Biomedical Engineering - Research Publications
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ItemNo Preview AvailableRisk of sudden unexpected death in epilepsy (SUDEP) with lamotrigine and other sodium channel-modulating antiseizure medications(WILEY, 2023-06)OBJECTIVE: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. METHODS: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. RESULTS: Proportions of cases and controls prescribed lamotrigine (P = 0.166), one NaM-ASM (P = 0.80), or ≥2NaM-ASMs (P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56; P = 0.054), one NaM-ASM (aHR = 0.8; P = 0.588) or ≥2 NaM-ASMs (aHR = 0.49; P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24; P = 0.031) or NaM-ASM use (aHR = 2.25; P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results. SIGNIFICANCE: This study provides additional evidence that lamotrigine and other NaM-ASMs are unlikely to be associated with an increased long-term risk of SUDEP, up to 16 years post-EMU admission.
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ItemP015 The effects of cathodal transcranial direct current stimulation in patienst with focal epilepsy (a pilot study)‘(Elsevier, 2017-03)Introduction: Over 65 million people live with epilepsy worldwide. Unfortunately, seizures can not be adequately controlled in a third of the affected individuals. Therefore, there is a definite need for adjunctive or alternative therapeutic approaches in this group of patients to control the recurrence of seizure attacks. Modulation of dysfunctional electrical brain activity by transcranial direct current stimulation (tDCS) seems to be a potentially valuable non-invasive alternative for epilepsy treatment in this population. Objectives: This pilot study aimed to assess the effects of a novel protocol called within-session repeated c-tDCS (9 min treatment - 20 min rest - 9 min treatment) on patients with focal epilepsy. Method: We conducted a small pilot study in patients admitted to the Video-EEG Monitoring Unit at the Royal Melbourne Hospital and as out patients at this hospital or St Vincent Hospital. Thirty patients have participated in this study to date. Twenty patients with focal epilepsy received one session of c-tDCS (9–20-9 protocol) over the temporal lobe in the affected hemisphere. One participant received c-tDCS on two consecutive days. The other nine patients received one session of sham tDCS with the same electrode montage and protocol. Short interval intracortical inhibition or SICI was measured with paired-pulse transcranial magnetic stimulation (TMS) before and after the tDCS intervention in 18 participants. Motor evoked potentials were recorded from first dorsal interosseous muscle in these participants. Participants were asked to record the time and the number of their seizures post tDCS treatment for 4 weeks in a seizure diary. Twenty-four participants returned their diaries. Results: All patients tolerated the c-tDCS protocol very well. One-way ANOVA showed that SICI was increased significantly in the experimental group compared to the sham group (F = 10.3, p = 0.005) (Fig. 1). The mean response ratio was −48.4 (SD = 54) for the experimental group vs. −8.3 (SD = 16.7) for sham group
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ItemStargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011-04)Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.
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ItemAssociation Between Psychiatric Comorbidities and Mortality in Epilepsy(LIPPINCOTT WILLIAMS & WILKINS, 2021-10)OBJECTIVE: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. METHODS: A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. RESULTS: Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02-1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. CONCLUSION: The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.
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ItemStandardized Brain MRI Acquisition Protocols Improve Statistical Power in Multicenter Quantitative Morphometry Studies(WILEY, 2020-01)BACKGROUND AND PURPOSE: In this study, we used power analysis to calculate required sample sizes to detect group-level changes in quantitative neuroanatomical estimates derived from MRI scans obtained from multiple imaging centers. Sample size estimates were derived from (i) standardized 3T image acquisition protocols and (ii) nonstandardized clinically acquired images obtained at both 1.5 and 3T as part of the multicenter Human Epilepsy Project. Sample size estimates were compared to assess the benefit of standardizing acquisition protocols. METHODS: Cortical thickness, hippocampal volume, and whole brain volume were estimated from whole brain T1-weighted MRI scans processed using Freesurfer v6.0. Sample sizes required to detect a range of effect sizes were calculated using (i) standard t-test based power analysis methods and (ii) a nonparametric bootstrap approach. RESULTS: A total of 32 participants were included in our analyses, aged 29.9 ± 12.62 years. Standard deviation estimates were lower for all quantitative neuroanatomical metrics when assessed using standardized protocols. Required sample sizes per group to detect a given effect size were markedly reduced when using standardized protocols, particularly for cortical thickness changes <.2 mm and hippocampal volume changes <10%. CONCLUSIONS: The use of standardized protocols yielded up to a five-fold reduction in required sample sizes to detect disease-related neuroanatomical changes, and is particularly beneficial for detecting subtle effects. Standardizing image acquisition protocols across scanners prior to commencing a study is a valuable approach to increase the statistical power of multicenter MRI studies.
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ItemEtiologies and characteristics of refractory status epilepticus cases in different areas of the world: Results from a global audit(WILEY, 2018-10)To describe the demographics, etiologies, types of status epilepticus (SE), and outcomes in people with refractory and super-refractory SE from around the world, we prospectively collected cases of refractory SE (RSE) treated with continuous intravenous anesthetic drugs in an intensive care unit setting through online questionnaires using "active surveillance." We collected information about 776 cases of RSE in 50 countries over 4 years. Control of SE was achieved in 74% of the cases. Neurologic outcomes were poor in 41% of patients, and 24% died. Good outcome was associated with younger age and a history of epilepsy. Etiology strongly influenced the outcome. Patients from Asia were younger, more frequently presented with convulsive SE, and were more frequently affected by infectious etiologies when compared with patients from Europe and the Americas. Despite these differences, outcomes were similar in all countries. Demographics of patients with RSE in a global audit are similar to those in prior single center series, providing evidence of generalizability of those studies. Important differences exist among patients with RSE from different regions of the world, but these do not seem to significantly influence patient outcomes.
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ItemWhite matter changes following experimental pediatric traumatic brain injury: an advanced diffusion-weighted imaging investigation(Springer (part of Springer Nature), 2021-01-07)Pediatric traumatic brain injury (pTBI) is a major community health concern. Due to ongoing maturation, injury to the brain at a young age can have devastating consequences in later life. However, how pTBI affects brain development, including white matter maturation, is still poorly understood. Here, we used advanced diffusion weighted imaging (DWI) to assess chronic white matter changes after experimental pTBI. Mice at post-natal day 21 sustained a TBI using the controlled cortical impact model and magnetic resonance imaging (MRI) was performed at 6 months post-injury using a 4.7 T Bruker scanner. Four diffusion shells with 81 directions and b-values of 1000, 3000, 5000, and 7000s/mm2 were acquired and analyzed using MRtrix3 software. Advanced DWI metrics, including fiber density, fiber cross-section and a combined fiber density and cross-section measure, were investigated together with three track-weighted images (TWI): the average pathlength map, mean curvature and the track density image. These advanced metrics were compared to traditional diffusion tensor imaging (DTI) metrics which indicated that TBI injured mice had reduced fractional anisotropy and increased radial diffusivity in the white matter when compared to age-matched sham controls. Consistent with previous findings, fiber density and TWI metrics appeared to be more sensitive to white matter changes than DTI metrics, revealing widespread reductions in fiber density and TWI metrics in pTBI mice compared to sham controls. These results provide additional support for the use of advanced DWI metrics in assessing white matter degeneration following injury and highlight the chronic outcomes that can follow pTBI.
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ItemMotor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience(BMJ PUBLISHING GROUP, 2021-02)BACKGROUND: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. METHODS: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. RESULTS: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. CONCLUSION: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.
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ItemBone Health in Rats With Temporal Lobe Epilepsy in the Absence of Anti-Epileptic Drugs(Frontiers Media, 2019-10-29)Rationale: Epilepsy patients often exhibit reduced bone mineral density and are at an increased risk of bone fracture. Whether these bone abnormalities are due to the use of anti-epileptic drugs (AED’s) or the disease itself is unknown. For example, although decreased bone health in epilepsy patients is generally attributed to the use of AED’s, seizures can also trigger a number of physiological processes that have the potential to affect bone. Therefore, to assess whether bone abnormalities occur in epilepsy in the absence of AED’s, the current study investigated mechanical characteristics and trabecular bone morphology in rats with chronic temporal lobe epilepsy. Methods: Ten-week old male Wistar rats underwent kainic acid-induced status epilepticus (SE; n = 7) or a sham procedure (n = 9). Rats were implanted with EEG recording electrodes at nine weeks post-SE, and video-EEG was continuously recorded for one week at 10- and 22-weeks post-SE to confirm that SE rats had spontaneous seizures. Open-field testing to assess locomotion was conducted at 23-weeks post-SE. At 24-weeks post-SE, rats were euthanized and tibia were extracted to determine trabecular morphology by micro-computed tomography (µCT), while femurs were used to investigate mechanical properties via 3-point bending. Results: All post-SE rats had spontaneous seizures at 10- and 22-weeks post-SE, while none of the sham rats had seizures. µCT trabecular analysis of tibia revealed no differences in total volume, bone volume, bone volume fraction, trabecular number, or trabecular separation between post-SE or sham rats, although post-SE rats did have increased trabecular thickness. There were also no group differences in total distance travelled in the open field suggesting that activity levels did not account for the increased trabecular thickness. In addition, no differences in mechanical properties of femurs were observed between the two groups. Conclusion: There was a lack of overt bone abnormalities in rats with chronic temporal lobe epilepsy in the absence of AED treatment. Although further studies are still needed, these findings may have important implications towards understanding the source (e.g., AED treatments) of bone abnormalities in epilepsy patients.