"PNP slows down" - linearly-reduced whole body joint velocities and altered gait patterns in polyneuropathy.

Introduction: Gait disturbances are a common consequence of polyneuropathy (PNP) and a major factor in patients' reduced quality of life. Less is known about the underlying mechanisms of PNP-related altered motor behavior and its distribution across the body. We aimed to capture whole body movements in PNP during a clinically relevant mobility test, i.e., the Timed Up and Go (TUG). We hypothesize that joint velocity profiles across the entire body would enable a deeper understanding of PNP-related movement alterations. This may yield insights into motor control mechanisms responsible for altered gait in PNP. Methods: 20 PNP patients (61 ± 14 years) and a matched healthy control group (CG, 60 ± 15 years) performed TUG at (i) preferred and (ii) fast movement speed, and (iii) while counting backward (dual-task). We recorded TUG duration (s) and extracted gait-related parameters [step time (s), step length (cm), and width (cm)] during the walking sequences of TUG and calculated center of mass (COM) velocity [represents gait speed (cm/s)] and joint velocities (cm/s) (ankles, knees, hips, shoulders, elbows, wrists) with respect to body coordinates during walking; we then derived mean joint velocities and ratios between groups. Results: Across all TUG conditions, PNP patients moved significantly slower (TUG time, gait speed) with prolonged step time and shorter steps compared to CG. Velocity profiles depend significantly on group designation, TUG condition, and joint. Correlation analysis revealed that joint velocities and gait speed are closely interrelated in individual subjects, with a 0.87 mean velocity ratio between groups. Discussion: We confirmed a PNP-related slowed gait pattern. Interestingly, joint velocities in the rest of the body measured in body coordinates were in a linear relationship to each other and to COM velocity in space coordinates, despite PNP. Across the whole body, PNP patients reduce, on average, their joint velocities with a factor of 0.87 compared to CG and thus maintain movement patterns in terms of velocity distributions across joints similarly to healthy individuals. This down-scaling of mean absolute joint velocities may be the main source for the altered motor behavior of PNP patients during gait and is due to the poorer quality of their somatosensory information. Clinical Trial Registration: https://drks.de/search/de, identifier DRKS00016999.

Abnormal neural oscillations during gait and dual-task in Parkinson's disease.

Gait dysfunctions are debilitating motor symptoms of Parkinson's disease (PD) and may result in frequent falling with health complications. The contribution of the motor-cognitive network to gait disturbance can be studied more thoroughly by challenging motor-cognitive dual-task gait performances. Gait is a complex motor task that requires an appropriate contribution from motor and cognitive networks, reflected in frequency modulations among several cortical and subcortical networks. Electrophysiological recordings by scalp electroencephalography and implanted deep brain stimulation (DBS) electrodes have unveiled modulations of specific oscillatory patterns in the cortical-subcortical circuits in PD. In this review, we summarize oscillatory contributions of the cortical, basal ganglia, mesencephalic locomotor, and cerebellar regions during gait and dual-task activities in PD. We detail the involvement of the cognitive network in dual-task settings and compare how abnormal oscillations in the specific frequency bands in the cortical and subcortical regions correlate with gait deficits in PD, particularly freezing of gait (FOG). We suggest that altered neural oscillations in different frequencies can cause derangements in broader brain networks, so neuromodulation and pharmacological therapies should be considered to normalize those network oscillations to improve challenged gait and dual-task motor functions in PD. Specifically, the theta and beta bands in premotor cortical areas, subthalamic nucleus, as well as alpha band activity in the brainstem prepontine nucleus, modulate under clinically effective levodopa and DBS therapies, improving gait and dual-task performance in PD with FOG, compared to PD without FOG and age-matched healthy control groups.

Cognitive task-related oscillations in human internal globus pallidus and subthalamic nucleus.

Recently it has been acknowledged that the basal ganglia nuclei play a major role in cognitive control; however, the contribution by their network remains unclear. Previous studies have demonstrated the role of the subthalamic nucleus (STN) in cognitive processing and suggested that its connections to cortical and other associated regions regulate response inhibition during conflict conditions. By contrast, the role of the internal globus pallidus (GPi) as the output nucleus before the thalamic relay has not yet been investigated during cognitive processing. We recorded local field potentials (LFPs) from externalized deep brain stimulation (DBS) electrodes implanted bilaterally in the GPi (n = 9 participants with dystonia) and STN (n = 8 participants with Parkinson's disease (PD)) during a primed flanker task. Both dystonia (GPi group) and PD participants (STN group) responded faster to the congruent trials than the incongruent trials. Overall, the dystonic GPi group was significantly faster than the PD STN group. LFPs showed elevated cue-triggered theta (3-7 Hz) power in GPi and STN groups in a similar way. Response-triggered LFP beta power (13-25 Hz) was significantly increased in the GPi group compared to the STN group. Results demonstrate that GPi activity appears to be critical in the cognitive processing of action selection and response during the presence of conflict tasks similar to the STN group.

Cortical and Cerebellar Oscillatory Responses to Postural Instability in Parkinson's Disease.

Introduction: Posture and balance dysfunctions critically impair activities of daily living of patients with progressing Parkinson's disease (PD). However, the neural mechanisms underlying postural instability in PD are poorly understood, and specific therapies are lacking. Previous electrophysiological studies have shown distinct cortical oscillations with a significant contribution of the cerebellum during postural control tasks in healthy individuals. Methods: We investigated cortical and mid-cerebellar oscillatory activity via electroencephalography (EEG) during a postural control task in 10 PD patients with postural instability (PDPI+), 11 PD patients without postural instability (PDPI-), and 15 age-matched healthy control participants. Relative spectral power was analyzed in the theta (4-7 Hz) and beta (13-30 Hz) frequency bands. Results: Time-dependent postural measurements computed by accelerometer signals showed poor performance in PDPI+ participants. EEG results revealed that theta power was profoundly lower in mid-frontal and mid-cerebellar regions during the postural control task in PDPI+, compared to PDPI- and control participants. In addition, theta power was correlated with postural control performance in PD subjects. No significant changes in beta power were observed. Additionally, oscillatory changes during the postural control task differed from the resting state. Conclusion: This study underlines the involvement of mid-frontal and mid-cerebellar regions in postural stability during a balance task and emphasizes the important role of theta oscillations therein for postural control in PD.

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry.

BACKGROUND AND OBJECTIVES: To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome. METHODS: Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non-rituximab-treated patients were analyzed retrospectively. RESULTS: Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation. DISCUSSION: We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE. CLASS OF EVIDENCE: This study provides Class IV evidence that rituximab is an effective treatment for some types of AE.

Rapid prototyping vaccine approach in mice against multi-drug resistant Gram-negative organisms from clinical isolates based on outer membrane vesicles.

Hospital-acquired infections due to multi-drug resistant Gram-negative organisms (MDRGNO) pose a major threat to global health. A vaccine preventing colonization and consecutive infection with MDRGNO could be particularly valuable, as therapeutic options become increasingly limited. Outer membrane vesicles (OMV) of Escherichia coli strain CFT073 as well as three MDRGNO strains that had caused severe infections in humans were administered intranasally to mice, with and without cholera toxin as an adjuvant. The humoral immune responses were comparatively matched with the sera of patients, who had suffered an infection caused by the respective bacterium. Additionally, systemic and local toxicity was evaluated. Intranasal vaccination with OMV could elicit solid humoral immune responses (total IgM and IgG), specific for the respective MDRGNO in mice; decoration of vital bacterial membranes with antibodies was comparable to patients who had survived systemic infection with the respective bacterial isolate. After intranasal vaccination of mice with OMV no signs of local or systemic toxicity were observed. Intranasal vaccination with OMV may open up a rapid vaccine approach to prevent colonization and/or infection with pathogenic MDRGNOs, especially in an outbreak setting within a hospital. It may also be an option for patients who have to undergo elective interventions in centers with a high risk of infection for certain common MDRGNO. Future studies need to include challenge experiments as well as phase I trials in humans.

Motion Biomarkers Showing Maximum Contrast Between Healthy Subjects and Parkinson's Disease Patients Treated With Deep Brain Stimulation of the Subthalamic Nucleus. A Pilot Study.

Background: Classic motion abnormalities in Parkinson's disease (PD), such as tremor, bradykinesia, or rigidity, are well-covered by standard clinical assessments such as the Unified Parkinson's Disease Rating Scale (UPDRS). However, PD includes motor abnormalities beyond the symptoms and signs as measured by UPDRS, such as the lack of anticipatory adjustments or compromised movement smoothness, which are difficult to assess clinically. Moreover, PD may entail motor abnormalities not yet known. All these abnormalities are quantifiable via motion capture and may serve as biomarkers to diagnose and monitor PD. Objective: In this pilot study, we attempted to identify motion features revealing maximum contrast between healthy subjects and PD patients with deep brain stimulation (DBS) of the nucleus subthalamicus (STN) switched off and on as the first step to develop biomarkers for detecting and monitoring PD patients' motor symptoms. Methods: We performed 3D gait analysis in 7 out of 26 PD patients with DBS switched off and on, and in 25 healthy control subjects. We computed feature values for each stride, related to 22 body segments, four time derivatives, left-right mean vs. difference, and mean vs. variance across stride time. We then ranked the feature values according to their distinguishing power between PD patients and healthy subjects. Results: The foot and lower leg segments proved better in classifying motor anomalies than any other segment. Higher degrees of time derivatives were superior to lower degrees (jerk > acceleration > velocity > displacement). The averaged movements across left and right demonstrated greater distinguishing power than left-right asymmetries. The variability of motion was superior to motion's absolute values. Conclusions: This small pilot study identified the variability of a smoothness measure, i.e., jerk of the foot, as the optimal signal to separate healthy subjects' from PD patients' gait. This biomarker is invisible to clinicians' naked eye and is therefore not included in current motor assessments such as the UPDRS. We therefore recommend that more extensive investigations be conducted to identify the most powerful biomarkers to characterize motor abnormalities in PD. Future studies may challenge the composition of traditional assessments such as the UPDRS.

Qualitative postural control differences in Idiopathic Parkinson's Disease vs. Progressive Supranuclear Palsy with dynamic-on-static platform tilt.

OBJECTIVES: We aimed to assess whether postural abnormalities in Progressive Supranuclear Palsy (PSP) and Idiopathic Parkinson's Disease (IPD) are qualitatively different by analysing spontaneous and reactive postural control. METHODS: We assessed postural control upon platform tilts in 17 PSP, 11 IPD patients and 18 healthy control subjects using a systems analysis approach. RESULTS: Spontaneous sway abnormalities in PSP resembled those of IPD patients. Spontaneous sway was smaller, slower and contained lower frequencies in both PSP and IPD as compared to healthy subjects. The amount of angular body excursions as a function of platform angular excursions (GAIN) in PSP was qualitatively different from both IPD and healthy subjects (GAIN cut-off value: 2.9, sensitivity of 94%, specificity of 72%). This effect was pronounced at the upper body level and at low as well as high frequencies. In contrast, IPD patients' stimulus-related body excursions were smaller compared to healthy subjects. Using a systems analysis approach, we were able to allocate these different postural strategies to differences in the use of sensory information as well as to different error correction efforts. CONCLUSIONS: While both PSP and IPD patients show abnormal postural control, the underlying pathology seems to be different. SIGNIFICANCE: The identification of disease-specific postural abnormalities shown here may be helpful for diagnostic as well as therapeutic discriminations of PSP vs. IPD.

Intermediate Latency-Evoked Potentials of Multimodal Cortical Vestibular Areas: Galvanic Stimulation.

INTRODUCTION: Human multimodal vestibular cortical regions are bilaterally anterior insulae and posterior opercula, where characteristic vestibular-related cortical potentials were previously reported under acoustic otolith stimulation. Galvanic vestibular stimulation likely influences semicircular canals preferentially. Galvanic stimulation was compared to previously established data under acoustic stimulation. METHODS: 14 healthy right-handed subjects, who were also included in the previous acoustic potential study, showed normal acoustic and galvanic vestibular-evoked myogenic potentials. They received 2,000 galvanic binaural bipolar stimuli for each side during EEG recording. RESULTS: Vestibular cortical potentials were found in all 14 subjects and in the pooled data of all subjects ("grand average") bilaterally. Anterior insula and posterior operculum were activated exclusively under galvanic stimulation at 25, 35, 50, and 80 ms; frontal regions at 30 and 45 ms. Potentials at 70 ms in frontal regions and at 110 ms at all of the involved regions could also be recorded; these events were also found using acoustic stimulation in our previous study. CONCLUSION: Galvanic semicircular canal stimulation evokes specific potentials in addition to those also found with acoustic otolith stimulation in identically located regions of the vestibular cortex. Vestibular cortical regions activate differently by galvanic and acoustic input at the peripheral sensory level. SIGNIFICANCE: Differential effects in vestibular cortical-evoked potentials may see clinical use in specific vertigo disorders.

Postural Stabilization Differences in Idiopathic Parkinson's Disease and Progressive Supranuclear Palsy during Self-Triggered Fast Forward Weight Lifting.

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Self-triggered, weighted movements appear to provoke falls in IPD, but not in PSP. Repeated self-triggered lifting of a 0.5-1-kg weight (<2% of body weight) with the dominant hand was performed in 17 PSP, 15 IPD with falling history, and 16 controls on a posturography platform. PSP showed excessive force scaling of weight and body motion with high-frequency multiaxial body sway, whereas IPD presented a delayed-onset forward body displacement. Differences in center of mass displacement apparent at very small weights indicate that both syndromes decompensate postural control already within stability limits. PSP may be subject to specific postural system devolution. IPD are susceptible to delayed forward falling. Differential physiotherapy strategies are suggested.

Neck Vibration Proprioceptive Postural Response Intact in Progressive Supranuclear Palsy unlike Idiopathic Parkinson's Disease.

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Postural responses to sensory anteroposterior tilt illusion by bilateral dorsal neck vibration were probed in both groups versus healthy controls on a static recording posture platform. Three distinct anteroposterior body mass excursion peaks (P1-P3) were observed. 18 IPD subjects exhibited well-known excessive response amplitudes, whereas 21 PSP subjects' responses remained unaltered to 22 control subjects. Neither IPD nor PSP showed response latency deficits, despite brainstem degeneration especially in PSP. The observed response patterns suggest that PSP brainstem pathology might spare the involved proprioceptive pathways and implies viability of neck vibration for possible biofeedback and augmentation therapy in PSP postural instability.

Effects of high-frequency stimulation of the internal pallidal segment on neuronal activity in the thalamus in parkinsonian monkeys.

Deep brain stimulation of the internal globus pallidus (GPi) is a major treatment for advanced Parkinson's disease. The effects of this intervention on electrical activity patterns in targets of GPi output, specifically in the thalamus, are poorly understood. The experiments described here examined these effects using electrophysiological recordings in two Rhesus monkeys rendered moderately parkinsonian through treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after sampling control data in the same animals. Analysis of spontaneous spiking activity of neurons in the basal ganglia-receiving areas of the ventral thalamus showed that MPTP-induced parkinsonism is associated with a reduction of firing rates of segments of the data that contained neither bursts nor decelerations, and with increased burst firing. Spectral analyses revealed an increase of power in the 3- to 13-Hz band and a reduction in the γ-range in the spiking activity of these neurons. Electrical stimulation of the ventrolateral motor territory of GPi with macroelectrodes, mimicking deep brain stimulation in parkinsonian patients (bipolar electrodes, 0.5 mm intercontact distance, biphasic stimuli, 120 Hz, 100 µs/phase, 200 µA), had antiparkinsonian effects. The stimulation markedly reduced oscillations in thalamic firing in the 13- to 30-Hz range and uncoupled the spiking activity of recorded neurons from simultaneously recorded local field potential (LFP) activity. These results confirm that oscillatory and nonoscillatory characteristics of spontaneous activity in the basal ganglia receiving ventral thalamus are altered in MPTP-induced parkinsonism. Electrical stimulation of GPi did not entrain thalamic activity but changed oscillatory activity in the ventral thalamus and altered the relationship between spikes and simultaneously recorded LFPs.

Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys.

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 µl of a 2.5-mM solution, injected at 0.1-0.2 µl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.

Movement kinematic after deep brain stimulation associated microlesions.

BACKGROUNDS: Deep brain stimulation is widely used for the treatment of movement disorders such as Parkinson's disease and dystonia. After the implantation of electrodes an immediate improvement of clinical symptoms has been described. It is unclear, whether movement kinematics are also changed by this 'microlesion effect'. METHODS: To gain further insight into these mechanisms, we studied arm, hand and finger movements preoperatively and immediately after the implantation of deep brain stimulation electrodes in patients with Parkinson's disease and dystonia. RESULTS: After implantation and without stimulation there was a clear reduction of clinical symptoms in both groups, as has been described previously. However, movement velocity was affected differently. Parkinsonian patients showed increased movement velocity postoperatively, whereas dystonic patients were significantly slower after electrode implantation. CONCLUSIONS: Lesioning and stimulation of these structures have the same beneficial clinical effects. Furthermore we suggest that globus pallidus internum lesions act by inhibiting a system which mainly acts upon muscular tone and limb posture whereas subthalamic stimulation or lesion causes a more unspecific disinhibition of movements.

Pattern of local field potential activity in the globus pallidus internum of dystonic patients during walking on a treadmill.

The basal ganglia (BG) are involved in gait. This notion is exemplified by observations that gait is disturbed by most diseases that affect the BG. However, it is unclear in what way the BG are activated during gait. One method to investigate the activity of the BG is to record local field potentials (LFPs) from electrodes placed in the BG for therapeutic purposes. Nowadays, the globus pallidus internum (GPi) represents the target for deep brain stimulation (DBS) in dystonia. LFPs recorded from this area have been shown to delineate activity associated with dystonic cramps but also activity that may be relevant for certain types of movement. In this study we recorded LFPs from DBS electrodes implanted into the GPi of eight patients with dystonia during walking on a treadmill machine and compared these data with data acquired during rest (sitting and standing). There was no difference in the power of frequency bands during the sitting and standing conditions. LFP power in the theta (4-8 Hz), alpha (8-12 Hz) and gamma (60-90 Hz) frequency bands was higher during walking than during the resting conditions. Beta (15-25 Hz) frequencies were the only frequencies that were down-regulated during walking. The amplitude of the theta and alpha frequency bands was modulated during the gait cycle. These data shed light on the function of the BG in patients with dystonia and demonstrate that, during gait, their overall activity increases in a specific way without showing increases of narrow frequency bands.

Vestibular-neck interaction in cerebellar patients.

Vestibulospinal reflexes are important for upright stance and locomotor control. Information from both the vestibular and the proprioceptive system must be combined centrally to guarantee appropriate compensation for a physical disturbance. Recent single-unit recordings from the monkey demonstrated vestibulo-proprioceptive interaction in the fastigial nucleus (deep cerebellar nucleus). The present study investigated whether integration of vestibular and proprioceptive signals is compromised in humans with cerebellar degeneration. Control subjects and patients were exposed to binaural, sinusoidal galvanic vestibular stimulation at 0.16 Hz, while their static head-on-trunk position was systematically altered in the head-horizontal plane from 60 degrees left to 60 degrees right. Controls responded to different head-on-trunk positions with fully compensatory changes in the direction of galvanically induced body sway, keeping it aligned with the head-frontal plane. In patients, this compensatory change was lacking. Findings support the assumption that the cerebellum plays a central role in the integration of vestibular and proprioceptive signals in humans. This form of impaired sensory interaction is probably a clinically important component of cerebellar stance and gait ataxia.