Codrin Lungu

Beta-Coupled High-Frequency Activity and Beta-Locked Neuronal Spiking in the Subthalamic Nucleus of Parkinson's Disease

Beta frequency (13–30 Hz) oscillatory activity in the subthalamic nucleus (STN) of Parkinsons disease (PD) has been shown to influence the temporal dynamics of high-frequency oscillations (HFOs; 200–500 Hz) and single neurons, potentially compromising the functional flexibility of the motor circuit. We examined these interactions by simultaneously recording both local field potential and single-unit activity from the basal ganglia of 15 patients with PD during deep brain stimulation (DBS) surgery of the bilateral STN. Phase-amplitude coupling (PAC) in the STN was specific to beta phase and HFO amplitude, and this coupling was strongest at the dorsal STN border. We found higher beta-HFO PAC near DBS lead contacts that were clinically effective compared with the remaining non-effective contacts, indicating that PAC may be predictive of response to STN DBS. Neuronal spiking was locked to the phase of 8–30 Hz oscillations, and the spatial topography of spike-phase locking (SPL) was similar to that of PAC. Comparisons of PAC and SPL showed a lack of spatiotemporal correlations. Beta-coupled HFOs and field-locked neurons had different preferred phase angles and did not co-occur within the same cycle of the modulating oscillation. Our findings provide additional support that beta-HFO PAC may be central to the pathophysiology of PD and suggest that field-locked neurons alone are not sufficient for the emergence of beta-coupled HFOs.

Epidemiology of tardive dyskinesia before and during the era of modern antipsychotic drugs

Late or tardive dyskinesias/dystonias (TD), contrary to expectation, have not disappeared with the use of expensive, modern antipsychotic drugs (APDs). Risk appears to be substantially lower than with older neuroleptics, and there is sparing of most acute movement disorders traditionally associated with APD treatment. However, risks of TD with modern APDs have been reduced much less than expected, by perhaps two- to threefold or even less, with substantial risks in the elderly. Major challenges in assessing prevalence or, preferably, incidence of TD arise from prolonged and erratic past exposure to various APDs, relatively recent use of modern APDs, and the occurrence of spontaneous movement disorders (about 5% and more in the elderly). TD risks associated with modern APDs may be similar to some older neuroleptics, especially those of low-moderate potency. Risperidone (and its active metabolite paliperidone), at high doses, may carry unusually high TD risk, whereas TD risk is low with clozapine, and perhaps quetiapine and aripiprazole. Optimistic expectations for the efficacy and neurological safety of modern APDs have encouraged their wide use in many conditions, sometimes off-label or in combinations, with little research support, increasing the chance of a higher prevalence of TD, especially at older ages. Measures to limit TD risk include: (1) critical, objective indications for APD use; (2) long-term use only for compelling or research-supported indications, primarily chronic psychotic illness that worsens when APD is slowly discontinued; (3) avoiding off-label indications; (4) using alternative treatments when APD treatment is elective, or early dyskinesia is identified; (5) using low but effective doses of single APDs, especially in the elderly; and (6) regular and specific examination for early TD.

Long-term follow-up of botulinum toxin therapy for focal hand dystonia: outcome at 10 years or more.

Previous studies have explored the efficacy and safety of botulinum neurotoxin (BoNT) treatment for Focal hand dystonia (FHD), but none have followed a large number of patients for 10 years or more.

The Use of Diagnostic Tests in Patients with Acute Ischemic Stroke

BACKGROUND Stroke is a leading cause of long-term disability in the United States. Inpatient hospital costs account for the majority of acute care costs of stroke with half the cost providing for room and board and 19% of total costs allocated to diagnostic testing. This study addresses the yield of common diagnostic tests in stroke and how frequently the results potentially impact early stroke management. METHODS We conducted a retrospective chart review of patients with acute ischemic stroke over 3 years from a single-center community-based teaching hospital. Results of carotid Doppler (CD), transcranial Doppler, extracranial magnetic resonance (MR) angiography (EMRA), intracranial MR angiography, transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and 24-hour Holter monitoring were reviewed. RESULTS Extracranial carotid artery imaging with CD and EMRA showed symptomatic ipsilateral stenosis in 7.9% and 13% of patients with stroke. TTE alone showed intracardiac thrombus in 1.5% of patients whereas TEE had a yield of 3.8%. Patent foramen ovale was seen in 16% of TEE and none were detected on TTE. The 24-hour Holter monitoring revealed newly detected atrial fibrillation in 9.4% of patients with stroke. CONCLUSIONS Standard diagnostic studies in acute stroke aimed at secondary stroke prevention are unlikely to yield results that warrant prolongation of hospitalization. Carotid endarterectomy is the only intervention with reasonable evidence suggesting benefit in the early period after stroke. Pursuing extracranial carotid artery imaging during initial hospitalization seems justifiable, especially given the high yield of CD and EMRA in the detection of treatable carotid artery stenosis.

Tractography patterns of subthalamic nucleus deep brain stimulation

Deep brain stimulation therapy is an effective symptomatic treatment for Parkinsons disease, yet the precise mechanisms responsible for its therapeutic effects remain unclear. Although the targets of deep brain stimulation are grey matter structures, axonal modulation is known to play an important role in deep brain stimulations therapeutic mechanism. Several white matter structures in proximity to the subthalamic nucleus have been implicated in the clinical benefits of deep brain stimulation for Parkinsons disease. We assessed the connectivity patterns that characterize clinically beneficial electrodes in Parkinsons disease patients, after deep brain stimulation of the subthalamic nucleus. We evaluated 22 patients with Parkinsons disease (11 females, age 57 ± 9.1 years, disease duration 13.3 ± 6.3 years) who received bilateral deep brain stimulation of the subthalamic nucleus at the National Institutes of Health. During an initial electrode screening session, one month after deep brain stimulation implantation, the clinical benefits of each contact were determined. The electrode was localized by coregistering preoperative magnetic resonance imaging and postoperative computer tomography images and the volume of tissue activated was estimated from stimulation voltage and impedance. Brain connectivity for the volume of tissue activated of deep brain stimulation contacts was assessed using probabilistic tractography with diffusion-tensor data. Areas most frequently connected to clinically effective contacts included the thalamus, substantia nigra, brainstem and superior frontal gyrus. A series of discriminant analyses demonstrated that the strength of connectivity to the superior frontal gyrus and the thalamus were positively associated with clinical effectiveness. The connectivity patterns observed in our study suggest that the modulation of white matter tracts directed to the superior frontal gyrus and the thalamus is associated with favourable clinical outcomes and may contribute to the therapeutic effects of deep brain stimulation. Our method can be further developed to reliably identify effective deep brain stimulation contacts and aid in the programming process.

Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict

Abstract Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue‐related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement‐related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta‐ and beta‐band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency‐specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict.

Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tanks contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies.

Octanoic acid in alcohol-responsive essential tremor: A randomized controlled study

Objective: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). Methods: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. Results: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F1,16 = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F1,16 = 6.1, p = 0.025). Conclusions: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. Classification of evidence: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes.

Limb-kinetic apraxia affects activities of daily living in Parkinson's disease: a multi-center study

Impaired dexterity (fine hand movements) is often present in Parkinsons disease (PD), even at early to moderate disease stages. It has a detrimental impact on activities of daily living (ADL) such as buttoning, contributing to reduced quality of life. Limb‐kinetic apraxia, a loss of the ability to make precise, independent but coordinated finger and hand movements, may contribute to impaired dexterity even more than bradykinesia per se. However, the impact of limb‐kinetic apraxia on ADL remains controversial. Our aim was to identify the strongest predictor of buttoning and unbuttoning in PD. It was hypothesized that coin rotation (a surrogate of limb‐kinetic apraxia) represents the most important determinant.

Chediak-Higashi syndrome presenting as young-onset levodopa-responsive parkinsonism

Chediak-Higashi syndrome (CHS) (OMIM #214500) is a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene, LYST, or CHS1. Typically, CHS presents, with variable degrees of oculocutaneous albinism, immunodeficiency, bleeding diathesis and hemophagocytic lymphohistiocytosis (HLH or the “accelerated phase”).1 Neurological involvement in CHS can include intellectual impairment, sensory-motor neuropathy, cerebellar disease, and dementia.2, 3 Parkinsonism and its response to dopaminergic therapy has rarely been reported.2,4,5 A subset of CHS patients have a muted pigmentary or hematological presentation while their neurological symptoms dominate their disease.6, 7 We a provide video illustration of his therapeutic response to levodopa along with skin pigment dilution features, brain imaging and leukocyte morphology in a young adult male with CHS whose clinical presentation is dominated by motor and non-motor parkinsonian symptoms with a brisk and sustained therapeutic response to levodopa therapy.