DSpace Angular :: Browsing by Author "Perera, Thushara"

Browsing by Author "Perera, Thushara"

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Acoustic Speech Analytics Are Predictive of Cerebellar Dysfunction in Multiple Sclerosis
(Springer, 2020-06) Noffs, Gustavo; Boonstra, Frederique; Perera, Thushara; Kolbe, Scott; Stankovich, Jim; Butzkueven, Helmut; Evans, Andrew; Vogel, Adam; van der Walt, Anneke
Speech production relies on motor control and cognitive processing and is linked to cerebellar function. In diseases where the cerebellum is impaired, such as multiple sclerosis (MS), speech abnormalities are common and can be detected by instrumental assessments. However, the potential of speech assessments to be used to monitor cerebellar impairment in MS remains unexplored. The aim of this study is to build an objectively measured speech score that reflects cerebellar function, pathology and quality of life in MS. Eighty-five people with MS and 21 controls participated in the study. Speech was independently assessed through objective acoustic analysis and blind expert listener ratings. Cerebellar function and overall disease disability were measured through validated clinical scores; cerebellar pathology was assessed via magnetic resonance imaging, and validated questionnaires informed quality of life. Selected speech variables were entered in a regression model to predict cerebellar function. The resulting model was condensed into one composite speech score and tested for prediction of abnormal 9-hole peg test (9HPT), and for correlations with the remaining cerebellar scores, imaging measurements and self-assessed quality of life. Slow rate of syllable repetition and increased free speech pause percentage were the strongest predictors of cerebellar impairment, complemented by phonatory instability. Those variables formed the acoustic composite score that accounted for 54% of variation in cerebellar function, correlated with cerebellar white matter volume (r = 0.3, p = 0.017), quality of life (r = 0.5, p < 0.001) and predicted an abnormal 9HPT with 85% accuracy. An objective multi-feature speech metric was highly representative of motor cerebellar impairment in MS.
An Ambulatory Tremor Score for Parkinson’s Disease
(IOS Press, 2016-08) Braybrook, Michelle; O'Connor, Sam; Churchward, Philip; Perera, Thushara; Farzanehfar, Parisa; Horne, Malcolm
BACKGROUND: While tremor in Parkinson's Disease (PD) can be characterised in the consulting room, its relationship to treatment and fluctuations can be clinically helpful. OBJECTIVE: To develop an ambulatory assessment of tremor of PD. METHODS: Accelerometry data was collected using the Parkinson's KinetiGraph System (PKG, Global Kinetics). An algorithm was developed, which could successfully distinguish been subjects with a resting or postural tremor that involved the wrist whose frequency was greater than 3 Hz. Percent of time that tremor was present (PTT) between 09 : 00 and 18 : 00 was calculated. RESULTS: This algorithm was applied to 85 people with PD who had been assessed clinically for the presence and nature of tremor. The Sensitivity and Selectivity of a PTT >/=0.8% was 92.5% and 92.9% in identifying tremor, providing that the tremor was not a fine kinetic and postural tremor or was not in the upper limb. A PTT >1% provide high likely hood of the presence of clinical meaningful tremor. These cut-offs were retested on a second cohort (n = 87) with a similar outcome. The Sensitivity and Selectivity of the combined group was 88.7% and 89.5% respectively. Using the PTT, 50% of 22 newly diagnosed patients had a PTT >1.0%.The PKG's simultaneous bradykinesia scores was used to find a threshold for the emergence of tremor. Tremor produced artefactual increase in the PKG's dyskinesia score in 1% of this sample. CONCLUSIONS: We propose this as a means of assessing the presence of tremor and its relationship to bradykinesia.
Anatomical targeting for electrode localization in subthalamic nucleus deep brain stimulation: A comparative study.
(Journal of NeuroImaging, 2023-06-08) Tonroe, Thomas; McDermott, Hugh; Pearce, Patrick; Acevedo, Nicola; Thevathasan, Wesley; Xu, San San; Bulluss, Kristian; Perera, Thushara
In deep brain stimulation (DBS), accurate electrode placement is essential for optimizing patient outcomes. Localizing electrodes enables insight into therapeutic outcomes and development of metrics for use in clinical trials. Methods of defining anatomical targets have been described with varying accuracy and objectivity. To assess variability in anatomical targeting, we compare four methods of defining an appropriate target for DBS of the subthalamic nucleus for Parkinson's disease.
The Appearance of Phosphenes Elicited Using a Suprachoroidal Retinal Prosthesis
(iOVS, 2016-09) Sinclair, Nicholas; Shivdasani, Mohit; Perera, Thushara; Gillespie, Lisa; McDermott, Hugh; Ayton, Lauren; Blamey, Peter
Purpose: Phosphenes are the fundamental building blocks for presenting meaningful visual information to the visually impaired using a bionic eye device. The aim of this study was to characterize the size, shape, and location of phosphenes elicited using a suprachoroidal retinal prosthesis. Methods: Three patients with profound vision loss due to retinitis pigmentosa were implanted with a suprachoroidal electrode array, which was used to deliver charge-balanced biphasic constant-current pulses at various rates, amplitudes, and durations to produce phosphenes. Tasks assessing phosphene appearance, location, overlap, and the patients' ability to recognize phosphenes were performed using a custom psychophysics setup. Results: Phosphenes were reliably elicited in all three patients, with marked differences in the reported appearances between patients and between electrodes. Phosphene shapes ranged from simple blobs to complex forms with multiple components in both space and time. Phosphene locations within the visual field generally corresponded to the retinotopic position of the stimulating electrodes. Overlap between phosphenes elicited from adjacent electrodes was observed with one patient, which reduced with increasing electrode separation. In a randomized recognition task, two patients correctly identified the electrode being stimulated for 57.2% and 23% of trials, respectively. Conclusions: Phosphenes of varying complexity were successfully elicited in all three patients, indicating that the suprachoroidal space is an efficacious site for electrically stimulating the retina. The recognition scores obtained with two patients suggest that a suprachoroidal implant can elicit phosphenes containing unique information. This information may be useful when combining phosphenes into more complex and meaningful images that provide functional vision.
Balance control systems in Parkinson’s disease and the impact of pedunculopontine area stimulation
(Brain, 2018-08) Perera, Thushara; Tan, Joy; Cole, Michael; Yohanandan, Shivanthan; Silberstein, Paul; Cook, Raymond; Peppard, Richard; Aziz, Tipu; Coyne, Terry; Brown, Peter; Silburn, Peter; Thevathasan, Wesley
Impaired balance is a major contributor to falls and diminished quality of life in Parkinson's disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson's disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson's disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional-integral-derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the 'pull test' to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson's disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = - 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson's disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation.
Clinical validation of a precision electromagnetic tremor measurement system in participants receiving deep brain stimulation for essential tremor
(IOP Publishing, 2016-08) Perera, Thushara; Yohanandan, Shivanthan; Thevathasan, Wesley; Jones, Mary; Peppard, Richard; Evans, Andrew; Tan, Joy; McKay, Colette; McDermott, Hugh
Tremor is characterized commonly through subjective clinical rating scales. Accelerometer-based techniques for objective tremor measurement have been developed in the past, yet these measures are usually presented as an unintuitive dimensionless index without measurement units. Here we have developed a tool (TREMBAL) to provide quantifiable and objective measures of tremor severity using electromagnetic motion tracking. We aimed to compare TREMBAL's objective measures with clinical tremor ratings and determine the test-retest reliability of our technique. Eight participants with ET receiving deep brain stimulation (DBS) therapy were consented. Tremor was simultaneously recorded using TREMBAL and video during DBS adjustment. After each adjustment, participants performed a hands-outstretched task (for postural tremor) and a finger-nose task (for kinetic tremor). Video recordings were de-identified, randomized, and shown to a panel of movement disorder specialists to obtain their ratings. Regression analysis and Pearson's correlations were used to determine agreement between datasets. Subsets of the trial were repeated to assess test-retest reliability. Tremor amplitude and velocity measures were in close agreement with mean clinical ratings (r > 0.90) for both postural and kinetic tremors. Test-retest reliability for both translational and rotational components of tremor showed intra-class correlations >0.80. TREMBAL assessments showed that tremor gradually improved with increasing DBS therapy-this was also supported by clinical observation. TREMBAL measurements are a sensitive, objective and reliable assessment of tremor severity. This tool may have application in clinical trials and in aiding automated optimization of deep brain stimulation.
Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity
(Elsevier, Inc., 2019-07) Sinclair, Nicholas; McDermott, Hugh; Fallon, James; Perera, Thushara; Brown, Peter; Bulluss, Kristian; Thevathasan, Wesley
Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500Hz) oscillation that typically has a duration of at least 10ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation - a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130Hz stimulation at increasing amplitudes (0.67-3.38mA), 'washout' of therapeutic effects, and non-therapeutic 20Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130Hz stimulation (p<.001). This modulation coincided with improvement in bradykinesia and rigidity (p<.001), and correlated with spontaneous beta band suppression (p<.001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400Hz), both of which decreased to around twice the 130Hz stimulation rate. Non-therapeutic stimulation at 20Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.
Evaluating machine learning algorithms estimating tremor severity ratings on the Bain-Findley scale
(IOP Publishing, 2016-11) Yohanandan, Shivanthan; Jones, Mary; Peppard, Richard; Tan, Joy; McDermott, Hugh; Perera, Thushara
Tremor is a debilitating symptom of some movement disorders. Effective treatment, such as deep brain stimulation (DBS), is contingent upon frequent clinical assessments using instruments such as the Bain–Findley tremor rating scale (BTRS). Many patients, however, do not have access to frequent clinical assessments. Wearable devices have been developed to provide patients with access to frequent objective assessments outside the clinic via telemedicine. Nevertheless, the information they report is not in the form of BTRS ratings. One way to transform this information into BTRS ratings is through linear regression models (LRMs). Another, potentially more accurate method is through machine learning classifiers (MLCs). This study aims to compare MLCs and LRMs, and identify the most accurate model that can transform objective tremor information into tremor severity ratings on the BTRS. Nine participants with upper limb tremor had their DBS stimulation amplitude varied while they performed clinical upper-extremity exercises. Tremor features were acquired using the tremor biomechanics analysis laboratory (TREMBAL). Movement disorder specialists rated tremor severity on the BTRS from video recordings. Seven MLCs and 6 LRMs transformed TREMBAL features into tremor severity ratings on the BTRS using the specialists’ ratings as training data. The weighted Cohen’s kappa ( w) defined the models’ rating accuracy. This study shows that the Random Forest MLC was the most accurate model ( w = 0.81) at transforming tremor information into BTRS ratings, thereby improving the clinical interpretation of tremor information obtained from wearable devices.
Factors Affecting Perceptual Thresholds in a Suprachoroidal Retinal Prosthesis
(The Association for Research in Vision and Ophthalmology Inc, 2014-10) Shivdasani, Mohit; Sinclair, Nicholas; Dimitrov, Peter; Varsamidis, Mary; Ayton, Lauren; Luu, Chi; Perera, Thushara; McDermott, Hugh; Blamey, Peter
PURPOSE: The suprachoroidal location for a retinal prosthesis provides advantages over other locations in terms of a simplified surgical procedure and a potentially more stable electrode-neural interface. The aim of this study was to assess the factors affecting perceptual thresholds, and to optimize stimulus parameters to achieve the lowest thresholds in patients implanted with a suprachoroidal retinal prosthesis. METHODS: Three patients with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal array. Perceptual thresholds measured on individual electrodes were analyzed as a function of stimulus (return configuration, pulse polarity, pulse width, interphase gap, and rate), electrode (area and number of ganged electrodes), and clinical (retinal thickness and electrode-retina distance) parameters. RESULTS: A total of 92.8% of 904 measurements made up to 680 days post implantation yielded thresholds (range, 44-436 nanocoulombs [nC]) below the safe charge limit. Thresholds were found to vary between individuals and to depend significantly on electrode-retina distance, negligibly on retinal thickness, and not on electrode area or the number of ganged electrodes. Lowest thresholds were achieved when using a monopolar return, anodic-first polarity, short pulse widths (100 μs) combined with long interphase gaps (500 μs), and high stimulation rates (≥400 pulses per second [pps]). CONCLUSIONS: With suprachoroidal stimulation, anodic-first pulses with a monopolar return are most efficacious. To enable high rates, an appropriate combination of pulse width and interphase gap must be chosen to ensure low thresholds and electrode voltages. Electrode-retina distance needs to be monitored carefully owing to its influence on thresholds. These results inform implantable stimulator specifications for a suprachoroidal retinal prosthesis. (ClinicalTrials.gov number, NCT01603576.).
The feasibility of using acoustic markers of speech for optimizing patient outcomes during randomized amplitude variation in deep brain stimulation: a proof of principle methods study
(Frontiers Media S.A., 2015-07-14) Vogel, Adam; McDermott, Hugh; Perera, Thushara; Jones, Mary; Peppard, Richard; McKay, Colette
Background: Deep brain stimulation (DBS) is an effective treatment for reducing symptoms of tremor. A common and typically subjectively determined adverse effect of DBS is dysarthria. Current assessment protocols are driven by the qualitative judgments of treating clinicians and lack the sensitivity and objectivity required to optimize patient outcomes where multiple stimulation parameters are trialed. Objective: To examine the effect of DBS on speech in patients receiving stimulation to the posterior sub-thalamic area (PSA) via randomized manipulation of amplitude parameters. Methods: Six patients diagnosed with tremor receiving treatment via DBS of the PSA were assessed in a double-blinded, within-subjects experimental protocol. Amplitude (i.e., voltage or current) was randomly adjusted across 10 settings, while speech samples (e.g., sustained vowel, counting to 10) were recorded to identify the patient-specific settings required for optimal therapeutic benefit (reduced tremor) with minimal adverse effects (altered speech). Speech production between stimulation parameters was quantified using acoustic analysis. Results: Speech changed as a response to DBS but those changes were not uniform across patients nor were they generally in line with changes in amplitude with the exception of reduced vocal control and increased mean silence length in two patients. Speech outcomes did not correlate with changes in tremor. Conclusion: Intra-individual changes in speech were detected as a response to modified amplitude; however, no clear pattern was observed across patients as a group. The use of objective acoustic measures allows for quantification of speech changes during DBS optimization protocols, even when those changes are subtle and potentially difficult to detect perceptually.
Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis
(SAGE Publishing, 2019-03) Boonstra, Frederique; Noffs, Gustavo; Perera, Thushara; Jokubaitis, Vilija; Vogel, Adam; Moffat, Bradford; Butzkueven, Helmut; Evans, Andrew; van der Walt, Anneke; Kolbe, Scott
BACKGROUND:: Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments. OBJECTIVES:: To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS. METHODS:: Fifteen healthy controls (46.1 +/- 15.4 years), 27 MS participants without tremor (46.7 +/- 11.6 years) and 42 with tremor (46.6 +/- 11.5 years) were included. Tremor was quantified using the Bain score (0-10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified. RESULTS:: Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor ( p < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity. CONCLUSION:: Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.
Identification of Characters and Localization of Images Using Direct Multiple-Electrode Stimulation With a Suprachoroidal Retinal Prosthesis
(IOVS, 2017-08) Shivdasani, Mohit; Sinclair, Nicholas; Gillespie, Lisa; Petoe, Matthew; Titchener, Samuel; Fallon, James; Perera, Thushara; Pardinas-Diaz, Darien; Barnes, Nick; Blamey, Peter; Bionic Vision Australia Consortium
Purpose: Retinal prostheses provide vision to blind patients by eliciting phosphenes through electrical stimulation. This study explored whether character identification and image localization could be achieved through direct multiple-electrode stimulation with a suprachoroidal retinal prosthesis. Methods: Two of three retinitis pigmentosa patients implanted with a suprachoroidal electrode array were tested on three psychophysical tasks. Electrode patterns were stimulated to elicit perception of simple characters, following which percept localization was tested using either static or dynamic images. Eye tracking was used to assess the association between accuracy and eye movements. Results: In the character identification task, accuracy ranged from 2.7% to 93.3%, depending on the patient and character. In the static image localization task, accuracy decreased from near perfect to <20% with decreasing contrast (patient 1). Patient 2 scored up to 70% at 100% contrast. In the dynamic image localization task, patient 1 recognized the trajectory of the image up to speeds of 64 deg/s, whereas patient 2 scored just above chance. The degree of eye movement in both patients was related to accuracy and, to some extent, stimulus direction. Conclusions: The ability to identify characters and localize percepts demonstrates the capacity of the suprachoroidal device to provide meaningful information to blind patients. The variation in scores across all tasks highlights the importance of using spatial cues from phosphenes, which becomes more difficult at low contrast. The use of spatial information from multiple electrodes and eye-movement compensation is expected to improve performance outcomes during real-world prosthesis use in a camera-based system. (ClinicalTrials.gov number, NCT01603576.).
An Instrumented Pull Test to Characterize Postural Responses
(Journal of Visualized Experiments: JoVE, 2019-04) Tan, Joy; Thevathasan, Wesley; McGinley, Jennifer; Brown, Peter; Perera, Thushara
Impairment of postural reflexes, termed postural instability, is a common and disabling deficit in Parkinson's disease. To assess postural reflexes, clinicians typically employ the pull test to grade corrective responses to a backward perturbation at the shoulders. However, the pull test is prone to issues with reliability and scaling (score/4). Here, we present an instrumented version of the pull test to more precisely quantify postural responses. Akin to the clinical test, pulls are manually administered except pull force is also recorded. Displacements of the trunk and feet are captured by a semi-portable motion tracking system. Raw data represent distance traveled (in millimeter units), making subsequent interpretation and analysis intuitive. The instrumented pull test also detects variabilities influencing pull test administration, such as pull force, thereby identifying and quantifying potential confounds that can be accounted for by statistical techniques. The instrumented pull test could have application in studies seeking to capture early abnormalities in postural responses, track postural instability over time, and detect responses to therapy.
Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging
(Elsevier, Inc., 2019-09) Horn, Andreas; Li, Ningfei; Dembek, Till; Kappel, Ari; Boulay, Chadwick; Ewert, Siobhan; Tietze, Anna; Husch, Andreas; Perera, Thushara; Neumann, Wolf-Julian; Reiser, Marco; Si, Hang; Oostenveld, Robert; Rorden, Christopher; Yeh, Fang-Cheng; Fang, Qianqian; Herrington, Todd; Vorwerk, Johannes; Kuhn, Andrea
Deep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment outcome, exact electrode placement is required. Moreover, to analyze the relationship between electrode location and clinical results, a precise reconstruction of electrode placement is required, posing specific challenges to the field of neuroimaging. Since 2014 the open source toolbox Lead-DBS is available, which aims at facilitating this process. The tool has since become a popular platform for DBS imaging. With support of a broad community of researchers worldwide, methods have been continuously updated and complemented by new tools for tasks such as multispectral nonlinear registration, structural/functional connectivity analyses, brain shift correction, reconstruction of microelectrode recordings and orientation detection of segmented DBS leads. The rapid development and emergence of these methods in DBS data analysis require us to revisit and revise the pipelines introduced in the original methods publication. Here we demonstrate the updated DBS and connectome pipelines of Lead-DBS using a single patient example with state-of-the-art high-field imaging as well as a retrospective cohort of patients scanned in a typical clinical setting at 1.5T. Imaging data of the 3T example patient is co-registered using five algorithms and nonlinearly warped into template space using ten approaches for comparative purposes. After reconstruction of DBS electrodes (which is possible using three methods and a specific refinement tool), the volume of tissue activated is calculated for two DBS settings using four distinct models and various parameters. Finally, four whole-brain tractography algorithms are applied to the patient's preoperative diffusion MRI data and structural as well as functional connectivity between the stimulation volume and other brain areas are estimated using a total of eight approaches and datasets. In addition, we demonstrate impact of selected preprocessing strategies on the retrospective sample of 51 PD patients. We compare the amount of variance in clinical improvement that can be explained by the computer model depending on the preprocessing method of choice. This work represents a multi-institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field.
Neurophysiological analysis of the clinical pull test
(American Physiological Society, 2018-08) Tan, Joy; Perera, Thushara; McGinley, Jennifer; Shivanthan, Yohanandan; Brown, Peter; Thevathasan, Wesley
Postural reflexes are impaired in conditions such as Parkinson's disease, leading to difficulty walking and falls. In clinical practice, postural responses are assessed using the 'pull test', where an examiner tugs the pre-warned, standing patient backwards at the shoulders and grades the response. However, validity of the pull test is debated with issues including scaling and variability in administration and interpretation. It is unclear whether to assess the first trial or only subsequent repeated trials. The ecological relevance of a forewarned backwards challenge is also debated. We therefore developed an instrumented version of the pull test to characterize responses and clarify how the test should be performed and interpreted. In thirty-three healthy participants, 'pulls' were manually administered and pull force measured. Trunk and step responses were assessed with motion tracking. We probed for the StartReact phenomenon (where pre-prepared responses are released early by a startling stimulus) by delivering concurrent normal or 'startling' auditory stimuli. We found that the first pull triggers a different response, including a larger step size suggesting more destabilization. This is consistent with 'first trial effects', reported by platform translation studies, where movement execution appears confounded by startle reflex-like activity. Thus, first pull test trials have clinical relevance and should not be discarded as practice. Supportive of ecological relevance, responses to repeated pulls exhibited StartReact, as previously reported with a variety of other postural challenges including those delivered with unexpected timing and direction. Examiner pull force significantly affected the postural response particularly the size of stepping.
Novel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor
(Frontiers in Neurology, 2018-07) Boonstra, Frederique; Perera, Thushara; Noffs, Gustavo; Marotta, Cassandra; Vogel, Adam; Evans, Andrew; Butzkueven, Helmut; Moffat, Bradford; Van der Walt, Anneke; Kolbe, Scott
INTRODUCTION: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardised protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. OBJECTIVE: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. METHODS: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a ‘brick-breaker’ joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analysed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. RESULTS: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531 to 0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p=0.01) during PLAY, but not during MOVE. CONCLUSION: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options.
Objective evaluation of bradykinesia in Parkinson’s disease using an inexpensive marker-less motion tracking system
(IOP Publishing, 2019-01) Lee, Wee Lih; Sinclair, Nicholas; Jones, Mary; Tan, Joy; Proud, Elizabeth; Peppard, Richard; McDermott, Hugh; Perera, Thushara
OBJECTIVE: Quantification of bradykinesia (slowness of movement) is crucial for the treatment and monitoring of Parkinson's disease. Subjective observational techniques are the de-facto 'gold standard', but such clinical rating scales suffer from poor sensitivity and inter-rater variability. Although various technologies have been developed for assessing bradykinesia in recent years, most still require considerable expertise and effort to operate. Here we present a novel method to utilize an inexpensive off-the-shelf hand-tracker (Leap Motion) to quantify bradykinesia. Approach: Eight participants with Parkinson's disease receiving benefit from deep brain stimulation were recruited for the study. Participants were assessed "on" and "off" stimulation, with the "on" condition repeated to evaluate reliability. Participants performed wrist pronation/supination, hand open/close, and finger-tapping tasks during each condition. Tasks were simultaneously captured by our software and rated by three clinicians. A linear regression model was developed to predict clinical scores and its performance was assessed with leave-one-out cross validation. Main Results: Aggregate bradykinesia scores predicted by our method were in strong agreement (R = 0.86) with clinical scores. The model was able to differentiate therapeutic states and comparison between the test-retest conditions yielded no significant difference (p = 0.50). Significance: These findings demonstrate that our method can objectively quantify bradykinesia in agreement with clinical observation and provide reliable measurements over time. The hardware is readily accessible, requiring only a modest computer and our software to perform assessments, thus making it suitable for both clinic- and home-based symptom tracking.
Objective evaluation of bradykinesia in Parkinson’s disease using an inexpensive marker-less motion tracking system
(IOP Publishing Ltd, 2019-01) Lih, Wee-Lih; Sinclair, Nicholas; Jones, Mary; Tan, Joy; Proud, Elizabeth; Peppard, Richard; McDermott, Hugh; Perera, Thushara
OBJECTIVE: Quantification of bradykinesia (slowness of movement) is crucial for the treatment and monitoring of Parkinson's disease. Subjective observational techniques are the de-facto 'gold standard', but such clinical rating scales suffer from poor sensitivity and inter-rater variability. Although various technologies have been developed for assessing bradykinesia in recent years, most still require considerable expertise and effort to operate. Here we present a novel method to utilize an inexpensive off-the-shelf hand-tracker (Leap Motion) to quantify bradykinesia. Approach: Eight participants with Parkinson's disease receiving benefit from deep brain stimulation were recruited for the study. Participants were assessed "on" and "off" stimulation, with the "on" condition repeated to evaluate reliability. Participants performed wrist pronation/supination, hand open/close, and finger-tapping tasks during each condition. Tasks were simultaneously captured by our software and rated by three clinicians. A linear regression model was developed to predict clinical scores and its performance was assessed with leave-one-out cross validation. Main Results: Aggregate bradykinesia scores predicted by our method were in strong agreement (R = 0.86) with clinical scores. The model was able to differentiate therapeutic states and comparison between the test-retest conditions yielded no significant difference (p = 0.50). Significance: These findings demonstrate that our method can objectively quantify bradykinesia in agreement with clinical observation and provide reliable measurements over time. The hardware is readily accessible, requiring only a modest computer and our software to perform assessments, thus making it suitable for both clinic- and home-based symptom tracking. .
OnabotulinumtoxinA treatment for MS-tremor modifies fMRI tremor response in central sensory-motor integration areas
(Elsevier B.V., 2020-02) Boonstra, Frederique; Evans, Andrew; Noffs, Gustavo; Perera, Thushara; Jokubaitis, Vilija; Stankovich, Jim; Vogel, Adam; Moffat, Bradford; Butzkueven, Helmut; Kolbe, Scott; van der Walt, Anneke
Background: Treatment of tremor in MS is an unmet need. OnabotulinumtoxinA (BoNT-A) has shown promising results; however, little is known regarding its effects on the brain. The clinical presentation of tremor MS is shown to depend on subcortical neural damage and cortical neural plasticity. This study aimed to identify effects of onabotulinumtoxinA (BoNT-A) on brain activation in MS and upper-limb tremor using functional MRI. Methods: Forty-three MS participants with tremor were randomized to receive intramuscular injections of placebo (n = 22) or BoNT-A (n = 21). Tremor was quantified using the Bain score (0–10) for severity, handwriting and Archimedes drawing at baseline, 6 weeks and 12 weeks. Functional MRI activation within two previously identified clusters, ipsilateral inferior parietal cortex (IPL) and remotor/supplementary motor cortex (SMC) of compensatory activity, was measured at baseline and 6 weeks. Results: Treatment with BoNT-A resulted in improved handwriting tremor at 6 weeks (p = 0.049) and 12 weeks (p= 0.014), and tremor severity -0.79 (p=0.007) at 12 weeks. Furthermore, the patients that received BoNT-A showed a reduction in activation within the IPL (p = 0.034), but not in the SMC. The change in IPL activation correlated with the reduction in tremor severity from baseline to 12 weeks (β = 0.608; p = 0.015) in the BoNTA group. No tremor and fMRI changes were seen in the placebo treated group. Conclusion: We have shown that reduction in MS-tremor severity after intramuscular injection with BoNT-A is associated with changes in brain activity in sensorimotor integration regions.
A palm-worn device to quantify rigidity in Parkinson’s disease
(Elsevier B.V., 2019-02) Perera, Thushara; Lee, Wee-Lih; Jones, Mary; Tan, Joy; Proud, Elizabeth; Begg, Angus; Sinclair, Nicholas; Peppard, Richard; McDermott, Hugh
BACKGROUND: Parkinsonian rigidity is identified on clinical examination as resistance to passive movement. Measurement of rigidity commonly relies on ordinal rating scales (MDS-UPDRS), however instrumented objective measures may provide greater mechanistic insight. NEW METHOD: We present a palm-worn instrument to objectively quantify rigidity on a continuous scale. The device employs a miniature motor to flex the third digit of the hand about the metacarpophalangeal joint whilst transducers record flexion/extension forces. We aim to determine congruence with the MDS-UPDRS, investigate sensitivity to the impact of deep brain stimulation (DBS) and contralateral movement, and make comparisons with healthy individuals. Eight participants with Parkinson's disease underwent evaluation during conditions: on and off DBS, and with and without contralateral limb movement to activate rigidity. During each DBS condition, wash-in/out effects were tracked using both our instrument and two blinded clinical raters. Sixteen healthy volunteers (age-matched/young) served as controls. RESULTS: Rigidity measured using our instrument had moderate agreement with the MDS-UPDRS and showed differences between therapeutic state, activation conditions, and disease/healthy cohorts. Rigidity gradually worsened over a one-hour period after DBS cessation, but improved more rapidly with DBS resumption. COMPARISON WITH EXISTING METHODS: Previous attempts to quantify rigidity include manual approaches where a clinician is required to manipulate limbs while sensors passively gather information, or large automated instruments to move the wrist or elbow. CONCLUSION: Given its ability to track changes in rigidity due to therapeutic intervention, our technique could have applications where continuous measurement is required or where a suitably qualified rater is absent.

Browsing by Author "Perera, Thushara"

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