Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice

eLife, Journal Year: 2022, Volume and Issue: 11

Published: July 4, 2022

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson’s disease (PD), but its underlying therapeutic mechanisms remain unclear. Since advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) antidromically activates cortex; (3) disrupts firing dynamics within STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used artifact-free GCaMP fiber photometry to investigate activity in nuclei during parkinsonian mice. To test whether observed changes were sufficient relieve symptoms, we then combined electrophysiological recording with targeted optical protocols. Our findings suggest that exerts effect through disruption movement-related activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments establish an approach for investigating other neuropsychiatric conditions.

Language: Английский

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Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 13, 2022

Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging individual hippocampal CA1 neurons during delivered at 40 Hz or 140 Hz, free electrical interference. powerfully depolarized somatic potentials without suppressing spike rate, especially Hz. Further, paced and timing frequency reduced timed spiking output in response to network theta-rhythmic (3-12 Hz) activity patterns. To determine whether directly impacts cellular processing inputs, optogenetically evoked depolarization soma. We found that DBS-evoked was correlated with DBS-mediated suppression neuronal responses optogenetic inputs. These results demonstrate produces powerful interferes ability respond creating an informational lesion.

Language: Английский

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Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

Neurotherapeutics, Journal Year: 2022, Volume and Issue: 19(4), P. 1193 - 1215

Published: April 11, 2022

In the face of a global epidemic drug addiction, neglecting to develop new effective therapies will perpetuate staggering human and economic costs substance use. This review aims summarize evaluate preclinical clinical studies deep brain stimulation (DBS) as novel therapy for refractory in hopes engage inform future research this promising treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library) was performed using keywords predefined inclusion criteria between 1974 6/18/2021 (registered on Open Science Registry). Selected articles were reviewed full text key details summarized analyzed understand DBS' therapeutic potential possible mechanisms action. The yielded 25 animal 22 studies. Animal showed that DBS targets such nucleus accumbens (NAc), insula, subthalamic reduces use seeking. All case series/reports (level 4/5 evidence), mostly targeting NAc with generally positive outcomes. From limited evidence literature, DBS, particularly NAc, appears be reasonable last resort option addictive disorders. We propose objective electrophysiological (e.g., local field potentials) neurochemical extracellular dopamine levels) biomarkers would assist monitoring progress developing closed-loop system. Preclinical literature also highlighted prefrontal cortex target, which should explored research.

Language: Английский

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Dynamic Activity Model of Movement Disorders: The Fundamental Role of the Hyperdirect Pathway

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(12), P. 2145 - 2150

Published: Nov. 20, 2023

Schematic illustration of cortically induced dynamic activity changes the output nuclei basal ganglia (the internal segment globus pallidus, GPi and substantia nigra pars reticulata, SNr) in healthy diseased states. The height dam along time course controls expression voluntary movements. Its alterations could cause a variety movement disorders, such as Parkinson's disease hyperkinetic disorders. © 2023 Authors. Movement Disorders published by Wiley Periodicals LLC on behalf International Parkinson Disorder Society. Malfunction (BG) results origin disorders (PD), dystonia, Huntington's (HD), levodopa-induced dyskinesia (LID), hemiballism. So far, two models have been proposed to explain their pathophysiology, especially for PD, based recordings neuronal animal patients.1 "firing rate model" proposes that mean firing rates BG, pallidus (GPi) reticulata (SNr), are increased, suppress thalamocortical activity, resulting bradykinesia.2 In pattern model," abnormal patterns oscillatory synchronized disturb movement-related signals.3 Alternatively, we propose "dynamic aiming pathophysiology unified manner. To explore how BG control movements, long studying response GPi/SNr cortical stimulation, which is presumed mimic excitation initiate movements (Fig. 1). normal state, electrical stimulation motor prefrontal cortices induces triphasic consisting early 1B, magenta), inhibition (blue), late (green) monkeys, rodents, probably humans. Each component mediated cortico-subthalamo (STN)-GPi/SNr hyperdirect, cortico-striato (Str)-GPi/SNr direct, cortico-Str-external pallido (GPe)-STN-GPi/SNr indirect pathways, respectively 1A).4-8 These three pathways would work during execution similar manner 1B,C).5 When about be initiated, signals through hyperdirect pathway first reach GPi/SNr, inhibit reset related ongoing prepare next action. Then, direct disinhibit release an appropriate at time. Finally, stop released pathway. conduction these short enough affect (<100 ms). spatial domain, inhibitory inputs terminate relatively small, limited area 1C, blue), whereas excitatory (magenta) over wide area,9, 10 thereby forming inhibitory-center excitatory-surround organization GPi/SNr. Inhibition center selected movement, surrounding continuously other unintended Indeed, activation suppressed facilitated movements.4, 7, 8, 11, 12 We also examining altered various disorder 2, plotted hyperkinetic-hypokinetic hypertonic-hypotonic plane) like discuss model. Monkeys treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),13 mice another 6-hydroxydopamine (6-OHDA),14 exhibit features bradykinesia can equated those observed PD patients. models, was greatly diminished PD), excitation, respectively, slightly enhanced or little changed. extent decrease paralleled severity bradykinesia.13 Systemic administration l-DOPA ameliorated restored inhibition, manifesting GPi.13 Thus, significant reduction leads capacity releasing intended bradykinesia.13, 14 reduced stems from hypoactivity dopamine D1 receptor-expressing Str neurons.12, 17 Enhanced STN additionally make less probable.18 DYT1 (DYT-TOR1A) dystonia mouse model overexpressing human torsinA exhibits hyperlocomotion, dystonic-like sustained co-contractions agonist antagonist muscles.15 this model, followed long-lasting entopeduncular nucleus (EPN, rodent equivalent GPi) GPe dystonia).15 This suggests neurotransmission enhanced. addition, spontaneous were bursts pauses. Somatotopy overlapped, single EPN/GPe neuron tended receive multiple inputs.15 One patient cervical exhibited GPi/GPe when examined stereotactic surgery.16 enhancement temporal domains strongly disinhibits thalamic causes muscle contractions even if original weak.9, 15 Overlapped somatotopy coactivation muscles overflow, is, unintentional distant sites. Furthermore, "sensory trick," touching involved/adjacent body parts, explained distinct GPi. Motor evoked sensory parts LID developed daily 6-OHDA-treated mice. parkinsonian largely SNr PD),14 after injection, showed involuntary recovered enhanced, PD).14 marked releases random times, suppression cannot once-released LID.14 most pathology HD striatum, where Str-GPe neurons degenerate stage, degeneration Str-GPi/SNr neurons.19 Selective elimination immunotoxin-mediated cell-targeting method transgenic caused hyperactivity stage HD.20 mice, without chorea HD).7 Similarly, bicuculline gabazine (GABAA receptor antagonist) injection into monkeys.21, 22 loss movements.7 Blocking lesioning muscimol agonist) hemiballism monkeys.4, 23 hemiballism).4 Besides, decreased, pauses GPi/GPe, main source.4 easily nor movements.4 some aspects rate/pattern associated disorders.1 Cortically PD). If repetitively induced, increased. Likewise, strong rates. On hand, degrees low-beta oscillation theta STN.3, 16, 24 Alterations interaction cortico-GPi/GPe/STN STN-GPe derived activity,24, 25 determining frequency. several manifestations not simply available models. Here, principal but unexplained signs tremor rigidity. Tremor rest predominantly involves distal limb characterized 4–6 Hz alternating agonist/antagonist pairs. MPTP-treated did usually develop low-frequency tremors.24 patients, typically tremors thalamus,3, 26-28 latter receives cerebellum, BG. A lesion thalamus abolished tremor, suggesting causal role.27, 28 Strong, spread cerebello-thalamic systems disynaptic projection cerebellar cortex via pontine nuclei29 eventually induce tremors. initiated cortico-BG loop amplified cortico-cerebellar interactions.30 tremor-related transferred spinal cord cortex. Velocity-dependent increased resistance passive stretching cogwheeling phenomenon typical rigidity PD. its may enhance long-latency stretch reflex, provide one relevant mechanism rigidity.31 descending cord, pedunculopontine tegmental (PPN) midbrain locomotor region, locomotion, gait, posture.32 send projections PPN, PPN decreases tone.32 dominant leading tone, hemiballism, hemiballism) opposite effects decreased tone. symptoms quite different between LID, nature imbalance rates, presence/absence overlapped Stereotactic surgery targeting GPi, deep brain (DBS) thermoablation, improves cardinal blockade bradykinesia, same time, + block).13 Restored enables disinhibiting activity.13 beneficial STN-DBS meant so simple include elements, afferent efferent axons soma STN, least effect likely disrupt signal transmission GPi.33-35 gives us better prospects more comprehensive view underlying pathophysiology. However, it oversimplify complex conditions has only Other neurotransmitters, including serotonin noradrenaline, well dopamine, disturbed monkeys patients,36, 37 neurodegeneration brainstem cerebral patients,38 contributing plethora symptoms. responses artificial cortex, need examine whether actual sum, implies balance plays essential role dysfunction Possible future therapeutic approaches will adaptive DBS delivers cortex,39 chemogenetic40/optogenetic optogenetic pathway.11 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: Design, Execution, Review Critique; (3) Manuscript: Writing draft, Critique. A.N.: 1A, 3A S.C.: 3B H.S.: N.H.: J.A.O.: thank S. Sato, H. Isogai, N. Suzuki, K. Awamura, Miyamoto, T. Sugiyama, M. Hayashi, technical support; Y. Yamagata critical reading manuscript. Financial disclosure research covered article. Atushi Nambu—funding sources: Japan Agency Medical Development (AMED); Society Promotion Science (JSPS); Ministry Education, Culture, Sports, Technology (MEXT). Satomi Chiken—funding (JSPS), Core Evolutional (CREST). Hiromi Sano—funding Nobuhiko Hatanaka—funding source: (JSPS). José Obeso—funding Fundacíón HM Hospitales; CIBERNED, Instituto Carlos III, Ministerio de Educación y Ciencias. Full financial previous months. (AMED), (MEXT), Eisai, Kyocera; publishing royalties: Igakushoin, MEDSi; honoraria: Otsuka Pharmaceutical, Kyowa Kirin, AMED, JSPS, (JST), FP, Tokyo Metropolitan Institute Sciences, Society, Japanese Basal Ganglia Narishige, Functional Neurosurgery, Clinical Neurophysiology; employment: National Physiological University Tokyo, Tamagawa University, Nagoya City Mie Kanazawa Kyoto Kindai University. Evolution (CREST); (MEXT); Fujita Health Aichi Gakuin Fundacíon Ciencia; Insightec, Biogen, Laboratorios Estebe, Editorial Viguera; Hospitales. No new data generated analyzed study.

Language: Английский

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Dynamic amplitude modulation of microstimulation evokes biomimetic onset and offset transients and reduces depression of evoked calcium responses in sensory cortices

Brain stimulation, Journal Year: 2023, Volume and Issue: 16(3), P. 939 - 965

Published: May 1, 2023

Intracortical microstimulation (ICMS) is an emerging approach to restore sensation people with neurological injury or disease. Biomimetic microstimulation, stimulus trains that mimic neural activity in the brain through encoding of onset and offset transients, could improve utility ICMS for brain-computer interface (BCI) applications, but how biomimetic affects activation not understood. Current "biomimetic" aim reproduce strong transients evoked by sensory input dynamic modulation parameters. Stimulus induced depression (decreases intensity over time) also a potential barrier clinical implementation feedback, may reduce this effect.

Language: Английский

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Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson's disease

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Nov. 30, 2023

Abstract Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides unique approach that allows cell type- projection-specific modulation mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research models plays pivotal role unraveling neuronal synaptic adaptations contribute to efficacy DBS PD treatment. DBS-induced responses rely on complex interplay between distributions presynaptic inputs, depression, intrinsic excitability postsynaptic neurons. This orchestration leads conversion firing patterns, enabling both antidromic orthodromic neural circuits. Understanding these vital decoding position- programming-dependent Furthermore, patterned emerging as promising strategy yielding long-lasting therapeutic benefits. Research may pave way development more enduring precise patterns. Advanced technologies, such adaptive or directional electrodes, can also be integrated circuit-specific neuromodulation. These insights hold potential greatly improve effectiveness advance new levels.

Language: Английский

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Systematic review of rodent studies of deep brain stimulation for the treatment of neurological, developmental and neuropsychiatric disorders

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 11, 2024

Abstract Deep brain stimulation (DBS) modulates local and widespread connectivity in dysfunctional networks. Positive results are observed several patient populations; however, the precise mechanisms underlying treatment remain unknown. Translational DBS studies aim to answer these questions provide knowledge for advancing field. Here, we systematically review literature on involving models of neurological, developmental neuropsychiatric disorders a synthesis current scientific landscape surrounding this topic. A systematic analysis was performed following PRISMA guidelines. 407 original articles were included. Data extraction focused study characteristics, including protocol, behavioural outcomes, action. The number published increased over years, 16 rat 13 mouse transgenic or healthy animals exposed external factors induce symptoms. Most targeted telencephalic structures with varying settings. outcomes reported 85.8% included studies. In psychiatric neurodevelopmental disorders, DBS-induced effects associated changes monoamines neuronal activity along mesocorticolimbic circuit. For movement improves symptoms via modulation striatal dopaminergic system. dementia epilepsy models, cellular molecular aspects hippocampus shown underlie symptom improvement. Despite limitations translating findings from preclinical clinical settings, rodent have contributed substantially our pathophysiology disease mechanisms. Direct inhibition/excitation neural activity, whereby pathological oscillatory within networks, is among major theories its mechanism. However, there fundamental mechanisms, optimal targets parameters that need be better understood improve therapy more individualized according patient’s predominant

Language: Английский

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Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor

eLife, Journal Year: 2024, Volume and Issue: 12

Published: July 29, 2024

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. neural substrates that encode this diversity are unclear. Here, we tested whether the spike activity cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across similar capable causing impairments. Using in vivo awake recordings as input data, trained supervised classifier model differentiate parameters mouse models for correctly assigned phenotypes based on single-neuron signatures. Spike signatures were shared etiologically but phenotypically disease models. Mimicking these pathophysiological optogenetics induced predicted impairments otherwise healthy mice. These data show promote behavioral presentation diseases.

Language: Английский

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Heterogeneity of Subthalamic Nucleus Neuronal Responses to Voluntary Movements in Parkinsonian Patients

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(6)

Published: March 1, 2025

ABSTRACT The subthalamic nucleus (STN), an important part of the motor control system, represents a prime target for deep brain stimulation (DBS) in patients with Parkinson's disease (PD). STN is involved several pathways regulating preparation and execution voluntary movements. However, neural mechanisms providing remain unclear. We analysed single‐unit activity entire spiking 21 PD who underwent standard‐of‐care DBS implantation procedures. asked to perform similar tasks during microelectrode EMG recording. used perievent wavelet spectrograms histograms analyse responses rhythmic nonrhythmic cells. showed that responsive neurons had more bursty firing pattern compared nonresponsive cells localized dorsolateral STN. Analysis revealed increase or decrease rate units, which could precede lag movement onset. also found short‐term phasic activation beta desynchronization preceding Finally, we observed transformation from bursting before then tonic inhibition movement. have shown complexity heterogeneity Our data suggests both performance. These support hypothesis be ‘feedforward’ ‘feedback’ processes control.

Language: Английский

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Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's Disease Mouse Model

Progress in Neurobiology, Journal Year: 2025, Volume and Issue: unknown, P. 102761 - 102761

Published: April 1, 2025

The subthalamic nucleus (STN) plays a crucial role in suppressing prepotent response tendency. prefrontal regions innervating the STN exhibit increased activity during stop-signal responses, and optogenetic activation of these neurons suppresses ongoing behavior. High-frequency electrical stimulation effectively treats motor symptoms Parkinson's disease (PD), yet its underlying circuit mechanisms remain unclear. Here, we investigated involvement STN-projecting premotor (M2) PD mouse models impact deep brain targeting (DBS-STN). We found that M2 exhibited enhanced burst firing synchronous oscillations model. Remarkably, high-frequency neurons, simulating antidromic DBS-STN relieved hyperexcitability. These changes were attributed to reduced frequency vs. current relationship through normalized hyperpolarization-activated inward (Ih). model displayed Ih, which was reversed by stimulation. Additionally, infusion ZD7288, an HCN channel blocker, into replicated effects In conclusion, our study reveals excessive excitability suppressive control M2-STN synapses Antidromic excitation alleviates this suppression, thereby improving impairment. findings provide insights circuit-level dynamics stimulation's therapeutic PD, suggesting could serve as potential targets for future strategies.

Language: Английский

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