Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
1.
Adv Sci (Weinh) ; : e2405293, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39283040

RESUMO

Two-photon high-speed fluorescence calcium imaging stands as a mainstream technique in neuroscience for capturing neural activities with high spatiotemporal resolution. However, challenges arise from the inherent tradeoff between acquisition speed and image quality, grappling with a low signal-to-noise ratio (SNR) due to limited signal photon flux. Here, a contrast-enhanced video-rate volumetric system, integrating a tunable acoustic gradient (TAG) lens-based high-speed microscopy with a TAG-SPARK denoising algorithm is demonstrated. The former facilitates high-speed dense z-sampling at sub-micrometer-scale intervals, allowing the latter to exploit the spatial redundancy of z-slices for self-supervised model training. This spatial redundancy-based approach, tailored for 4D (xyzt) dataset, not only achieves >700% SNR enhancement but also retains fast-spiking functional profiles of neuronal activities. High-speed plus high-quality images are exemplified by in vivo Purkinje cells calcium observation, revealing intriguing dendritic-to-somatic signal convolution, i.e., similar dendritic signals lead to reverse somatic responses. This tailored technique allows for capturing neuronal activities with high SNR, thus advancing the fundamental comprehension of neuronal transduction pathways within 3D neuronal architecture.

2.
Res Sq ; 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39149481

RESUMO

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control.

3.
J Neurol Sci ; 461: 123060, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38810429

RESUMO

INTRODUCTION: Previous research has identified that people with cerebellar ataxia (CA) showed impaired reward-related decision-making in the Iowa Gambling Task (IGT). To investigate the mechanisms underlying this impairment, we examined CA participants' combination of performance in the IGT, which predominantly tests reward seeking, and the modified IGT (mIGT), which mainly assesses punishment avoidance. METHODS: Fifty participants with CA and one hundred controls completed the IGT and mIGT. Task performance in each of the five twenty-trial blocks was compared between groups and the learning rates were assessed with simple linear regressions. Each participant's IGT score and mIGT score were compared. RESULTS: CA participants performed worse than controls in both the IGT and the mIGT, especially in the last block (IGT: -0.24 ± 10.05 vs. 3.88 ± 10.31, p = 0.041; mIGT: 2.72 ± 7.62 vs. 8.65 ± 8.64, p < 0.001). In contrast to the controls, those with CA did not significantly improve their scores over time in either task. Controls performed better in the mIGT than the IGT, while CA participants' scores in the two tasks showed no significant difference. IGT and mIGT performance did not correlate with ataxia severity or depressive symptoms. CONCLUSION: Individuals with CA showed impaired performance in both the IGT and mIGT, which indicates disruption in both short-term reward seeking and short-term punishment avoidance. Therefore, these results suggest that reduced sensitivity to long-term consequences drives the risky decision-making in CA.


Assuntos
Ataxia Cerebelar , Tomada de Decisões , Jogo de Azar , Recompensa , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Ataxia Cerebelar/fisiopatologia , Ataxia Cerebelar/psicologia , Tomada de Decisões/fisiologia , Jogo de Azar/psicologia , Jogo de Azar/fisiopatologia , Adulto , Testes Neuropsicológicos , Idoso
4.
Sci Transl Med ; 16(747): eadl1408, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38748772

RESUMO

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.


Assuntos
Cerebelo , Tremor Essencial , Neurônios , Núcleo Olivar , Tremor Essencial/fisiopatologia , Animais , Humanos , Núcleo Olivar/fisiopatologia , Cerebelo/fisiopatologia , Camundongos , Masculino , Optogenética , Feminino , Estimulação Encefálica Profunda , Pessoa de Meia-Idade , Eletroencefalografia , Idoso
5.
Cerebellum ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066397

RESUMO

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward.

6.
Clin Neurophysiol Pract ; 8: 143-160, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37593693

RESUMO

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders.

7.
Acta Neuropathol ; 146(2): 301-318, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37335342

RESUMO

Essential Tremor (ET) is a prevalent neurological disease characterized by an 8-10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca2+) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a "leaky channel" biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This 'leaky' RyR1 signature was not seen in control or Parkinson's disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca2+ leak via RyR1 may contribute to tremor pathophysiology.


Assuntos
Cálcio , Canal de Liberação de Cálcio do Receptor de Rianodina , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Cálcio/metabolismo , Tremor/metabolismo , Cerebelo/metabolismo , Retículo Endoplasmático/metabolismo , Músculo Esquelético/metabolismo
8.
Bioeng Transl Med ; 8(2): e10432, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36925695

RESUMO

Tracking kinematic details of motor behaviors is a foundation to study the neuronal mechanism and biology of motor control. However, most of the physiological motor behaviors and movement disorders, such as gait, balance, tremor, dystonia, and myoclonus, are highly dependent on the overall momentum of the whole-body movements. Therefore, tracking the targeted movement and overall momentum simultaneously is critical for motor control research, but it remains an unmet need. Here, we introduce the intrinsic oscillatory property (IOP), a fundamental mechanical principle of physics, as a method for motion tracking in a force plate. The overall kinetic energy of animal motions can be transformed into the oscillatory amplitudes at the designed IOP frequency of the force plate, while the target movement has its own frequency features and can be tracked simultaneously. Using action tremor as an example, we reported that force plate-based IOP approach has superior performance and reliability in detecting both tremor severity and tremor frequency, showing a lower level of coefficient of variation (CV) compared with video- and accelerometer-based motion tracking methods and their combination. Under the locomotor suppression effect of medications, therapeutic effects on tremor severity can still be quantified by dynamically adjusting the overall locomotor activity detected by IOP. We further validated IOP method in optogenetic-induced movements and natural movements, confirming that IOP can represent the intensity of general rhythmic and nonrhythmic movements, thus it can be generalized as a common approach to study kinematics.

9.
Ann Clin Transl Neurol ; 10(4): 462-483, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36738196

RESUMO

Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond.


Assuntos
Canais de Cálcio Tipo T , Tremor Essencial , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Tremor Essencial/tratamento farmacológico , Tremor , Gânglios da Base
10.
Ann Clin Transl Neurol ; 10(1): 48-57, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36401598

RESUMO

OBJECTIVE: The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively measure ICBs in cerebellar disorders, we aim to develop and validate a new scale, Cerebellar Impulsivity-Compulsivity Assessment (CIA). METHODS: We recruited 62 cerebellar ataxia cases, categorized into those with ICBs and those without. We developed a preliminary version of CIA, containing 17 questions. We studied the internal consistency, test-retest reliability, and inter-rater reliability to formulate the final version of CIA, which constitutes only 10 questions. The receiver operating characteristic curve (ROC) was generated to assess the sensitivity and specificity of CIA. RESULTS: Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test-retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity. INTERPRETATION: CIA is a novel tool to assess ICBs in cerebellar ataxia and broaden our understanding of the cerebellum-related cognitive and behavioral symptoms.


Assuntos
Ataxia Cerebelar , Doenças Cerebelares , Humanos , Ataxia Cerebelar/diagnóstico , Reprodutibilidade dos Testes , Cerebelo , Comportamento Impulsivo
11.
Cerebellum ; 22(5): 985-1001, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36070135

RESUMO

The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the cerebellum contributes to insights into the pathophysiology of these movement disorders and holds promise in advancing therapeutic development. Non-invasive techniques such as electroencephalogram and magnetoencephalogram can record neural signals with high temporal resolution at the millisecond level, which is uniquely suitable to interrogate cerebellar physiology. These techniques have recently been implemented to study cerebellar physiology in healthy subjects as well as individuals with movement disorders. In the present review, we focus on the current understanding of cerebellar physiology using these techniques to study movement disorders.


Assuntos
Ataxia Cerebelar , Distúrbios Distônicos , Transtornos dos Movimentos , Humanos , Cerebelo/fisiologia , Tremor
13.
J Neurol Sci ; 435: 120198, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35299120

RESUMO

Essential tremor (ET) is one of the most common neurological disorders and can be highly disabling. In recent years, studies on the clinical perspectives and pathophysiology have advanced our understanding of ET. Specifically, clinical heterogeneity of ET, with co-existence of tremor and other neurological features such as dystonia, ataxia, and cognitive dysfunction, has been identified. The cerebellum has been found to be the key brain region for tremor generation, and structural alterations of the cerebellum have been extensively studied in ET. Finally, four main ET pathophysiologies have been proposed: 1) environmental exposures to ß-carboline alkaloids and the consequent olivocerebellar hyper-excitation, 2) cerebellar GABA deficiency, 3) climbing fiber synaptic pathology with related cerebellar oscillatory activity, 4) extra-cerebellar oscillatory activity. While these four theories are not mutually exclusive, they can represent distinctive ET subtypes, indicating multiple types of abnormal brain circuitry can lead to action tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.


Assuntos
Tremor Essencial , Ataxia , Encéfalo/patologia , Cerebelo/patologia , Humanos , Tremor
14.
Sci Adv ; 8(6): eabm6393, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35138901

RESUMO

The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes ß-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.


Assuntos
Autofagia Mediada por Chaperonas , Doença de Parkinson , Animais , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Camundongos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética
15.
Cerebellum ; 21(3): 425-431, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34341893

RESUMO

Enhanced cerebellar oscillations have recently been identified in essential tremor (ET) patients as a key pathophysiological change. Since ET is considered a heterogeneous group of diseases, we investigated whether cerebellar oscillations differ in ET subtypes (familial vs. sporadic). This study aims to determine cerebellar physiology in familial and sporadic ET. Using surface electroencephalogram, we studied cerebellar physiology in 40 ET cases (n = 22 familial and n = 18 sporadic) and 20 age-matched controls. Both familial and sporadic ET cases had an increase in the intensity of cerebellar oscillations when compared to controls. Interestingly, cerebellar oscillations correlated with tremor severity in familial ET but not in sporadic ET. Our study demonstrated that ET cases have enhanced cerebellar oscillations, and the different relationships between cerebellar oscillations and tremor severity in familial and sporadic ET suggest diverse cerebellar pathophysiology.


Assuntos
Tremor Essencial , Cerebelo , Eletroencefalografia , Humanos , Modalidades de Fisioterapia , Tremor
16.
Mov Disord ; 36(6): 1440-1445, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33497495

RESUMO

BACKGROUND: Climbing fibers (CFs) innervate Purkinje cells (PCs) with 1:1 relationship to ensure proper cerebellar function. Although CFs abnormally extend into the parallel fiber domain of PC dendrites in essential tremor (ET), the architecture of CFs in relation to PCs has yet to be investigated in detail. OBJECTIVE: The aim of this work was to study the architecture of CFs in relation to PCs in ET. METHODS: The number of PC somas and PC dendrites that a single CF crossed was quantified in the postmortem cerebellum of 15 ET cases and 15 control cases. RESULTS: In ET, CFs crossed a greater number of PC somas and PC dendrites than in control cases, raising the possibility that there is abnormal CF wiring onto the PCs. Interestingly, the increase in CF-PC crossings positively correlated with tremor severity. CONCLUSIONS: Patients with ET have increased CF crossings on PC dendrites. This abnormal architectural arrangement may contribute to synchronous brain activity and tremor. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Tremor Essencial , Células de Purkinje , Cerebelo , Dendritos , Humanos , Sinapses
17.
J Vis Exp ; (159)2020 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-32478739

RESUMO

Conventional histological analysis and cell culture systems are insufficient to simulate in vivo physiological and pathological dynamics completely. Multiphoton microscopy (MPM) has become one of the most popular imaging modalities for biomedical study at cellular levels in vivo, advantages include high resolution, deep tissue penetration and minimal phototoxicity. We have designed an MPM imaging platform with a customized mouse eye holder and a stereotaxic stage for imaging ocular surface in vivo. Dual fluorescent protein reporter mouse enables visualization of cell nuclei, cell membranes, nerve fibers, and capillaries within the ocular surface. In addition to multiphoton fluorescence signals, acquiring second harmonic generation (SHG) simultaneously allows for the characterization of collagenous stromal architecture. This platform can be employed for intravital imaging with accurate positioning across the entire ocular surface, including cornea and conjunctiva.


Assuntos
Túnica Conjuntiva/fisiopatologia , Córnea/fisiopatologia , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Animais , Camundongos
18.
Sci Rep ; 10(1): 9840, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32528132

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

20.
Sci Rep ; 10(1): 8278, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427942

RESUMO

Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson's disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.


Assuntos
Estimulação Encefálica Profunda/métodos , Hipercinese/terapia , Levodopa/efeitos adversos , Nitrocompostos/efeitos adversos , Propionatos/efeitos adversos , Núcleo Subtalâmico/fisiologia , Animais , Polaridade Celular , Modelos Animais de Doenças , Humanos , Hipercinese/induzido quimicamente , Masculino , Ratos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA