Browsing by Author "Thevathasan, Wesley"

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    Alternate subthalamic nucleus deep brain stimulation parameters to manage motor symptoms of Parkinson’s disease: Systematic review and meta-analysis
    (John Wiley & Sons, 2018-09) Conway, Zachary; Silburn, Peter; Thevathasan, Wesley; O'Maley, Karen; Naughton, Geraldine; Cole, Michael
    ABSTRACT Background The use of alternate frequencies, amplitudes and pulse widths to manage motor symptoms in Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) is of clinical interest, but currently lacks systematic evidence. Objective/Hypothesis Systematically review whether alternate STN-DBS settings influence the therapy's efficacy for managing PD motor symptoms. Methods Systematic searches identified studies that; involved bilateral STN-DBS PD patients; manipulated ≥1 STN-DBS parameter (e.g. amplitude); assessed ≥1 motor symptom (e.g. tremor); and contrasted the experimental and chronic stimulation settings. A Mantel-Haenszel random-effects meta-analysis compared the UPDRS-III sub-scores at low (60-Hz) and high frequencies (≥130 Hz). Inter-study heterogeneity was assessed with the Cohen's χ2 and I2 index, while the standard GRADE evidence assessment examined strength of evidence. Results The meta-analysis indicated a very low quality for the pooled evidence due to risks of bias, significant heterogeneity and imprecision. Separate analyses involving studies that attempted to maintain the total electrical energy derived by increasing amplitude at 60-Hz frequencies suggested that low-frequency STN-DBS reduced UPDRS-III sub-scores by 5.8 points (95% CI=1.5-10.2; Z=2.6; P=0.009) compared to frequencies ≥130 Hz. This alternate stimulation strategy may be beneficial for those with severe axial symptoms post STN-DBS, however, benefits may only be short-term. Conclusion(s) The meta-analysis reported a very low quality of evidence for the efficacy of low-frequency STN-DBS for managing PD motor symptoms. Furthermore, it highlighted that lower amplitudes lead to the re-emergence of motor symptoms and further research is needed to understand the potential benefits of alternate STN-DBS parameters for PD patients. This article is protected by copyright. All rights reserved.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    On the neural basis of deep brain stimulation evoked resonant activity
    (IOP Publishing, 2019-08) Sinclair, Nicholas; Fallon, James; Bulluss, Kristian; Thevathasan, Wesley; McDermott, Hugh
    Objective: Deep brain stimulation can be a remarkably effective treatment for Parkinson’s disease and other conditions; however, an electrophysiological feedback signal is needed to improve surgical accuracy and for optimising therapy according to patient needs. Evoked responses may provide such a signal, although it is crucial to determine that recorded potentials are of neural origin and not a consequence of stimulation artefacts. Here, we use several in vitro and in vivo methods to establish the neural basis of resonant deep brain stimulation evoked activity. Approach: Recordings were obtained from deep brain stimulation electrodes in saline, in feline brain regions not expected to produce resonant neural responses, and in fourteen subthalamic nuclei in people with Parkinson’s disease following stimulation with 60 μs per phase biphasic current pulses with different polarities. Main results: Electrodes in saline did not exhibit stimulation artefacts beyond 1 ms. Changing the pulse polarity reversed the stimulation artefact. Electrodes in feline brain elicited early latency activity (<5ms); however, the activity did not resemble a decaying oscillation. Electrodes in human subthalamic nuclei evoked resonant neural activity that was not reversed by changing the pulse polarity. The latency of resonant peaks from stimuli with opposing polarities differed by about the expected amount and were strongly correlated (ρ = 0.998, p < 0.001). Resonant peak amplitudes were also strongly correlated (ρ = 0.945, p < 0.001). Significance: The absence of resonant activity in recordings from electrodes in saline and feline brain, in addition to findings that resonant activity occurs in the subthalamic nucleus but not neighbouring white matter regions, demonstrates that such activity is not an artefact of the stimulation and recording system. Furthermore, non-reversal of resonant activity with changing pulse polarity in human subthalamic nuclei indicates that it is independent from stimulation artefact. Thus, these methods provide strong evidence of the neural basis of deep brain stimulation evoked resonant activity.
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    Pedunculopontine Nucleus Deep Brain Stimulation in Parkinson’s Disease: A Clinical Review
    (Wiley, 2017-09) Thevathasan, Wesley; Debu, Bettina; Bloem, Bastiaan; Blahak, Christian; Butson, Christopher; Czernecki, Virgine; Foltynie, Thomas; Fraix, Valerie; Grabli, David; Joint, Carole; Lozano, Andres; Okum, Michael; Ostrem, Jill; Pavese, Nicola; Schrader, Christoph; Tai, Chun-Hwei; Krauss, Joachim; Moro, Elena
    Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. (c) 2017 International Parkinson and Movement Disorder Society.
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    Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology
    (Karger AG, Basel, 2016-10) Hamani, Clement; Aziz, Tipu; Bloem, Bastiaan; Brown, Peter; Chabardes, Stephen; Coyne, Terry; Foote, Kelly; Garcia-Rill, Edgar; Hirsch, Etienne; Lozano, Andres; Mazzone, Paolo; Okun, Michael; Hutchison, William; Silburn, Peter; Zrinzo, Ludvic; Alam, Mesbah; Goetz, Laurent; Pereira, Erlick; Rughani, Anand; Thevathasan, Wesley; Moro, Elena; Krauss, Joachim
    Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.
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    Subthalamic Nucleus Deep Brain Stimulation Evokes Resonant Neural Activity
    (Wiley Periodicals, Inc., 2018-05) Sinclair, Nicholas; McDermott, Hugh; Bulluss, Kristian; Fallon, James; Perera, Thushara; Xu, San San; Brown, Peter; Thevathasan, Wesley
    Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes.
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    Tailoring Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease Using Evoked Resonant Neural Activity
    (Frontiers in Human Neuroscience, 2020-02) Thevathasan, Wesley; Sinclair, Nicholas; Bulluss, Kristian; McDermott, Hugh
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    Targeting the centromedian thalamic nucleus for deep brain stimulation
    (BMJ Publishing Group Ltd, 2020-01) Warren, Aaron; Dalic, Linda; Thevathasan, Wesley; Roten, Annie; Bulluss, Kristian; Archer, John
    OBJECTIVES: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by: (1) developing a structural MRI approach for CM visualisation, (2) identifying the CM's neurophysiological characteristics using microelectrode recordings (MERs) and (3) mapping connectivity from CM-DBS sites using functional MRI (fMRI). METHODS: 19 patients with LGS (mean age=28 years) underwent presurgical 3T MRI using magnetisation-prepared 2 rapid acquisition gradient-echoes (MP2RAGE) and fMRI sequences; 16 patients proceeded to bilateral CM-DBS implantation and intraoperative thalamic MERs. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge detection. Mixed-effects analysis compared two MER features (spike firing rate and background noise) between ventrolateral, CM and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions of interest. RESULTS: The CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal and parafasicular nuclei. At the group level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20%-25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex. CONCLUSIONS: In the largest clinical trial of DBS undertaken in patients with LGS to date, we show that accurate targeting of the CM is achievable using 3T MP2RAGE MRI. Intraoperative MERs may provide additional localising features in some cases; however, their utility is limited by interpatient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive and sensorimotor processes.
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    Towards guided and automated programming of subthalamic area stimulation in Parkinson’s disease
    (Brain Communications, 2022-01-13) San San, Xu; Sinclair, Nicholas; Bullus, Kristian; Perera, Thushara; Lee, Wee-lih; McDermott, Hugh; Thevathasan, Wesley
    Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation in Parkinson’s disease can be an arduous process, with outcomes highly dependent on clinician expertise. This study aims to assess whether neuronal signals recorded intraoperatively in awake patients, and the anatomical location of contacts, can assist programming. In a cohort of 14 patients with Parkinson’s disease, implanted with subthalamic nucleus deep brain stimulation, the four contacts on each lead in the 28 hemispheres were ranked according to proximity to a nominated ideal anatomical location and power of the following neuronal signals: evoked resonant neural activity, beta oscillations and high-frequency oscillations. We assessed how these rankings predicted, on each lead: (i) the motor benefit from deep brain stimulation applied through each contact and (ii) the ‘ideal’ contact to apply deep brain stimulation. The ranking of contacts according to each factor predicted motor benefit from subthalamic nucleus deep brain stimulation, as follows: evoked resonant neural activity; r2 = 0.50, Akaike information criterion 1039.9, beta; r2 = 0.50, Akaike information criterion 1041.6, high-frequency oscillations; r2 = 0.44, Akaike information criterion 1057.2 and anatomy; r2 = 0.49, Akaike information criterion 1048.0. Combining evoked resonant neural activity, beta and high-frequency oscillations ranking data yielded the strongest predictive model (r2 = 0.61, Akaike information criterion 1021.5). The ‘ideal’ contact (yielding maximal benefit) was ranked first according to each factor in the following proportion of hemispheres; evoked resonant neural activity 18/28, beta 17/28, anatomy 16/28, high-frequency oscillations 7/28. Across hemispheres, the maximal available deep brain stimulation benefit did not differ from that yielded by contacts chosen by clinicians for chronic therapy or contacts ranked first according to evoked resonant neural activity. Evoked resonant neural activity, beta oscillations and anatomy similarly predicted how motor benefit from subthalamic nucleus deep brain stimulation varied across contacts on each lead. This could assist programming by providing a probability ranking of contacts akin to a ‘monopolar survey’. However, these factors identified the ‘ideal’ contact in only a proportion of hemispheres. More advanced signal processing and anatomical techniques may be needed for the full automation of contact selection.
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    Tremor Reduction by Deep Brain Stimulation Is Associated With Gamma Power Suppression in Parkinson's Disease
    (John Wiley and Sons, 2015-07) Beudel, Martjin; Little, Simon; Pogosyan, Alek; Ashkan, Keyoumars; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Hariz, Marwan; Bogdanovic, Marko; Cheeran, Binith; Green, Alexander; Aziz, Tipu; Thevathasan, Wesley; Brown, Peter
    Objectives Rest tremor is a cardinal symptom of Parkinson's disease (PD), and is readily suppressed by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The therapeutic effect of the latter on bradykinesia and rigidity has been associated with the suppression of exaggerated beta (13–30 Hz) band synchronization in the vicinity of the stimulating electrode, but there is no correlation between beta suppression and tremor amplitude. In the present study, we investigate whether tremor suppression is related to suppression of activities at other frequencies. Materials and Methods We recorded hand tremor and contralateral local field potential (LFP) activity from DBS electrodes during stimulation of the STN in 15 hemispheres in 11 patients with PD. DBS was applied with increasing voltages starting at 0.5 V until tremor suppression was achieved or until 4.5 V was reached. Results Tremor was reduced to 48.9% ± 10.9% of that without DBS once stimulation reached 2.5–3 V (t14 = −4.667, p < 0.001). There was a parallel suppression of low gamma (31–45 Hz) power to 92.5% ± 3% (t14 = −2.348, p = 0.034). This was not seen over a band containing tremor frequencies and their harmonic (4–12 Hz), or over the beta band. Moreover, low gamma power correlated with tremor severity (mean r = 0.43 ± 0.14, p = 0.008) within subjects. This was not the case for LFP power in the other two bands. Conclusions Our findings support a relationship between low gamma oscillations and PD tremor, and reinforce the principle that the subthalamic LFP is a rich signal that may contain information about the severity of multiple different Parkinsonian features.
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    Understanding the human pedunculopontine nucleus in Parkinson's disease
    (Springer, 2016-07) Fytagoridis, Anders; Silburn, Peter; Coyne, Terry; Thevathasan, Wesley
    This paper presents the Brisbane experience of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) in Parkinson's disease (PD). Clinical outcomes along with studies of the mechanisms and neurophysiology of PPN in PD patients with severe freezing of gait (FoG) and postural imbalance (PI) are summarised and presented. Our results indicate that PPN DBS improves FoG and falls in the relatively uncommon group of PD patients who respond well to medication other than for continuing on time FoG and falls. Our studies indicate that bilateral DBS is more beneficial than unilateral DBS, and that the more caudal region of the PPN seems preferable for stimulation. There is evidence that rapid-release programs for initiation and correction of gait and posture are modulated by the PPN, possibly to some extent independently of the cerebral cortex. These functions were found to be impaired in PD patients with severe FoG/PI, but to some extent corrected by bilateral PPN DBS.
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    What is the therapeutic mechanism of pedunculopontine nucleus stimulation in Parkinson's disease?
    (Elsevier, Inc., 2018-06) Thevathasan, Wesley; Moro, Elena
    Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is an experimental treatment for in Parkinson's disease (PD) which offers a fairly circumscribed benefit for gait freezing and perhaps balance impairment. The benefit on gait freezing is variable and typically incomplete, which may reflect that the clinical application is yet to be optimised or reflect a fundamental limitation of the therapeutic mechanism. Thus, a better understanding of the therapeutic mechanism of PPN DBS may guide the further development of this therapy. The available evidence supports that the PPN is underactive in PD due to a combination of both degeneration and excessive inhibition. Low frequency PPN DBS could enhance PPN network activity, perhaps via disinhibition. A clinical implication is that in some PD patients, the PPN may be too degenerate for PPN DBS to work. Reaction time studies report that PPN DBS mediates a very specific benefit on pre-programmed movement. This seems relevant to the pathophysiology of gait freezing, which can be argued to reflect impaired release of pre-programmed adjustments to locomotion. Thus, the benefit of PPN DBS on gait freezing could be akin to that mediated by external cues. Alpha band activity is a prominent finding in local field potential recordings from PPN electrodes in PD patients. Alpha band activity is implicated in the suppression of task irrelevant processes and thus the effective allocation of attention (processing resources). Attentional deficits are prominent in patients with PD and gait freezing and PPN alpha activity has been observed to drop out prior to gait freezing episodes and to increase with levodopa. This raises the hypothesis that PPN DBS could support or emulate PPN alpha activity and consequently enhance the allocation of attention. Although PPN DBS has not been convincingly shown to increase general alertness or attention, it remains possible that PPN DBS may enhance the allocation of processing resources within the motor system, or "motor attention". For example, this could facilitate the 'switching' of motor state between continuation of pattern generated locomotion towards the intervention of pre-programmed adjustments. However, if the downstream consequence of PPN DBS on movement is limited to a circumscribed unblocking of pre-programmed movement, then this may have a similarly circumscribed degree of benefit for gait. If this is the case, then it may be possible to identify patients who may benefit most from PPN DBS. For example, those in whom pre-programmed deficits are the major contributors to gait freezing.
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    Where and what is the PPN and what is its role in locomotion?
    (Oxford University Press on behalf of the Guarantors of Brain, 2015-05-01) Windels, Francois; Thevathasan, Wesley; Silburn, Peter; Sah, Pankaj
    This scientific commentary refers to ‘The integrative role of the pedunculopontine nucleus in human gait’, by Lau et al. (doi:10.1093/brain/awv047).