Anxiety provokes balance deficits that are selectively dopa-responsive in Parkinson's disease.

Previous research has suggested that balance impairments may be linked to anxiety in PD, yet there is little empirical evidence to support this link in PD. This study aimed to evaluate the influence of anxiety on balance, and also examine whether dopaminergic treatment modulates the influence of anxiety on balance. Forty-two participants (10 high anxious PD [HA-PD]; 11 low anxious PD [LA-PD], 21 controls [HC]) performed 10 quiet standing trials on a force platform in two virtual environments: LOW threat; on a plank located on the ground; HIGH threat; on an elevated plank. After each 30-s trial, participants rated their anxiety. PD participants were tested both ON and OFF dopaminergic medication, and center of gravity (COG) deviations in anterior-posterior (AP) and medio-lateral (ML) directions were recorded. Results showed that all groups reported significantly greater levels of anxiety when standing in the HIGH condition compared to the LOW and HA-PD reported greater levels of anxiety compared to both other groups. All participants significantly reduced their COG position to be closer to center in the ML plane during the HIGH compared to LOW threat condition. HA-PD participants were the only group to reduce their lean significantly in the AP plane while standing in the HIGH compared to the LOW condition. HA-PD participants also had significantly greater variability in the COG displacement in both the AP and ML planes compared to LA-PD participants. Although dopaminergic medication significantly reduced self-reported anxiety, it had limited effects on balance. In conclusion, this study provides strong evidence that anxiety does influence balance control in PD, especially those who are highly anxious. Dopamine appears to modulate anxiety, but further research is needed to evaluate whether dopaminergic treatment is optimal for anxiety induced balance deficits.

Evaluating the Link Between Dopaminergic Treatment, Gait Impairment, and Anxiety in Parkinson's Disease.

BACKGROUND: Anxiety is the most under-recognized nonmotor symptom of Parkinson's disease (PD), yet it is unclear whether motor impairment exacerbates anxiety observed in PD, or vice versa. The current study examined: (1) whether movement (i.e., walking vs. standing) elevates distress in PD; (2) how dopaminergic treatment influences anxiety specifically while walking; and (3) whether these responses are worse in PD patients with gait impairments (compared to those without). METHODS: Twenty healthy control participants (HC), 17 PD participants without gait impairments (PD-GI), and 14 PD participants with gait impairments (PD+GI) performed two tasks (stand vs. walk) in two virtual environments: (1) LOW threat; (2) HIGH threat. This protocol was completed in on and off dopaminergic states (to evaluate the effect of exacerbating motor symptoms). RESULTS: PD+GI reported greater levels of anxiety compared to PD-GI and HC overall. All participants reported greater levels of anxiety and had higher skin conductance levels (SCLs) when walking compared to standing. The HIGH threat condition also generated greater levels of anxiety in all participants, compared to LOW threat, especially when required to walk. Notably, only PD+GI reported greater levels of anxiety when walking compared to standing in the LOW threat environment. Dopaminergic medication reduced self-reported levels of anxiety, but did not significantly change SCL. CONCLUSION: This study provides evidence that movement exacerbates anxiety in all older adults, but is particularly influential in those with gait impairments, which emphasizes the importance of optimally treating movement impairments as a method of reducing movement driven anxiety.

Virtually-induced threat in Parkinson's: Dopaminergic interactions between anxiety and sensory-perceptual processing while walking.

Research evidence has suggested that anxiety influences gait in PD, with an identified dopa-sensitive gait response in highly anxious PD. It has been well-established that accurate perception of the environment and sensory feedback is essential for gait. Arguably since sensory and perceptual deficits have been noted in PD, anxiety has the potential to exacerbate movement impairments, since one might expect that reducing resources needed to overcome or compensate for sensory-perceptual deficits may lead to even more severe gait impairments. It is possible that anxiety in threatening situations might consume more processing resources, limiting the ability to process information about the environment or one's own movement (sensory feedback) especially in highly anxious PD. Therefore, the current study aimed to (i) evaluate whether processing of threat-related aspects of the environment was influenced by anxiety, (ii) evaluate whether anxiety influences the ability to utilize sensory feedback in PD while walking in threatening situations, and (iii) further understand the role of dopaminergic medication on these processes in threatening situations in PD. Forty-eight participants (24 HC; 12 Low Anxious [LA-PD], 12 Highly Anxious [HA-PD]) completed 20 walking trials in virtual reality across a plank that was (i) located on the ground (GROUND) (ii) located above a deep pit (ELEVATED); while provided with or without visual feedback about their lower limbs (+VF; -VF). After walking across the plank, participants were asked to judge the width of the plank they had just walked across. The plank varied in size from 60-100 cm. Both ON and OFF dopaminergic medication states were evaluated in PD. Gait parameters, judgment error and self-reported anxiety levels were measured. Results showed that HA-PD reported greater levels of anxiety overall (p<0.001) compared to HC and LA-PD, and all participants reported greater anxiety during the ELEVATED condition compared to GROUND (p=0.01). PD had similar judgment error as HC. Additionally, medication state did not significantly influence judgment error in PD. More importantly, HA-PD were the only group that did not adjust their step width when feedback was provided during the GROUND condition. However, medication facilitated a reduction in ST-CV when visual feedback was available only in the HA-PD group. Therefore, the current study provides evidence that anxiety may interfere with information processing, especially utilizing sensory feedback while walking. Dopaminergic medication appears to improve utilization of sensory feedback in stressful situations by reducing anxiety and/or improving resource allocation especially in those with PD who are highly anxious.

Anxiety-provoked gait changes are selectively dopa-responsive in Parkinson's disease.

In order to understand how dopamine modulates the effect of anxiety on gait, the goal of this study was to use virtual reality to provoke anxiety in Parkinson's disease (PD) (in both ON and OFF states) and quantify its effect on gait. Seventeen participants with PD and 20 healthy age-matched controls were instructed to walk in a virtual environment in two anxiety-provoking conditions: (i) across a plank that was located on the GROUND and (ii) across an ELEVATED plank. All participants with PD completed this experiment in both the ON and OFF states, and were then striated into groups based on baseline trait anxiety scores for further analyses. Anxiety (skin conductance and self-report) and spatiotemporal aspects of gait were measured. Overall, the ELEVATED condition resulted in greater skin conductance levels and self-reported anxiety levels. Additionally, all participants demonstrated slower gait with increased step-to-step variability when crossing the ELEVATED plank compared with the plank on the GROUND. The results showed that dopaminergic treatment selectively improved gait in only the highly anxious PD group, by significantly improving velocity, step length, step time and step-to-step variability specifically when walking across the ELEVATED plank (ON vs. OFF comparison). In conclusion, only highly trait anxious participants with PD benefitted from dopaminergic treatment, specifically when walking in the anxiety-provoking environment. Improvements to gait during anxious walking might be a result of dopaminergic medication acting in two ways: (i) improving the basal ganglia's capacity to process information and (ii) reducing the load from anxiety and subsequently making more resources available to effectively process other competing inputs.

Does manipulating the speed of visual flow in virtual reality change distance estimation while walking in Parkinson's disease?

Although dopaminergic replacement therapy is believed to improve sensory processing in PD, while delayed perceptual speed is thought to be caused by a predominantly cholinergic deficit, it is unclear whether sensory-perceptual deficits are a result of corrupt sensory processing, or a delay in updating perceived feedback during movement. The current study aimed to examine these two hypotheses by manipulating visual flow speed and dopaminergic medication to examine which influenced distance estimation in PD. Fourteen PD and sixteen HC participants were instructed to estimate the distance of a remembered target by walking to the position the target formerly occupied. This task was completed in virtual reality in order to manipulate the visual flow (VF) speed in real time. Three conditions were carried out: (1) BASELINE: VF speed was equal to participants' real-time movement speed; (2) SLOW: VF speed was reduced by 50 %; (2) FAST: VF speed was increased by 30 %. Individuals with PD performed the experiment in their ON and OFF state. PD demonstrated significantly greater judgement error during BASELINE and FAST conditions compared to HC, although PD did not improve their judgement error during the SLOW condition. Additionally, PD had greater variable error during baseline compared to HC; however, during the SLOW conditions, PD had significantly less variable error compared to baseline and similar variable error to HC participants. Overall, dopaminergic medication did not significantly influence judgement error. Therefore, these results suggest that corrupt processing of sensory information is the main contributor to sensory-perceptual deficits during movement in PD rather than delayed updating of sensory feedback.

Does anxiety cause freezing of gait in Parkinson's disease?

Individuals with Parkinson's disease (PD) commonly experience freezing of gait under time constraints, in narrow spaces, and in the dark. One commonality between these different situations is that they may all provoke anxiety, yet anxiety has never been directly examined as a cause of FOG. In this study, virtual reality was used to induce anxiety and evaluate whether it directly causes FOG. Fourteen patients with PD and freezing of gait (Freezers) and 17 PD without freezing of gait (Non-Freezers) were instructed to walk in two virtual environments: (i) across a plank that was located on the ground (LOW), (ii) across a plank above a deep pit (HIGH). Multiple synchronized motion capture cameras updated participants' movement through the virtual environment in real-time, while their gait was recorded. Anxiety levels were evaluated after each trial using self-assessment manikins. Freezers performed the experiment on two separate occasions (in their ON and OFF state). Freezers reported higher levels of anxiety compared to Non-Freezers (p < 0.001) and all patients reported greater levels of anxiety when walking across the HIGH plank compared to the LOW (p < 0.001). Freezers experienced significantly more freezing of gait episodes (p = 0.013) and spent a significantly greater percentage of each trial frozen (p = 0.005) when crossing the HIGH plank. This finding was even more pronounced when comparing Freezers in their OFF state. Freezers also had greater step length variability in the HIGH compared to the LOW condition, while the step length variability in Non-Freezers did not change. In conclusion, this was the first study to directly compare freezing of gait in anxious and non-anxious situations. These results present strong evidence that anxiety is an important mechanism underlying freezing of gait and supports the notion that the limbic system may have a profound contribution to freezing in PD.

Dopaminergic contributions to distance estimation in Parkinson's disease: a sensory-perceptual deficit?

Recent research has found that perceptual deficits exist in Parkinson's disease (PD), yet the link between perception and movement impairments is not well understood. Inaccurate estimation of distance has the potential to be an underlying cause of movement impairments. Alternatively, those with PD may not be able to perceive their own movements accurately. The main objectives of these studies were to evaluate (1) whether distance estimation is influenced by static perception compared to perception during movement in PD, (2) how visual motion processing contributes to distance estimation during movement, and (3) how dopaminergic medication contributes to these distance estimation deficits. Thirty-seven participants (19 individuals with PD, 18 age-matched healthy control (HC) participants) estimated distance to a remembered target in a total of 48 trials, in 4 randomized blocks. Estimation conditions included: (i) static perception (laser): participants pointed with a laser, (ii) active dynamic perception (walk): participants walked to the estimated position, (iii) passive dynamic perception (wheelchair): participants were pushed in a wheelchair while they gave their estimate. PD patients completed this protocol twice; once OFF and once ON dopaminergic medication. Participants with PD and HC did not differ in judgment accuracy during the static perception (laser) condition. However, those with PD had greater amounts of error compared to HC participants while estimating distance during active dynamic perception (walk). Interestingly, those with PD significantly underestimated the target position compared to healthy control participants across all conditions. Individuals with PD also demonstrated greater variability in their judgments overall. There was no significant influence of dopaminergic medication in any of the conditions. Individuals with PD demonstrated distance estimation deficits only when required to actively move through their environment. In contrast to estimations made with movement, neither static perception (laser) nor passive dynamic perceptions (wheelchair) revealed significant differences in the magnitude of error between the two groups. Thus perceptual estimation deficits appear to be amplified during movement, which may be suggestive of an underlying sensory processing deficit which leads to a problem integrating vision and self-motion information.

Functional analysis of concealment: a novel application of prospect and refuge theory.

According to prospect-refuge theory, humans prefer environments that afford protection from threat (refuge), but also provide large fields of view (prospect). Prospect-refuge theory in the past has traditionally only been applied to humans, but many of the same contingencies governing spatial preference ought to also hold true in animals. The focus of this study was to examine if this phenomena also occurs in animals. Gerbils were placed in an arena containing three dome shaped refuges that varied in prospect-refuge levels. A simulated predator was released during the trial to examine how contextual factors may influence the degree of prospect and refuge preferred. The results indicate a preference for the enclosed refuge at stimulus onset even though this was not reflective of what happened prior to predator release. The results suggest spatial preferences in animals are influenced by prospect-refuge considerations in certain contexts.

Spatial cognition in the gerbil: computing optimal escape routes from visual threats.

Previous studies in our laboratory have shown that when presented with a sudden stimulus simulating an oncoming predator, Mongolian gerbils can compute the optimal trajectory to a safe refuge, taking into account the position of the threat, the location of a clearly visible refuge, and several other contextual variables as well. In the present studies, the main goal was to explore the abilities of gerbils to use mental representations of spaces that were visually occluded by opaque barriers to compute efficient escape trajectories. In all studies, gerbils were placed into a round open field containing a single refuge. On each trial, an overhead visual stimulus was caused to 'fly' overhead, eliciting robust escape movements from the gerbils. By manipulating the shape and position of a series of opaque barriers that were interposed between the gerbils and the refuge, we were able to show that gerbils can compute the shortest route to an invisible target, even when the available routes to the target are made complex by using elaborate barrier shapes. These findings suggest that gerbils can maintain representations of their locations with respect to salient environmental landmarks and refuges, even when such locations are not continuously visible.

Plasticity of the association between visual space and action space in a blind-walking task.

Many experiments have shown that a brief visual preview provides sufficient information to complete certain kinds of movements (reaching, grasping, and walking) with high precision. This suggests that participants must possess a calibration between visual target location and the kinaesthetic, proprioceptive, and/or vestibular stimulation generated during movement towards the target. We investigated the properties of this calibration using a cue-conflict paradigm in which participants were trained with mismatched locomotor and visual input. After training, participants were presented with visual targets and were asked to either walk to them or locate them in a spatial updating task. Our results showed that the training was sufficient to produce significant, systematic miscalibrations of the association between visual space and action space. These findings suggest that the association between action space and visual space is modifiable by experience. This plasticity could be either due to modification of a simple, task-specific sensory motor association or it could reflect a change in the gain of a path integration signal or a reorganisation of the relationship between perceived space and action space. We suggest further experiments that might help to distinguish between these possibilities.

Short-term memory impairment and reduced hippocampal c-Fos expression in an animal model of fetal alcohol syndrome.

BACKGROUND: Previous work in our laboratory has shown that exposure to ethanol during the brain growth spurt impairs spatial short-term memory in rats on the delayed matching-to-place (DMP) version of the Morris water maze. The objectives of this study were to ascertain whether this impairment could: 1) be prevented by increasing the length of encoding time and 2) be related to hippocampal c-Fos expression. METHODS: Using an artificial rearing model, male Long-Evans rats were fed 6.5 g/Kg/day of ethanol from postnatal days 6-9, with controls fed an isocaloric amount of maltose dextrin. As adults, rats in each treatment condition were trained and subsequently tested on either the DMP version of the Morris water maze, or on a random platform version (RAN) that incorporated the same performance requirements, but disallowed spatial learning. Brains were processed for c-Fos expression. RESULTS: Ethanol-exposed rats showed longer search trials during training and took longer to learn the DMP task. When the delay between search and recall trials was increased from 60 sec to 120 min, the performance of ethanol-exposed rats was impaired compared with that of controls after a 10 sec, but not after a 45 sec, encoding time. Brain c-Fos expression was increased in hippocampus, prefrontal cortex and visual cortex in rats trained on the DMP compared to the RAN task. Furthermore, in the DMP-trained rats, hippocampal c-Fos expression was lower in ethanol-exposed rats. CONCLUSIONS: These results suggest that the short-term memory impairment of ethanol-exposed rats 1) can be improved slightly by an increase in encoding time and 2) is related to a decrease in c-Fos expression in the hippocampus.

The contributions of static visual cues, nonvisual cues, and optic flow in distance estimation.

By systematically varying cue availability in the stimulus and response phases of a series of same-modality and cross-modality distance matching tasks, we examined the contributions of static visual information, idiothetic information, and optic flow information. The experiment was conducted in a large-scale, open, outdoor environment. Subjects were presented with information about a distance and were then required to turn 180 before producing a distance estimate. Distance encoding and responding occurred via: (i) visually perceived target distance, or (ii) traversed distance through either blindfolded locomotion or during sighted locomotion. The results demonstrated that subjects performed with similar accuracy across all conditions. In conditions in which the stimulus and the response were delivered in the same mode, when visual information was absent, constant error was minimal; whereas, when visual information was present, overestimation was observed. In conditions in which the stimulus and response modes differed, a consistent error pattern was observed. By systematically comparing complementary conditions, we found that the availability of visual information during locomotion (particularly optic flow) led to an 'under-perception' of movement relative to conditions in which visual information was absent during locomotion.

Visually guided locomotion in the gerbil: a comparison of open- and closed-loop control.

Two experiments were conducted in order to explore the effects of visual feedback on control of locomotion in the gerbil. In the first experiment, gerbils were trained to run down an alleyway towards a visual target in order to obtain food reward. One group of animals was trained to run to a target whose size never varied while another group was trained to run to a target whose size varied randomly from trial to trial. On some trials, the target's size was changed dynamically during running to determine whether gerbils used this dynamic size change information to compute time to collision (tau). Results suggested that neither group used retinal image size information but both groups seemed able to compute tau. In a second experiment, gerbils were trained in the same way as in experiment 1, but on some trials the target was extinguished during the run. In this condition, probe trials showed that gerbils used retinal image size to compute target distance. Collectively, the results showed that gerbils were able to rapidly and flexibly utilize available information to complete a visually guided running task. The results are discussed in the context of the psychophysics of cue combination and its neural underpinnings.

A comparison of visual and nonvisual sensory inputs to walked distance in a blind-walking task.

Two experiments were conducted in order to assess the contribution of locomotor information to estimates of egocentric distance in a walking task. In the first experiment, participants were either shown, or led blind to, a target located at a distance ranging from 4 to 10 m and were then asked to indicate the distance to the target by walking to the location previously occupied by the target. Participants in both the visual and locomotor conditions were very accurate in this task and there was no significant difference between conditions. In the second experiment, a cue-conflict paradigm was used in which, without the knowledge of the participants, the visual and locomotor targets (the targets they were asked to walk to) were at two different distances. Most participants did not notice the conflict, but despite this their responses showed evidence that they had averaged the visual and locomotor inputs to arrive at a walked estimate of distance. Together, these experiments demonstrate that, although they showed poor awareness of their position in space without vision, in some conditions participants were able to use such nonvisual information to arrive at distance estimates as accurate as those given by vision.