Limb Freezing Research Articles

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

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. 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. 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. 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 mechanisms of movement recovery after freezing in Parkinson's disease

Involuntary interruptions of upper limb movements, referred to as “upper limb freezing” (ULF) belong to the most disabling symptoms of Parkinson's disease (PD). Our study aimed to explore the cortical neuronal mechanisms underlying the reinstation of regular movement after a freezing episode and to control them by voluntary stops. We hypothesized that this movement recovery after a freeze would be accompanied by a decrease of beta power (13-30Hz) over the primary sensorimotor cortex (electrode “C3”). We recorded a 62-channel surface EEG in 14 PD patients during a repetitive finger tapping task. After performing time-frequency analysis of the EEG data we segmented it to i) regular finger taps, ii) ULF episodes, and iii) voluntary movement stops (VS). We analysed cortical activity during each movement modality and later focused on the last 500ms of ULF and VS and the first half of the following regular tap. At the beginning of regular finger taps we found decreased alpha power (6-12Hz) over C3 (P = 0.01). During ULF, there was no significant activity modulation in the alpha and beta frequency bands, whereas beta power increased over C3 during VS (P = 0.0038). When tapping was reinstated after a freeze, we found that 100ms before movement onset beta power decreased first present over C3, followed by fronto-central electrodes and then reaching the ipsilateral right fronto-temporal electrodes when reinstating regular tapping (P = 0.0256). Initiating movement after a VS showed a different pattern with a decrease of parieto-occipital beta activity 200ms prior to the first tap (P = 0.044). Our findings suggest that PD freezers make use of different cortical pathways when re-initiating movement after ULF or VS. This includes either fronto-central or parieto-occipital pathways. These findings may help to customize novel neuromodulation strategies to counteract freezing behaviour.

Symmetric and asymmetric bimanual coordination and freezing of gait in Parkinsonian patients in drug phases

Freezing of gait (FOG) is a debilitating symptom in patients with Parkinson's disease (PD), which may be associated with motor control impairments in tasks other than gait. This study aimed to examine whether symmetric and asymmetric bimanual coordination is impaired in PD with FOG (PD +FOG) patients and whether dual-task and drug phases may affect bimanual coordination in these patients. Twenty PD +FOG patients, 20 PD patients without FOG (PD -FOG) performed symmetric and asymmetric functional bimanual tasks (reach to and pick up a box and open a drawer to press a pushbutton inside it, respectively) under single-task and dual-task conditions. PD patients were evaluated during on- and off-drug phases. Kinematic and coordination measures were calculated for each task. PD +FOG patients demonstrated exacerbated impairments of bimanual coordination while performing goal-directed bimanual tasks, which was more evident in the asymmetric bimanual task and under dual-task conditions, highlighting the need for rehabilitation interventions for bimanual tasks that include different cognitive loads in these patients. Interestingly, 25% and 5% of participants in the PD +FOG and -FOG groups developed upper limb freezing 2 years later, respectively. This study aimed to examine whether symmetric and asymmetric bimanual coordination is impaired in Parkinson's disease with freezing of gait (PD +FOG) patients and whether dual-task and drug phases may affect bimanual coordination in these patients. PD +FOG patients demonstrated exacerbated impairment of bimanual coordination while performing goal-directed bimanual tasks, highlighting the need for rehabilitation interventions for bimanual tasks that include different cognitive loads in these patients.

Machine Learning Based Analysis of the Upper Limb Freezing During Handwriting in Parkinson's Disease Patients

Freezing of the upper limb in Parkinson's disease patients occurring during writing tests constitutes the research subject of the present paper. Digitisation of the writing and drawing tests coupled with artificial intelligence techniques have demonstrated accurate results in supporting the diagnostics of Parkinson's disease. In the digital setting, the analysis of freezing episodes did not get much attention. The main goal of the present paper is to determine if the neighbourhood of the point where freezing occurred possesses sufficient discriminating power to distinguish between the Parkinson's disease patients and healthy control individuals. For each freezing episode, time intervals of one second before and after are considered. These intervals are described by the hand movement's kinematic and pressure parameters. These parameters are used as features for the standard machine learning workflow that applies a nested cross-validation loop. The paper's main findings have demonstrated that analysis of the freezing neighbourhoods allows distinguishing Parkinson's disease patients from age matched healthy controls. The best results were achieved based on the movements occurring one second after the freezing episode. Kinematic and pressure-based features describing these movements have allowed training classifiers whose accuracy, precision, and recall have reached the values of 0.86, 0.86 and 0.93, respectively. Furthermore, the achieved results are comparable to those available in the literature

Transitions between repetitive tapping and upper limb freezing show impaired movement-related beta band modulation

ObjectiveFreezing phenomena in idiopathic Parkinson’s disease (PD) constitute an important unaddressed therapeutic need. Changes in cortical neurophysiological signatures may precede a single freezing episode and indicate the evolution of abnormal motor network processes. Here, we hypothesize that the movement-related power modulation in the beta-band observed during regular finger tapping, deteriorates in the transition period before upper limb freezing (ULF). MethodsWe analyzed a 36-channel EEG of 13 patients with PD during self-paced repetitive tapping of the right index finger. In offline analysis, we compared the transition period immediately before ULF (‘transition’) with regular tapping regarding movement-related power modulation and interregional phase synchronization. ResultsFrom time-frequency analyses, we observed that the tap cycle related beta-band power modulation over the left sensorimotor area was diminished in the transition period before ULF. Furthermore, increased beta-band power was observed in the transition period compared to regular tapping centered over the left centro-parietal and right frontal areas. Phase synchronization between the left fronto-parietal areas and the left sensorimotor area was elevated during transition compared to regular tapping. ConclusionTogether, these results indicate that diminished beta band power modulation and increased phase synchronization precede ULF. SignificanceWe demonstrate that pathological cortical motor processing is present in the transition phase from regular tapping to an ULF episode.

P57 Investigating the Role of the Primary Motor Cortex in Upper Limb Freezing

P57 Investigating the Role of the Primary Motor Cortex in Upper Limb Freezing

FV17 Mechanisms of cortical compensation of Upper Limb Freezing in patients with idiopathic Parkinson’s disease

FV17 Mechanisms of cortical compensation of Upper Limb Freezing in patients with idiopathic Parkinson’s disease

Does transcranial direct current stimulation during writing alleviate upper limb freezing in people with Parkinson’s disease? A pilot study

Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) can boost motor performance in Parkinson’s disease (PD) when it is applied at rest. However, the potential supplementary therapeutic effect of the concurrent application of tDCS during the training of motor tasks is largely unknown. The present study examined the effects of tDCS on upper limb motor blocks during a freezing-provoking writing task (the funnel task) requiring up- and down-stroke movements at alternating amplitudes. Ten PD patients and 10 age-matched controls underwent two sessions of writing combined with 20 min of anodal or sham tDCS on the left M1 in a randomized cross-over design. The primary outcome was the number of upper limb freezing episodes during five trials of the funnel task on a touch-sensitive tablet. PD patients showed a significant reduction in freezing episodes during tDCS compared to sham. No effects of tDCS were found for the amplitude, variability and speed of the strokes outside the freezing episodes. However, patients who reported freezing episodes in daily life (N = 6) showed a beneficial effect of tDCS on stroke characteristics. These results indicate a subgroup-dependent variability in response to non-invasive brain stimulation applied during the performance of motor tasks in PD. This warrants future studies to examine tDCS as an adjuvant tool for training programs aimed to reduce motor deficits related to freezing.

Abstract: Directional Freezing and Vitrification of Whole Limbs for Future Transplantation and Organ Banking

INTRODUCTION: According to the World Health Organisation, less than 10% of humanities needs for transplantable organs are being met. No data is available for vascularized composite tissue allotransplantations (VCA), yet these cases are further complicated by the need for an instantly available and compatible recipient. VCA containing skin, fat, blood vessels, bone, bone marrow and nerve are the ultimate tool available to date in reconstructive surgery. Widespread use of this tool is hindered in part by the availability of limbs which can survive a limited amount of time disconnected from the body. Cryobiology is the scientific field which investigates biology at low temperatures. Cryobiologists have long sought to cryopreserve biological samples ranging from single cells to complex organs and whole animals. Vitrification is the transformation of a substance into a non-crystalline amorphous solid using rapid heat removal. Directional freezing is a technique, consisting of highly controlled and cell-friendly ice crystal morphology that significantly reduces mechanical damage. Extremely efficient heat removal and controlled ice crystal propagation make it suitable for freezing both small and large volumes alike. Combining Directional freezing and VCA may open the door for “Organ Banking”. If composite tissue could be frozen and then thawed without damage, non transplanted tissue and organ waste would be reduced, potentially enabling better donor and recipient availability and match. METHODS: We used directional freezing and vitrification on a syngeneic heterotrophic rat hindlimb transplant model and monitored the animals and transplanted limbs for up to 72 hours. Cell and tissue samples were taken for culture and histology. RESULTS: Immediately upon thawing the donor hindlimb blood vessels and tissue felt similar to the recipient’s. Following revascularization reperfusion was clinically evident by color and bleeding from distal sites to the anastomosis. Limb survival was noted up to 72 hours post op. Tissue samples including muscle, skin and blood vessels where taken at 24, 48 and 72 hours from transplantation. Histology demonstrated viable myocytes, intact intimal lining of blood vessels and all skin layers. CONCLUSION: Whole limb freezing and reimplantation using directional freezing and vitrification is feasible in small animal models. Based on our current achievements we intend to develop protocols for limb cryopreservation in large animals, aiming to advance the field of cryobiology towards the ambitious goal of human organ banking.

Cortical correlates of susceptibility to upper limb freezing in Parkinson's disease.

Freezing behavior is an unmet symptom in Parkinson's disease (PD), which reflects its complex pathophysiology. Freezing behavior can emerge when attentional capacity is reduced, i.e. under dual task interference. In this study, we characterized the cortical network signatures underlying the susceptibility to freezing during continuous finger tapping. Fourteen PD patients with STN-DBS and thirteen age- and gender-matched healthy controls performed continuous tapping with the index finger as single motor task and during dual tasking. Synchronized EEG and mechanogram of the finger tapping were recorded. Subsequently, we analyzed cortical activity and cortico-cortical phase synchronization. We correlated these spectral measures with the biomechanically confirmed numbers of freezing episodes during finger tapping. During dual tasking compared to the single motor task, PD patients showed an increase of cortico-cortical phase synchronization over the left prefrontal area from 13 to 30Hz. This correlated with increased occurrence of freezing episodes. Interestingly, PD patients lacked the increase of prefrontal cortico-cortical synchronization from 4 to 7Hz during dual tasking as observed in healthy controls. Dual task interference led to an increase of left prefrontal beta band synchronization (13-30Hz) in PD and this increment predicted the number of freezing episodes. This increment may underscore the relevance of prefrontal executive dysfunction in freezing susceptibility. These findings enhance our understanding of the pathological network mechanisms behind increased susceptibility to freezing behavior.

Amplitude Manipulation Evokes Upper Limb Freezing during Handwriting in Patients with Parkinson's Disease with Freezing of Gait.

BackgroundRecent studies show that besides freezing of gait (FOG), many people with Parkinson’s disease (PD) also suffer from freezing in the upper limbs (FOUL). Up to now, it is unclear which task constraints provoke and explain upper limb freezing.ObjectiveTo investigate whether upper limb freezing and other kinematic abnormalities during writing are provoked by (i) gradual changes in amplitude or by (ii) sustained amplitude generation in patients with and without freezing of gait.MethodsThirty-four patients with PD, including 17 with and 17 without FOG, performed a writing task on a touch-sensitive writing tablet requiring writing at constant small and large size as well as writing at gradually increasing and decreasing size. Patients of both groups were matched for disease severity, tested while ‘on’ medication and compared to healthy age-matched controls.ResultsFifty upper limb freezing episodes were detected in 10 patients, including 8 with and 2 without FOG. The majority of the episodes occurred when participants had to write at small or gradually decreasing size. The occurrence of FOUL and the number of FOUL episodes per patient significantly correlated with the occurrence and severity of FOG. Patients with FOUL also showed a significantly smaller amplitude in the writing parts outside the freezing episodes.ConclusionsCorroborating findings of gait research, the current study supports a core problem in amplitude control underlying FOUL, both in maintaining as well as in flexibly adapting the cycle size.

Neuromuscular correlates of subthalamic stimulation and upper limb freezing in Parkinson’s disease

ObjectiveThe pathophysiology of deep brain stimulation mechanisms and resistant freezing phenomena in idiopathic Parkinson’s disease (iPD) remains incompletely understood. Further studies on the neuromuscular substrates are needed. MethodsWe analyzed 16 patients with advanced iPD and bilateral subthalamic nucleus stimulation, and 13 age- and gender-matched healthy controls. Patients were tested after overnight withdrawal of medication with ‘stimulation off’ (StimOff) and ‘stimulation on’ (StimOn). Subjects performed continuous tapping of the right index finger with simultaneous recordings of biomechanical registration, EMG of finger flexors and extensors, and EEG. First, we analyzed EEG and EMG spectral measures comparing StimOff with healthy controls and StimOff with StimOn (irrespective of freezing). Second, we contrasted ‘regular (unimpaired) tapping’ and ‘freezing’ resistant to subthalamic neurostimulation as obtained in StimOn. ResultsiPD showed increased intermuscular coherence around 8Hz in StimOff that was reduced in StimOn. This 8Hz muscular activity was not coherent to cortical activity. ‘Freezing’ episodes showed increased muscle activity of finger flexors and extensors at 6–9Hz, and increased cortical activity at 7–11Hz. During transition from regular tapping to ‘freezing’ the cortical activity first increased over the left sensorimotor area followed by a spread to the left frontal and right parietal areas. ConclusionsWe identified neuromuscular motor network features of subthalamic neurostimulation therapy and resistant upper limb freezing that point to increased low-frequency muscular and cortical activity. SignificanceTogether, our findings demonstrate several motor network abnormalities associated with upper limb freezing that may translate into future research on freezing of gait in iPD.

The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD).

Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion-extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large amount of ULMB were observed when initiating anti-phase coordination at 2 Hz, as well as after both externally-cued switches and in 'catch trials' with distracting auditory cues when no switch was required. Dopamine replacement was not found to influence the frequency of ULMB in either experiment. Therefore, ULMB likely result from non-hypodopaminergic impairments associated with PD. Specifically, ULMB may be caused by an inability to shift attentional control under increased cognitive demand that could be associated with hypoactivation in motor and prefrontal areas.

Gait and upper limb variability in Parkinson’s disease patients with and without freezing of gait

Patients with Parkinson's disease (PD) and freezing of gait (FOG) (freezers) demonstrate high gait variability. The objective of this study was to determine whether freezers display a higher variability of upper limb movements and elucidate if these changes correlate with gait. We were the first group to compare directly objectively measured gait and upper limb movement variability of freezers between freezing episodes. Patients with objectively verified FOG (n=11) and PD patients without FOG (non-freezers) (n=11) in a non-randomized medication condition (OFF/ON) were analyzed. Uncued antiphasic finger tapping and forearm diadochokinetic movements were analyzed via three-dimensional ultrasound kinematic measurements. Gait variability of straight gait was assessed using ground reaction forces. Freezers had shorter stride length (p=0.004) and higher stride length variability (p=0.005) in the medication OFF condition. Movement variability was not different during finger tapping or diadochokinesia between the groups. There was a trend towards more freezing of the upper limb during finger tapping for the freezers (p=0.07). Variability in stride length generation and stride timing was not associated with variability of upper limb movement in freezers. Our findings demonstrate that: (1) freezers have a higher spatial gait variability between freezing episodes; (2) freezing-like episodes of the upper limb occur in PD patients, and tend to be more pronounced among freezers than non-freezers for finger tapping; (3) spatial and temporal upper extremity variability is equally affected in freezers and non-freezers in an uncued task. Upper limb freezing is not correlated to lower limb freezing, implicating a different pathophysiology.

Freezing in Parkinson's disease: A spatiotemporal motor disorder beyond gait

Freezing of gait (FOG) is an incapacitating problem in Parkinson's disease that is difficult to manage therapeutically. We tested the hypothesis that impaired rhythm and amplitude control is a common mechanism of freezing which is also present during other rhythmic tasks. Therefore, we compared the occurrence and spatiotemporal profiles of freezing episodes during upper limb motion, lower limb motion, and FOG. Eleven freezers, 12 non-freezers, and 11 controls performed a rhythmic bilateral finger movement task. The triggering effect of movement speed, amplitude, and coordination pattern was evaluated. Regression slopes and spectral analysis addressed the spatial and temporal kinematic changes inherent to freezing episodes. The FOG Questionnaire score significantly predicted severity of upper limb freezing, present in 9 freezers, and of foot freezing, present in 8 freezers. Similar to gait, small-amplitude movements tended to trigger upper limb freezing, which was preceded by hastened movement and a strong amplitude breakdown. Upper limb freezing power spectra were broadband, including increased energy in the "freeze band" (3-8 Hz). Contrary to FOG, unilateral upper limb freezing was common and occurred mainly on the disease-dominant side. The findings emphasize that a core motor problem underlies freezing which can affect various movement effectors. This deficit may originate on the disease-dominant body side and interfere with amplitude and timing regulation during repetitive limb movements. These results may shift current thinking on the origins of freezing as being not exclusively a gait failure.