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Liu M, Meng Y, Ouyang S, Zhai M, Yang L, Yang Y, Wang Y. Neuromodulation technologies improve functional recovery after brain injury: From bench to bedside. Neural Regen Res 2026; 21:506-520. [PMID: 39851132 DOI: 10.4103/nrr.nrr-d-24-00652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/05/2024] [Indexed: 01/26/2025] Open
Abstract
Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited. This limited plasticity serves as a primary barrier to functional recovery after brain injury. Neuromodulation technologies represent one of the fastest-growing fields in medicine. These techniques utilize electricity, magnetism, sound, and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury. Therefore, this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury. Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury. However, studies report negative findings, potentially due to variations in stimulation protocols, differences in observation periods, and the severity of functional impairments among participants across different clinical trials. Additionally, we observed that different neuromodulation techniques share remarkably similar mechanisms, including promoting neuroplasticity, enhancing neurotrophic factor release, improving cerebral blood flow, suppressing neuroinflammation, and providing neuroprotection. Finally, considering the advantages and disadvantages of various neuromodulation techniques, we propose that future development should focus on closed-loop neural circuit stimulation, personalized treatment, interdisciplinary collaboration, and precision stimulation.
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Affiliation(s)
- Mei Liu
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
| | - Yijing Meng
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
| | - Siguang Ouyang
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
| | - Meng'ai Zhai
- Department of Neurosurgery, The 904 Hospital of PLA, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Likun Yang
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
| | - Yang Yang
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
| | - Yuhai Wang
- Department of Neurosurgery, Wuxi Clinical College of Anhui Medical University (The 904 Hospital of PLA), Wuxi, Jiangsu Province, China
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Hussain SJ, Freedberg MV. Debunking the Myth of Excitatory and Inhibitory Repetitive Transcranial Magnetic Stimulation in Cognitive Neuroscience Research. J Cogn Neurosci 2025; 37:1009-1022. [PMID: 39785679 DOI: 10.1162/jocn_a_02288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Repetitive TMS (rTMS) is a powerful neuroscientific tool with the potential to noninvasively identify brain-behavior relationships in humans. Early work suggested that certain rTMS protocols (e.g., continuous theta-burst stimulation, intermittent theta-burst stimulation, high-frequency rTMS, low-frequency rTMS) predictably alter the probability that cortical neurons will fire action potentials (i.e., change cortical excitability). However, despite significant methodological, conceptual, and technical advances in rTMS research over the past few decades, overgeneralization of early rTMS findings has led to a stubbornly persistent assumption that rTMS protocols by their nature induce behavioral and/or physiological inhibition or facilitation, even when they are applied to nonmotor cortical sites or under untested circumstances. In this Perspectives article, we offer a "public service announcement" that summarizes the origins of this problematic assumption, highlighting limitations of seminal studies that inspired them and results of contemporary studies that violate them. Next, we discuss problems associated with holding this assumption, including making brain-behavior inferences without confirming the locality and directionality of neurophysiological changes. Finally, we provide recommendations for researchers to eliminate this misguided assumption when designing and interpreting their own work, emphasizing results of recent studies showing that the effects of rTMS on neurophysiological metrics and their associated behaviors can be caused by mechanisms other than binary changes in excitability of the stimulated brain region or network. Collectively, we contend that no rTMS protocol is by its nature either excitatory or inhibitory, and that researchers must use caution with these terms when forming experimental hypotheses and testing brain-behavior relationships.
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Long J, Niu M, Liao X, Han K, Chen J, Su W, Wang X, Liu J, Zhang Y, Zhang H. Feasibility, safety, and efficacy of high-dose intermittent theta burst stimulation in children with autism spectrum disorder: study protocol for a pilot randomized sham-controlled trial. Front Psychiatry 2025; 16:1549982. [PMID: 40230821 PMCID: PMC11995711 DOI: 10.3389/fpsyt.2025.1549982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/17/2025] [Indexed: 04/16/2025] Open
Abstract
Background Autism spectrum disorders (ASD) are common neurodevelopmental disorders, mainly caused by disrupted excitation/inhibition balance and synaptic plasticity. Intermittent theta burst stimulation (iTBS) is a variant of excitatory repetitive transcranial magnetic stimulation, inducing long-term potentiation-like plasticity. In recent years, there has been a growing interest in high-dose iTBS as a therapeutic tool for psychiatric disorders. We aim to preliminarily investigate the feasibility, safety, and efficacy of high-dose iTBS in children with autism spectrum disorder (ASD). Methods A randomized controlled pilot trial with a 4-week intervention will be conducted. Forty children with ASD will be randomized into either the intervention or control group. The intervention group will receive 5400-pulse iTBS per day, while the control group will receive sham iTBS. Feasibility will be evaluated through recruitment, intervention adherence, and assessment completion. Safety will be assessed by comparing the rates of drop-outs attributed to adverse events and the rates of serious adverse events The efficacy outcomes include the Autism Behavior Checklist, Social Responsiveness Scale, 2nd Edition, Childhood Autism Rating Scale, Autism Treatment Evaluation Checklist and Repetitive Behavior Scale-Revised. Resting-state electroencephalogram and functional near-infrared spectroscopy will be employed to quantify alterations in functional brain connectivity and cerebral haemodynamics. Salivary levels of oxytocin, growth hormone, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 are measured to reflect the biochemical response to iTBS. These indicators will be assessed at baseline and at the end of the intervention. Discussion This trial will evaluate the feasibility, safety, and efficacy of high-dose iTBS treatment in children with ASD. The proposed study will provide pilot data to inform the feasibility and design of larger sample-size trials. Clinical trial registration http://www.chictr.org.cn, identifier ChiCTR2400089757.
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Affiliation(s)
- Junzi Long
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
- Division of Brain Sciences, Changping Laboratory, Beijing, China
| | - Maoyuan Niu
- School of Rehabilitation, Capital Medical University, Beijing, China
- China Autism Rehabilitation Research Center, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
| | - Xingxing Liao
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
- Division of Brain Sciences, Changping Laboratory, Beijing, China
| | - Kaiyue Han
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
| | - Jiarou Chen
- Department of Neurorehabilitation, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenlong Su
- SanBo Brain Hospital, Capital Medical University, Beijing, China
| | - Xianna Wang
- China Autism Rehabilitation Research Center, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
| | - Jianjun Liu
- China Autism Rehabilitation Research Center, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
| | - Yan Zhang
- China Autism Rehabilitation Research Center, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
| | - Hao Zhang
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
- Division of Brain Sciences, Changping Laboratory, Beijing, China
- China Autism Rehabilitation Research Center, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, China
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Pennington KR, Debs L, Chung S, Bava J, Garin CM, Vale FL, Bick SK, Englot DJ, Terry AV, Constantinidis C, Blake DT. Basal forebrain activation improves working memory in senescent monkeys. Brain Stimul 2025; 18:185-194. [PMID: 39924100 PMCID: PMC12076211 DOI: 10.1016/j.brs.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/13/2025] [Accepted: 02/01/2025] [Indexed: 02/11/2025] Open
Abstract
Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent Rhesus monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in each animal over 8-12 weeks, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor in five animals produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration in two animals. Brain stimulation led to acute increases in cerebrospinal fluid levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF), in four animals. Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral in three animals. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging.
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Affiliation(s)
- Kendyl R Pennington
- Dept Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Luca Debs
- Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Sophia Chung
- Neuroscience Program, Vanderbilt University, Nashville, TN, 37235, USA
| | - Janki Bava
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA
| | - Clément M Garin
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA
| | - Fernando L Vale
- Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Sarah K Bick
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA; Dept Neurosurgery, Vanderbilt University, Nashville, TN, USA
| | - Dario J Englot
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA; Dept Neurosurgery, Vanderbilt University, Nashville, TN, USA
| | - Alvin V Terry
- Dept Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Christos Constantinidis
- Neuroscience Program, Vanderbilt University, Nashville, TN, 37235, USA; Dept Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA; Dept Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
| | - David T Blake
- Dept Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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Pennington KR, Debs L, Chung S, Bava J, Garin CM, Vale FL, Bick SK, Englot DJ, Terry AV, Constantinidis C, Blake DT. Basal forebrain activation improves working memory in senescent monkeys. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.01.582925. [PMID: 39574741 PMCID: PMC11580932 DOI: 10.1101/2024.03.01.582925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2024]
Abstract
Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in 8-12 weeks across all animals, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration. Brain stimulation led to acute increases in cerebrospinal levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF). Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging.
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Affiliation(s)
- Kendyl R Pennington
- Dept Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
| | - Luca Debs
- Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA
| | - Sophia Chung
- Neuroscience Program, Vanderbilt University, Nashville, TN 37235
| | - Janki Bava
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
| | - Clément M Garin
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
| | - Fernando L Vale
- Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA
| | - Sarah K Bick
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
- Dept Neurosurgery, Vanderbilt University, Nashville TN
| | - Dario J Englot
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
- Dept Neurosurgery, Vanderbilt University, Nashville TN
| | - Alvin V Terry
- Dept Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA
| | - Christos Constantinidis
- Neuroscience Program, Vanderbilt University, Nashville, TN 37235
- Dept Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
- Dept Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
| | - David T Blake
- Dept Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
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Tang VM, Blumberger DM. Transcranial magnetic stimulation for the rehabilitation of patients with addiction: current status and future prospects. Expert Rev Med Devices 2024; 21:943-954. [PMID: 39323104 DOI: 10.1080/17434440.2024.2404962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 09/12/2024] [Indexed: 09/27/2024]
Abstract
INTRODUCTION Substance use disorders (SUDs) are severe conditions that remain extremely challenging to treat in clinical practice. With high rates of non-response to current treatment options and several SUDs with no approved interventions, novel therapies are needed. Repetitive transcranial magnetic stimulation (rTMS) can non-invasively modulate the neurocircuitry of brain-based disorders, and investigation into its therapeutic potential for SUDs is growing rapidly. AREAS COVERED In this review, we summarize the clinical research to date evaluating its safety and efficacy for various SUDs. We highlight the investigations comparing different stimulation parameters to present our current understanding on optimal stimulation parameters. Additionally, we cover key research avenues in the use of neuroimaging to guide treatment, cue-induction paradigms, and adjunctive or combination treatments that may optimize outcomes. EXPERT OPINION Evidence of rTMS as an effective treatment for certain SUDs has emerged and is preliminary for others. There are a growing number of studies showing benefit and meta-analyses suggesting that rTMS can significantly reduce substance craving and consumption. However, the optimal approach has not been determined, and there is a great deal of heterogeneity in rTMS protocols and mixed outcomes. Further research into strategies for enhancing precision will be crucial in moving the field forward.
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Affiliation(s)
- Victor M Tang
- Addictions Division, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Daniel M Blumberger
- Addictions Division, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Temerty Centre for Therapeutic Brain Intervention, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Chang KY, Tik M, Mizutani-Tiebel Y, Taylor P, van Hattem T, Falkai P, Padberg F, Bulubas L, Keeser D. Dose-Dependent Target Engagement of a Clinical Intermittent Theta Burst Stimulation Protocol: An Interleaved Transcranial Magnetic Stimulation-Functional Magnetic Resonance Imaging Study in Healthy People. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2024:S2451-9022(24)00244-1. [PMID: 39182723 DOI: 10.1016/j.bpsc.2024.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Intermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as a therapeutic intervention in mental health; however, the understanding of its mechanisms is still incomplete. Prior magnetic resonance imaging (MRI) studies have mainly used offline iTBS or short sequences in concurrent transcranial magnetic stimulation (TMS)-functional MRI (fMRI). This study investigated a full 600-stimuli iTBS protocol using interleaved TMS-fMRI in comparison with 2 control conditions in healthy subjects. METHODS In a crossover design, 18 participants underwent 3 sessions of interleaved iTBS-fMRI: 1) the left DLPFC at 40% resting motor threshold (rMT) intensity, 2) the left DLPFC at 80% rMT intensity, and 3) the left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood oxygen level-dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS-induced electric field strength at the target sites. RESULTS Whole-brain analysis showed increased activation in several regions following iTBS. Specifically, the left DLPFC, as well as the bilateral M1, anterior cingulate cortex, and insula, showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was observed with neither 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and electric field intensities were only correlated for M1 stimulation and not for the DLPFC conditions. CONCLUSIONS This interleaved TMS-fMRI study showed dosage- and target-specific BOLD activation during a 600-stimuli iTBS protocol in healthy individuals. Future studies may use our approach for investigating target engagement in clinical samples.
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Affiliation(s)
- Kai-Yen Chang
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
| | - Martin Tik
- High Field MR Center, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; Brain Stimulation Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
| | - Yuki Mizutani-Tiebel
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
| | - Paul Taylor
- Department of Psychology, LMU Munich, Munich, Germany
| | - Timo van Hattem
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
| | - Peter Falkai
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
| | - Frank Padberg
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany.
| | - Lucia Bulubas
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
| | - Daniel Keeser
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany; Neuroimaging Core Unit Munich, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Mental Health, Partner Site Munich-Augsburg, Germany
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Kim DW, Moon HC, Lee BH, Park HY. Decoding Arc transcription: a live-cell study of stimulation patterns and transcriptional output. Learn Mem 2024; 31:a054024. [PMID: 39260877 PMCID: PMC11407692 DOI: 10.1101/lm.054024.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/05/2024] [Indexed: 09/13/2024]
Abstract
Activity-regulated cytoskeleton-associated protein (Arc) plays a crucial role in synaptic plasticity, a process integral to learning and memory. Arc transcription is induced within a few minutes of stimulation, making it a useful marker for neuronal activity. However, the specific neuronal activity patterns that initiate Arc transcription have remained elusive due to the inability to observe mRNA transcription in live cells in real time. Using a genetically encoded RNA indicator (GERI) mouse model that expresses endogenous Arc mRNA tagged with multiple GFPs, we investigated Arc transcriptional activity in response to various electrical field stimulation patterns. The GERI mouse model was generated by crossing the Arc-PBS knock-in mouse, engineered with binding sites in the 3' untranslated region (UTR) of Arc mRNA, and the transgenic mouse expressing the cognate binding protein fused to GFP. In dissociated hippocampal neurons, we found that the pattern of stimulation significantly affects Arc transcription. Specifically, theta-burst stimulation consisting of high-frequency (100 Hz) bursts delivered at 10 Hz frequency induced the highest rate of Arc transcription. Concurrently, the amplitudes of nuclear calcium transients also reached their peak with 10 Hz burst stimulation, indicating a correlation between calcium concentration and transcription. However, our dual-color single-cell imaging revealed that there were no significant differences in calcium amplitudes between Arc-positive and Arc-negative neurons upon 10 Hz burst stimulation, suggesting the involvement of other factors in the induction of Arc transcription. Our live-cell RNA imaging provides a deeper insight into the complex regulation of transcription by activity patterns and calcium signaling pathways.
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Affiliation(s)
- Dong Wook Kim
- Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyungseok C Moon
- Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea
| | - Byung Hun Lee
- Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea
| | - Hye Yoon Park
- Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea
- Institute of Applied Physics, Seoul National University, Seoul 08826, Republic of Korea
- Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Weisend JE, Carlson AP, Shuttleworth CW. Spreading Depolarization Induces a Transient Potentiation of Excitatory Synaptic Transmission. Neuroscience 2024; 551:323-332. [PMID: 38821241 PMCID: PMC11246225 DOI: 10.1016/j.neuroscience.2024.05.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Spreading depolarization (SD) is a slowly propagating wave of prolonged activation followed by a period of synaptic suppression. Some prior reports have shown potentiation of synaptic transmission after recovery from synaptic suppression and noted similarities with the phenomenon of long-term potentiation (LTP). Since SD is increasingly recognized as participating in diverse neurological disorders, it is of interest to determine whether SD indeed leads to a generalized and sustained long-term strengthening of synaptic connections. We performed a characterization of SD-induced potentiation, and tested whether distinctive features of SD, including adenosine accumulation and swelling, contribute to reports of SD-induced plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the hippocampal CA1 subregion of murine brain slices, and SD elicited using focal microinjection of KCl. A single SD was sufficient to induce a consistent potentiation of slope and amplitude of fEPSPs. Both AMPA- and NMDA-receptor mediated components were enhanced. Potentiation peaked ∼20 min after SD recovery and was sustained for ∼30 min. However, fEPSP amplitude and slope decayed over an extended 2-hour recording period and was estimated to reach baseline after ∼3 h. Potentiation was saturated after a single SD and adenosine A1 receptor activation did not mask additional potentiation. Induction of LTP with theta-burst stimulation was not altered by prior induction of SD and molecular mediators known to block LTP induction did not block SD-induced potentiation. Together, these results indicate an intermediate duration potentiation that is distinct from hippocampal LTP and may have implications for circuit function for 1-2 h following SD.
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Affiliation(s)
- Jordan E Weisend
- Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
| | - Andrew P Carlson
- Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
| | - C William Shuttleworth
- Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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Browne CJ, Sheeba SR, Astill T, Baily A, Deblieck C, Mucci V, Cavaleri R. Assessing the synergistic effectiveness of intermittent theta burst stimulation and the vestibular ocular reflex rehabilitation protocol in the treatment of Mal de Debarquement Syndrome: a randomised controlled trial. J Neurol 2024; 271:2615-2630. [PMID: 38345630 PMCID: PMC11055743 DOI: 10.1007/s00415-024-12215-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 01/19/2024] [Accepted: 01/20/2024] [Indexed: 04/28/2024]
Abstract
INTRODUCTION Mal de Debarquement Syndrome (MdDS) is a rare central vestibular disorder characterised by a constant sensation of motion (rocking, swaying, bobbing), which typically arises after motion experiences (e.g. sea, air, and road travel), though can be triggered by non-motion events. The current standard of care is non-specific medications and interventions that only result in mild-to-moderate improvements. The vestibular ocular reflex (VOR) rehabilitation protocol, a specialised form of rehabilitation, has shown promising results in reducing symptoms amongst people with MdDS. Accumulating evidence suggests that it may be possible to augment the effects of VOR rehabilitation via non-invasive brain stimulation protocols, such as theta burst stimulation (TBS). METHODS The aim of this randomised controlled trial was to evaluate the effectiveness of intermittent TBS (iTBS) over the dorsolateral prefrontal cortex in enhancing the effectiveness of a subsequently delivered VOR rehabilitation protocol in people with MdDS. Participants were allocated randomly to receive either Sham (n = 10) or Active (n = 10) iTBS, followed by the VOR rehabilitation protocol. Subjective outcome measures (symptom ratings and mental health scores) were collected 1 week pre-treatment and for 16 weeks post-treatment. Posturography (objective outcome) was recorded each day of the treatment week. RESULTS Significant improvements in subjective and objective outcomes were reported across both treatment groups over time, but no between-group differences were observed. DISCUSSION These findings support the effectiveness of the VOR rehabilitation protocol in reducing MdDS symptoms. Further research into iTBS is required to elucidate whether the treatment has a role in the management of MdDS. TRN: ACTRN12619001519145 (Date registered: 04 November 2019).
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Affiliation(s)
- Cherylea J Browne
- School of Science, Western Sydney University, Sydney, NSW, Australia.
- Brain Stimulation and Rehabilitation (BrainStAR) Laboratory, Western Sydney University, Sydney, NSW, Australia.
- Translational Neuroscience Facility, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.
- Western Sydney University, Translational Health and Research Institute, Sydney, NSW, Australia.
| | - S R Sheeba
- School of Science, Western Sydney University, Sydney, NSW, Australia
- Brain Stimulation and Rehabilitation (BrainStAR) Laboratory, Western Sydney University, Sydney, NSW, Australia
| | - T Astill
- Brain Stimulation and Rehabilitation (BrainStAR) Laboratory, Western Sydney University, Sydney, NSW, Australia
- School of Health Sciences, Western Sydney University, Sydney, NSW, Australia
| | - A Baily
- School of Health Sciences, Western Sydney University, Sydney, NSW, Australia
| | - C Deblieck
- Laboratory of Equilibrium Investigations and Aerospace (LEIA), University of Antwerp, Antwerp, Belgium
| | - V Mucci
- School of Science, Western Sydney University, Sydney, NSW, Australia
| | - R Cavaleri
- Brain Stimulation and Rehabilitation (BrainStAR) Laboratory, Western Sydney University, Sydney, NSW, Australia
- Western Sydney University, Translational Health and Research Institute, Sydney, NSW, Australia
- School of Health Sciences, Western Sydney University, Sydney, NSW, Australia
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11
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Savarimuthu A, Ponniah RJ. Receive, Retain and Retrieve: Psychological and Neurobiological Perspectives on Memory Retrieval. Integr Psychol Behav Sci 2024; 58:303-318. [PMID: 36738400 DOI: 10.1007/s12124-023-09752-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2023] [Indexed: 02/05/2023]
Abstract
Memory and learning are interdependent processes that involve encoding, storage, and retrieval. Especially memory retrieval is a fundamental cognitive ability to recall memory traces and update stored memory with new information. For effective memory retrieval and learning, the memory must be stabilized from short-term memory to long-term memory. Hence, it is necessary to understand the process of memory retention and retrieval that enhances the process of learning. Though previous cognitive neuroscience research has focused on memory acquisition and storage, the neurobiological mechanisms underlying memory retrieval and its role in learning are less understood. Therefore, this article offers the viewpoint that memory retrieval is essential for selecting, reactivating, stabilizing, and storing information in long-term memory. In arguing how memories are retrieved, consolidated, transmitted, and strengthened for the long term, the article will examine the psychological and neurobiological aspects of memory and learning with synaptic plasticity, long-term potentiation, genetic transcription, and theta oscillation in the brain.
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Affiliation(s)
- Anisha Savarimuthu
- Department of Humanities and Social Sciences, National Institute of Technology, Tiruchirappalli, India
| | - R Joseph Ponniah
- Department of Humanities and Social Sciences, National Institute of Technology, Tiruchirappalli, India.
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12
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Goldenkoff ER, Deluisi JA, Destiny DP, Lee TG, Michon KJ, Brissenden JA, Taylor SF, Polk TA, Vesia M. The behavioral and neural effects of parietal theta burst stimulation on the grasp network are stronger during a grasping task than at rest. Front Neurosci 2023; 17:1198222. [PMID: 37954875 PMCID: PMC10637360 DOI: 10.3389/fnins.2023.1198222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 10/05/2023] [Indexed: 11/14/2023] Open
Abstract
Repetitive transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical settings to modulate human cortical activity. The effects of TMS on neural activity depend on the excitability of specific neural populations at the time of stimulation. Accordingly, the brain state at the time of stimulation may influence the persistent effects of repetitive TMS on distal brain activity and associated behaviors. We applied intermittent theta burst stimulation (iTBS) to a region in the posterior parietal cortex (PPC) associated with grasp control to evaluate the interaction between stimulation and brain state. Across two experiments, we demonstrate the immediate responses of motor cortex activity and motor performance to state-dependent parietal stimulation. We randomly assigned 72 healthy adult participants to one of three TMS intervention groups, followed by electrophysiological measures with TMS and behavioral measures. Participants in the first group received iTBS to PPC while performing a grasping task concurrently. Participants in the second group received iTBS to PPC while in a task-free, resting state. A third group of participants received iTBS to a parietal region outside the cortical grasping network while performing a grasping task concurrently. We compared changes in motor cortical excitability and motor performance in the three stimulation groups within an hour of each intervention. We found that parietal stimulation during a behavioral manipulation that activates the cortical grasping network increased downstream motor cortical excitability and improved motor performance relative to stimulation during rest. We conclude that constraining the brain state with a behavioral task during brain stimulation has the potential to optimize plasticity induction in cortical circuit mechanisms that mediate movement processes.
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Affiliation(s)
| | - Joseph A. Deluisi
- School of Kinesiology, University of Michigan, Ann Arbor, MI, United States
| | - Danielle P. Destiny
- Department of Psychology, University of Michigan, Ann Arbor, MI, United States
| | - Taraz G. Lee
- Department of Psychology, University of Michigan, Ann Arbor, MI, United States
| | - Katherine J. Michon
- Department of Psychology, University of Michigan, Ann Arbor, MI, United States
| | - James A. Brissenden
- Department of Psychology, University of Michigan, Ann Arbor, MI, United States
| | - Stephan F. Taylor
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
| | - Thad A. Polk
- Department of Psychology, University of Michigan, Ann Arbor, MI, United States
| | - Michael Vesia
- School of Kinesiology, University of Michigan, Ann Arbor, MI, United States
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13
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Aoki Y, Yokoi T, Morikawa S, Kuga N, Ikegaya Y, Sasaki T. Effects of theta phase precessing optogenetic intervention on hippocampal neuronal reactivation and spatial maps. iScience 2023; 26:107233. [PMID: 37534136 PMCID: PMC10392074 DOI: 10.1016/j.isci.2023.107233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/04/2023] [Accepted: 06/23/2023] [Indexed: 08/04/2023] Open
Abstract
As animals explore environments, hippocampal place cells sequentially fire at progressively earlier phases of theta oscillations in hippocampal local field potentials. In this study, we evaluated the network-level significance of theta phase-entrained neuronal activity in organizing place cell spike patterns. A closed-loop system was developed in which optogenetic stimulation with a temporal pattern replicating theta phase precession is delivered to hippocampal CA1 neurons when rats traversed a particular region on a linear track. Place cells that had place fields during phase precessing stimulation, but not random phase stimulation, showed stronger reactivation during hippocampal sharp-wave ripples in a subsequent rest period. After the rest period, place cells with place fields that emerged during phase precessing stimulation showed more stable place fields. These results imply that neuronal reactivation and stability of spatial maps are mediated by theta phase precession in the hippocampus.
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Affiliation(s)
- Yuki Aoki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Taiki Yokoi
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-Ku, Sendai 980-8578, Japan
| | - Shota Morikawa
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Institute for AI and Beyond, The University of Tokyo, Tokyo 113-0033, Japan
| | - Nahoko Kuga
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-Ku, Sendai 980-8578, Japan
| | - Yuji Ikegaya
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Institute for AI and Beyond, The University of Tokyo, Tokyo 113-0033, Japan
- Center for Information and Neural Networks, 1-4 Yamadaoka, Suita City, Osaka 565-0871, Japan
| | - Takuya Sasaki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-Ku, Sendai 980-8578, Japan
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14
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Boscutti A, Murphy N, Cho R, Selvaraj S. Noninvasive Brain Stimulation Techniques for Treatment-Resistant Depression: Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation. Psychiatr Clin North Am 2023; 46:307-329. [PMID: 37149347 DOI: 10.1016/j.psc.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Transcranial magnetic stimulation is a safe, effective, and well-tolerated intervention for depression; it is currently approved for treatment-resistant depression. This article summarizes the mechanism of action, evidence of clinical efficacy, and the clinical aspects of this intervention, including patient evaluation, stimulation parameters selection, and safety considerations. Transcranial direct current stimulation is another neuromodulation treatment for depression; although promising, the technique is not currently approved for clinical use in the United States. The final section outlines the open challenges and future directions of the field.
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Affiliation(s)
- Andrea Boscutti
- Louis. A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Nicholas Murphy
- Baylor College of Medicine, Menninger Department of Psychiatry and Behavioral Sciences, Houston, TX, USA; The Menninger Clinic, Houston, TX, USA
| | - Raymond Cho
- Baylor College of Medicine, Menninger Department of Psychiatry and Behavioral Sciences, Houston, TX, USA; The Menninger Clinic, Houston, TX, USA
| | - Sudhakar Selvaraj
- Louis. A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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15
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Useinovic N, Near M, Cabrera OH, Boscolo A, Milosevic A, Harvey R, Newson A, Chastain-Potts S, Quillinan N, Jevtovic-Todorovic V. Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice. Exp Biol Med (Maywood) 2023; 248:641-655. [PMID: 37309741 PMCID: PMC10350807 DOI: 10.1177/15353702231170003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 03/11/2023] [Indexed: 06/14/2023] Open
Abstract
General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator (Crem), cAMP responsive element-binding protein 1 (Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin (Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.
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Affiliation(s)
- Nemanja Useinovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Michelle Near
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Omar Hoseá Cabrera
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Annalisa Boscolo
- Institute of Anesthesia and Intensive Care, Padua University Hospital, Padua 35128. Italy
- Department of Medicine (DIMED), University of Padua, Padua 35128, Italy
| | - Andjelko Milosevic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rachel Harvey
- Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Adre Newson
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Shelby Chastain-Potts
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Nidia Quillinan
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Neuronal Injury and Plasticity Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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16
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Clennell B, Steward TGJ, Hanman K, Needham T, Benachour J, Jepson M, Elley M, Halford N, Heesom K, Shin E, Molnár E, Drinkwater BW, Whitcomb DJ. Ultrasound modulates neuronal potassium currents via ionotropic glutamate receptors. Brain Stimul 2023; 16:540-552. [PMID: 36731773 DOI: 10.1016/j.brs.2023.01.1674] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/27/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Focused ultrasound stimulation (FUS) has the potential to provide non-invasive neuromodulation of deep brain regions with unparalleled spatial precision. However, the cellular and molecular consequences of ultrasound stimulation on neurons remains poorly understood. We previously reported that ultrasound stimulation induces increases in neuronal excitability that persist for hours following stimulation in vitro. In the present study we sought to further elucidate the molecular mechanisms by which ultrasound regulates neuronal excitability and synaptic function. OBJECTIVES To determine the effect of ultrasound stimulation on voltage-gated ion channel function and synaptic plasticity. METHODS Primary rat cortical neurons were exposed to a 40 s, 200 kHz pulsed ultrasound stimulus or sham-stimulus. Whole-cell patch clamp electrophysiology, quantitative proteomics and high-resolution confocal microscopy were employed to determine the effects of ultrasound stimulation on molecular regulators of neuronal excitability and synaptic function. RESULTS We find that ultrasound exposure elicits sustained but reversible increases in whole-cell potassium currents. In addition, we find that ultrasound exposure activates synaptic signalling cascades that result in marked increases in excitatory synaptic transmission. Finally, we demonstrate the requirement of ionotropic glutamate receptor (AMPAR/NMDAR) activation for ultrasound-induced modulation of neuronal potassium currents. CONCLUSION These results suggest specific patterns of pulsed ultrasound can induce contemporaneous enhancement of both neuronal excitability and synaptic function, with implications for the application of FUS in experimental and therapeutic settings. Further study is now required to deduce the precise molecular mechanisms through which these changes occur.
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Affiliation(s)
- Benjamin Clennell
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, BS1 3NY, UK
| | - Tom G J Steward
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, BS1 3NY, UK
| | - Kaliya Hanman
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | - Tom Needham
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | - Janette Benachour
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | - Mark Jepson
- Wolfson Bioimaging Facility, Faculty of Life Sciences, University of Bristol, Bristol, BS8 1TD, UK
| | - Meg Elley
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, BS1 3NY, UK
| | - Nathan Halford
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, BS1 3NY, UK
| | - Kate Heesom
- Proteomics Facility Faculty of Life Sciences, University Walk, University of Bristol, Bristol, BS8 1TD, UK
| | - Eunju Shin
- School of Life Sciences, Keele University, ST5 5BG, UK
| | - Elek Molnár
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | | | - Daniel J Whitcomb
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, BS1 3NY, UK.
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17
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Ng E, Wong EHY, Lipsman N, Nestor SM, Giacobbe P. Adverse childhood experiences and repetitive transcranial magnetic stimulation outcomes for depression. J Affect Disord 2023; 320:716-724. [PMID: 36206889 DOI: 10.1016/j.jad.2022.09.153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/21/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND History of adverse childhood experiences (ACEs) is associated with poorer treatment outcomes in depression. How ACEs affect outcomes from repetitive transcranial magnetic stimulation (rTMS) is not well-defined. The primary aim was to investigate whether ACEs affect depression outcomes in patients receiving high frequency rTMS, either deep TMS (dTMS) or intermittent theta burst stimulation (iTBS), to the left dorsolateral prefrontal cortex. METHODS The Hamilton Depression Rating Scale (HAMD-17) was collected at baseline and every 2 weeks for 4-6 weeks. Outcomes included improvement in HAMD-17 and remission. The ACE-10 questionnaire was used to quantify categories of ACEs. Data from 99 patients with MDD receiving an acute rTMS course were analyzed. RESULTS Patients had a mean of 2.4 ACEs (SD 2.5). No significant differences in outcomes were found between dTMS or iTBS so these data were pooled. Using a continuous ACE variable showed no significant impact on outcomes. Using a categorical ACE variable (0, 1, 2, 3, 4 or more) did not reveal significant effects of ACEs on outcomes. Higher ACE was associated with steeper decrease in HAMD-17 only from baseline to week 2 but not at other times. LIMITATIONS This was an open-label study. The well-validated ACE questionnaire does not measure severity or frequency of adversities. CONCLUSIONS Patients with depression receiving rTMS reported on average 2.4 ACEs. ACE scores may lead to a steeper early decline in HAMD-17 but did not otherwise impact depression outcomes. Presence of high levels of ACEs should not preclude consideration of rTMS for depression.
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Affiliation(s)
- Enoch Ng
- University of Toronto, Department of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada
| | - Emily H Y Wong
- University of Toronto, Department of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada
| | - Nir Lipsman
- Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Harquail Centre for Neuromodulation, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University of Toronto, Department of Surgery, 149 College Street, Toronto, Ontario M5T 1P5, Canada
| | - Sean M Nestor
- University of Toronto, Department of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Harquail Centre for Neuromodulation, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
| | - Peter Giacobbe
- University of Toronto, Department of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Harquail Centre for Neuromodulation, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
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18
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Shing N, Walker MC, Chang P. The Role of Aberrant Neural Oscillations in the Hippocampal-Medial Prefrontal Cortex Circuit in Neurodevelopmental and Neurological Disorders. Neurobiol Learn Mem 2022; 195:107683. [PMID: 36174886 DOI: 10.1016/j.nlm.2022.107683] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 09/09/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022]
Abstract
The hippocampus (HPC) and medial prefrontal cortex (mPFC) have well-established roles in cognition, emotion, and sensory processing. In recent years, interests have shifted towards developing a deeper understanding of the mechanisms underlying interactions between the HPC and mPFC in achieving these functions. Considerable research supports the idea that synchronized activity between the HPC and the mPFC is a general mechanism by which brain functions are regulated. In this review, we summarize current knowledge on the hippocampal-medial prefrontal cortex (HPC-mPFC) circuit in normal brain function with a focus on oscillations and highlight several neurodevelopmental and neurological disorders associated with aberrant HPC-mPFC circuitry. We further discuss oscillatory dynamics across the HPC-mPFC circuit as potentially useful biomarkers to assess interventions for neurodevelopmental and neurological disorders. Finally, advancements in brain stimulation, gene therapy and pharmacotherapy are explored as promising therapies for disorders with aberrant HPC-mPFC circuit dynamics.
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Affiliation(s)
- Nathanael Shing
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, WC1N 3BG, UK; Department of Medicine, University of Central Lancashire, Preston, PR17BH, UK
| | - Matthew C Walker
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Pishan Chang
- Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT.
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19
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Membrane electrical properties of mouse hippocampal CA1 pyramidal neurons during strong inputs. Biophys J 2022; 121:644-657. [PMID: 34999132 PMCID: PMC8873947 DOI: 10.1016/j.bpj.2022.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/21/2021] [Accepted: 01/05/2022] [Indexed: 11/24/2022] Open
Abstract
In this work, we highlight an electrophysiological feature often observed in recordings from mouse CA1 pyramidal cells that has so far been ignored by experimentalists and modelers. It consists of a large and dynamic increase in the depolarization baseline (i.e., the minimum value of the membrane potential between successive action potentials during a sustained input) in response to strong somatic current injections. Such an increase can directly affect neurotransmitter release properties and, more generally, the efficacy of synaptic transmission. However, it cannot be explained by any currently available conductance-based computational model. Here we present a model addressing this issue, demonstrating that experimental recordings can be reproduced by assuming that an input current modifies, in a time-dependent manner, the electrical and permeability properties of the neuron membrane by shifting the ionic reversal potentials and channel kinetics. For this reason, we propose that any detailed model of ion channel kinetics for neurons exhibiting this characteristic should be adapted to correctly represent the response and the synaptic integration process during strong and sustained inputs.
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20
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Zhang BBB, Kan RLD, Giron CG, Lin TTZ, Yau SY, Kranz GS. Dose-response relationship between iTBS and prefrontal activation during executive functioning: A fNIRS study. Front Psychiatry 2022; 13:1049130. [PMID: 36606127 PMCID: PMC9807664 DOI: 10.3389/fpsyt.2022.1049130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults. METHODS Twenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional near-infrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation. RESULTS After stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t (17) = 2.203, P = 0.042, d = 0.523] and 100% iTBS [t (17) = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t (17) = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation. CONCLUSION The linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT.
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Affiliation(s)
- Bella B B Zhang
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Rebecca L D Kan
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Cristian G Giron
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Tim T Z Lin
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Suk-Yu Yau
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.,Mental Health Research Center (MHRC), The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Georg S Kranz
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.,Mental Health Research Center (MHRC), The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.,Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria.,The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hung Hom, Hong Kong SAR, China
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21
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Dose-response of intermittent theta burst stimulation of the prefrontal cortex: a TMS-EEG study. Clin Neurophysiol 2022; 136:158-172. [DOI: 10.1016/j.clinph.2021.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 12/01/2021] [Accepted: 12/26/2021] [Indexed: 01/01/2023]
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22
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Cheng P, Zhou Y, Xu LZ, Chen YF, Hu RL, Zou YL, Li ZX, Zhang L, Shun Q, Yu X, Li LJ, Li WH. Clinical application of repetitive transcranial magnetic stimulation for post-traumatic stress disorder: A literature review. World J Clin Cases 2021; 9:8658-8665. [PMID: 34734044 PMCID: PMC8546820 DOI: 10.12998/wjcc.v9.i29.8658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/30/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
The efficacy of traditional treatment for post-traumatic stress disorder (PTSD) is still unsatisfactory. Repetitive transcranial magnetic stimulation (rTMS) has been widely used in the treatment of various types of mental disorders, including PTSD. Although rTMS has been demonstrated to be effective in many cases, there are still arguments regarding its mechanism and protocol. This review aims to summarize the origin, development, principle, and future direction of rTMS and introduce this neuro-stimulation therapy to relevant clinicians.
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Affiliation(s)
- Peng Cheng
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Ying Zhou
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Li-Zhi Xu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Ya-Fei Chen
- Xiangya Medical School, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ruo-Lin Hu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Yi-Ling Zou
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Ze-Xuan Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Li Zhang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Qi Shun
- Research Center for Brain Science and Human-like Intelligence, Xi’an Jiaotong University, Xi’an 710049, Shannxi Province, China
| | - Xun Yu
- Product Department, Solide Brain Medical Technology, Ltd., Xi’an 710043, Shannxi Province, China
| | - Ling-Jiang Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Wei-Hui Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
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Izadi A, Schedlbauer A, Ondek K, Disse G, Ekstrom AD, Cowen SL, Shahlaie K, Gurkoff GG. Early Intervention via Stimulation of the Medial Septal Nucleus Improves Cognition and Alters Markers of Epileptogenesis in Pilocarpine-Induced Epilepsy. Front Neurol 2021; 12:708957. [PMID: 34557145 PMCID: PMC8452867 DOI: 10.3389/fneur.2021.708957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 06/28/2021] [Indexed: 11/13/2022] Open
Abstract
Over one-third of patients with temporal lobe epilepsy are refractory to medication. In addition, anti-epileptic drugs often exacerbate cognitive comorbidities. Neuromodulation is an FDA treatment for refractory epilepsy, but patients often wait >20 years for a surgical referral for resection or neuromodulation. Using a rodent model, we test the hypothesis that 2 weeks of theta stimulation of the medial septum acutely following exposure to pilocarpine will alter the course of epileptogenesis resulting in persistent behavioral improvements. Electrodes were implanted in the medial septum, dorsal and ventral hippocampus, and the pre-frontal cortex of pilocarpine-treated rats. Rats received 30 min/day of 7.7 Hz or theta burst frequency on days 4-16 post-pilocarpine, prior to the development of spontaneous seizures. Seizure threshold, spikes, and oscillatory activity, as well as spatial and object-based learning, were assessed in the weeks following stimulation. Non-stimulated pilocarpine animals exhibited significantly decreased seizure threshold, increased spikes, and cognitive impairments as compared to vehicle controls. Furthermore, decreased ventral hippocampal power (6-10 Hz) correlated with both the development of spikes and impaired cognition. Measures of spikes, seizure threshold, and cognitive performance in both acute 7.7 Hz and theta burst stimulated animals were statistically similar to vehicle controls when tested during the chronic phase of epilepsy, weeks after stimulation was terminated. These data indicate that modulation of the septohippocampal circuit early after pilocarpine treatment alters the progression of epileptic activity, resulting in elevated seizure thresholds, fewer spikes, and improved cognitive outcome. Results from this study support that septal theta stimulation has the potential to serve in combination or as an alternative to high frequency thalamic stimulation in refractory cases and that further research into early intervention is critical.
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Affiliation(s)
- Ali Izadi
- Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States.,Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Amber Schedlbauer
- Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States
| | - Katelynn Ondek
- Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States.,Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Gregory Disse
- Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Arne D Ekstrom
- Department of Psychology, University of Arizona, Tucson, AZ, United States.,McKnight Brain Institute, University of Arizona, Tucson, AZ, United States
| | - Stephen L Cowen
- Department of Psychology, University of Arizona, Tucson, AZ, United States.,McKnight Brain Institute, University of Arizona, Tucson, AZ, United States
| | - Kiarash Shahlaie
- Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States.,Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Gene G Gurkoff
- Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States.,Center for Neuroscience, University of California, Davis, Davis, CA, United States
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24
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Solomon EA, Sperling MR, Sharan AD, Wanda PA, Levy DF, Lyalenko A, Pedisich I, Rizzuto DS, Kahana MJ. Theta-burst stimulation entrains frequency-specific oscillatory responses. Brain Stimul 2021; 14:1271-1284. [PMID: 34428553 PMCID: PMC9161680 DOI: 10.1016/j.brs.2021.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND Brain stimulation has emerged as a powerful tool in human neuroscience, becoming integral to next-generation psychiatric and neurologic therapeutics. Theta-burst stimulation (TBS), in which electrical pulses are delivered in rhythmic bouts of 3-8 Hz, seeks to recapitulate neural activity seen endogenously during cognitive tasks. A growing literature suggests that TBS can be used to alter or enhance cognitive processes, but little is known about how these stimulation events influence underlying neural activity. OBJECTIVE Our study sought to investigate the effect of direct electrical TBS on mesoscale neural activity in humans by asking (1) whether TBS evokes persistent theta oscillations in cortical areas, (2) whether these oscillations occur at the stimulated frequency, and (3) whether stimulation events propagate in a manner consistent with underlying functional and structural brain architecture. METHODS We recruited 20 neurosurgical epilepsy patients with indwelling electrodes and delivered direct cortical TBS at varying locations and frequencies. Simultaneous iEEG was recorded from non-stimulated electrodes and analyzed to understand how TBS influences mesoscale neural activity. RESULTS We found that TBS rapidly evoked theta rhythms in widespread brain regions, preferentially at the stimulation frequency, and that these oscillations persisted for hundreds of milliseconds post stimulation offset. Furthermore, the functional connectivity between recording and stimulation sites predicted the strength of theta response, suggesting that underlying brain architecture guides the flow of stimulation through the brain. CONCLUSIONS By demonstrating that cortical TBS induces frequency-specific oscillatory responses, our results suggest this technology can be used to directly and predictably influence the activity of cognitively-relevant brain networks.
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Affiliation(s)
- Ethan A Solomon
- University of Pennsylvania, Perelman School of Medicine, Philadelphia PA 19104, USA; University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA.
| | - Michael R Sperling
- Thomas Jefferson University Hospital, Department of Neurology, Philadelphia PA 19107, USA
| | - Ashwini D Sharan
- Thomas Jefferson University Hospital, Department of Neurosurgery, Philadelphia PA 19107, USA
| | - Paul A Wanda
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA
| | - Deborah F Levy
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA
| | - Anastasia Lyalenko
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA
| | - Isaac Pedisich
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA
| | - Daniel S Rizzuto
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA; Nia Therapeutics Inc., Bala Cynwyd, PA 19004, USA
| | - Michael J Kahana
- University of Pennsylvania, Department of Psychology, Philadelphia PA 19104, USA.
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Theta-burst versus 20 Hz repetitive transcranial magnetic stimulation in neuropathic pain: A head-to-head comparison. Clin Neurophysiol 2021; 132:2702-2710. [PMID: 34217600 DOI: 10.1016/j.clinph.2021.05.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 03/24/2021] [Accepted: 05/12/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVE High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent "theta-burst" stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain. METHODS Forty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks. RESULTS Pain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095-3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques. CONCLUSIONS High-frequency rTMS appeared superior to iTBS for neuropathic pain relief. SIGNIFICANCE Adequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation.
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26
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Comparative Study of a Continuous Train of Theta-Burst Stimulation for a Duration of 20 s (cTBS 300) versus a Duration of 40 s (cTBS 600) in a Pre-Stimulation Relaxed Condition in Healthy Volunteers. Brain Sci 2021; 11:brainsci11060737. [PMID: 34205963 PMCID: PMC8230207 DOI: 10.3390/brainsci11060737] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 11/16/2022] Open
Abstract
As variable after effects have been observed following phasic muscle contraction prior to continuous theta-burst stimulation (cTBS), we here investigated two cTBS protocols (cTBS300 and cTBS600) in 20 healthy participants employing a pre-relaxed muscle condition including visual feedback on idle peripheral surface EMG activity. Furthermore, we assessed corticospinal excitability measures also from a pre-relaxed state to better understand the potential impact of these proposed contributors to TBS. Motor-evoked potential (MEP) magnitude changes were assessed for 30 min. The linear model computed across both experimental paradigms (cTBS300 and cTBS600) revealed a main effect of TIME COURSE (p = 0.044). Separate exploratory analysis for cTBS300 revealed a main effect of TIME COURSE (p = 0.031), which did not maintain significance after Greenhouse-Geisser correction (p = 0.073). For cTBS600, no main effects were observed. An exploratory analysis revealed a correlation between relative SICF at 2.0 ms (p = 0.006) and after effects (relative mean change) of cTBS600, which did not survive correction for multiple testing. Our findings thereby do not support the hypothesis of a specific excitability modulating effect of cTBS applied to the human motor-cortex in setups with pre-relaxed muscle conditions.
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27
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Determining the optimal pulse number for theta burst induced change in cortical excitability. Sci Rep 2021; 11:8726. [PMID: 33888752 PMCID: PMC8062542 DOI: 10.1038/s41598-021-87916-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 04/06/2021] [Indexed: 12/19/2022] Open
Abstract
Theta-burst stimulation (TBS) is a form of non-invasive neuromodulation which is delivered in an intermittent (iTBS) or continuous (cTBS) manner. Although 600 pulses is the most common dose, the goal of these experiments was to evaluate the effect of higher per-dose pulse numbers on cortical excitability. Sixty individuals were recruited for 2 experiments. In Experiment 1, participants received 600, 1200, 1800, or sham (600) iTBS (4 visits, counterbalanced, left motor cortex, 80% active threshold). In Experiment 2, participants received 600, 1200, 1800, 3600, or sham (600) cTBS (5 visits, counterbalanced). Motor evoked potentials (MEP) were measured in 10-min increments for 60 min. For iTBS, there was a significant interaction between dose and time (F = 3.8296, p = 0.01), driven by iTBS (1200) which decreased excitability for up to 50 min (t = 3.1267, p = 0.001). For cTBS, there was no overall interaction between dose and time (F = 1.1513, p = 0.33). Relative to sham, cTBS (3600) increased excitability for up to 60 min (t = 2.0880, p = 0.04). There were no other significant effects of dose relative to sham in either experiment. Secondary analyses revealed high within and between subject variability. These results suggest that iTBS (1200) and cTBS (3600) are, respectively, the most effective doses for decreasing and increasing cortical excitability.
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Shortened tethering filaments stabilize presynaptic vesicles in support of elevated release probability during LTP in rat hippocampus. Proc Natl Acad Sci U S A 2021; 118:2018653118. [PMID: 33875591 DOI: 10.1073/pnas.2018653118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Long-term potentiation (LTP) is a cellular mechanism of learning and memory that results in a sustained increase in the probability of vesicular release of neurotransmitter. However, previous work in hippocampal area CA1 of the adult rat revealed that the total number of vesicles per synapse decreases following LTP, seemingly inconsistent with the elevated release probability. Here, electron-microscopic tomography (EMT) was used to assess whether changes in vesicle density or structure of vesicle tethering filaments at the active zone might explain the enhanced release probability following LTP. The spatial relationship of vesicles to the active zone varies with functional status. Tightly docked vesicles contact the presynaptic membrane, have partially formed SNARE complexes, and are primed for release of neurotransmitter upon the next action potential. Loosely docked vesicles are located within 8 nm of the presynaptic membrane where SNARE complexes begin to form. Nondocked vesicles comprise recycling and reserve pools. Vesicles are tethered to the active zone via filaments composed of molecules engaged in docking and release processes. The density of tightly docked vesicles was increased 2 h following LTP compared to control stimulation, whereas the densities of loosely docked or nondocked vesicles congregating within 45 nm above the active zones were unchanged. The tethering filaments on all vesicles were shorter and their attachment sites shifted closer to the active zone. These findings suggest that tethering filaments stabilize more vesicles in the primed state. Such changes would facilitate the long-lasting increase in release probability following LTP.
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29
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Loprinzi PD, Moore D, Loenneke JP. Does Aerobic and Resistance Exercise Influence Episodic Memory through Unique Mechanisms? Brain Sci 2020; 10:E913. [PMID: 33260817 PMCID: PMC7761124 DOI: 10.3390/brainsci10120913] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Aerobic and resistance exercise (acute and chronic) independently and collectively induce beneficial responses in the brain that may influence memory function, including an increase in cerebral blood flow, neurogenesis, neuroelectrical alterations, and protein production. However, whether aerobic and resistance exercise improve memory via similar or distinct mechanisms has yet to be fully explained. Here, we review the unique influence of aerobic and resistance exercise on neural modulation, proteins, receptors, and ultimately, episodic memory. Resistance training may optimize neural communication, information processing and memory encoding by affecting the allocation of attentional resources. Moreover, resistance exercise can reduce inflammatory markers associated with neural communication while increasing peripheral and central BDNF (brain-derived neurotrophic factor) production. Aerobic training increases hippocampal levels of BDNF and TrkB (Tropomyosin receptor kinase B), protein kinases and glutamatergic proteins. Likewise, both aerobic and anaerobic exercise can increase CREB (cAMP response element-binding protein) phosphorylation. Thus, we suggest that aerobic and resistance exercise may influence episodic memory via similar and, potentially, distinct mechanisms.
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Affiliation(s)
- Paul D. Loprinzi
- Exercise & Memory Laboratory, Department of Health, Exercise Science and Recreation Management, The University of Mississippi, Oxford, MS 38677, USA;
| | - Damien Moore
- Exercise & Memory Laboratory, Department of Health, Exercise Science and Recreation Management, The University of Mississippi, Oxford, MS 38677, USA;
| | - Jeremy P. Loenneke
- Kevser Ermin Applied Physiology Laboratory, Department of Health, Exercise Science and Recreation Management, The University of Mississippi, Oxford, MS 38677, USA;
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Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease. Exp Brain Res 2020; 238:1707-1714. [PMID: 32671422 DOI: 10.1007/s00221-020-05880-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022]
Abstract
Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell's laboratory in the early 2000s, which was named 'theta burst stimulation' (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, 'closed loop' stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John's contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.
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31
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Philip NS, Barredo J, Aiken E, Larson V, Jones RN, Shea MT, Greenberg BD, van ‘t Wout-Frank M. Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder. Am J Psychiatry 2019; 176:939-948. [PMID: 31230462 PMCID: PMC6824981 DOI: 10.1176/appi.ajp.2019.18101160] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD. METHODS Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors. RESULTS Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity. CONCLUSIONS iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.
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Affiliation(s)
- Noah S. Philip
- Address correspondence to: Noah S. Philip MD, Providence VA Medical Center, 830 Chalkstone Ave, Providence RI 02908;
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Hill AT, McModie S, Fung W, Hoy KE, Chung SW, Bertram KL. Impact of prefrontal intermittent theta-burst stimulation on working memory and executive function in Parkinson's disease: A double-blind sham-controlled pilot study. Brain Res 2019; 1726:146506. [PMID: 31634450 DOI: 10.1016/j.brainres.2019.146506] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/18/2019] [Accepted: 10/09/2019] [Indexed: 02/08/2023]
Abstract
Cognitive impairment is a prevalent non-motor feature of Parkinson's disease (PD) which can present even in early stages of the disease. Impairments in executive processing and working memory (WM) are common and have been attributed, in part, to abnormalities within the dorsolateral prefrontal cortex (DLPFC) and broader fronto-striatal circuitry. Previous studies in cognitively normal adults have suggested intermittent Theta Burst Stimulation (iTBS), an excitatory plasticity-inducing non-invasive brain stimulation technique, can enhance these cognitive functions. Fourteen participants with a diagnosis of idiopathic PD received either Active or Sham iTBS over the left DLPFC across two separate experimental sessions as part of a double-blind sham-controlled crossover experimental design. The Berg's Card Sorting Test (BCST) and N-Back tasks, which measure executive function and WM respectively, were administered prior to iTBS and again five- and 30-minutes following stimulation. Despite being well-tolerated, iTBS failed to modulate performance on any of the cognitive outcome measures. This finding was further supported by Bayes Factor analyses which indicated moderate levels of support for the null hypothesis overall. This initial pilot study therefore does not support single-session iTBS as an efficacious method for modulating either executive processes or WM in PD. We discuss potential reasons for this finding along with directions for future research.
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Affiliation(s)
- Aron T Hill
- Neurology Department, The Alfred Hospital, Melbourne, Australia; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
| | - Salar McModie
- Neurology Department, The Alfred Hospital, Melbourne, Australia
| | - Wilson Fung
- Neurology Department, The Alfred Hospital, Melbourne, Australia
| | - Kate E Hoy
- Epworth Centre for Innovation in Mental Health, Epworth HealthCare and Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia; Monash Alfred Psychiatry Research Centre, The Alfred and Monash University, Central Clinical School, Victoria, Australia
| | - Sung-Wook Chung
- Monash Alfred Psychiatry Research Centre, The Alfred and Monash University, Central Clinical School, Victoria, Australia
| | - Kelly L Bertram
- Neurology Department, The Alfred Hospital, Melbourne, Australia; Neurosciences, Central Clinical School, Monash University, Victoria, Australia
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Long-Term Potentiation and Excitability in the Hippocampus Are Modulated Differently by θ Rhythm. eNeuro 2018; 5:eN-CFN-0236-18. [PMID: 30627662 PMCID: PMC6325566 DOI: 10.1523/eneuro.0236-18.2018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 11/02/2018] [Accepted: 11/05/2018] [Indexed: 01/27/2023] Open
Abstract
Oscillations in the brain facilitate neural processing and cognitive functions. This study investigated the dependence of long-term potentiation (LTP), a neural correlate of memory, on the phase of the hippocampal θ rhythm, a prominent brain oscillation. Multichannel field potentials and current source-sinks were analyzed in hippocampal CA1 of adult male rats under urethane anesthesia. A single burst (five pulses at 200 Hz) stimulation of stratum oriens (OR) induced LTP of the basal dendritic excitatory sink (ES), which was maximal when the burst was delivered at ∼340° and ∼160° of the distal dendritic θ rhythm. Apical dendritic sink evoked by stratum radiatum (RAD) stimulation also showed biphasic maxima at ∼30° and ∼210° of the distal dendritic θ rhythm, about 50° phase delay to basal dendritic LTP. By contrast, maximal population spike (PS) excitability, following single-pulse excitation of the basal or mid-apical dendrites, occurred at a θ phase of ∼140°, and maximal basal dendritic ES occurred at ∼20°; γ (30–57 Hz) activity recorded in CA1 RAD had maximal power at ∼300° of the distal dendritic θ rhythm, different from the phases of maximal LTP. LTP induced during the rising θ phase was NMDA receptor sensitive. It is suggested that the θ phase modulation of CA1 PS excitability is mainly provided by θ-rhythmic proximal inhibition, while dendritic LTP is also modulated by dendritic inhibition and excitation, specific to basal and apical dendrites. In summary, basal and apical dendritic synaptic plasticity and spike excitability are facilitated at different θ phases in a compartmental fashion.
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Perellón-Alfonso R, Kralik M, Pileckyte I, Princic M, Bon J, Matzhold C, Fischer B, Šlahorová P, Pirtošek Z, Rothwell J, Kojovic M. Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. Eur J Neurosci 2018; 48:1990-2000. [DOI: 10.1111/ejn.14077] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 07/09/2018] [Accepted: 07/14/2018] [Indexed: 12/13/2022]
Affiliation(s)
| | - Magdalena Kralik
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
- Department of Philosophy; University of Vienna; Vienna Austria
| | - Indre Pileckyte
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
| | - Matic Princic
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
| | - Jurij Bon
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
| | - Caspar Matzhold
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
- Department of Philosophy; University of Vienna; Vienna Austria
| | - Benjamin Fischer
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
- Department of Philosophy; University of Vienna; Vienna Austria
| | - Petra Šlahorová
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
- Department of Philosophy; University of Vienna; Vienna Austria
| | - Zvezdan Pirtošek
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
| | - John Rothwell
- Institute of Neurology; University College London; London UK
| | - Maja Kojovic
- Department of Neurology; University Medical Centre Ljubljana; Ljubljana Slovenia
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Urban BE, Xiao L, Dong B, Chen S, Kozorovitskiy Y, Zhang HF. Imaging neuronal structure dynamics using 2-photon super-resolution patterned excitation reconstruction microscopy. JOURNAL OF BIOPHOTONICS 2018; 11:10.1002/jbio.201700171. [PMID: 28976633 PMCID: PMC7313398 DOI: 10.1002/jbio.201700171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 08/31/2017] [Accepted: 09/28/2017] [Indexed: 05/11/2023]
Abstract
Visualizing fine neuronal structures deep inside strongly light-scattering brain tissue remains a challenge in neuroscience. Recent nanoscopy techniques have reached the necessary resolution but often suffer from limited imaging depth, long imaging time or high light fluence requirements. Here, we present two-photon super-resolution patterned excitation reconstruction (2P-SuPER) microscopy for 3-dimensional imaging of dendritic spine dynamics at a maximum demonstrated imaging depth of 130 μm in living brain tissue with approximately 100 nm spatial resolution. We confirmed 2P-SuPER resolution using fluorescence nanoparticle and quantum dot phantoms and imaged spiny neurons in acute brain slices. We induced hippocampal plasticity and showed that 2P-SuPER can resolve increases in dendritic spine head sizes on CA1 pyramidal neurons following theta-burst stimulation of Schaffer collateral axons. 2P-SuPER further revealed nanoscopic increases in dendritic spine neck widths, a feature of synaptic plasticity that has not been thoroughly investigated due to the combined limit of resolution and penetration depth in existing imaging technologies.
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Affiliation(s)
- Ben E. Urban
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
| | - Lei Xiao
- Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA
| | - Biqin Dong
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
| | - Siyu Chen
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
| | | | - Hao F. Zhang
- Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA
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Jimenez S, Mordillo-Mateos L, Dileone M, Campolo M, Carrasco-Lopez C, Moitinho-Ferreira F, Gallego-Izquierdo T, Siebner HR, Valls-Solé J, Aguilar J, Oliviero A. Effects of patterned peripheral nerve stimulation on soleus spinal motor neuron excitability. PLoS One 2018; 13:e0192471. [PMID: 29451889 PMCID: PMC5815584 DOI: 10.1371/journal.pone.0192471] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 01/03/2018] [Indexed: 11/24/2022] Open
Abstract
Spinal plasticity is thought to contribute to sensorimotor recovery of limb function in several neurological disorders and can be experimentally induced in animals and humans using different stimulation protocols. In healthy individuals, electrical continuous Theta Burst Stimulation (TBS) of the median nerve has been shown to change spinal motoneuron excitability in the cervical spinal cord as indexed by a change in mean H-reflex amplitude in the flexor carpi radialis muscle. It is unknown whether continuous TBS of a peripheral nerve can also shift motoneuron excitability in the lower limb. In 26 healthy subjects, we examined the effects of electrical TBS given to the tibial nerve in the popliteal fossa on the excitability of lumbar spinal motoneurons as measured by H-reflex amplitude of the soleus muscle evoked by tibial nerve stimulation. Continuous TBS was given at 110% of H-reflex threshold intensity and compared to non-patterned regular electrical stimulation at 15 Hz. To disclose any pain-induced effects, we also tested the effects of TBS at individual sensory threshold. Moreover, in a subgroup of subjects we evaluated paired-pulse inhibition of H-reflex. Continuous TBS at 110% of H-reflex threshold intensity induced a short-term reduction of H-reflex amplitude. The other stimulation conditions produced no after effects. Paired-pulse H-reflex inhibition was not modulated by continuous TBS or non-patterned repetitive stimulation at 15 Hz. An effect of pain on the results obtained was discarded, since non-patterned 15 Hz stimulation at 110% HT led to pain scores similar to those induced by EcTBS at 110% HT, but was not able to induce any modulation of the H reflex amplitude. Together, the results provide first time evidence that peripheral continuous TBS induces a short-lasting change in the excitability of spinal motoneurons in lower limb circuitries. Future studies need to investigate how the TBS protocol can be optimized to produce a larger and longer effect on spinal cord physiology and whether this might be a useful intervention in patients with excessive excitability of the spinal motorneurons.
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Affiliation(s)
- Samuel Jimenez
- FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
- Physiotherapy Department, Centro Superior de Estudios Universitarios La Salle, Universidad Autónoma de Madrid, Madrid, Spain
- Physiotherapy Department, Alcalá de Henares University, Alcalá de Henares Spain
| | | | - Michele Dileone
- FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
- CINAC, HM Puerta del Sur, Hospitales de Madrid, Móstoles, Spain
| | - Michela Campolo
- FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
- EMG and Motor Control Section, Neurology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | | | - Fabricia Moitinho-Ferreira
- FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
- Sarah Network of Rehabilitation Hospitals, Salvador de Bahia, Brazil
| | | | - Hartwig R. Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Hvidovre, Denmark
- Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Josep Valls-Solé
- EMG and Motor Control Section, Neurology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Juan Aguilar
- Experimental Neurophysiology Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
| | - Antonio Oliviero
- FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
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Jannati A, Block G, Oberman LM, Rotenberg A, Pascual-Leone A. Interindividual variability in response to continuous theta-burst stimulation in healthy adults. Clin Neurophysiol 2017; 128:2268-2278. [PMID: 29028501 DOI: 10.1016/j.clinph.2017.08.023] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 07/10/2017] [Accepted: 08/23/2017] [Indexed: 01/21/2023]
Abstract
OBJECTIVE We used complete-linkage cluster analysis to identify healthy subpopulations with distinct responses to continuous theta-burst stimulation (cTBS). METHODS 21 healthy adults (age±SD, 36.9±15.2years) underwent cTBS of left motor cortex. Natural log-transformed motor evoked potentials (LnMEPs) at 5-50min post-cTBS (T5-T50) were calculated. RESULTS Two clusters were found; Group 1 (n=12) that showed significant MEP facilitation at T15, T20, and T50 (p's<0.006), and Group 2 (n=9) that showed significant suppression at T5-T15 (p's<0.022). LnMEPs at T10 and T40 were best predictors of, and together accounted for 80% of, cluster assignment. In an exploratory analysis, we examined the roles of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) polymorphisms in the cTBS response. Val66Met participants showed greater facilitation at T10 than Val66Val participants (p=0.025). BDNF and cTBS intensity predicted 59% of interindividual variability in LnMEP at T10. APOE did not significantly affect LnMEPs at any time point (p's>0.32). CONCLUSIONS Data-driven cluster analysis can identify healthy subpopulations with distinct cTBS responses. T10 and T40 LnMEPs were best predictors of cluster assignment. T10 LnMEP was influenced by BDNF polymorphism and cTBS intensity. SIGNIFICANCE Healthy adults can be sorted into subpopulations with distinct cTBS responses that are influenced by genetics.
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Affiliation(s)
- Ali Jannati
- Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Gabrielle Block
- Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Lindsay M Oberman
- Neuroplasticity and Autism Spectrum Disorder Program, Department of Psychiatry and Human Behavior, E.P. Bradley Hospital, Warrent Alpert Medical School of Brown University, East Providence, RI, USA
| | - Alexander Rotenberg
- Neuromodulation Program and Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alvaro Pascual-Leone
- Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Institut Guttman de Neurorehabilitació, Universitat Autónoma de Barcelona, Badalona, Barcelona, Spain.
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Noda Y, Zomorrodi R, Saeki T, Rajji TK, Blumberger DM, Daskalakis ZJ, Nakamura M. Resting-state EEG gamma power and theta–gamma coupling enhancement following high-frequency left dorsolateral prefrontal rTMS in patients with depression. Clin Neurophysiol 2017; 128:424-432. [DOI: 10.1016/j.clinph.2016.12.023] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/07/2016] [Accepted: 12/23/2016] [Indexed: 10/20/2022]
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Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning. Proc Natl Acad Sci U S A 2016; 113:13209-13214. [PMID: 27799552 DOI: 10.1073/pnas.1616206113] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca2+ type 2.1 (CaV2.1) channels. However, the contribution of regulation of CaV2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg2+ The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of CaV2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.
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Suppa A, Huang YZ, Funke K, Ridding M, Cheeran B, Di Lazzaro V, Ziemann U, Rothwell J. Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects. Brain Stimul 2016; 9:323-335. [DOI: 10.1016/j.brs.2016.01.006] [Citation(s) in RCA: 391] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/14/2016] [Accepted: 01/21/2016] [Indexed: 01/08/2023] Open
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Form and Function of Sleep Spindles across the Lifespan. Neural Plast 2016; 2016:6936381. [PMID: 27190654 PMCID: PMC4848449 DOI: 10.1155/2016/6936381] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 03/16/2016] [Indexed: 01/11/2023] Open
Abstract
Since the advent of EEG recordings, sleep spindles have been identified as hallmarks of non-REM sleep. Despite a broad general understanding of mechanisms of spindle generation gleaned from animal studies, the mechanisms underlying certain features of spindles in the human brain, such as “global” versus “local” spindles, are largely unknown. Neither the topography nor the morphology of sleep spindles remains constant throughout the lifespan. It is likely that changes in spindle phenomenology during development and aging are the result of dramatic changes in brain structure and function. Across various developmental windows, spindle activity is correlated with general cognitive aptitude, learning, and memory; however, these correlations vary in strength, and even direction, depending on age and metrics used. Understanding these differences across the lifespan should further clarify how these oscillations are generated and their function under a variety of circumstances. We discuss these issues, and their translational implications for human cognitive function. Because sleep spindles are similarly affected in disorders of neurodevelopment (such as schizophrenia) and during aging (such as neurodegenerative conditions), both types of disorders may benefit from therapies based on a better understanding of spindle function.
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Fung TK, Law CS, Leung LS. Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo. J Neurophysiol 2016; 115:3264-74. [PMID: 27052581 DOI: 10.1152/jn.00188.2016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 04/05/2016] [Indexed: 12/12/2022] Open
Abstract
Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing-generating synaptic excitation before a spike-results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of -10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60-120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of -10 ms to 0 ms but no LTD at ES intervals of -20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus.
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Affiliation(s)
- Thomas K Fung
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Clayton S Law
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - L Stan Leung
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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Lu GL, Lee CH, Chiou LC. Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long-term potentiation and preventing depotentiation. Neuropharmacology 2016; 107:168-180. [PMID: 26965217 DOI: 10.1016/j.neuropharm.2016.03.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/19/2016] [Accepted: 03/01/2016] [Indexed: 01/30/2023]
Abstract
The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (≧30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS-1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re-potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations.
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Affiliation(s)
- Guan-Ling Lu
- Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Hsu Lee
- Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lih-Chu Chiou
- Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Reserach Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan.
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Hippocampal-Prefrontal Theta Oscillations Support Memory Integration. Curr Biol 2016; 26:450-7. [DOI: 10.1016/j.cub.2015.12.048] [Citation(s) in RCA: 171] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/09/2015] [Accepted: 12/09/2015] [Indexed: 12/27/2022]
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Koops S, van Dellen E, Schutte MJL, Nieuwdorp W, Neggers SFW, Sommer IEC. Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial. Schizophr Bull 2016; 42. [PMID: 26221051 PMCID: PMC4681555 DOI: 10.1093/schbul/sbv100] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Auditory verbal hallucinations (AVH) in schizophrenia are resistant to antipsychotic medication in approximately 25% of patients. Treatment with repetitive transcranial magnetic stimulation (rTMS) for refractory AVH has shown varying results. A stimulation protocol using continuous theta burst rTMS (TB-rTMS) showed high efficacy in open label studies. We tested TB-rTMS as a treatment strategy for refractory AVH in a double-blind, placebo-controlled trial. METHODS Seventy-one patients with AVH were randomly allocated to TB-rTMS or placebo treatment. They received 10 TB-rTMS or sham treatments over the left temporoparietal cortex in consecutive days. AVH severity was assessed at baseline, end of treatment and follow-up using the Psychotic Symptom Rating Scale (PSYRATS) and the Auditory Hallucinations Rating Scale (AHRS). Other schizophrenia-related symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS Seven patients dropped out before completing the study. In the remaining 64, AVH improved significantly after treatment in both groups as measured with both PSYRATS and AHRS. PANSS positive and general subscores also decreased, but the negative subscores did not. However, improvement did not differ significantly between the TB-rTMS and the placebo group on any outcome measure. CONCLUSIONS Symptom reduction could be achieved in patients with medication-resistant hallucinations, even within 1 week time. However, as both groups showed similar improvement, effects were general (ie, placebo-effects) rather than specific to treatment with continuous TB-rTMS. Our findings highlight the importance of double-blind trials including a sham-control condition to assess efficacy of new treatments such as TMS.
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Affiliation(s)
- Sanne Koops
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands; Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Edwin van Dellen
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands;,Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Maya J. L. Schutte
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands;,Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Wendy Nieuwdorp
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands;,Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Sebastiaan F. W. Neggers
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands;,Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Iris E. C. Sommer
- Psychiatry Department, University Medical Center Utrecht, Utrecht, The Netherlands;,Brain Center Rudolf Magnus, Utrecht, The Netherlands
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Abstract
This review covers the spatial and temporal rules governing induction of hippocampal long-term potentiation (LTP) by theta-burst stimulation. Induction of LTP in field CA1 by high frequency stimulation bursts that resemble the burst discharges (complex-spikes) of hippocampal pyramidal neurons involves a multiple-step mechanism. A single burst is insufficient for LTP induction because it evokes both excitatory and inhibitory currents that partially cancel and limit postsynaptic depolarization. Bursts repeated at the frequency (~5 Hz) of the endogenous theta rhythm induce maximal LTP, primarily because this frequency disables feed-forward inhibition and allows sufficient postsynaptic depolarization to activate voltage-sensitive NMDA receptors. The disinhibitory process, referred to as "priming", involves presynaptic GABA autoreceptors that inhibit GABA release. Activation of NMDA receptors allows a calcium flux into dendritic spines that serves as the proximal trigger for LTP. We include new data showing that theta-burst stimulation is more efficient than other forms of stimulation for LTP induction. In addition, we demonstrate that associative interactions between synapses activated during theta-bursts are limited to major dendritic domains since such interactions occur within apical or basal dendritic trees but not between them. We review evidence that recordings of electrophysiological responses during theta burst stimulation can help to determine if experimental manipulations that affect LTP do so by affecting events antecedent to the induction process, such as NMDA receptor activation, or downstream signaling cascades that result from postsynaptic calcium fluxes. Finally, we argue that theta-burst LTP represents a minimal model for stable, non-decremental LTP that is more sensitive to a variety of experimental manipulations than is LTP induced by other stimulation paradigms. This article is part of a Special Issue entitled SI: Brain and Memory.
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Affiliation(s)
- John Larson
- Psychiatric Institute, Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL 60612, United States.
| | - Erin Munkácsy
- Barshop Institute for Longevity and Aging Studies, Department of Cell and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, United States
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Migliore M, De Simone G, Migliore R. Effect of the initial synaptic state on the probability to induce long-term potentiation and depression. Biophys J 2015; 108:1038-46. [PMID: 25762316 PMCID: PMC4375721 DOI: 10.1016/j.bpj.2014.12.048] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 12/03/2014] [Accepted: 12/10/2014] [Indexed: 12/28/2022] Open
Abstract
Long-term potentiation (LTP) and long-term depression (LTD) are the two major forms of long-lasting synaptic plasticity in the mammalian neurons, and are directly related to higher brain functions such as learning and memory. Experimentally, they are characterized by a change in the strength of a synaptic connection induced by repetitive and properly patterned stimulation protocols. Although many important details of the molecular events leading to LTP and LTD are known, experimenters often report problems in using standard induction protocols to obtain consistent results, especially for LTD in vivo. We hypothesize that a possible source of confusion in interpreting the results, from any given experiment on synaptic plasticity, can be the intrinsic limitation of the experimental techniques, which cannot take into account the actual state and peak conductance of the synapses before the conditioning protocol. In this article, we investigate the possibility that the same experimental protocol may result in different consequences (e.g., LTD instead of LTP), according to the initial conditions of the stimulated synapses, and can generate confusing results. Using biophysical models of synaptic plasticity and hippocampal CA1 pyramidal neurons, we study how, why, and to what extent the phenomena observed at the soma after induction of LTP/LTD reflects the actual (local) synaptic state. The model and the results suggest a physiologically plausible explanation for why LTD induction is experimentally difficult to obtain. They also suggest experimentally testable predictions on the stimulation protocols that may be more effective.
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Affiliation(s)
- Michele Migliore
- Institute of Biophysics, National Research Council, Palermo, Italy.
| | - Giada De Simone
- Institute of Biophysics, National Research Council, Palermo, Italy
| | - Rosanna Migliore
- Institute of Biophysics, National Research Council, Palermo, Italy
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Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS treatment for depression? Depress Anxiety 2015; 32:182-92. [PMID: 25450537 DOI: 10.1002/da.22335] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/17/2014] [Accepted: 10/21/2014] [Indexed: 12/13/2022] Open
Abstract
Major depressive disorder (MDD) is a common debilitating condition where only one third of patients achieve remission after the first antidepressant treatment. Inadequate efficacy and adverse effects of current treatment strategies call for more effective and tolerable treatment options. Transcranial magnetic stimulation (TMS) is a noninvasive approach to manipulate brain activity and alter cortical excitability. There has been more than 15 years of research on the use of repetitive form of TMS (rTMS) for the treatment of patients with depression, which has shown it to be an effective antidepressant treatment. Even though rTMS treatment has shown efficacy in treating depression, there is a high degree of interindividual variability in response. A newer form of rTMS protocol, known as theta-burst stimulation (TBS), has been shown to produce similar if not greater effects on brain activity than standard rTMS. TBS protocols have a major advantage over standard rTMS approaches in their reduced administration duration. Conventional rTMS procedures last between 20 and 45 min, as compared to TBS paradigms that require 1 to 3 min of stimulation. Recently, a small number of studies have suggested that TBS has similar or better efficacy in treating depression compared to rTMS. Optimization, identification of response predictors, and clarification of neurobiological mechanisms of TBS is required if it is to be further developed as a less time intensive, safe, and effective treatment for MDD.
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Affiliation(s)
- Sung Wook Chung
- Monash Alfred Psychiatry Research Centre, Central Clinical School, The Alfred and Monash University, Melbourne, Australia
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Lynch G, Cox CD, Gall CM. Pharmacological enhancement of memory or cognition in normal subjects. Front Syst Neurosci 2014; 8:90. [PMID: 24904313 PMCID: PMC4033242 DOI: 10.3389/fnsys.2014.00090] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 04/30/2014] [Indexed: 12/14/2022] Open
Abstract
The possibility of expanding memory or cognitive capabilities above the levels in high functioning individuals is a topic of intense discussion among scientists and in society at large. The majority of animal studies use behavioral endpoint measures; this has produced valuable information but limited predictability for human outcomes. Accordingly, several groups are pursuing a complementary strategy with treatments targeting synaptic events associated with memory encoding or forebrain network operations. Transcription and translation figure prominently in substrate work directed at enhancement. Notably, the question of why new proteins would be needed for a now-forming memory given that learning-driven synthesis presumably occurred throughout the immediate past has been largely ignored. Despite this conceptual problem, and some controversy, recent studies have reinvigorated the idea that selective gene manipulation is a plausible route to enhancement. Efforts to improve memory by facilitating synaptic encoding of information have also progressed, in part due of breakthroughs on mechanisms that stabilize learning-related, long-term potentiation (LTP). These advances point to a reductionistic hypothesis for a diversity of experimental results on enhancement, and identify under-explored possibilities. Cognitive enhancement remains an elusive goal, in part due to the difficulty of defining the target. The popular view of cognition as a collection of definable computations seems to miss the fluid, integrative process experienced by high functioning individuals. The neurobiological approach obviates these psychological issues to directly test the consequences of improving throughput in networks underlying higher order behaviors. The few relevant studies testing drugs that selectively promote excitatory transmission indicate that it is possible to expand cortical networks engaged by complex tasks and that this is accompanied by capabilities not found in normal animals.
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Affiliation(s)
- Gary Lynch
- Department of Psychiatry and Human Behavior, University of California Irvine, CA, USA ; Department of Anatomy and Neurobiology, University of California Irvine, CA, USA
| | - Conor D Cox
- Department of Anatomy and Neurobiology, University of California Irvine, CA, USA
| | - Christine M Gall
- Department of Anatomy and Neurobiology, University of California Irvine, CA, USA
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Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions. J Neurosci 2013; 33:9364-84. [PMID: 23719805 DOI: 10.1523/jneurosci.4660-12.2013] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
In vitro studies suggest that the intracellular C terminus of Neuroligin1 (NL1) could play a central role in the maturation of excitatory synapses. However, it is unknown how this activity affects synapses in vivo, and whether it may impact the development of complex behaviors. To determine how NL1 influences the state of glutamatergic synapses in vivo, we compared the synaptic and behavioral phenotypes of mice overexpressing a full-length version of NL1 (NL1FL) with mice overexpressing a version missing part of the intracellular domain (NL1ΔC). We show that overexpression of full-length NL1 yielded an increase in the proportion of synapses with mature characteristics and impaired learning and flexibility. In contrast, the overexpression of NL1ΔC increased the number of excitatory postsynaptic structures and led to enhanced flexibility in mnemonic and social behaviors. Transient overexpression of NL1FL revealed that elevated levels are not necessary to maintain synaptic and behavioral states altered earlier in development. In contrast, overexpression of NL1FL in the fully mature adult was able to impair normal learning behavior after 1 month of expression. These results provide the first evidence that NL1 significantly impacts key developmental processes that permanently shape circuit function and behavior, as well as the function of fully developed neural circuits. Overall, these manipulations of NL1 function illuminate the significance of NL1 intracellular signaling in vivo, and enhance our understanding of the factors that gate the maturation of glutamatergic synapses and complex behavior. This has significant implications for our ability to address disorders such as autism spectrum disorders.
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