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

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

A Critical Evaluation of Inflammatory Markers in Huntington’s Disease Plasma

BACKGROUND: Huntington’s Disease (HD) is a hereditary, progressive neurodegenerative disorder characterised by both neurological and systemic symptoms. In HD, immune changes can be observed before the onset of overt clinical features raising the possibility that immune markers in plasma could be used to track disease progression. It has previously been demonstrated that a widespread, progressive innate immune response is detectable in plasma throughout the course of HD. OBJECTIVE: The aim of the present study was to investigate the potential of several components of innate immunity as plasma biomarkers in HD. METHODS: We utilised antibody-based detection technologies as well as mass spectrometric quantification, multiple reaction monitoring (MRM-MS). RESULTS: Levels of several markers previously described as altered in HD, such as clusterin, complement component 4, complement component 9 and α-2 macroglobulin did not differ between healthy controls and HD subjects as measured by Luminex, ELISA or MRM-MS. C-reactive protein was decreased in early HD, while the other immune markers tested were unaltered. CONCLUSIONS: Of the immune markers tested in this study, none showed potential to track with HD disease progression

Analysis of ACTH and cortisol in control, premanifest and stage II/III HD cohorts.

<p>A: Mean ACTH concentrations over 24 hour sampling period in the three groups. B: Mean ACTH concentrations over 24 hour sampling period in the three groups. C: FT analysis of ACTH plotting strength/power (%) against frequency (minutes) of ACTH oscillations for the three groups. D: FT analysis of cortisol plotting strength/power (%) against frequency (minutes) of cortisol oscillations for the three groups. E: Mean molar cortisol:ACTH ratio over 24 hour sampling period in the three groups.</p

Hormone levels in control, premanifest and stage II/III HD cohorts.

<p>P-value = p-value from linear regression of specified variable on age and gender (or else by gender as indicated), L indicates that logs were taken of the specified variable prior to linear regression; P indicates Freedman and Lane permutation tests were performed to account to non-normality, LP indicates Freedman and Lane permutation tests were performed after taking logs of the specified variable. In all cases, age and gender were adjusted for.</p><p>Data are presented as Mean ±SD for normally distributed data and as median [minimum–maximum] for skewed data.</p

Analysis of LH in control, premanifest and stage II/III HD cohorts.

<p>A: Mean LH concentrations over 24 hour sampling period for female subjects in the three groups. B: Mean LH concentrations over 24 hour sampling period for male subjects in the three groups. C: FT analysis of LH plotting strength/power (%) against frequency (minutes) of LH oscillations for the three groups.</p

Demographic characteristics and clinical features of controls, pre-manifest and stage II/III HD cohorts.

<p>Data presented as median (range).</p