effect induced by QPS5. QPS5 induces the LTP like effect more constantly than other NIBS methods.
95 Is the contralesional hemisphere a suitable target for noninvasive brain stimulation after stroke? Winston D. Byblow a,c, Cathy M. Stinear b,c a Department of Sport & Exercise Science, University of Auckland, Auckland, New Zealand b Department of Medicine, University of Auckland, Auckland, New Zealand c Centre for Brain Research, University of Auckland, Auckland, New Zealand Stroke is the leading cause of adult disability and there are no treatments that can repair neural damage that results from stroke. Functional recovery for many patients is modest and therefore adjuvants to traditional therapies are urgently required. This talk will revisit the use of non-invasive brain stimulation (NIBS) as a potential adjuvant for stroke rehabilitation, which is well documented in clinical neurophysiological research, but not routinely used in clinical practice. One tenet is that functional restoration may be enhanced using techniques that increase excitability in the hemisphere in which the lesion has occurred, through LTP-like mechanisms, and this has led to some promising outcomes. Perhaps more contentious is the idea that the nonstroke (contralesional) hemisphere is also a target for NIBS that aim to suppress neuronal excitability. This idea is fostered by a model of interhemispheric competition that espouses an elevation in neural excitability within the contralesional hemisphere. The majority of neurophysiological studies investigating interhemispheric imbalance have been conducted with patients at the chronic stage after stroke, with only a few exceptions. The heightened contralesional excitability may reflect neurophysiological processes that exacerbate functional deficits through interhemispheric competition (via transcallosal inhibition). However, at the chronic stage these changes might also reflect a pattern of use (i.e., learned non-use of the weak or paretic side) and activity-dependent plastic reorganisation in the non-stroke hemisphere. From recent studies of motor neurophysiology, I will describe how the contralesional hemisphere may be a viable target for excitability suppression at the chronic stage, but that this is not ‘one-size-fits-all’. Finally, I will present neurophysiological and clinical data from a large sample of patients spanning
336
Abstracts / Brain Stimulation 8 (2015) 326e342
the initial days, weeks and months at the sub-acute stage after stroke. These data indicate interhemispheric imbalance is driven primarily, if not exclusively through diminished excitability in the lesioned hemisphere.
96 The mechanism of functional recovery of upper extremity motor function among patients with chronic stroke: Modulation of cortical and spinal interneuron Toshiyuki Fujiwara MD, PhD a, Kaoru Honaga MD, PhD b, Michiyuki Kawakami MD, PhD b, Atsuko Nishimoto b, Kaoru Abe c, Katsuhiro Mizuno MD, PhD b, Mitsuhiko Kodama MD, PhD a, Yoshihisa MasakadoMD PhD a, Tetsuya Tsuji MD, PhD b, Meigen Liu MD, PhD b a Department of Rehabilitation Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193 Japan b Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8587 Japan c Department of Rehabilitation Medicine, Keio University Hospital, 35 Shinanomachi, Shinjuku, Tokyo 160-8587 Japan Background: We hypothesized that functional recovery of upper extremity motor function is based on cortical and spinal plasticity. Objectives: The purpose of this study was to investigate the roles of intracortical inhibition and reciprocal inhibition in functional recovery. Methods: Participants were 61 patients with chronic hemiparetic stroke. The participants were applied hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy for 3 weeks. The FuglMeyer test upper extremity motor score (FM) and modified Ashworth scale (MAS) were assessed before (T0), immediately after (T1) and 3 months after (T2) the end of HANDS therapy. A paired pulse TMS paradigm was applied to assess short intracortical inhibition (SICI). Reciprocal inhibition (RI) was assessed with H reflex conditioning-test paradigm. Results: FM and MAS were improved until T2. The change of FM from T0 to T2 was correlated with the change in affected SICI from T0 toT1. The change of wrist MAS from T0 to T1 was correlated with the change of RI. Conclusions: In chronic stroke patients with moderate or severe hemiparesis, functional improvement of upper extremity were based on cortical and spinal plasticity.
97 The BDNF Val66Met polymorphism modulates motor cortex plasticity, induced by prolonged anodal transcranial direct current stimulation, in older adults R. Puri a, M.R. Hinder a, J.J. Summers a,b a University of Tasmania, Australia b Liverpool John Moores University, UK Introduction: The brain derived neurotrophic factor (BDNF) Val66Met polymorphism is thought to play an important role in modulating cortical plasticity induced by non-invasive brain stimulation (NIBS) in younger adults. Additionally, the intensity and duration of stimulation are also key determinants of NIBS-induced plasticity. However, little is known of the impact of these factors on plasticity mechanisms in older adults. Methods: Fifty older adults underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS) over left primary motor cortex for 10 mins and 20 mins. Single pulse transcranial magnetic stimulation was used to assess corticospinal excitability before and every 5 minutes for 30 minutes following atDCS.
Results: Overall, Met carriers (n ¼13) showed statistically significant enhanced post-stimulation facilitation compared to Val66Val homozygotes (n ¼ 37). However, this difference was only apparent following 20 mins (p ¼ 0.002) but not 10 mins (p ¼ 0.219) of atDCS. Moreover, Met carriers, but not Val66Val homozygotes, exhibited a significantly greater facilitatory response (p ¼ 0.046) to 20 min atDCS compared to that observed following 10 min atDCS. Discussion: In older adults, the BDNF Val66Met polymorphism plays an important role in modulating motor cortex plasticity. This crucial finding could aid the development of more targeted and efficient NIBS protocols for both healthy and diseased aged populations, which is of particular importance in light of the ageing demographic.
98 Movement speed-dependent modulation on the activity of spinal inhibitory circuits Shinji Kubota a,b, Masato Hirano a, Yoshiki Koizume a, Shigeo Tanabe c, Kozo Funase a a Human Motor Control Laboratory, Division of Human Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, Japan b Research Fellow of the Japan Society for the Promotion of Science c Faculty of Rehabilitation, School of Health Sciences, Fujita Health University, Japan Introduction: The modulation of spinal inhibitory circuit induced by visuomotor training have been shown in previous studies. However, it is not clarified that the changes in spinal inhibitory circuit are affected by movement speed. We hypothesized that the activity of spinal inhibitory circuits would show movement speeddependent changes. Methods: Fourteen healthy subjects participated in the experiment. Each subject was assigned to two groups; (1) slow movement group (0.5Hz rhythm), (2) fast movement group (1.5Hz rhythm). Subjects were instructed to move their ankle as precisely as possible from 10 deg of dorsi-flexion to 10 deg of planter-flexion at 0.5 Hz or 1.5 Hz rhythm for 15 seconds. The training session consisted of six blocks with five trials. The performance was quantified by the difference subtracting from the actual deg and target deg (10 deg of dorsi- and planter-flexion). The degree of reciprocal Ia inhibition, presynaptic inhibition (D1 inhibition) and the ratio of the maximum H-reflex amplitude versus maximum M-wave (Hmax/ Mmax) were recorded before, immediately after, 15 minutes after, and 30 minutes after of the training session. Results: All subject showed improvement in performance across blocks. The degree of D1 inhibition was increased both groups. In contrast, the degree of reciprocal Ia inhibition was only increased in the fast movement group. Hmax/Mmax was not changed after training session. Discussion: Our results indicated that the changes in presynaptic inhibition are not related to movement speed but to the visuomotor training. The movement speed is critical for inducing the activity changes in reciprocal Ia inhibition.
99 The inter-individual variability of quadripulse stimulation (QPS) Enomoto H a, Kadowaki S a, Abe M a, Nakamura K a, Kobayashi S a, Murakami T a, Hanajima R b,c, Terao Y c, Hamada M c, Ugawa Y a a Department of Neurology, Fukushima Medical University, Fukushima b Department of Neurology Kitasato University School of Medicine, Kanagawa c Department of Neurology, The University of Tokyo, Tokyo
Going forward, future trials need to focus efforts on providing a link between the intended neuromodulatory effect of their chosen treatment protocol and known mechanisms of migraine pathogenesis.
93 Deep repetitive transcranial magnetic stimulation (rTMS) to bilateral dorsomedial prefrontal cortex in autism spectrum disorder Peter G. Enticott a,b, Bernadette M. Fitzgibbon b, Melissa Kirkovski a,b, Amity Green b, David Elliot b, Abraham Zangen c, Paul B. Fitzgerald b a Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne, Australia b Monash Alfred Psychiatry Research Centre, The Alfred and Central Clinical School, Monash University, Melbourne, Australia c Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Autism spectrum disorder (ASD) is characterised by impairments in social relating, which have been linked to abnormal activation within ‘social brain’ networks that include dorsomedial prefrontal cortex (dmPFC). Despite a high prevalence (currently 1 in 68 children), at present there are no validated biomedical treatments for ASD that target core symptoms. Across two studies, we investigated whether high-frequency (5 Hz) stimulation of bilateral dmPFC, using a deep rTMS coil to achieve the necessary depth of stimulation, could induce clinical, cognitive, and neurobiological changes among ‘high-functioning’ adults with ASD. Study One involved a randomised, sham-controlled clinical trial of deep rTMS to bilateral dmPFC in 28 adults with ASD. Participants received active or sham deep rTMS each weekday for two weeks. Clinical and cognitive assessments were conducted before, after, and one-month following the treatment phase. There was a significant decrease in self-reported clinical ratings of social impairment for those in the active condition, but no change for participants allocated to sham stimulation. Study Two was an open-label study where 12 adults with ASD received 16 active treatments over 4 weeks. Participants underwent positron emission tomography (PET) to assess brain glucose metabolism before and after the treatment course, while clinical and cognitive assessments were conducted before, after, 1-month, 3-months, and 6-months following treatment. Preliminary findings indicate a number of clinical and cognitive improvements, and associated changes in neural activity. These data provide preliminary support for the safety and efficacy of deep rTMS to dmPFC in ASD, and suggest effects on neural networks that support the integration and understanding of social information.
94 Age influence on the quadri-pulse stimulation (QPS) induced LTP like effect R. Hanajima a,b, N. Tanaka b, R. Tsutsumi a, H. Enomoto c, M. Abe c, K. Nakamura c, S. Kobayashi c, M. Hamada b, T. Shimizu b, Y. Terao b, Y. Ugawa c a Department of Neurology Kitasato University School of Medicine, Kanagawa b Department of Neurology, The University of Tokyo, Tokyo c Department of Neurology, Fukushima Medical University, Fukushima Introduction: The inter-individual variability is one of topics in the human neuro-plasticity induced by non-invasive brain stimulation (NIBS). Almost half participants did not show expected plasticity after the theater burst stimulation (TBS) or paired associative stimulation (PAS) (“non-responder”). In this paper, we studied the
335
inter-individual variability of QPS, especially focusing the subject’s age effect on the variability of QPS. Methods: The subjects were 92 healthy volunteers (Grop1: 16 participants around 35 years of age, Group2: 23 round 45yrs and Group3: 53 around 65yrs.) We gave repeated bursts of four monophasic TMS pulses separated by inter-pulse intervals of 5ms every 5sec for 30minutes (QPS-5). We measured 10 MEPs before and at 6 time points after QPS up to 30minuts. We evaluated all the subjects as a responder or non-responder following a previous paper’s criteria. “Non-responder” was defined as the ones whose average MEP ratio (5-30 minutes) was equal or less than 1. We also compared the degree of MEP enhancement between the above three groups. Results: Among all participants, the rate of responders was 68% (non-responders 32%). The rate of responders was 88% (nonresponder 12%) for Group 1, 74% (non-responder 26%) for group 2 and 58% (non-responder 42%) for group 3. The average size ratio (5-30 minutes) was 1.54, 1.74and 1.25 for group 1, 2, 3, respectively. The older the subjects were, the smaller was the size ratio. Conclusion: The age of the subject considerably affected the long term potentiation (LTP) like effect induced by QPS5. QPS5 induces the LTP like effect more constantly than other NIBS methods.
95 Is the contralesional hemisphere a suitable target for noninvasive brain stimulation after stroke? Winston D. Byblow a,c, Cathy M. Stinear b,c a Department of Sport & Exercise Science, University of Auckland, Auckland, New Zealand b Department of Medicine, University of Auckland, Auckland, New Zealand c Centre for Brain Research, University of Auckland, Auckland, New Zealand Stroke is the leading cause of adult disability and there are no treatments that can repair neural damage that results from stroke. Functional recovery for many patients is modest and therefore adjuvants to traditional therapies are urgently required. This talk will revisit the use of non-invasive brain stimulation (NIBS) as a potential adjuvant for stroke rehabilitation, which is well documented in clinical neurophysiological research, but not routinely used in clinical practice. One tenet is that functional restoration may be enhanced using techniques that increase excitability in the hemisphere in which the lesion has occurred, through LTP-like mechanisms, and this has led to some promising outcomes. Perhaps more contentious is the idea that the nonstroke (contralesional) hemisphere is also a target for NIBS that aim to suppress neuronal excitability. This idea is fostered by a model of interhemispheric competition that espouses an elevation in neural excitability within the contralesional hemisphere. The majority of neurophysiological studies investigating interhemispheric imbalance have been conducted with patients at the chronic stage after stroke, with only a few exceptions. The heightened contralesional excitability may reflect neurophysiological processes that exacerbate functional deficits through interhemispheric competition (via transcallosal inhibition). However, at the chronic stage these changes might also reflect a pattern of use (i.e., learned non-use of the weak or paretic side) and activity-dependent plastic reorganisation in the non-stroke hemisphere. From recent studies of motor neurophysiology, I will describe how the contralesional hemisphere may be a viable target for excitability suppression at the chronic stage, but that this is not ‘one-size-fits-all’. Finally, I will present neurophysiological and clinical data from a large sample of patients spanning
336
Abstracts / Brain Stimulation 8 (2015) 326e342
the initial days, weeks and months at the sub-acute stage after stroke. These data indicate interhemispheric imbalance is driven primarily, if not exclusively through diminished excitability in the lesioned hemisphere.
96 The mechanism of functional recovery of upper extremity motor function among patients with chronic stroke: Modulation of cortical and spinal interneuron Toshiyuki Fujiwara MD, PhD a, Kaoru Honaga MD, PhD b, Michiyuki Kawakami MD, PhD b, Atsuko Nishimoto b, Kaoru Abe c, Katsuhiro Mizuno MD, PhD b, Mitsuhiko Kodama MD, PhD a, Yoshihisa MasakadoMD PhD a, Tetsuya Tsuji MD, PhD b, Meigen Liu MD, PhD b a Department of Rehabilitation Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193 Japan b Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8587 Japan c Department of Rehabilitation Medicine, Keio University Hospital, 35 Shinanomachi, Shinjuku, Tokyo 160-8587 Japan Background: We hypothesized that functional recovery of upper extremity motor function is based on cortical and spinal plasticity. Objectives: The purpose of this study was to investigate the roles of intracortical inhibition and reciprocal inhibition in functional recovery. Methods: Participants were 61 patients with chronic hemiparetic stroke. The participants were applied hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy for 3 weeks. The FuglMeyer test upper extremity motor score (FM) and modified Ashworth scale (MAS) were assessed before (T0), immediately after (T1) and 3 months after (T2) the end of HANDS therapy. A paired pulse TMS paradigm was applied to assess short intracortical inhibition (SICI). Reciprocal inhibition (RI) was assessed with H reflex conditioning-test paradigm. Results: FM and MAS were improved until T2. The change of FM from T0 to T2 was correlated with the change in affected SICI from T0 toT1. The change of wrist MAS from T0 to T1 was correlated with the change of RI. Conclusions: In chronic stroke patients with moderate or severe hemiparesis, functional improvement of upper extremity were based on cortical and spinal plasticity.
97 The BDNF Val66Met polymorphism modulates motor cortex plasticity, induced by prolonged anodal transcranial direct current stimulation, in older adults R. Puri a, M.R. Hinder a, J.J. Summers a,b a University of Tasmania, Australia b Liverpool John Moores University, UK Introduction: The brain derived neurotrophic factor (BDNF) Val66Met polymorphism is thought to play an important role in modulating cortical plasticity induced by non-invasive brain stimulation (NIBS) in younger adults. Additionally, the intensity and duration of stimulation are also key determinants of NIBS-induced plasticity. However, little is known of the impact of these factors on plasticity mechanisms in older adults. Methods: Fifty older adults underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS) over left primary motor cortex for 10 mins and 20 mins. Single pulse transcranial magnetic stimulation was used to assess corticospinal excitability before and every 5 minutes for 30 minutes following atDCS.
Results: Overall, Met carriers (n ¼13) showed statistically significant enhanced post-stimulation facilitation compared to Val66Val homozygotes (n ¼ 37). However, this difference was only apparent following 20 mins (p ¼ 0.002) but not 10 mins (p ¼ 0.219) of atDCS. Moreover, Met carriers, but not Val66Val homozygotes, exhibited a significantly greater facilitatory response (p ¼ 0.046) to 20 min atDCS compared to that observed following 10 min atDCS. Discussion: In older adults, the BDNF Val66Met polymorphism plays an important role in modulating motor cortex plasticity. This crucial finding could aid the development of more targeted and efficient NIBS protocols for both healthy and diseased aged populations, which is of particular importance in light of the ageing demographic.
98 Movement speed-dependent modulation on the activity of spinal inhibitory circuits Shinji Kubota a,b, Masato Hirano a, Yoshiki Koizume a, Shigeo Tanabe c, Kozo Funase a a Human Motor Control Laboratory, Division of Human Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, Japan b Research Fellow of the Japan Society for the Promotion of Science c Faculty of Rehabilitation, School of Health Sciences, Fujita Health University, Japan Introduction: The modulation of spinal inhibitory circuit induced by visuomotor training have been shown in previous studies. However, it is not clarified that the changes in spinal inhibitory circuit are affected by movement speed. We hypothesized that the activity of spinal inhibitory circuits would show movement speeddependent changes. Methods: Fourteen healthy subjects participated in the experiment. Each subject was assigned to two groups; (1) slow movement group (0.5Hz rhythm), (2) fast movement group (1.5Hz rhythm). Subjects were instructed to move their ankle as precisely as possible from 10 deg of dorsi-flexion to 10 deg of planter-flexion at 0.5 Hz or 1.5 Hz rhythm for 15 seconds. The training session consisted of six blocks with five trials. The performance was quantified by the difference subtracting from the actual deg and target deg (10 deg of dorsi- and planter-flexion). The degree of reciprocal Ia inhibition, presynaptic inhibition (D1 inhibition) and the ratio of the maximum H-reflex amplitude versus maximum M-wave (Hmax/ Mmax) were recorded before, immediately after, 15 minutes after, and 30 minutes after of the training session. Results: All subject showed improvement in performance across blocks. The degree of D1 inhibition was increased both groups. In contrast, the degree of reciprocal Ia inhibition was only increased in the fast movement group. Hmax/Mmax was not changed after training session. Discussion: Our results indicated that the changes in presynaptic inhibition are not related to movement speed but to the visuomotor training. The movement speed is critical for inducing the activity changes in reciprocal Ia inhibition.
99 The inter-individual variability of quadripulse stimulation (QPS) Enomoto H a, Kadowaki S a, Abe M a, Nakamura K a, Kobayashi S a, Murakami T a, Hanajima R b,c, Terao Y c, Hamada M c, Ugawa Y a a Department of Neurology, Fukushima Medical University, Fukushima b Department of Neurology Kitasato University School of Medicine, Kanagawa c Department of Neurology, The University of Tokyo, Tokyo