RESUMEN

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

Asunto(s)

RESUMEN

OBJECTIVES: Studies examining electromyography (EMG)-guided laryngeal onobotulinumtoxinA (BTxA) injection for chronic cough reveal promising efficacy, however, are limited by small cohorts and absent quantifiable outcomes. It further remains unclear if pulmonary disease limits efficacy, or if vagal motor neuropathy prognosticates response. We hypothesize BTxA injection results in qualitative improvement in cough, decrease in Cough Severity Index (CSI), no change in Voice Handicap Index-10 (VHI-10), and complication rates comparable to historical data. We also examine the correlation of pulmonary comorbidities and vocal fold hypomobility with treatment efficacy. STUDY DESIGN: Retrospective review. METHODS: Charts for patients receiving percutaneous adductor compartment BTxA injection for cough were reviewed for the binary outcome of patient-reported presence or absence of improvement. Generalized estimating equations regression models were used to analyze the change in CSI (ΔCSI) and the correlation of ΔCSI with qualitative outcomes. Multivariable analyses were used to examine correlation of vocal fold hypomobility and pulmonary disease with qualitative outcomes and ΔCSI. RESULTS: Forty-seven patients underwent 197 BTxA injections from June 2012 to June 2022. A statistical proportion of 0.698 (0.599-0.813, p < 0.0001) or 69.8% of injections resulted in subjective improvement. Mean ΔCSI was -2.12 (0.22-4.02, p < 0.05), indicating overall improvement. With and without subjective improvement, estimated ΔCSI was -4.43 and +2.68, respectively (p < 0.0001). VHI-10 did not change (0.69, p = 0.483). Neither pulmonary disease nor vocal fold hypomobility correlated with subjective improvement or ΔCSI. Dysphagia occurred following 15 (7.6%) injections with no aspiration pneumonia or hospitalization. CONCLUSIONS: BTxA injection to the laryngeal adductors may effectively treat cough with limited risk for serious complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1749-1756, 2024.

Asunto(s)

RESUMEN

Introduction: The therapeutic efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) may be limited for some patients by the presence of stimulation-related side effects. Such effects are most often attributed to electrical current spread beyond the target region. Prior computational modeling studies have suggested that changing the degree of asymmetry of the individual phases of the biphasic, stimulus pulse may allow for more selective activation of neural elements in the target region. To the extent that different neural elements contribute to the therapeutic vs. side-effect inducing effects of DBS, such improved selectivity may provide a new parameter for optimizing DBS to increase the therapeutic window. Methods: We investigated the effect of six different pulse geometries on cortical and myogenic evoked potentials in eight patients with PD whose leads were temporarily externalized following STN DBS implant surgery. DBS-cortical evoked potentials were quantified using peak to peak measurements and wavelets and myogenic potentials were quantified using RMS. Results: We found that the slope of the recruitment curves differed significantly as a function of pulse geometry for both the cortical- and myogenic responses. Notably, this effect was observed most frequently when stimulation was delivered using a monopolar, as opposed to a bipolar, configuration. Discussion: Manipulating pulse geometry results in differential physiological effects at both the cortical and neuromuscular level. Exploiting these differences may help to expand DBS' therapeutic window and support the potential for incorporating pulse geometry as an additional parameter for optimizing therapeutic benefit.

RESUMEN

The impact of pulse timing is an important factor in our understanding of how to effectively modulate the basal ganglia thalamocortical (BGTC) circuit. Single pulse low-frequency DBS-evoked potentials generated through electrical stimulation of the subthalamic nucleus (STN) provide insight into circuit activation, but how the long-latency components change as a function of pulse timing is not well-understood. We investigated how timing between stimulation pulses delivered in the STN region influence the neural activity in the STN and cortex. DBS leads implanted in the STN of five patients with Parkinson's disease were temporarily externalized, allowing for the delivery of paired pulses with inter-pulse intervals (IPIs) ranging from 0.2 to 10 ms. Neural activation was measured through local field potential (LFP) recordings from the DBS lead and scalp EEG. DBS-evoked potentials were computed using contacts positioned in dorsolateral STN as determined through co-registered post-operative imaging. We quantified the degree to which distinct IPIs influenced the amplitude of evoked responses across frequencies and time using the wavelet transform and power spectral density curves. The beta frequency content of the DBS evoked responses in the STN and scalp EEG increased as a function of pulse-interval timing. Pulse intervals <1.0 ms apart were associated with minimal to no change in the evoked response. IPIs from 1.5 to 3.0 ms yielded a significant increase in the evoked response, while those >4 ms produced modest, but non-significant growth. Beta frequency activity in the scalp EEG and STN LFP response was maximal when IPIs were between 1.5 and 4.0 ms. These results demonstrate that long-latency components of DBS-evoked responses are pre-dominantly in the beta frequency range and that pulse interval timing impacts the level of BGTC circuit activation.

RESUMEN

Parkinson's disease is a neurological disease with cardinal motor signs including bradykinesia and tremor. Although beta-band hypersynchrony in the cortico-basal ganglia network is thought to contribute to disease manifestation, the resulting effects on network connectivity are unclear. We examined local field potentials from a non-human primate across the naïve, mild, and moderate disease states (model was asymmetric, left-hemispheric dominant) and probed power spectral density as well as cortico-cortical and cortico-subthalamic connectivity using both coherence and Granger causality, which measure undirected and directed effective connectivity, respectively. Our network included the left subthalamic nucleus (L-STN), bilateral primary motor cortices (L-M1, R-M1), and bilateral premotor cortices (L-PMC, R-PMC). Results showed two distinct peaks (Peak A at 5-20 Hz, Peak B at 25-45 Hz) across all analyses. Power and coherence analyses showed widespread increases in power and connectivity in both the Peak A and Peak B bands with disease progression. For Granger causality, increases in Peak B connectivity and decreases in Peak A connectivity were associated with the disease. Induction of mild disease was associated with several changes in connectivity: (1) the cortico-subthalamic connectivity in the descending direction (L-PMC to L-STN) decreased in the Peak A range while the reciprocal, ascending connectivity (L-STN to L-PMC) increased in the Peak B range; this may play a role in generating beta-band hypersynchrony in the cortex, (2) both L-M1 to L-PMC and R-M1 to R-PMC causalities increased, which may either be compensatory or a pathologic effect of disease, and (3) a decrease in connectivity occurred from the R-PMC to R-M1. The only significant change seen between mild and moderate disease was increased right cortical connectivity, which may reflect compensation for the left-hemispheric dominant moderate disease state.

RESUMEN

OBJECTIVES: To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming. MATERIALS AND METHODS: Serial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement. RESULTS: In the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45-0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands. CONCLUSIONS: Our findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.

Asunto(s)

RESUMEN

Neural oscillatory changes within and across different frequency bands are thought to underlie motor dysfunction in Parkinson's disease (PD) and may serve as biomarkers for closed-loop deep brain stimulation (DBS) approaches. Here, we used neural oscillatory signals derived from chronically implanted cortical and subcortical electrode arrays as features to train machine learning algorithms to discriminate between naive and mild PD states in a nonhuman primate model. Local field potential (LFP) data were collected over several months from a 12-channel subdural electrocorticography (ECoG) grid and a 6-channel custom array implanted in the subthalamic nucleus (STN). Relative to the naive state, the PD state showed elevated primary motor cortex (M1) and STN power in the beta, high gamma, and high-frequency oscillation (HFO) bands and decreased power in the delta band. Theta power was found to be decreased in STN but not M1. In the PD state there was elevated beta-HFO phase-amplitude coupling (PAC) in the STN. We applied machine learning with support vector machines with radial basis function (SVM-RBF) kernel and k-nearest neighbors (KNN) classifiers trained by features related to power and PAC changes to discriminate between the naive and mild states. Our results show that the most predictive feature of parkinsonism in the STN was high beta (∼86% accuracy), whereas it was HFO in M1 (∼98% accuracy). A feature fusion approach outperformed every individual feature, particularly in the M1, where ∼98% accuracy was achieved with both classifiers. Overall, our data demonstrate the ability to use various frequency band power to classify the clinical state and are also beneficial in developing closed-loop DBS therapeutic approaches.NEW & NOTEWORTHY Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson's disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Asunto(s)

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for different neurological diseases, despite the lack of comprehension of its mechanism of action. The use of nonhuman primates (NHPs) has been historically important in advancing this field and presents a unique opportunity to uncover the therapeutic mechanisms of DBS, opening the way for optimization of current applications and the development of new ones. To be informative, research using NHPs should make use of appropriate electrode implantation tools. In the present work, the authors report on the feasibility and accuracy of targeting different deep brain regions in NHPs using a commercially available frameless stereotactic system (microTargeting platform). METHODS: Seven NHPs were implanted with DBS electrodes, either in the subthalamic nucleus or in the cerebellar dentate nucleus. A microTargeting platform was designed for each animal and used to guide implantation of the electrode. Imaging studies were acquired preoperatively for each animal, and were subsequently analyzed by two independent evaluators to estimate the electrode placement error (EPE). The interobserver variability was assessed as well. RESULTS: The radial and vector components of the EPE were estimated separately. The magnitude of the vector of EPE was 1.29 ± 0.41 mm and the mean radial EPE was 0.96 ± 0.63 mm. The interobserver variability was considered negligible. CONCLUSIONS: These results reveal the suitability of this commercial system to enhance the surgical insertion of DBS leads in the primate brain, in comparison to rigid traditional frames. Furthermore, our results open up the possibility of performing frameless stereotaxy in primates without the necessity of relying on expensive methods based on intraoperative imaging.

Asunto(s)

RESUMEN

Electrophysiologic mapping remains an integral component of deep brain stimulation (DBS) surgical procedures, particularly in movement disorder cases where functional maps are used to guide DBS lead placement in patients with Parkinson's disease, dystonia, or tremor. Overall, the goal of the surgical procedure is to implant the distal end of a chronic, multicontact depth electrode into a specific brain region for the purpose of delivering therapeutic electrical stimulation. Regions that are currently targeted for patients with movement disorders include the subthalamic nucleus, the ventral intermediate nucleus of the thalamus, and the globus pallidus. Multiple imaging modalities are used initially to derive a stereotactic plan and guide the initial microelectrode trajectory. Changes in neuronal firing rate and pattern, both spontaneous and in response to somatosensory stimulation, are used to establish the location of the tip of the microelectrode(s), while acute stimulation can be used to estimate the proximity of neighboring brain regions. In this chapter, we will provide an overview of the microelectrode recording process as it is commonly applied to refine image-based targeting of lead placement for DBS surgery.

Asunto(s)

RESUMEN

Many studies suggest that Parkinson's disease (PD) is associated with changes in neuronal activity patterns throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts the presupplementary motor area (pre-SMA) and SMA proper (SMAp), cortical areas known to be involved in movement planning and motor control. In this study, local field potentials (LFPs) were recorded in the pre-SMA/SMAp of a nonhuman primate during a visually cued reaching task. Recordings were made in the same subject in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism. We found that in the naive animal, well before a go-cue providing instruction of reach onset and direction was given, LFP activity was dynamically modulated in both high (20-30 Hz) and low beta (10-20 Hz) bands, and the magnitude of this modulation (e.g., decrease/increase in beta amplitude for each band, respectively) correlated linearly with reaction time (RT) on a trial-to-trial basis, suggesting it may predictively encode for RT. Consistent with this hypothesis, we observed that this activity was more prominent within the pre-SMA compared with SMAp. In the parkinsonian state, however, pre-SMA/SMAp beta band modulation was disrupted, particularly in the high beta band, such that the predictive encoding of RT was significantly diminished. In addition, the predictive encoding of RT preferentially within pre-SMA over SMAp was lost. These findings add to our understanding of the role of pre-SMA/SMAp in motor behavior and suggest a fundamental role of these cortical areas in early preparatory and premovement processes that are altered in parkinsonism. NEW & NOTEWORTHY Goal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in parkinsonism is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in pre-SMA/SMAp beta band modulation to the pathogenesis of motor disturbances in parkinsonism.

Asunto(s)

RESUMEN

Salmonellosis is a bacterial disease that causes acute gastroenteritis, with sudden onset of headache, abdominal pain, diarrhoea, nausea and sometimes vomiting. Infection is often associated with the consumption of foods prepared using raw eggs. During July to August 2008 an outbreak at an aged care facility (ACF) in New South Wales was confirmed as Salmonella Typhimurium phage type 44 (Stm 44) in eight of 45 residents. Two additional probable cases also occurred. Cases were located in each unit of the ACF and for 5 cases, onset of diarrhoea was between 45 to 64 hours (median of 46 hours) after consumption of a dessert containing raw eggs. Onset for 5 further cases occurred up to 9 days after this meal. Eggs were supplied to the ACF from a local farm. Stm 44 was detected on an egg in an unopened box at the ACF from this supplier. The raw-egg dessert was epidemiologically implicated as the likely source of the Salmonella and delayed onset cases may have resulted from ingestion of a smaller dose of Salmonella, or ongoing transmission through cross-contamination of kitchen machinery or surfaces. This outbreak demonstrates that inadequate cooking of eggs continues to pose a risk for Salmonella infection in settings with vulnerable populations. The findings of the investigation provide support for the importance of food safety regulations and demand further advocacy for measures to reduce the risks associated with the distribution, storage and preparation of shell eggs.

Asunto(s)