Chronic Subthalamic Nucleus Stimulation in Parkinson's Disease: Optimal Frequency for Gait Depends on Stimulation Site and Axial Symptoms

Axial symptoms emerge in a significant proportion of patients with Parkinson's disease (PD) within 5 years of deep brain stimulation (STN-DBS). Lowering the stimulation frequency may reduce these symptoms. The objectives of the current study were to establish the relationship between gait performance and STN-DBS frequency in chronically stimulated patients with PD, and to identify factors underlying variability in this relationship. Twenty-four patients treated chronically with STN-DBS (>4 years) were studied off-medication. The effect of stimulation frequency (40–140 Hz, 20 Hz-steps, constant energy) on gait was assessed in 6 sessions spread over 1 day. Half of the trials/session involved walking through a narrow doorway. The influence of stimulation voltage was investigated separately in 10 patients. Gait was measured using 3D motion capture and axial symptoms severity was assessed clinically. A novel statistical method established the optimal frequency(ies) for each patient by operating on frequency-tuning curves for multiple gait parameters. Narrowly-tuned optimal frequencies (20 Hz bandwidth) were found in 79% of patients. Frequency change produced a larger effect on gait performance than voltage change. Optimal frequency varied between patients (between 60 and 140 Hz). Contact site in the right STN and severity of axial symptoms were independent predictors of optimal frequency (P = 0.009), with lower frequencies associated with more dorsal contacts and worse axial symptoms. We conclude that gait performance is sensitive to small changes in STN-DBS frequency. The optimal frequency varies considerably between patients and is associated with electrode contact site and severity of axial symptoms. Between-subject variability of optimal frequency may stem from variable pathology outside the basal ganglia

Plasma melatonin is reduced in Huntington's disease

This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24-hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease

Chronic Subthalamic Nucleus Stimulation in Parkinson's Disease: Optimal Frequency for Gait Depends on Stimulation Site and Axial Symptoms

Axial symptoms emerge in a significant proportion of patients with Parkinson's disease (PD) within 5 years of deep brain stimulation (STN-DBS). Lowering the stimulation frequency may reduce these symptoms. The objectives of the current study were to establish the relationship between gait performance and STN-DBS frequency in chronically stimulated patients with PD, and to identify factors underlying variability in this relationship. Twenty-four patients treated chronically with STN-DBS (>4 years) were studied off-medication. The effect of stimulation frequency (40–140 Hz, 20 Hz-steps, constant energy) on gait was assessed in 6 sessions spread over 1 day. Half of the trials/session involved walking through a narrow doorway. The influence of stimulation voltage was investigated separately in 10 patients. Gait was measured using 3D motion capture and axial symptoms severity was assessed clinically. A novel statistical method established the optimal frequency(ies) for each patient by operating on frequency-tuning curves for multiple gait parameters. Narrowly-tuned optimal frequencies (20 Hz bandwidth) were found in 79% of patients. Frequency change produced a larger effect on gait performance than voltage change. Optimal frequency varied between patients (between 60 and 140 Hz). Contact site in the right STN and severity of axial symptoms were independent predictors of optimal frequency (P = 0.009), with lower frequencies associated with more dorsal contacts and worse axial symptoms. We conclude that gait performance is sensitive to small changes in STN-DBS frequency. The optimal frequency varies considerably between patients and is associated with electrode contact site and severity of axial symptoms. Between-subject variability of optimal frequency may stem from variable pathology outside the basal ganglia

Investigating the Relationships Between Hypothalamic Volume and Measures of Circadian Rhythm and Habitual Sleep in Premanifest Huntington’s Disease

Objective: Pathological changes within the hypothalamus have been proposed to mediate circadian rhythm and habitual sleep disturbances in individuals with Huntington’s disease (HD). However, investigations examining the relationships between hypothalamic volume and circadian rhythm and habitual sleep in individuals with HD are sparse. This study aimed to comprehensively evaluate the relationships between hypothalamic pathology and circadian rhythm and habitual sleep disturbances in individuals with premanifest HD. Methods: Thirty-two individuals with premanifest HD and twenty-nine healthy age- and gender-matched controls participated in this dual-site, cross-sectional study. Magnetic resonance imaging scans were performed to evaluate hypothalamic volume. Circadian rhythm and habitual sleep were assessed via measurement of morning and evening cortisol and melatonin levels, wrist-worn actigraphy, the Consensus Sleep Diary and sleep questionnaires. Information on mood, physical activity levels and body composition were also collected. Results: Compared to healthy controls, individuals with premanifest HD displayed significantly reduced grey matter volume in the hypothalamus, decreased habitual sleep efficiency and increased awakenings; however, no alterations in morning cortisol or evening melatonin release were noted in individuals with premanifest HD. While differences in the associations between hypothalamic volume and cortisol and melatonin output existed in individuals with premanifest HD compared to healthy controls, no consistent associations were observed between hypothalamic volume and circadian rhythm or habitual sleep outcomes. Conclusion: While significant differences in associations between hypothalamic volume and cortisol and melatonin existed between individuals with premanifest HD and healthy controls, no differences in circadian markers were observed between the groups. This suggests that circadian regulation is maintained despite hypothalamic pathology, perhaps via neural compensation. Longitudinal studies are required to further understand the relationships between the hypothalamus and circadian rhythm and habitual sleep disturbances in HD as the disease course lengthens

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma

Biofluid Biomarkers in Huntington's Disease

Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability

Maintaining balance against force perturbations:impaired mechanisms unresponsive to levodopa in Parkinson's disease

There is evidence that postural instability associated with Parkinson's disease (PD) is not adequately improved by levodopa, implying involvement of nondopaminergic pathways. However, the mechanisms contributing to postural instability have yet to be fully identified and tested for their levodopa responsiveness. In this report we investigate balance processes that resist external forces to the body when standing. These include in-place responses and the transition to protective stepping. Forward and backward shoulder pulls were delivered using two force-feedback-controlled motors and were randomized for direction, magnitude, and onset. Sixteen patients with PD were tested OFF and ON levodopa, and 16 healthy controls were tested twice. Response behavior was quantified from 3-dimensional ground reaction forces and kinematic measurements of body segments and total body center-of-mass (CoM) motion. In-place responses resisting the pull were significantly smaller in PD as reflected in reduced horizontal anteroposterior ground reaction force and increased CoM displacement. Ankle, knee, and hip moments contributing to this resistance were smaller in PD, with the knee extensor moment to backward pulls being the most affected. The threshold force needed to evoke a step was also smaller for PD in the forward direction. Protective steps evoked by suprathreshold pulls showed deficits in PD in the backward direction, with steps being shorter and more steps being required to arrest the body. Levodopa administration had no significant effect on either in-place or protective stepping deficits. We conclude that processes employed to maintain balance in the face of external forces show impairment in PD consistent with disruption to nondopaminergic systems