Using a standalone ear-EEG device for focal-onset seizure detection.

BACKGROUND: Seizure detection is challenging outside the clinical environment due to the lack of comfortable, reliable, and practical long-term neurophysiological monitoring devices. We developed a novel, discreet, unobstructive in-ear sensing system that enables long-term electroencephalography (EEG) recording. This is the first study we are aware of that systematically compares the seizure detection utility of in-ear EEG with that of simultaneously recorded intracranial EEG. In addition, we present a similar comparison between simultaneously recorded in-ear EEG and scalp EEG. METHODS: In this foundational research, we conducted a clinical feasibility study and validated the ability of the ear-EEG system to capture focal-onset seizures against 1255 hrs of simultaneous ear-EEG data along with scalp or intracranial EEG in 20 patients with refractory focal epilepsy (11 with scalp EEG, 8 with intracranial EEG, and 1 with both). RESULTS: In a blinded, independent review of the ear-EEG signals, two epileptologists were able to detect 86.4% of the seizures that were subsequently identified using the clinical gold standard EEG modalities, with a false detection rate of 0.1 per day, well below what has been reported for ambulatory monitoring. The few seizures not detected on the ear-EEG signals emanated from deep within the mesial temporal lobe or extra-temporally and remained very focal, without significant propagation. Following multiple sessions of recording for a median continuous wear time of 13 hrs, patients reported a high degree of tolerance for the device, with only minor adverse events reported by the scalp EEG cohort. CONCLUSIONS: These preliminary results demonstrate the potential of using ear-EEG to enable routine collection of complementary, prolonged, and remote neurophysiological evidence, which may permit real-time detection of paroxysmal events such as seizures and epileptiform discharges. This study suggests that the ear-EEG device may assist clinicians in making an epilepsy diagnosis, assessing treatment efficacy, and optimizing medication titration.

Disaster Preparedness: Hospital Pharmacy Strategy for Prioritized Inventory Management and Drug Procurement on Vancouver Island.

Disaster events can increase demand for medication supplies and interfere with supply chains, leading to compromised care in hospitals. Providing an organized response to an additional surge of disaster-related patients requires pre-planned emergency management procedures. Hospital pharmacists can address this with prioritized drug procurement and inventory management strategies which may improve the availability of key medications for a disaster response. Previous disaster events have provided insight on medications used to treat disaster-related injuries and exacerbations of medical conditions in emergency departments. This article provides a detailed description of Vancouver Island's hospital pharmacy strategy for the procurement and minimum stock levels of high priority medications in preparation for a disaster.

Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes.

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Where Do Parkinson's Disease Patients Look While Walking?

BACKGROUND: Parkinson's disease (PD) is associated with gait and visuomotor abnormalities, but it is not clear where PD patients look during ambulation. OBJECTIVE: We sought to characterize the visual areas of interest explored by PD patients, with and without freezing of gait (FOG), compared to healthy volunteers (HVs). METHODS: Using an eye-tracking device, we compared visual fixation patterns in 17 HVs and 18 PD patients, with and without FOG, during an ambulatory and a nonambulatory, computer-based task. RESULTS: During ambulation, PD patients with FOG fixated more on proximal areas of the ground and less on the target destination. PD patients without FOG displayed a fixation pattern more similar to that of HVs. Similar patterns were observed during the nonambulatory, computer-based task. CONCLUSIONS: Our findings suggest increased dependence on visual feedback from nearby areas in the environment in PD patients with FOG, even in the absence of motor demands. © 2022 International Parkinson and Movement Disorder Society.

Association of Epileptiform Abnormality on Electroencephalography with Development of Epilepsy After Acute Brain Injury.

BACKGROUND/OBJECTIVES: Epileptiform abnormalities (EA) on continuous electroencephalography (cEEG) are associated with increased risk of acute seizures; however, data on their association with development of long-term epilepsy are limited. We aimed to investigate the association of EA in patients with acute brain injury (ABI): ischemic or hemorrhagic stroke, traumatic brain injury, encephalitis, or posterior reversible encephalopathy syndrome, and subsequent development of epilepsy. METHODS: This was a retrospective, single-center study of patients with ABI who had at least 6 hours of cEEG during the index admission between 1/1/2017 and 12/31/2018 and at least 12 months of follow-up. We compared patients with EAs; defined as lateralized periodic discharges (LPDs), lateralized rhythmic delta activity (LRDA), generalized periodic discharges (GPDs), and sporadic interictal epileptiform discharges (sIEDs) to patients without EAs on cEEG. The primary outcome was the new development of epilepsy, defined as the occurrence of spontaneous clinical seizures following hospital discharge. Secondary outcomes included time to development of epilepsy and use of anti-seizure medications (ASMs) at the time of last follow-up visit. RESULTS: One hundred and one patients with ABI met study inclusion criteria. Thirty-one patients (30.7%) had EAs on cEEG. The median (IQR) time to cEEG was 2 (1-5) days. During a median (IQR) follow-up period of 19.1 (16.2-24.3) months, 25.7% of patients developed epilepsy; the percentage of patients who developed epilepsy was higher in those with EAs compared to those without EAs (41.9% vs. 18.6%, p = 0.025). Patients with EAs were more likely to be continued on ASMs during follow-up compared to patients without EAs (67.7% vs. 38.6%, p = 0.009). Using multivariable Cox regression analysis, after adjusting for age, mental status, electrographic seizures on cEEG, sex, ABI etiology, and ASM treatment on discharge, patients with EAs had a significantly increased risk of developing epilepsy compared to patients without EA (hazard ratio 3.39; 95% CI 1.39-8.26; p = 0.007). CONCLUSIONS: EAs on cEEG in patients with ABI are associated with a greater than three-fold increased risk of new-onset epilepsy. cEEG findings in ABI may therefore be a useful risk stratification tool for assessing long-term risk of seizures and serve as a biomarker for new-onset epilepsy.

Continuous Intraoperative Neurophysiological Monitoring of the Motor Pathways Using Depth Electrodes During Surgical Resection of an Epileptogenic Lesion: A Novel Technique.

BACKGROUND AND IMPORTANCE: Intraoperative neurophysiological monitoring of the motor pathways during epilepsy surgery is essential to safely achieve maximal resection of the epileptogenic zone. Motor evoked potential (MEP) recording is usually performed intermittently during resection using a handheld stimulator or continuously through an electrode array placed on the motor cortex. We present a novel variation of continuous MEP acquisition through previously implanted depth electrodes in the perirolandic cortex. CLINICAL PRESENTATION: A 60-yr-old woman with a history of a left frontal meningioma (World Health Organization [WHO] grade II) treated with surgical resection and radiation presented with residual right hemiparesis and refractory epilepsy. Imaging demonstrated a perirolandic lesion with surrounding edema and mass effect in the prior surgical site, suspicious for radiation necrosis versus tumor recurrence. Presurgical electrocorticography (ECoG) with orthogonal, stereotactically implanted depth electrodes (stereoelectroencephalography [SEEG]) of the perirolandic cortex captured seizure onsets from the supplementary motor area (SMA) and primary motor cortex (PMC). The patient underwent a left frontal craniotomy for repeat resection and tissue diagnosis. Intraoperative ECoG and MEPs were obtained continuously with direct cortical stimulation through the indwelling SEEG electrodes in the PMC. Maximal resection was achieved with preservation of direct cortical MEPs and without deterioration of her baseline hemiparesis. Biopsy revealed radiation necrosis. At 30-mo follow-up, the patient had only rare seizures (Engel class IIB). CONCLUSION: Intraoperative cortical MEP acquisition through implanted SEEG electrode arrays is a potentially safe and effective alternative approach to continuously monitor the motor pathways during the resection of a perirolandic epileptogenic lesion, without the need for surgical interruptions.

Baseline identification of clonal V(D)J sequences for DNA-based minimal residual disease detection in multiple myeloma.

Tracking of clonal immunoglobulin V(D)J rearrangement sequences by next generation sequencing is highly sensitive for minimal residual disease in multiple myeloma. However, previous studies have found variable rates of V(D)J sequence identification at baseline, which could limit tracking. Here, we aimed to define the factors influencing the identification of clonal V(D)J sequences. Bone marrow mononuclear cells from 177 myeloma patients underwent V(D)J sequencing by the LymphoTrack assays (Invivoscribe). As a molecular control for tumor cell content, we sequenced the samples using our in-house myeloma panel myTYPE. V(D)J sequence clonality was identified in 81% of samples overall, as compared with 95% in samples where tumor-derived DNA was detectable by myTYPE. Clonality was detected more frequently in patients with lambda-restricted disease, mainly because of increased detection of kappa gene rearrangements. Finally, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: From the initial pull used for aspirate smear, to the final pull that is commonly used for research. In conclusion, baseline clonality detection rates of 95% or higher are feasible in multiple myeloma. Optimal performance depends on the use of good quality aspirates and/or subsequent tumor cell enrichment.

Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

Creative Music Therapy in an Acute Care Setting for Older Patients with Delirium and Dementia.

BACKGROUND/AIMS: The acute hospital ward can be unfamiliar and stressful for older patients with impaired cognition, rendering them prone to agitation and resistive to care. Extant literature shows that music therapy can enhance engagement and mood, thereby ameliorating agitated behaviours. This pilot study evaluates the impact of a creative music therapy (CMT) programme on mood and engagement in older patients with delirium and/or dementia (PtDD) in an acute care setting. We hypothesize that CMT improves engagement and pleasure in these patients. METHODS: Twenty-five PtDD (age 86.5 ± 5.7 years, MMSE 6/30 ± 5.4) were observed for 90 min (30 min before, 30 min during, and 30 min after music therapy) on 3 consecutive days: day 1 (control condition without music) and days 2 and 3 (with CMT). Music interventions included music improvisation such as spontaneous music making and playing familiar songs of patient's choice. The main outcome measures were mood and engagement assessed with the Menorah Park Engagement Scale (MPES) and Observed Emotion Rating Scale (OERS). RESULTS: Wilcoxon signed-rank test showed a statistically significant positive change in constructive and passive engagement (Z = 3.383, p = 0.01) in MPES and pleasure and general alertness (Z = 3.188,p = 0.01) in OERS during CMT. The average pleasure ratings of days 2 and 3 were higher than those of day 1 (Z = 2.466, p = 0.014). Negative engagement (Z = 2.582, p = 0.01) and affect (Z = 2.004, p = 0.045) were both lower during CMT compared to no music. CONCLUSION: These results suggest that CMT holds much promise to improve mood and engagement of PtDD in an acute hospital setting. CMT can also be scheduled into the patients' daily routines or incorporated into other areas of care to increase patient compliance and cooperation.

Marked olfactory impairment in idiopathic intracranial hypertension.

OBJECTIVE: Many long-duration astronauts develop signs of elevated intracranial pressure and have neuro-ophthalmological findings similar to idiopathic intracranial hypertension (IIH) patients. Some also present with nasal congestion and subjective olfactory impairment. We prospectively evaluated olfactory function in IIH patients and the effect of 6° head-down tilt, which simulates the headward fluid shifting in microgravity, as spaceflight analogues. DESIGN: Olfaction was tested for all subjects in upright and 6° head-down tilt positions using two different measures: University of Pennsylvania Smell Identification Test and Olfactory Threshold Sniffin' Sticks with phenylethyl alcohol. RESULTS: IIH patients (n=19) had significant impairment on both olfactory measures compared with matched controls (n=19). The olfactory threshold dilution levels were 9.07 (95% CI 1.85 to 5.81) and 3.83 (95% CI 7.04 to 11.10), p=0.001, and smell identification scores were 35.61 (95% CI 34.03 to 37.18) and 32.47 (95% CI 30.85 to 34.09), p=0.008, for control and IIH subjects, respectively. The threshold detection was mildly impaired in head-down tilt compared with upright position in the combined subjects (6.05 (95% CI 4.58 to 7.51) vs 6.85 (95% CI 5.43 to 8.27), p=0.004). CONCLUSIONS: We demonstrated that IIH patients have marked impairment in olfactory threshold levels, out of proportion to smell identification impairment. There was also impairment in olfactory threshold in head-down tilt compared with upright positioning, but not for smell identification. The underlying mechanisms for olfactory threshold dysfunction in IIH patients need further exploration.

Nostril-specific olfactory modulation of visual perception in binocular rivalry.

It is known that olfaction and vision can work in tandem to represent object identities. What is yet unclear is the stage of the sensory processing hierarchy at which the two types of inputs converge. Here we study this issue through a well established visual phenomenon termed binocular rivalry. We show that smelling an odor from one nostril significantly enhances the dominance time of the congruent visual image in the contralateral visual field, relative to that in the ipsilateral visual field. Moreover, such lateralization-based enhancement extends to category selective regions so that when two images of words and human body, respectively, are engaged in rivalry in the central visual field, smelling natural human body odor from the right nostril increases the dominance time of the body image compared with smelling it from the left nostril. Semantic congruency alone failed to produce this effect in a similar setting. These results, taking advantage of the anatomical and functional lateralizations in the olfactory and visual systems, highlight the functional dissociation of the two nostrils and provide strong evidence for an object-based early convergence of olfactory and visual inputs in sensory representations.

Binaral rivalry in the presence of visual perceptual and semantic influences.

When two different odorants are presented simultaneously to the two nostrils, we experience alternations in olfactory percepts, a phenomenon called binaral rivalry. Little is known about the nature of such alternations. Here we investigate this issue by subjecting unstable and stable olfactory percepts to the influences of visual perceptual or semantic cues as participants engage in simultaneous samplings of either two different odorants (binaral) or a single odorant and water (mononaral), one to each nostril. We show that alternations of olfactory percepts in the binaral setting persist in the presence of visual perceptual and semantic modulations. We also show that perceptual cues have a stronger effect than semantic cues in the binaral case, whereas their effects are comparable in the mononaral setting. Our findings provide evidence that an inherent, stimulus-driven process underlies binaral rivalry despite its general susceptibility to top-down influences.

Assessment of drug-induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96-well platform.

High-throughput applicable screens for identifying drug-induced mitochondrial impairment are necessary in the pharmaceutical industry. Hence, we evaluated the XF96 Extracellular Flux Analyzer, a 96-well platform that measures changes in the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells. The sensitivity of the platform was bench-marked with known modulators of oxidative phosphorylation and glycolysis. Sixteen therapeutic agents were screened in HepG2 cells for mitochondrial effects. Four of these compounds, thiazolidinediones, were also tested in primary feline cardiomyocytes for cell-type specific effects. We show that the XF96 platform is a robust, sensitive system for analyzing drug-induced mitochondrial impairment in whole cells. We identified changes in cellular respiration and acidification upon addition of therapeutic agents reported to have a mitochondrial effect. Furthermore, we show that respiration and acidification changes upon addition of the thiazoldinediones were cell-type specific, with the rank order of mitochondrial impairment in whole cells being in accord with the known adverse effects of these drugs.

Reduced recruitment of orbitofrontal cortex to human social chemosensory cues in social anxiety.

Social anxiety refers to the prevalent and debilitating experience of fear and anxiety of being scrutinized in social situations. It originates from both learned (e.g. adverse social conditioning) and innate (e.g. shyness) factors. Research on social anxiety has traditionally focused on negative emotions induced by visual and auditory social cues in socially anxious clinical populations, and posits a dysfunctional orbitofrontal-amygdala circuit as a primary etiological mechanism. Yet as a trait, social anxiety is independent of one's specific emotional state. Here we probe the neural substrate of intrinsic social anxiety by employing a unique type of social stimuli, airborne human social chemosensory cues that are inherently social, ubiquitously present, and yet operating below verbal awareness. We show that the adopted social chemosensory cues were not perceived to be human-related, did not differentially bias self-report of anxiety or autonomic nervous system responses, yet individuals with elevated social anxiety demonstrated a reduced recruitment of the orbitofrontal cortex to social chemosensory cues. No reciprocal activity in the amygdala was observed. Our findings point to an intrinsic neural substrate underlying social anxiety that is not associated with prior adverse social conditioning, thereby providing the first neural evidence for the inherent social aspect of this enigmatic phenomenon.

Entangled chemosensory emotion and identity: familiarity enhances detection of chemosensorily encoded emotion.

Biologically significant, natural human body odors covey emotion and identity--two qualities shown to build on dissociated modules in face and voice perceptions. To what extent such segregation applies to chemosensory processing of body odors has hardly been studied. The current study probes this issue by recruiting heterosexual couples, who are genetically independent yet sexually and emotionally engaged to one another, as both odor donors and odor judges, and comparing their sensitivities to the chemosensory emotional cues from their partner vs. those from opposite-sex strangers. We demonstrate that familiarity subconsciously sharpens one's sensitivity to chemosensory emotional cues, which increases as a function of the time couples have spent together. Nevertheless, the specific chemosensory identity and emotional content remain undelineated and inaccessible to verbal awareness. Our findings reveal a different pattern from those of face and voice perceptions and provide insights into the mechanisms and interplays of chemosensory emotion and identity processings.

Olfaction modulates visual perception in binocular rivalry.

Vision is widely accepted as the dominant sense in larger primates including humans, whereas olfaction is often considered a vestigial sense yielding only obscure object representations [1]. It is well documented that vision drives olfactory perception [2, 3], but there has been little indication that olfaction could modulate visual perception. Here we introduce smells to a well-established visual phenomenon termed binocular rivalry, perceptual alternations that occur when distinctively different images are separately presented to the two eyes [4]. We show that an odorant congruent to one of the competing images prolongs the time that image is visible and shortens its suppression time in a manner that is automatic, essentially independent of cognitive control, and partly subconscious. Our findings provide the first direct evidence that an olfactory cue biases the dynamic process of binocular rivalry, thereby demonstrating olfactory modulation of visual perception-an effect that has been hitherto unsuspected.