Jorik Nonnekes

Freezing of gait: a practical approach to management

Freezing of gait is a common and disabling symptom in patients with parkinsonism, characterised by sudden and brief episodes of inability to produce effective forward stepping. These episodes typically occur during gait initiation or turning. Treatment is important because freezing of gait is a major risk factor for falls in parkinsonism, and a source of disability to patients. Various treatment approaches exist, including pharmacological and surgical options, as well as physiotherapy and occupational therapy, but evidence is inconclusive for many approaches, and clear treatment protocols are not available. To address this gap, we review medical and non-medical treatment strategies for freezing of gait and present a practical algorithm for the management of this disorder, based on a combination of evidence, when available, and clinical experience of the authors. Further research is needed to formally establish the merits of our proposed treatment protocol.

Are postural responses to backward and forward perturbations processed by different neural circuits

Startle pathways may contribute to rapid accomplishment of postural stability. Here we investigate the possible influence of a startling auditory stimulus (SAS) on postural responses. We formulated four specific questions: (1) can a concurrent SAS shorten the onset of automatic postural responses?; and if so (2) is this effect different for forward versus backward perturbations?; (3) does this effect depend on prior knowledge of the perturbation direction?; and (4) is this effect different for low- and high-magnitude perturbations? Balance was perturbed in 11 healthy participants by a movable platform that suddenly translated forward or backward. Each participant received 160 perturbations, 25% of which were combined with a SAS. We varied the direction and magnitude of the perturbations, as well as the prior knowledge of perturbation direction. Perturbation trials were interspersed with SAS-only trials. The SAS accelerated and strengthened postural responses with clear functional benefits (better balance control), but this was only true for responses that protected against falling backwards (i.e. in tibialis anterior and rectus femoris). These muscles also demonstrated the most common SAS-triggered responses without perturbation. Increasing the perturbation magnitude accelerated postural responses, but again with a larger acceleration for backward perturbations. We conclude that postural responses to backward and forward perturbations may be processed by different neural circuits, with influence of startle pathways on postural responses to backward perturbations. These findings give directions for future studies investigating whether deficits in startle pathways may explain the prominent backward instability seen in patients with Parkinsons disease and progressive supranuclear palsy.

StartReact Restores Reaction Time in HSP: Evidence for Subcortical Release of a Motor Program

Startling acoustic stimuli (SAS) can accelerate reaction times (“StartReact” effect), but the underlying mechanism remains unclear. Both direct release of a subcortically stored motor program and a subcortically mediated trigger for a cortically stored motor program have been hypothesized. To distinguish between these hypotheses, we examined the StartReact effect in humans with pure hereditary spastic paraplegia (HSP). Delayed reaction times in HSP patients in trials both with and without a SAS would argue in favor of a cortically stored response. We instructed 12 HSP patients and 12 matched controls to respond as rapidly as possible to a visual imperative stimulus, in two different conditions: dorsiflexion of the dominant ankle; or flexion of the dominant wrist. In 25% of trials, a SAS was delivered simultaneously with the imperative stimulus. Before these tests, subjects received five SAS while standing to verify normal function of the reticulospinal tract in HSP. Latencies of startle responses in sternocleidomastoid and tibialis anterior muscles were comparable between patients and controls. During the ankle dorsiflexion task, HSP patients had an average 19 ms delay in reaction times compared with controls. Administration of a SAS accelerated ankle dorsiflexion in both groups, but more so in the patients, which completely normalized their latencies. The wrist flexion task yielded no differences in onset latencies between HSP patients and controls. The reticulospinal tract seems unaffected in HSP patients, because startle reflex onsets were normal. The corticospinal tract was affected, as reflected by delayed ankle dorsiflexion reaction times. These delayed onsets in HSP were normalized when the imperative stimulus was combined with a SAS, presumably through release of a subcortically stored motor program conveyed by the preserved reticulospinal tract.

Neurorehabilitation for Parkinson's disease: Future perspectives for behavioural adaptation

Parkinsons disease is a common neurodegenerative disorder, resulting in both motor and non-motor symptoms that significantly reduce quality of life. Treatment consists of both pharmaceutical and non-pharmaceutical treatment approaches. Neurorehabilitation is an important non-pharmaceutical treatment approach, and a prime component of this is formed by the training of behavioural adaptations that can assist patients to cope better with their motor and non-motor symptoms. Optimal delivery of neurorehabilitation requires a tailor-made, personalized approach. In this review we discuss the great potential for growth in the field of neurorehabilitation. Specifically, we will focus on four relatively new developments: visual rehabilitation (because Parkinson patients are very dependent on optimal vision); cueing delivered by wearable devices (allowing for objective, continuous, and quantitative detection of mobility problems, such that cueing can be delivered effectively in an on-demand manner - i.e., with external cues being delivered only at a time when they are needed most); exergaming (to promote compliance with exercise programs); and telemedicine (allowing for delivery of expert rehabilitation advice to the patients own home). Evidence in these new fields is growing, based on good clinical trials, fuelling hope that state-of-the-art neurorehabilitation can make a real impact on improving the quality of life of patients affected by Parkinsons disease.

What startles tell us about control of posture and gait

Recently, there has been an increase in studies evaluating startle reflexes and StartReact, many in tasks involving postural control and gait. These studies have provided important new insights. First, several experiments indicate a superimposition of startle reflex activity on the postural response during unexpected balance perturbations. Overlap in the expression of startle reflexes and postural responses emphasizes the possibility of, at least partly, a common substrate for these two types of behavior. Second, it is recognized that the range of behaviors, susceptible to StartReact, has expanded considerably. Originally this work was concentrated on simple voluntary ballistic movements, but gait initiation, online step adjustments and postural responses can be initiated earlier by a startling stimulus as well, indicating advanced motor preparation of posture and gait. Third, recent experiments on StartReact using TMS and patients with corticospinal lesions suggest that this motor preparation involves a close interaction between cortical and subcortical structures. In this review, we provide a comprehensive overview on startle reflexes, StartReact, and their interaction with posture and gait.

Subcortical Structures in Humans Can Be Facilitated by Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability. Interestingly, in recent animal studies facilitatory effects of tDCS have also been observed on subcortical structures. Here, we sought to provide evidence for the potential of tDCS to facilitate subcortical structures in humans as well. Subjects received anodal-tDCS and sham-tDCS on two separate testing days in a counterbalanced order. After stimulation, we assessed the effect of tDCS on two responses that arise from subcortical structures; (1) wrist and ankle responses to an imperative stimulus combined with a startling acoustic stimulus (SAS), and (2) automatic postural responses to external balance perturbations with and without a concurrent SAS. During all tasks, response onsets were significantly faster following anodal-tDCS compared to sham-tDCS, both in trials with and without a SAS. The effect of tDCS was similar for the dominant and non-dominant leg. The SAS accelerated the onsets of ankle and wrist movements and the responses to backward, but not forward perturbations. The faster onsets of SAS-induced wrist and ankle movements and automatic postural responses following stimulation provide strong evidence that, in humans, subcortical structures - in particular the reticular formation - can be facilitated by tDCS. This effect may be explained by two mechanisms that are not mutually exclusive. First, subcortical facilitation may have resulted from enhanced cortico-reticular drive. Second, the applied current may have directly stimulated the reticular formation. Strengthening reticulospinal output by tDCS may be of interest to neurorehabilitation, as there is evidence for reticulospinal compensation after corticospinal lesions.

Deficits Underlying Impaired Visually Triggered Step Adjustments in Mildly Affected Stroke Patients

Background. The ability to make step adjustments while walking is often impaired following a stroke, but the basic sensorimotor control deficits responsible have not been established. Objective. To identify these deficits in Patients who have recovered from stroke leaving only mild lower limb impairment. Methods. Ten stroke and 10 age-matched control patients stepped onto an illuminated rectangle. In 40% of trials it jumped 140 mm either medially or laterally when the stepping foot left the ground, thus provoking a mid-step adjustment. In a separate block, patients performed the same task but with the body supported by a frame to eliminate balance responses. Results. Irrespective of support condition stroke patients produced short-latency foot trajectory adjustments compatible with a fast-acting, possibly subcortical, visuomotor process. However, the latency was slightly but significantly longer for the contralesional leg (148 ms) than the ipsilesional leg (141 ms) and longer than for controls (129 ms). Stroke patients’ foot adjustments were executed slower and undershot the target more than controls. These deficits were most pronounced in the medial direction when the body was unsupported. The pattern of undershooting was the same for ipsilesional and contralesional legs. Conclusions. Mildly impaired stroke patients have deficits in initiating and executing visually triggered step adjustments but more profound difficulties with balance control during the adjustment, which caused them to suppress mid-step adjustments of foot placement in the medial direction where balance demands were greatest. Paradoxically, such suppression outside the laboratory may also threaten balance if it leads to unsafe foot placement or obstacle collision.

Unraveling the mechanisms underlying postural instability in Parkinson’s disease using dynamic posturography

Postural instability, one of the cardinal symptoms of Parkinson’s disease (PD), has devastating consequences for affected patients. Better strategies to prevent falls are needed, but this calls for an improved understanding of the complex mechanisms underlying postural instability. We must also improve our ability to timely identify patients at risk of falling. Dynamic posturography is a promising avenue to achieve these goals. The latest moveable platforms can deliver ‘real-life’ balance perturbations, permitting study of everyday fall circumstances. Dynamic posturography studies have shown that PD patients have fundamental problems in scaling their postural responses in accordance with the need of the actual balance task at hand. On-going studies evaluate the predictive ability of impaired posturography performance for daily life falls. We also review recent work aimed at exploring balance correcting steps in PD, and the presumed interaction between startle pathways and postural responses.

StartReact effects support different pathophysiological mechanisms underlying freezing of gait and postural instability in Parkinson's disease.

Introduction The pathophysiology underlying postural instability in Parkinson’s disease is poorly understood. The frequent co-existence with freezing of gait raises the possibility of shared pathophysiology. There is evidence that dysfunction of brainstem structures contribute to freezing of gait. Here, we evaluated whether dysfunction of these structures contributes to postural instability as well. Brainstem function was assessed by studying the StartReact effect (acceleration of latencies by a startling acoustic stimulus (SAS)). Methods We included 25 patients, divided in two different ways: 1) those with postural instability (HY = 3, n = 11) versus those without (HY<3, n = 14); and 2) those with freezing (n = 11) versus those without freezing (n = 14). We also tested 15 matched healthy controls. We tested postural responses by translating a balance platform in the forward direction, resulting in backward balance perturbations. In 25% of trials, the start of the balance perturbation was accompanied by a SAS. Results The amplitude of automatic postural responses and length of the first balance correcting step were smaller in patients with postural instability compared to patients without postural instability, but did not differ between freezers and non-freezers. In contrast, the StartReact effect was intact in patients with postural instability but was attenuated in freezers. Discussion We suggest that the mechanisms underlying freezing of gait and postural instability in Parkinson’s disease are at least partly different. Underscaling of automatic postural responses and balance-correcting steps both contribute to postural instability. The attenuated StartReact effect was seen only in freezers and likely reflects inadequate representation of motor programs at upper brainstem level.

Unmasking levodopa resistance in Parkinson's disease

Some motor and nonmotor features associated with Parkinsons disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine‐sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose‐limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several nonmotor features (eg, specific cognitive functions), the response to levodopa is fairly complex, with a combination of levodopa‐responsive, levodopa‐resistant, and even levodopa‐induced characteristics. A possible explanation relates to the mixed presence of underlying dopaminergic and nondopaminergic brain lesions. We suggest that clinicians take these possibilities into account before concluding that symptoms or signs of PD are totally levodopa resistant.