Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

On-Demand Cueing for Freezing of Gait in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Cueing can alleviate freezing of gait (FOG) in people with Parkinson's disease (PD), but using the same cues continuously in daily life may compromise effectiveness. Therefore, we developed the DeFOG-system to deliver personalized auditory cues on detection of a FOG episode. OBJECTIVES: We aimed to evaluate the effects of DeFOG during a FOG-provoking protocol: (1) after 4 weeks of DeFOG-use in daily life against an active control group; (2) after immediate DeFOG-use (within-group) in different medication states. METHOD: In this randomized controlled trial, 63 people with PD and daily FOG were allocated to the DeFOG or active control group. Both groups received feedback on their daily living step counts using the device, but the DeFOG group also received on-demand cueing. Video-rated FOG severity was compared pre- and post-intervention through a FOG-provoking protocol administered at home off and on-medication, but without using DeFOG. Within-group effects were tested by comparing FOG during the protocol with and without DeFOG. RESULTS: DeFOG-use during the 4 weeks was similar between groups, but we found no between-group differences in FOG-severity. However, the within-group analysis showed that FOG was alleviated by DeFOG (effect size d = 0.57), regardless of medication state. Combining DeFOG and medication yielded an effect size of d = 0.67. CONCLUSIONS: DeFOG reduced FOG considerably in a population of severe freezers both off and on medication. Nonetheless, 4 weeks of DeFOG-use in daily life did not ameliorate FOG during the protocol unless DeFOG was worn. These findings suggest that on-demand cueing is only effective when used, similar to other walking aids. © 2024 International Parkinson and Movement Disorder Society.

Left Vagus Stimulation Modulates Contralateral Subthalamic ß Power Improving the Gait in Parkinson's Disease.

BACKGROUND: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). OBJECTIVES: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). METHODS: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (ß band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition. RESULTS: The left taVNS induced a reduction of the total ß power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced ß reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. CONCLUSIONS: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subthalamic and nigral neurons are differentially modulated during parkinsonian gait.

The parkinsonian gait disorder and freezing of gait are therapeutically demanding symptoms with considerable impact on quality of life. The aim of this study was to assess the role of subthalamic and nigral neurons in the parkinsonian gait control using intraoperative microelectrode recordings of basal ganglia neurons during a supine stepping task. Twelve male patients (56 ± 7 years) suffering from moderate idiopathic Parkinson's disease (disease duration 10 ± 3 years, Hoehn and Yahr stage 2), undergoing awake neurosurgery for deep brain stimulation, participated in the study. After 10 s resting, stepping at self-paced speed for 35 s was followed by short intervals of stepping in response to random 'start' and 'stop' cues. Single- and multi-unit activity was analysed offline in relation to different aspects of the stepping task (attentional 'start' and 'stop' cues, heel strikes, stepping irregularities) in terms of firing frequency, firing pattern and oscillatory activity. Subthalamic nucleus and substantia nigra neurons responded to different aspects of the stepping task. Of the subthalamic nucleus neurons, 24% exhibited movement-related activity modulation as an increase of the firing rate, suggesting a predominant role of the subthalamic nucleus in motor aspects of the task, while 8% of subthalamic nucleus neurons showed a modulation in response to the attentional cues. In contrast, responsive substantia nigra neurons showed activity changes exclusively associated with attentional aspects of the stepping task (15%). The firing pattern of subthalamic nucleus neurons revealed gait-related firing regularization and a drop of beta oscillations during the stepping performance. During freezing episodes instead, there was a rise of beta oscillatory activity. This study shows for the first time specific, task-related subthalamic nucleus and substantia nigra single-unit activity changes during gait-like movements in humans with differential roles in motor and attentional control of gait. The emergence of perturbed firing patterns in the subthalamic nucleus indicates a disrupted information transfer within the gait network, resulting in freezing of gait.

Greater prefrontal activation during sitting toe tapping predicts severer freezing of gait in Parkinson's disease: an fNIRS study.

OBJECTIVE: Previous studies have revealed that, compared with Parkinson's disease (PD) patients without freezing of gait (FoG), the ones with FoG showed greater prefrontal activation while doing lower-limb movements involving standing, walking and turning, which require both locomotor and balance control. However, the relation between FoG and pure locomotor control as well as its underlying mechanism remain unclear. METHODS: A total of 56 PD subjects were recruited and allocated to PD-FoG and PD-noFoG subgroups, and 34 age-matched heathy adults were included as heathy control (HC). Functional near-infrared spectroscopy was used to measure their prefrontal activation in a sitting lower-limb movement task, wherein subjects were asked to sit and tap their right toes as big and as fast as possible. RESULTS: Result of one-way ANOVA (Group: PD-FoG vs. PD-noFoG vs. HC) revealed greater activation in the right prefrontal cortex in the PD-FoG group than in the other 2 groups. Linear mixed-effects model showed consistent result. Furthermore, the right prefrontal activation positively correlated with the severity of FoG symptoms in PD-FoG patients. CONCLUSION: These findings suggested that PD patients with FoG require additional cognitive resources to compensate their damaged automaticity in locomotor control, which is more pronounced in severe FoG patients than milder ones.

Detection and prediction of freezing of gait with wearable sensors in Parkinson's disease.

Freezing of gait (FoG) is one of the most distressing symptoms of Parkinson's Disease (PD), commonly occurring in patients at middle and late stages of the disease. Automatic and accurate FoG detection and prediction have emerged as a promising tool for long-term monitoring of PD and implementation of gait assistance systems. This paper reviews the recent development of FoG detection and prediction using wearable sensors, with attention on identifying knowledge gaps that need to be filled in future research. This review searched the PubMed and Web of Science databases to collect studies that detect or predict FoG with wearable sensors. After screening, 89 of 270 articles were included. The data description, extracted features, detection/prediction methods, and classification performance were extracted from the articles. As the number of papers of this area is increasing, the performance has been steadily improved. However, small datasets and inconsistent evaluation processes still hinder the application of FoG detection and prediction with wearable sensors in clinical practice.

The validation of a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q).

OBJECTIVE: This study aimed to develop a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q) and investigate its validity and reliability. METHODS: After translating the NFOG-Q according to a standardised protocol, 56 patients with Parkinson's disease (PD) were administered it. Additionally, the MDS-UPDRS parts II and III, Hoehn and Yahr (H&Y) stage, and number of falls over 1 month were evaluated. Spearman's correlation coefficients (rho) were used to determine construct validity, and Cronbach's alpha (α) was used to examine reliability. RESULTS: The interquartile range of the NFOG-Q scores was 10.0-25.3 (range 0-29). The NFOG-Q scores were strongly correlated with the MDS-UPDRS part II, items 2.12 (walking and balance), 2.13 (freezing), 3.11 (freezing of gait), and 3.12 (postural stability) and the postural instability and gait difficulty score (rho = 0.515-0.669), but only moderately related to the MDS-UPDRS item 3.10 (gait), number of falls, disease duration, H&Y stage, and time of the Timed Up-and-Go test (rho = 0.319-0.434). No significant correlations were observed between age and the time of the 10-m walk test. The internal consistency was excellent (α = 0.96). CONCLUSIONS: The Japanese version of the NFOG-Q is a valid and reliable tool for assessing the severity of freezing in patients with PD.

Freezing of gait assessment with inertial measurement units and deep learning: effect of tasks, medication states, and stops.

BACKGROUND: Freezing of gait (FOG) is an episodic and highly disabling symptom of Parkinson's Disease (PD). Traditionally, FOG assessment relies on time-consuming visual inspection of camera footage. Therefore, previous studies have proposed portable and automated solutions to annotate FOG. However, automated FOG assessment is challenging due to gait variability caused by medication effects and varying FOG-provoking tasks. Moreover, whether automated approaches can differentiate FOG from typical everyday movements, such as volitional stops, remains to be determined. To address these questions, we evaluated an automated FOG assessment model with deep learning (DL) based on inertial measurement units (IMUs). We assessed its performance trained on all standardized FOG-provoking tasks and medication states, as well as on specific tasks and medication states. Furthermore, we examined the effect of adding stopping periods on FOG detection performance. METHODS: Twelve PD patients with self-reported FOG (mean age 69.33 ± 6.02 years) completed a FOG-provoking protocol, including timed-up-and-go and 360-degree turning-in-place tasks in On/Off dopaminergic medication states with/without volitional stopping. IMUs were attached to the pelvis and both sides of the tibia and talus. A temporal convolutional network (TCN) was used to detect FOG episodes. FOG severity was quantified by the percentage of time frozen (%TF) and the number of freezing episodes (#FOG). The agreement between the model-generated outcomes and the gold standard experts' video annotation was assessed by the intra-class correlation coefficient (ICC). RESULTS: For FOG assessment in trials without stopping, the agreement of our model was strong (ICC (%TF) = 0.92 [0.68, 0.98]; ICC(#FOG) = 0.95 [0.72, 0.99]). Models trained on a specific FOG-provoking task could not generalize to unseen tasks, while models trained on a specific medication state could generalize to unseen states. For assessment in trials with stopping, the agreement of our model was moderately strong (ICC (%TF) = 0.95 [0.73, 0.99]; ICC (#FOG) = 0.79 [0.46, 0.94]), but only when stopping was included in the training data. CONCLUSION: A TCN trained on IMU signals allows valid FOG assessment in trials with/without stops containing different medication states and FOG-provoking tasks. These results are encouraging and enable future work investigating automated FOG assessment during everyday life.

Levodopa responsive freezing of gait is associated with reduced norepinephrine transporter binding in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

Dynamic functional connectivity reveals hyper-connected pattern and abnormal variability in freezing of gait of Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. METHODS: In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. RESULTS: Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). CONCLUSIONS: Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG.

Levodopa alters resting-state functional connectivity more selectively in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a debilitating motor symptom of Parkinson's disease (PD). Although PD dopaminergic medication (L-DOPA) seems to generally reduce FOG severity, its effect on neural mechanisms of FOG remains to be determined. The purpose of this study was to quantify the effect of L-DOPA on brain resting-state functional connectivity in individuals with FOG. Functional magnetic resonance imaging was acquired at rest in 30 individuals living with PD (15 freezers) in the ON- and OFF- medication state. A seed-to-voxel analysis was performed with seeds in the bilateral basal ganglia nuclei, the thalamus and the mesencephalic locomotor region. In freezers, medication-state contrasts revealed numerous changes in resting-state functional connectivity, not modulated by L-DOPA in non-freezers. In freezers, L-DOPA increased the functional connectivity between the seeds and regions including the posterior parietal, the posterior cingulate, the motor and the medial prefrontal cortices. Comparisons with non-freezers revealed that L-DOPA generally normalizes brain functional connectivity to non-freezers levels but can also increase functional connectivity, possibly compensating for dysfunctional networks in freezers. Our findings suggest that L-DOPA could contribute to a better sensorimotor, attentional, response inhibition and limbic processing to prevent FOG when triggers are encountered but could also contribute to FOG by interfering with the processing capacity of the striatum. This study shows that levodopa taken to control PD symptoms induces changes in functional connectivity at rest, in freezers only. Increases (green) in functional connectivity of GPe, GPi, putamen and thalamus with cognitive, sensorimotor and limbic cortical regions of the Interference model (blue) was observed. Our results suggest that levodopa can normalize connections similar to non-freezers or increases connectivity to compensate for dysfunctional networks.

Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

BACKGROUND: Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. METHODS: We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. RESULTS: Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. CONCLUSIONS: These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study.

BACKGROUND: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). OBJECTIVE: The aim was to reveal the mechanisms of "OFF-period" FOG (OFF-FOG) and "levodopa-unresponsive" FOG (ONOFF-FOG) in PD. METHODS: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF-FOG, 15 PD patients with OFF-FOG, and 15 PD patients without FOG (Non-FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF-FOG patients. RESULTS: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF-FOG and OFF-FOG) compared to Non-FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF-FOG patients reduced compared to OFF-FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF-FOG patients, and high-frequency repetitive TMS distinctly improved gait in ONOFF-FOG patients, accompanied by enhanced SICI. CONCLUSIONS: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF-FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comparative analysis of freezing of gait in distinct Parkinsonism types by diffusion tensor imaging method and cognitive profiles.

Freezing of gait (FOG) is an episodic gait pattern that is common in advanced Parkinson's disease (PD) and other atypical parkinsonism syndromes. Recently, disturbances in the pedunculopontine nucleus (PPN) and its connections have been suggested to play a critical role in the development of FOG. In this study, we aimed to demonstrate possible disturbances in PPN and its connections by performing the diffusion tensor imaging (DTI) technique. We included 18 patients of PD with FOG [PD-FOG], 13 patients of PD without FOG [PD-nFOG] and 12 healthy subjects as well as a group of patients with progressive supranuclear palsy (PSP), an atypical parkinsonism syndrome which is very often complicated with FOG [6 PSP-FOG, 5 PSP-nFOG]. To determine the specific cognitive parameters that can be related to FOG, deliberate neurophysiological evaluations of all the individuals were performed. The comparative analyses and correlation analyses were performed to reveal the neurophysiological and DTI correlates of FOG in either group. We have found disturbances in values reflecting microstructural integrity of the bilateral superior frontal gyrus (SFG), bilateral fastigial nucleus (FN), left pre-supplementary motor area (SMA) in the PD-FOG group relative to the PD-nFOG group. The analysis of the PSP group also demonstrated disturbance in left pre-SMA values in the PSP-FOG group likewise, while negative correlations were determined between right STN, left PPN values and FOG scores. In neurophysiological assessments, lower performances for visuospatial functions were demonstrated in FOG ( +) individuals for either patient group. The disturbances in the visuospatial abilities may be a critical step for the occurrence of FOG. Together with the results of DTI analyses, it might be suggested that impairment in the connectivity of disturbed frontal areas with disordered basal ganglia, maybe the key factor for the occurrence of FOG in the PD group, whereas left PPN which is a nondopaminergic nucleus may play a more prominent role in the process of FOG in PSP. Moreover, our results support the relationship between right STN, and FOG as mentioned before, as well as introduce the importance of FN as a new structure that may be involved in FOG pathogenesis.

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease.

BACKGROUND AND PURPOSE: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. METHODS: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. RESULTS: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. CONCLUSIONS: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait.

Freezing of gait is a debilitating symptom in advanced Parkinson's disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson's disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait. Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson's disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel 'bandwidth model,' which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson's disease.

Freezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.

The development of a home-based technology to improve gait in people with Parkinson's disease: a feasibility study.

BACKGROUND: People with Parkinson's disease (PwP) may experience gait impairment and freezing of gait (FOG), a major cause of falls. External cueing, including visual (e.g., spaced lines on the floor) and auditory (e.g., rhythmic metronome beats) stimuli, are considered effective in alleviating mobility deficits and FOG. Currently, there is a need for a technology that delivers automatic, individually adjusted cues in the homes of PwP. The aims of this feasibility study were to describe the first step toward the development of a home-based technology that delivers external cues, test its effect on gait, and assess user experience. METHODS: Iterative system development was performed by our multidisciplinary team. The system was designed to deliver visual and auditory cues: light stripes projected on the floor and metronome beats, separately. Initial testing was performed using the feedback of five healthy elderly individuals on the cues' clarity (clear visibility of the light stripes and the sound of metronome beats) and discomfort experienced. A pilot study was subsequently conducted in the homes of 15 PwP with daily FOG. We measured participants' walking under three conditions: baseline (with no cues), walking with light stripes, and walking to metronome beats. Outcome measures included step length and step time. User experience was also captured in semi-structured interviews. RESULTS: Repeated-measures ANOVA of gait assessment in PwP revealed that light stripes significantly improved step length (p = 0.009) and step time (p = 0.019) of PwP. No significant changes were measured in the metronome condition. PwP reported that both cueing modalities improved their gait, confidence, and stability. Most PwP did not report any discomfort in either modality and expressed a desire to have such a technology in their homes. The metronome was preferred by the majority of participants. CONCLUSIONS: This feasibility study demonstrated the usability and potential effect of a novel cueing technology on gait, and represents an important first step toward the development of a technology aimed to prevent FOG by delivering individually adjusted cues automatically. A further full-scale study is needed. Trial registration This study was registered in ClinicalTrials.gov at 1/2/2022 NCT05211687.

Assessment of the psychometric properties of the Italian version of the New Freezing of Gait Questionnaire (NFOG-Q-IT) in people with Parkinson disease: a validity and reliability study.

INTRODUCTION: Freezing of gait (FOG) in Parkinson's disease (PD) is a challenging clinical symptom to assess, due to its episodic nature. A valid and reliable tool is the New FOG Questionnaire (NFOG-Q) used worldwide to measure FOG symptoms in PD. OBJECTIVE: The aim of this study was to translate, to culturally adapt, and to test the psychometric characteristics of the Italian version of the NFOG-Q (NFOG-Q-It). METHODS: The translation and cultural adaptation was based on ISPOR TCA guidelines to finalize the 9-item NFOG-Q-It. Internal consistency was assessed in 181 Italian PD native speakers who experienced FOG using Cronbach's alpha. Cross-cultural analysis was tested using the Spearman's correlation between the NFOG-Q-It and the Modified Hoehn-Yahr Scale (M-H&Y). To assess construct validity, correlations among NFOG-Q-It, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Falls Efficacy Scale-International (FES-I), the 6-min Walking Test (6MWT), the Mini Balance Evaluation System Test (Mini-BESTest) and the Short Physical Performance Battery (SPPB) were investigated. RESULTS: The Italian N-FOGQ had high internal consistency (Cronbach's α = 0.859). Validity analysis showed significant correlations between NFOG-Q-IT total score and M-H&Y scores (r = 0.281 p < 0.001), MDS-UPDRS (r = 0.359 p < 0.001), FES-I (r = 0.230 p = 0.002), Mini BESTest (r = -0.256 p = 0.001) and 6MWT (r = -0.166 p = 0.026). No significant correlations were found with SPPB, MOCA and MMSE. CONCLUSION: The NFOG-It is a valuable and reliable tool for assessing FOG symptoms, duration and frequency in PD subjects. Results provide the validity of NFOG-Q-It by reproducing and enlarging previous psychometric data.