RESUMEN
Modern functional neurosurgery for movement disorders such as Parkinson's disease, tremor, and dystonia involves the placement of focal lesions or the application of deep brain stimulation (DBS) within circuits that modulate motor function. Precise targeting of these motor structures can be further refined by the use of electrophysiological approaches. In particular, microelectrode recordings enable the delineation of neuroanatomic structures. In the course of these operations, there is an opportunity not only to map basal ganglia structures but also to gain insights into how disturbances in neural activity produce movement disorders. In this review, we aim to highlight what the field has uncovered thus far about movement disorders through DBS. The work to date lays the foundation for future studies that will shed further light on dysfunctional circuits mediating diseases of the nervous system and how we might modulate these circuits therapeutically.
Asunto(s)
Ganglios Basales/fisiopatología , Trastornos Distónicos/fisiopatología , Trastornos Distónicos/terapia , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Temblor/fisiopatología , Temblor/terapia , Ganglios Basales/cirugía , Estimulación Encefálica Profunda , Trastornos Distónicos/cirugía , Humanos , Procedimientos Neuroquirúrgicos , Enfermedad de Parkinson/cirugía , Temblor/cirugíaRESUMEN
Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson's disease (n = 19) and essential tremor (n = 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile "rate" and "oscillation" models of Parkinson's disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders.
Asunto(s)
Temblor Esencial , Neuronas , Enfermedad de Parkinson , Núcleo Subtalámico , Ritmo beta , Estimulación Encefálica Profunda , Temblor Esencial/fisiopatología , Humanos , Neuronas/fisiología , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/fisiopatologíaRESUMEN
The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.
Asunto(s)
Estimulación Acústica , Estimulación Encefálica Profunda , Enfermedad de Parkinson , Porción Reticular de la Sustancia Negra , Núcleo Subtalámico , Humanos , Núcleo Subtalámico/fisiología , Masculino , Persona de Mediana Edad , Femenino , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Anciano , Porción Reticular de la Sustancia Negra/fisiología , Estimulación Encefálica Profunda/métodos , Estimulación Acústica/métodos , Percepción Auditiva/fisiología , Potenciales Evocados Auditivos/fisiología , Sustancia Negra/fisiología , AdultoRESUMEN
C-terminus of HSP70 interacting protein (CHIP) is an E3 ubiquitin ligase and HSP70 cochaperone. Mutations in the CHIP encoding gene are the cause of two forms of neurodegenerative conditions: spinocerebellar ataxia autosomal dominant type 48 (SCA48) and autosomal recessive type 16 (SCAR16). The mechanisms underlying CHIP-associated diseases are currently unknown. Mitochondrial dysfunction, specifically dysfunction in mitochondrial autophagy (mitophagy), is increasingly being implicated in neurodegenerative diseases and loss of CHIP has been demonstrated to result in mitochondrial dysfunction in multiple animal models, although how CHIP is involved in mitophagy regulation has been previously unknown. Here, we demonstrate that CHIP acts as a negative regulator of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy pathway, promoting the degradation of PINK, impairing Parkin translocation to the mitochondria, and suppressing mitophagy in response to mitochondrial stress. We also show that loss of CHIP enhances neuronal mitophagy in a PINK1 and Parkin dependent manner in Caenorhabditis elegans. Furthermore, we find that multiple disease-associated mutations in CHIP dysregulate mitophagy both in vitro and in vivo in C. elegans neurons, a finding which could implicate mitophagy dysregulation in CHIP-associated diseases.
RESUMEN
External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13-30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD.
Asunto(s)
Estimulación Encefálica Profunda , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Globo Pálido/fisiología , Señales (Psicología) , Núcleo Subtalámico/fisiología , Neuronas/fisiología , Estimulación Encefálica Profunda/métodosRESUMEN
BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.
Asunto(s)
Estimulación Encefálica Profunda , Temblor Esencial , Humanos , Temblor Esencial/terapia , Imagen por Resonancia Magnética , Tálamo/diagnóstico por imagen , Tálamo/cirugía , Resultado del Tratamiento , TemblorRESUMEN
BACKGROUND: The loss of the ability to swim following deep brain stimulation (DBS), although rare, poses a worrisome risk of drowning. It is unclear what anatomic substrate and neural circuitry underlie this phenomenon. We report a case of cervical dystonia with lost ability to swim and dance during active stimulation of globus pallidus internus. We investigated the anatomical underpinning of this phenomenon using unique functional and structural imaging analysis. METHODS: Tesla (3T) functional MRI (fMRI) of the patient was used during active DBS and compared with a cohort of four matched patients without this side effect. Structural connectivity mapping was used to identify brain network engagement by stimulation. RESULTS: fMRI during stimulation revealed significant (Pbonferroni<0.0001) stimulation-evoked responses (DBS ONAsunto(s)
Estimulación Encefálica Profunda
, Globo Pálido
, Humanos
, Globo Pálido/diagnóstico por imagen
, Globo Pálido/fisiología
, Estimulación Encefálica Profunda/efectos adversos
, Estimulación Encefálica Profunda/métodos
, Resultado del Tratamiento
, Imagen por Resonancia Magnética
RESUMEN
BACKGROUND: There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). OBJECTIVE: Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. METHODS: We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. RESULTS: The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). CONCLUSION: We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei-including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)-across different DBS frequencies. MATERIALS AND METHODS: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim-across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. RESULTS: Our model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. CONCLUSIONS: The result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.
Asunto(s)
Estimulación Encefálica Profunda , Núcleo Subtalámico , Humanos , Ganglios Basales/fisiología , Núcleo Subtalámico/fisiología , Tálamo/fisiología , Neuronas/fisiologíaRESUMEN
A total of 15 individuals with cervical dystonia and good outcome after pallidal deep brain stimulation underwent resting-state functional magnetic resonance imaging under three conditions: stimulation using a priori clinically determined optimal settings (ON-Op), non-optimal settings (ON-NOp), and stimulation off (OFF). ON-Op > OFF and ON-Op > ON-NOp were both associated with significant deactivation within sensorimotor cortex (changes not seen with ON-NOp > OFF). Brain responses to stimulation were related to individual long-term clinical improvement (R = 0.73, R2 = 0.53, p = 0.001). The relationship was consistent when this model included four additional patients with generalized or truncal dystonia. These findings highlight the potential for immediate imaging-based biomarkers of clinical efficacy. ANN NEUROL 2022;92:418-424.
Asunto(s)
Estimulación Encefálica Profunda , Tortícolis , Encéfalo , Estimulación Encefálica Profunda/métodos , Globo Pálido/fisiología , Humanos , Tortícolis/diagnóstico por imagen , Tortícolis/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Multiple system atrophy with parkinsonism (MSA-P) is a progressive condition with no effective treatment. OBJECTIVE: The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA-P. METHODS: Six patients were included. Changes in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), Parkinson's Disease Questionnaire (PDQ-39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated. RESULTS: DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS-UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects. CONCLUSIONS: Globus pallidus pars interna and externa DBS for patients with MSA-P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS-UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Globo Pálido/cirugía , Núcleo Subtalámico/cirugía , Estimulación Encefálica Profunda/efectos adversos , Atrofia de Múltiples Sistemas/terapia , Atrofia de Múltiples Sistemas/etiología , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown. OBJECTIVES: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts. METHODS: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band. RESULTS: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications. CONCLUSIONS: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Estudios Longitudinales , Estimulación Encefálica Profunda/métodos , Núcleo Subtalámico/fisiología , Ganglios Basales , Dopaminérgicos/uso terapéutico , Ritmo beta/fisiologíaRESUMEN
BACKGROUND: Spinal cord stimulation (SCS) has been investigated as a potential therapeutic option for managing refractory symptoms in patients with Parkinson's disease (PD). OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of SCS in PD. METHOD: A comprehensive literature search was conducted on PubMed and Web of Science to identify SCS studies reporting Unified Parkinson Disease Rating Scale-III (UPDRS-III) or Visual Analogue Scale (VAS) score changes in PD cohorts with at least 3 patients and a follow-up period of at least 1 month. Treatment effect was measured as the mean change in outcome scores and analyzed using an inverse variance random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale and funnel plots. RESULTS: A total of 11 studies comprising 76 patients were included. Nine studies involving 72 patients reported an estimated decrease of 4.43 points (95% confidence interval [CI]: 2.11; 6.75, p < 0.01) in UPDRS-III score, equivalent to a 14% reduction. The axial subscores in 48 patients decreased by 2.35 points (95% CI: 1.26; 3.45, p < 0.01, 20% reduction). The pooled effect size of five studies on back and leg pain VAS scores was calculated as 4.38 (95% CI: 2.67; 6.09, p < 0.001), equivalent to a 59% reduction. CONCLUSIONS: Our analysis suggests that SCS may provide significant motor and pain benefits for patients with PD, although the results should be interpreted with caution due to several potential limitations including study heterogeneity, open-label designs, small sample sizes, and the possibility of publication bias. Further research using larger sample sizes and placebo-/sham-controlled designs is needed to confirm effectiveness.
Asunto(s)
Enfermedad de Parkinson , Estimulación de la Médula Espinal , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Estimulación de la Médula Espinal/métodos , Dolor/etiologíaRESUMEN
OBJECTIVE: The antiseizure effects of vagus nerve stimulation (VNS) are thought to be mediated by the modulation of afferent thalamocortical circuitry. Cross-frequency phase-amplitude coupling (PAC) is a mechanism of hierarchical network coordination across multiple spatiotemporal scales. In this study, we leverage local field potential (LFP) recordings from the centromedian (CM) (n = 3) and anterior (ATN) (n = 2) nuclei in five patients with tandem thalamic deep brain stimulation and VNS to study neurophysiological changes in the thalamus in response to VNS. MATERIALS AND METHODS: Bipolar LFP data were recorded from contact pairs spanning target nuclei in VNS "on" and "off" states. RESULTS: Active VNS was associated with increased PAC between theta, alpha, and beta phase and gamma amplitude in CM (q < 0.05). Within the ATN, PAC changes also were observed, although these were less robust. In both nuclei, active VNS also modulated interhemispheric bithalamic functional connectivity. CONCLUSIONS: We report that VNS is associated with enhanced PAC and coordinated interhemispheric interactions within and between thalamic nuclei, respectively. These findings advance understanding of putative neurophysiological effects of acute VNS and contextualize previous animal and human studies showing distributed cortical synchronization after VNS.
Asunto(s)
Estimulación del Nervio Vago , Animales , Humanos , TálamoRESUMEN
Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system, and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited. We further report that silencing the expression of HRI resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy, suggesting that HRI may control proteostasis in the cytosol at least in part through chaperone-assisted selective autophagy. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of overexpressed α-synuclein, a protein known to aggregate in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month-old Hri-/- mice as compared with Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response that could be leveraged to bolster the clearance of cytotoxic protein aggregates.
Asunto(s)
Autofagia , Microglía/metabolismo , Agregado de Proteínas , Proteínas Serina-Treonina Quinasas/metabolismo , Médula Espinal/metabolismo , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Células HEK293 , Células HeLa , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Noqueados , Microglía/patología , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Médula Espinal/patología , eIF-2 Quinasa/genéticaRESUMEN
Deep brain stimulation (DBS) depends on precise delivery of electrical current to target tissues. However, the specific brain structures responsible for best outcome are still debated. We applied probabilistic stimulation mapping to a retrospective, multidisorder DBS dataset assembled over 15 years at our institution (ntotal = 482 patients; nParkinson disease = 303; ndystonia = 64; ntremor = 39; ntreatment-resistant depression/anorexia nervosa = 76) to identify the neuroanatomical substrates of optimal clinical response. Using high-resolution structural magnetic resonance imaging and activation volume modeling, probabilistic stimulation maps (PSMs) that delineated areas of above-mean and below-mean response for each patient cohort were generated and defined in terms of their relationships with surrounding anatomical structures. Our results show that overlap between PSMs and individual patients' activation volumes can serve as a guide to predict clinical outcomes, but that this is not the sole determinant of response. In the future, individualized models that incorporate advancements in mapping techniques with patient-specific clinical variables will likely contribute to the optimization of DBS target selection and improved outcomes for patients. ANN NEUROL 2021;89:426-443.
Asunto(s)
Anorexia Nerviosa/terapia , Estimulación Encefálica Profunda/métodos , Trastorno Depresivo Resistente al Tratamiento/terapia , Distonía/terapia , Enfermedad de Parkinson/terapia , Temblor/terapia , Adulto , Anciano , Mapeo Encefálico , Conectoma , Femenino , Globo Pálido/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelación Específica para el Paciente , Probabilidad , Estudios Retrospectivos , Núcleo Subtalámico/diagnóstico por imagen , Resultado del Tratamiento , Núcleos Talámicos Ventrales/diagnóstico por imagenRESUMEN
BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Basal de Meynert , Cognición , Estimulación Encefálica Profunda/métodos , Globo Pálido , Humanos , Enfermedad de Parkinson/complicacionesRESUMEN
BACKGROUND: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery. METHODS: This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations. RESULTS: BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08. CONCLUSIONS: Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Glucosilceramidasa , Enfermedad de Parkinson , Glucosilceramidasa/genética , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Mutación , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
BACKGROUND: Patients with Parkinson's disease might develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. OBJECTIVES: To study whether lateralized stimulation (unilateral 50% amplitude reduction) for ≥21 days results in ≥0.13 m/s faster gait velocity in the dopaminergic ON state in these patients, and its effects on motor and axial function, quantitative gait and speech measures, quality of life, and selected cognitive tasks. METHODS: Randomized, double-blinded, double-crossover trial. RESULTS: In 22 participants (51-79 years old, 15 women), there were no significant changes in gait velocity, quality of life, cognitive, and speech measures. Reducing left-sided amplitude resulted in a 2.5-point improvement in axial motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (P = 0.005, uncorrected) and a 1.9-point improvement in the Freezing of Gait Questionnaire (P = 0.024, uncorrected). CONCLUSIONS: Lateralized subthalamic stimulation does not result in meaningful improvement in gait velocity in patients with Parkinson's disease who develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. Left subthalamic overstimulation may contribute to axial deterioration in these patients. © 2022 International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Núcleo Subtalámico , Anciano , Estimulación Encefálica Profunda/métodos , Femenino , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/terapia , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapia , Calidad de Vida , Núcleo Subtalámico/fisiología , Resultado del TratamientoRESUMEN
Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.