Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Background Freezing of gait(FOG)is a common,disabling symptom of Parkinson’s disease(PD),but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers.The main focus of this review is to summarize the possible mechanisms underlying FOG,the risk factors for screening and predicting the onset of FOG,and the clinical trials involving various therapeutic strategies.In addition,the limitations and recommendations for future research design are also discussed.Main body In the mechanism section,we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG.In the risk factor section,gait disorders,PIGD phenotype,lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence.In the treatment section,we summarized the clinical trials of pharmacological and non-pharmacological treatments.Despite the limited effectiveness of current medications for FOG,especially levodopa resistant FOG,there were some drugs that showed promise such as istradefylline and rasagiline.Non-pharmacological treatments encompass invasive brain and spinal cord stimulation,noninvasive repetitive transcranial magnetic stimulation(rTMS)or transcranial direct current stimulation(tDCS)and vagus nerve stimulation(VNS),and physiotherapeutic approaches including cues and other training strategies.Several novel therapeutic strategies seem to be effective,such as rTMS over supplementary motor area(SMA),dual-site DBS,spinal cord stimulation(SCS)and VNS.Of physiotherapy,wearable cueing devices seem to be generally effective and promising.Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration.Several risk factors of FOG have been identified,but need combinatorial optimization for predicting FOG more precisely.Although firm conclusions cannot be drawn on therapeutic efficacy,the literature suggested that some therapeutic strategies showed promise.

Effect of low versus high frequency stimulation on freezing of gait and other axial symptoms in Parkinson patients with bilateral STN DBS:a mini-review

Some studies have shown that low frequency stimulation(LFS,most commonly 60 Hz),compared to high frequency stimulation(HFS,most commonly 130 Hz),has beneficial effects,short-term or even long-term,on improving freezing of gait(FOG)and other axial symptoms,including speech and swallowing function,in Parkinson disease(PD)patients with bilateral subthalamic nucleus deep brain stimulation(STN DBS).However,other studies failed to confirm this.It seems not clear what determines the difference in response to LFS.Differences in study design,such as presence or absence of FOG,exact LFS used(60 Hz versus 80 Hz),study size,open label versus randomized double blind assessment,retrospective versus prospective evaluation,medication On or Off state,total electric energy delivered maintained or not with the change in frequency,and the location of active contacts could all potentially affect the results.This mini-review goes over the literature with the aforementioned factors in mind,focusing on the effect of LFS versus HFS on FOG and other axial symptoms in PD with bilateral STN DBS,in an effort to extract the essential data to guide our clinical management of axial symptoms and explore the potential underlying mechanisms as well.Overall,LFS of 60 Hz seems to be consistently effective in patients with FOG at the usual HFS in regards to improving FOG,speech,swallowing function and other axial symptoms,though LFS could reduce tremor control in some patients.Whether LFS simply addresses the axial symptoms in the context of HFS or has other beneficial effects requires further studies,along with the mechanism.

Pilot study of atomoxetine in patients with Parkinson’s disease and dopa-unresponsive Freezing of Gait

Background:Freezing of gait(FoG)is a common and debilitating condition in Parkinson’s disease(PD)associated with executive dysfunction.A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency.This pilot study explores the effects of atomoxetine on gait in PD patients with dopaunresponsive FoG using a novel paradigm for objective gait assessment.Findings:Ten patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study.Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning,while performing a dual task.Clinical,and subjective assessments of gait,quality of life,and safety were also administered.The primary outcome was a validated subjective assessment for FoG(FOG-Q).Atomoxetine was well tolerated,however,no significant change was observed in the primary outcome.The gait analysis protocol correlated well with clinical scales,but not with subjective assessments.DBS patients were more likely to increase gait velocity(p=0.033),and improved in other clinical assessments.Conclusions:Objective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population,and may be superior correlates of FoG severity than subjective measures.These findings can inform future trials in this population.

Stepping up to meet the challenge of freezing of gait in Parkinson’s disease

There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.

Attention-Based Deep Learning Model for Early Detection of Parkinson’s Disease

Parkinson’s disease(PD),classified under the category of a neurological syndrome,affects the brain of a person which leads to the motor and non-motor symptoms.Among motor symptoms,one of the major disabling symptom is Freezing of Gait(FoG)that affects the daily standard of living of PD patients.Available treatments target to improve the symptoms of PD.Detection of PD at the early stages is an arduous task due to being indistinguishable from a healthy individual.This work proposed a novel attention-basedmodel for the detection of FoG events and PD,andmeasuring the intensity of PD on the United Parkinson’s Disease Rating Scale.Two separate datasets,that is,UCF Daphnet dataset for detection of Freezing of Gait Events and PhysioNet Gait in PD Dataset were used for training and validating on their respective problems.The results show a definite rise in the various performance metrics when compared to landmark models on these problems using these datasets.These results strongly suggest that the proposed state of the art attention-based deep learning model provide a consistent as well as an efficient solution to the selected problem.High valueswere obtained for various performance metrics like accuracy of 98.74%for detection FoG,98.72%for detection of PD and 98.05%for measuring the intensity of PD on UPDRS.The model was also analyzed for robustness against noisy samples,where also model exhibited consistent performance.These results strongly suggest that the proposed model provides a better classification method for selected problem.

Modulating arousal to overcome gait impairments in Parkinson’s disease:how the noradrenergic system may act as a double-edged sword

In stressful or anxiety-provoking situations,most people with Parkinson’s disease(PD)experience a general worsening of motor symptoms,including their gait impairments.However,a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations.Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight(USA)and ParkinsonNEXT(NL)cohorts,we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment.Crucially,these strategies differ along an axis of arousal-some act to heighten,whereas others diminish,overall sympathetic tone.Together,our observations suggest that arousal may act as a double-edged sword for gait control in PD.We propose a theoretical,neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals,while alleviating them in others.Specifically,we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system:namely,that arousal is related to task performance by an inverted u-shaped curve(the so-called Yerkes and Dodson relationship).We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression,by regulating arousal and by mediating network-level functional integration across the brain.The ability of the locus coeruleus to facilitate dynamic‘cross-talk’between distinct,otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD.In the presence of suboptimal arousal,compensatory networks may be too segregated to allow for adequate compensation.Conversely,with supraoptimal arousal,increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional.Because the locus coeruleus degenerates with disease progression,finetuning of this delicate balance becomes increasingly difficult,heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub-or supraoptimal state of arousal to improve gait performance.Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

Idiopathic Basal Ganglia Calcification Presented with Progressive Supranuclear Palsy-like Features

Fahr＇s disease, or idiopathic basal ganglia calcification （IBGC）, is a rare neurological syndrome characterized by abnormal calcified deposits located mostly in bilateral basal ganglia and dentate nucleus, and also in cerebral cortex, thalamus, hippocampus, cerebellar, and subcortical white matter. Clinically, it presents various symptoms, including parkinsonism （presented in 57% of the patientsL chorea （ 19%）, tremors （8%）, dystonia （8%）, athetosis （5%）~ and orofacial dyskinesia （3%）.