Motor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson's Disease Symptoms in a Rat Model.

Deep brain stimulation (DBS) in Parkinson's disease (PD) alters neuronal function and network communication to improve motor symptoms. The subthalamic nucleus (STN) is the most common DBS target for PD, but some patients experience adverse effects on memory and cognition. Previously, we reported that DBS of the ventral anterior (VA) and ventrolateral (VL) nuclei of the thalamus and at the interface between the two (VA|VL), collectively VA-VL, relieved forelimb akinesia in the hemiparkinsonian 6-hydroxydopamine (6-OHDA) rat model. To determine the mechanism(s) underlying VA-VL DBS efficacy, we examined how motor cortical neurons respond to VA-VL DBS using single-unit recording electrodes in anesthetized 6-OHDA lesioned rats. VA-VL DBS increased spike frequencies of primary (M1) and secondary (M2) motor cortical pyramidal cells and M2, but not M1, interneurons. To explore the translational merits of VA-VL DBS, we compared the therapeutic window, rate of stimulation-induced dyskinesia onset, and effects on memory between VA-VL and STN DBS. VA-VL and STN DBS had comparable therapeutic windows, induced dyskinesia at similar rates in hemiparkinsonian rats, and adversely affected performance in the novel object recognition (NOR) test in cognitively normal and mildly impaired sham animals. Interestingly, a subset of sham rats with VA-VL implants showed severe cognitive deficits with DBS off. VA-VL DBS improved NOR test performance in these animals. We conclude that VA-VL DBS may exert its therapeutic effects by increasing pyramidal cell activity in the motor cortex and interneuron activity in the M2, with plausible potential to improve memory in PD.

Anatomical Correlates of Uncontrollable Laughter With Unilateral Subthalamic Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for the management of motor complications in Parkinson's disease. Uncontrollable laughter has been reported as a rare side effect of STN stimulation. The precise mechanism responsible for this unique phenomenon remains unclear. We examined in detail the DBS electrode position and stimulation parameters in two patients with uncontrollable laughter during programming after STN-DBS surgery and illustrated the anatomical correlates of the acute mood changes with STN stimulation. CASE REPORT: Unilateral STN-DBS induced uncontrollable laughter with activation of the most ventral contacts in both patients. However, the location of the electrodes responsible for this adverse effect differed between the patients. In the first patient, the DBS lead was placed more inferiorly and medially within the STN. In the second patient, the DBS lead was implanted more anteriorly and inferiorly than initially planned at the level of the substantia nigra reticulata (SNr). CONCLUSION: Unilateral STN-DBS can induce acute uncontrollable laughter with activation of electrodes located more anterior, medial, and inferior in relationship with the standard stereotactic STN target. We suggest that simulation of ventral and medial STN, surrounding limbic structures or the SNr, is the most plausible anatomical substrate responsible for this acute mood and behavioral change. Our findings provide insight into the complex functional neuroanatomical relationship of the STN and adjacent structures important for mood and behavior. DBS programming with more dorsal and lateral contacts within the STN should be entertained to minimize the emotional side effects.

Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome.

BACKGROUND: There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD. OBJECTIVE: The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research. METHODS: A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways. RESULTS: Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation. CONCLUSION: PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. © 2017 International Parkinson and Movement Disorder Society.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Deep brain stimulation significantly decreases disability from low back pain in patients with advanced Parkinson's disease.

BACKGROUND: Up to 60% of Parkinson's disease (PD) patients suffer from low back pain (LBP) during the course of their disease. How LBP affects daily functional status and how to manage this aspect of PD has not been adequately explored. METHODS: We examined 16 patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN DBS) who met the inclusion criteria for moderate disability from LBP, as classified by the Oswestry Low Back Pain Disability Index (OLBPD). RESULTS: Thirteen of 16 patients had attempted additional treatments for LBP, including medical management, massage, chiropractic, epidural steroid injections and/or surgery, with minimal relief. Following DBS, there was a significant improvement in the OLBPD at both the 6-month and 1-year time points (p < 0.02, p < 0.005, respectively). A mean improvement of 31.7% on the OLBPD score was noted. The Visual Analogue Scale (VAS) similarly decreased significantly at 1 year (p = 0.015). There was no correlation between the OLBPD score and other measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), age and other nonmotor symptoms. CONCLUSION: Given the prevalent yet undertreated disability associated with LBP in PD, these results are novel in that they show that STN DBS has a significant positive effect on disability associated with LBP.

Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat.

Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinson's disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.

Evaluation of a prototype point-of-care instrument based on monochromatic x-ray fluorescence spectrometry: potential for monitoring trace element status of subjects with neurodegenerative disease.

Assessment of trace elements such as Cu, Zn, and Se in patients with neurodegenerative disease, such as Alzheimer's (AD) and Parkinson's disease (PD), may be useful in etiologic studies and in assessing the risk of developing these conditions. A prototype point-of-care (POC) instrument based on monochromatic x-ray fluorescence (M-XRF) was assembled and evaluated for the determination of Cu, Zn, and Se in whole blood, plasma, and urine. The prototype instrument was validated using certified reference materials for Cu and Zn in serum/plasma, and the reported bias and relative imprecision were <10%. The M-XRF prototype performance was further assessed using human specimens collected from AD and PD subjects, and was found to be satisfactory (<20% bias) for monitoring Cu and Zn levels in plasma and whole blood. However, the prototype M-XRF sensitivity was not sufficient for quantifying Cu, Zn, or Se in urine. Nonetheless, while validating the prototype instrument, body fluids (whole blood, plasma, and urine) were collected from 19 AD patients, 23 PD patients, and 24 controls specifically for trace element analysis using well-validated methods based on inductively coupled plasma mass spectrometry (ICP-MS). This limited biomonitoring study provided robust data for up to 16 elements including Sb, As, Ba, Cd, Cs, Co, Cr, Cu, Hg, Pb, Mo, Se, Tl, Sn, Zn, and U in plasma, whole blood, and urine. The results did not indicate any significant differences in most trace elements studied between AD or PD patients compared to controls, although the sample size is limited. A statistically significant increase in plasma Se was identified for PD patients relative to AD patients, but this could be due to age differences.

Subclinical zinc deficiency in Alzheimer's disease and Parkinson's disease.

To evaluate zinc status in Alzheimer's disease and Parkinson's disease, 29 patients with Alzheimer's disease, 30 patients with Parkinson's disease, and 29 age- and sex-matched controls were studied. All patients and controls were older than age 50, and all zinc and copper supplements were prohibited beginning 30 days prior to study. Patients were diagnosed by standard criteria. Blood zinc and urine zinc were measured. Urine zinc was measured in a casual specimen, standardized for dilution by reference to creatinine content. Results showed a significantly lower blood zinc in patients with Alzheimer's and patients with Parkinson's than in controls. Urine zinc excretion, normalized to urine creatinine excretion, was not significantly different in either patient group compared to controls. These patients are probably zinc deficient because of nutritional inadequacy.