Medical Bionics - Research Publications

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    Clinical outcomes of deep brain stimulation for obsessive-compulsive disorder: Insight as a predictor of symptom changes.
    Acevedo, N ; Rossell, S ; Castle, D ; Groves, C ; Cook, M ; McNeill, P ; Olver, J ; Meyer, D ; Perera, T ; Bosanac, P (Wiley, 2024-02)
    AIM: Deep brain stimulation (DBS) is a safe and effective treatment option for people with refractory obsessive-compulsive disorder (OCD). Yet our understanding of predictors of response and prognostic factors remains rudimentary, and long-term comprehensive follow-ups are lacking. We aim to investigate the efficacy of DBS therapy for OCD patients, and predictors of clinical response. METHODS: Eight OCD participants underwent DBS stimulation of the nucleus accumbens (NAc) in an open-label longitudinal trial, duration of follow-up varied between 9 months and 7 years. Post-operative care involved comprehensive fine tuning of stimulation parameters and adjunct multidisciplinary therapy. RESULTS: Six participants achieved clinical response (35% improvement in obsessions and compulsions on the Yale Brown Obsessive Compulsive Scale (YBOCS)) within 6-9 weeks, response was maintained at last follow up. On average, the YBOCS improved by 45% at last follow up. Mixed linear modeling elucidated directionality of symptom changes: insight into symptoms strongly predicted (P = 0.008) changes in symptom severity during DBS therapy, likely driven by initial changes in depression and anxiety. Precise localization of DBS leads demonstrated that responders most often had their leads (and active contacts) placed dorsal compared to non-responders, relative to the Nac. CONCLUSION: The clinical efficacy of DBS for OCD is demonstrated, and mediators of changes in symptoms are proposed. The symptom improvements within this cohort should be seen within the context of the adjunct psychological and biopsychosocial care that implemented a shared decision-making approach, with flexible iterative DBS programming. Further research should explore the utility of insight as a clinical correlate of response. The trial was prospectively registered with the ANZCTR (ACTRN12612001142820).
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    Anatomical targeting for electrode localization in subthalamic nucleus deep brain stimulation: A comparative study
    Tonroe, T ; McDermott, H ; Pearce, P ; Acevedo, N ; Thevathasan, W ; Xu, SS ; Bulluss, K ; Perera, T (WILEY, 2023-09)
    BACKGROUND AND PURPOSE: 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. METHODS: The methods compared are direct visualization, red nucleus-based indirect targeting, mid-commissural point-based indirect targeting, and automated template-based targeting. This study assessed 226 hemispheres in 113 DBS recipients (39 females, 73 males, 62.2 ± 7.7 years). We utilized the electrode placement error (the Euclidean distance between the defined target and closest DBS electrode) as a metric for comparative analysis. Pairwise differences in electrode placement error across the four methods were compared using the Kruskal-Wallis H-test and Wilcoxon signed-rank tests. RESULTS: Interquartile ranges of the differences in electrode placement error spanned 1.18-1.56 mm. A Kruskal-Wallis H-test reported a statistically significant difference in the median of at least two groups (H(5) = 41.052, p < .001). Wilcoxon signed-rank tests reported statistically significant difference in two comparisons: direct visualization versus red nucleus-based indirect, and direct visualization versus automated template-based methods (T < 9215, p < .001). CONCLUSIONS: All methods were similarly discordant in their relative accuracy, despite having significant technical differences in their application. The differing protocols and technical aspects of each method, however, have the implication that one may be more practical depending on the clinical or research application at hand.
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    Flexible neural recording electrodes based on reduced graphene oxide interfaces
    Dong, M ; Chen, P ; Zhou, K ; Liu, M ; Thomas, S ; Coleman, HA ; Li, D ; Fallon, JB ; Majumder, M ; Parkington, HC ; Forsythe, JS (ELSEVIER SCIENCE SA, 2023-12-15)
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    Experienced Meditators Show Multifaceted Attention-Related Differences in Neural Activity
    Bailey, NW ; Baell, O ; Payne, JE ; Humble, G ; Geddes, H ; Cahill, I ; Hill, AT ; Chung, SW ; Emonson, M ; Murphy, OW ; Fitzgerald, PB (Springer, 2023-11-01)
    Objectives: Mindfulness meditation (MM) is suggested to improve attention. Research has explored this using the “attentional-blink” (AB) task, where stimuli are rapidly presented, and a second target stimulus (T2) is often missed if presented ~300 ms after an initial target stimulus (T1). Previous research has shown improved task accuracy during the AB task and altered neural activity following an intensive 3-month MM retreat. We tested whether these results replicated in a community sample of typical meditators. Method: Thirty-one mindfulness meditators and 30 non-meditators completed an AB task while electroencephalography (EEG) was recorded. Between-group comparisons were made for task accuracy, event-related potential activity (posterior-N2 and P3b), theta and alpha oscillatory phase synchronisation to stimuli presentation, and alpha-power. The primary aim was to examine effects within the time windows reported in previous research. Additional exploratory aims assessed effects across broader time windows. Results: No differences were detected in task accuracy or neural activity within our primary hypotheses. However, exploratory analyses showed posterior-N2 and theta phase synchronisation (where the phase of theta oscillations were synchronised to stimuli onset) effects indicating meditators showed a priority towards attending to T2 stimuli (p < 0.01). Meditators also showed more alpha-phase synchronisation, and lower alpha-power (with smaller amplitudes of activity in the alpha frequency) when processing T2 stimuli (p < 0.025). Conclusions: Our results showed multiple differences in neural activity that suggested enhanced attention in meditators. The neural activity patterns in meditators aligned with theoretical perspectives on activity associated with enhanced cognitive performance. These include enhanced alpha “gating” mechanisms (where alpha activity acts as a filter between sensory and higher order neural processes), increased oscillatory synchronisation to stimuli, and more equal allocation of neural activity across stimuli. However, meditators did not show higher task accuracy, nor were the effects consistent with our primary hypotheses or previous research. Preregistration: This study was not preregistered.
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    Developing the supraparticle technology for round window-mediated drug administration into the cochlea
    Gunewardene, N ; Ma, Y ; Lam, P ; Wagstaff, S ; Cortez-Jugo, C ; Hu, Y ; Caruso, F ; Richardsona, RT ; Wise, AK (ELSEVIER, 2023-09)
    The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as '(Chi/Alg)SPs', to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 μg of NT3 loaded per SP that weights ~50 μg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 μg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 μg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss.
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    Hybrid optogenetic and electrical stimulation for greater spatial resolution and temporal fidelity of cochlear activation
    Thompson, AC ; Wise, AK ; Hart, WL ; Needham, K ; Fallon, JB ; Gunewardene, N ; Stoddart, PR ; Richardson, RT (IOP PUBLISHING LTD, 2020-10)
    OBJECTIVE: Compared to electrical stimulation, optogenetic stimulation has the potential to improve the spatial precision of neural activation in neuroprostheses, but it requires intense light and has relatively poor temporal kinetics. We tested the effect of hybrid stimulation, which is the combination of subthreshold optical and electrical stimuli, on spectral and temporal fidelity in the cochlea by recording multiunit activity in the inferior colliculus of channelrhodopsin (H134R variant) transgenic mice. APPROACH: Pulsed light or biphasic electrical pulses were delivered to cochlear spiral ganglion neurons of acutely deafened mice, either as individual stimuli or as hybrid stimuli for which the timing of the electrical pulse had a varied delay relative to the start of the optical pulse. Response thresholds, spread of activation and entrainment data were obtained from multi-unit recordings from the auditory midbrain. MAIN RESULTS: Facilitation occurred when subthreshold electrical stimuli were applied at the end of, or up to 3.75 ms after subthreshold optical pulses. The spread of activation resulting from hybrid stimulation was significantly narrower than electrical-only and optical-only stimulation (p < 0.01), measured at equivalent suprathreshold levels of loudness that are relevant to cochlear implant users. Furthermore, temporal fidelity, measured as maximum following rates to 300 ms pulse trains bursts up to 240 Hz, was 2.4-fold greater than optical-only stimulation (p < 0.05). SIGNIFICANCE: By significantly improving spectral resolution of electrical- and optical-only stimulation and the temporal fidelity of optical-only stimulation, hybrid stimulation has the potential to increase the number of perceptually independent stimulating channels in a cochlear implant.
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    The effects of aging and musicianship on the use of auditory streaming cues
    Sauve, SA ; Marozeau, J ; Zendel, BR ; Fu, Q-J (PUBLIC LIBRARY SCIENCE, 2022-09-22)
    Auditory stream segregation, or separating sounds into their respective sources and tracking them over time, is a fundamental auditory ability. Previous research has separately explored the impacts of aging and musicianship on the ability to separate and follow auditory streams. The current study evaluated the simultaneous effects of age and musicianship on auditory streaming induced by three physical features: intensity, spectral envelope and temporal envelope. In the first study, older and younger musicians and non-musicians with normal hearing identified deviants in a four-note melody interleaved with distractors that were more or less similar to the melody in terms of intensity, spectral envelope and temporal envelope. In the second study, older and younger musicians and non-musicians participated in a dissimilarity rating paradigm with pairs of melodies that differed along the same three features. Results suggested that auditory streaming skills are maintained in older adults but that older adults rely on intensity more than younger adults while musicianship is associated with increased sensitivity to spectral and temporal envelope, acoustic features that are typically less effective for stream segregation, particularly in older adults.
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    Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats
    Payne, SC ; Romas, E ; Hyakumura, T ; Muntz, F ; Fallon, JB (FRONTIERS MEDIA SA, 2022-11-21)
    Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 μs pulse width, 50 μs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11-17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal-Wallis: P < 0.05). However, stimulated CIA rats (n = 5-6) had significantly decreased inflammatory scores and ankle swelling (Kruskal-Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.
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    Can brain signals and anatomy refine contact choice for deep brain stimulation in Parkinson's disease?
    Xu, SS ; Lee, W-L ; Perera, T ; Sinclair, NC ; Bulluss, KJ ; McDermott, HJ ; Thevathasan, W (BMJ PUBLISHING GROUP, 2022-12)
    INTRODUCTION: Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS. METHODS: We evaluated 92 hemispheres of 47 patients with Parkinson's disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms. RESULTS: The probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance. CONCLUSION: This work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.
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    Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome
    Dalic, LJ ; Warren, AEL ; Spiegel, C ; Thevathasan, W ; Roten, A ; Bulluss, KJ ; Archer, JS (WILEY, 2022-12)
    OBJECTIVE: Epilepsy treatment trials typically rely on seizure diaries to determine seizure frequency, but these are time-consuming and difficult to maintain accurately. Fast, reliable, and objective biomarkers of treatment response are needed, particularly in Lennox-Gastaut syndrome (LGS), where high seizure frequency and comorbid cognitive and behavioral issues are additional obstacles to accurate diary-keeping. Here, we measured generalized paroxysmal fast activity (GPFA), a key interictal electrographic feature of LGS, and correlated GPFA burden with seizure diaries during a thalamic deep brain stimulation (DBS) treatment trial (Electrical Stimulation of the Thalamus in Epilepsy of Lennox-Gastaut Phenotype [ESTEL]). METHODS: GPFA and electrographic seizure counts from intermittent, 24-h electroencephalograms (EEGs) were compared to 3-month diary-recorded seizure counts in 17 young adults with LGS (mean age ± SD = 24.9 ± 6.6) in the ESTEL study, a randomized clinical trial of DBS lasting 12 months (comprising a 3-month baseline and 9 months of postimplantation follow-up). RESULTS: Baseline median seizures measured by diaries numbered 2.6 (interquartile range [IQR] = 1.4-5) per day, compared to 284 (IQR = 120.5-360) electrographic seizures per day, confirming that diaries capture only a small fraction of seizure burden. Across all patient EEGs, the average number of GPFA discharges per hour of sleep was 138 (IQR =72-258). GPFA duration and frequency, quantified over 2-h windows of sleep EEG, were significantly associated with diary-recorded seizure counts over 3-month intervals (p < .001, η2 p  = .30-.48). For every GPFA discharge, there were 20-25 diary seizures witnessed over 3 months. There was high between-patient variability in the ratio between diary seizure burden and GPFA burden; however, within individual patients, the ratio was similar over time, such that the percentage change from pre-DBS baseline in seizure diaries strongly correlated with the percentage change in GPFA. SIGNIFICANCE: When seeking to optimize treatment in patients with LGS, monitoring changes in GPFA may allow rapid titration of treatment parameters, rather than waiting for feedback from seizure diaries.