Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Touch-screen automatisms in the digital age.

OBJECTIVE: To describe a novel set of gestural automatisms related to the use of digital screens on smartphones and tablets in patients with epilepsy. METHODS: Representative patients were selected from among those admitted to the Epilepsy Monitoring Unit at the Toronto Western Hospital between April 2016 and January 2020, and included if they exhibited automatisms clearly related to or mimicking digital device use. RESULTS: In total 5 patients were included, 4 female. All had temporal lobe epilepsy: 2 had left mesial temporal sclerosis and 3 had normal imaging. Nearly equal numbers of seizures began with right (5/9) and left (4/9) temporal onsets, with most automatisms occurring after seizure propagation to bilateral temporal involvement (6/9). Left-handed automatisms were most common (8/9). The majority of the automatisms (7/9) were perseverative on device usage prior to the seizure. CONCLUSION: Gestural automatisms appear related to the contemporary lived experience, culture, and habitual behaviour of patients with epilepsy. In the modern era, the use of smartphones and tablets are both common and habitual for many, and this case series shows that touch-screen automatisms may be added to the semiological panoply of temporal lobe seizures.

Intraoperative hemodialysis with supra- and infradiaphragmatic catheters for liver transplantation.

PURPOSE: The benefits of intraoperative dialysis during orthotopic liver transplantation remain controversial. In patients with anuric renal failure and portopulmonary hypertension, maintaining venous return during caval clamping and unclamping along with minimizing fluid overload is critical to avoiding right ventricular strain and failure. CLINICAL FEATURES: We present the case of a 54-yr-old female who underwent orthotopic liver transplantation for alcohol-related liver disease with acute decompensation including severe hepatorenal syndrome (anuric requiring dialysis), probable hepatopulmonary syndrome, moderate pulmonary hypertension (right ventricular systolic pressure, 44 mm Hg), hepatic encephalopathy (grade 2), and esophageal varices. Prior to incision, pulmonary arterial pressures were 48/28 (mean, 35) mm Hg with a central venous pressure of 30 mm Hg, cardiac output of 7.4 L·min-1, and pulmonary vascular resistance of 98 dynes·sec·cm-5. In the context of right ventricular strain and volume overload observed on transthoracic echocardiography, we inserted an additional dialysis catheter into the right femoral vein. We initiated dialysis using the two catheters as a circuit (femoral line to the dialysis machine; blood was reinjected via the subclavian line) acting as a limited venovenous bypass, allowing right ventricular offloading and hemodialysis throughout the case. We removed 4.5 L via hemodialysis during the surgery, while avoiding acidosis, hyperkalemia, and sodium shifts. The patient tolerated reperfusion adequately despite pre-existing right ventricular dilation and dysfunction. CONCLUSION: We report on the use two hemodialysis catheters in a patient undergoing orthotopic liver transplantation as a circuit for simultaneous anuric hepatorenal syndrome and moderate pulmonary hypertension with right ventricular dilation and dysfunction. We believe this technique was instrumental in the patient's successful transplant.

RéSUMé: OBJECTIF: Les avantages de la dialyse peropératoire pendant une transplantation hépatique orthotopique demeurent controversés. Chez la patientèle atteinte d'insuffisance rénale anurique et d'hypertension portopulmonaire, il est essentiel de maintenir le retour veineux pendant le clampage et le déclampage de la veine cave ainsi que de minimiser la surcharge hydrique, afin d'éviter la déformation et l'insuffisance ventriculaires droites. CARACTéRISTIQUES CLINIQUES : Nous présentons le cas d'une femme de 54 ans qui a bénéficié d'une transplantation hépatique orthotopique pour une maladie hépatique liée à l'alcool avec une décompensation aiguë comprenant un syndrome hépatorénal sévère (anurie nécessitant une dialyse), un syndrome hépatopulmonaire probable, une hypertension pulmonaire modérée (pression systolique ventriculaire droite, 44 mm Hg), une encéphalopathie hépatique (grade 2) et des varices œsophagiennes. Avant l'incision, les pressions artérielles pulmonaires étaient de 48/28 (moyenne, 35) mm Hg avec une pression veineuse centrale de 30 mm Hg, un débit cardiaque de 7,4 L·min−1 et une résistance vasculaire pulmonaire de 98 dynes·sec·cm−5. Dans le contexte de la déformation ventriculaire et de la surcharge volémique droites observées à l'échocardiographie transthoracique, nous avons inséré un cathéter de dialyse supplémentaire dans la veine fémorale droite. Nous avons amorcé la dialyse en créant un circuit avec les deux cathéters (ligne fémorale en direction de l'appareil de dialyse; sang réinjecté via la ligne sous-clavière) agissant comme un pontage veino-veineux limité, permettant la décharge du ventricule droit et l'hémodialyse tout au long du cas. Nous avons retiré 4,5 L par hémodialyse pendant la chirurgie, tout en évitant l'acidose, l'hyperkaliémie et les changements en sodium plasmatique. La patiente a toléré la reperfusion de manière adéquate malgré la dilatation et le dysfonctionnement préexistants du ventricule droit. CONCLUSION: Nous rapportons l'utilisation de deux cathéters d'hémodialyse pour créer un circuit chez une patiente bénéficiant d'une transplantation hépatique orthotopique pour le traitement d'un syndrome hépatorénal anurique simultané à une hypertension pulmonaire modérée avec dilatation et dysfonctionnement du ventricule droit. Nous pensons que cette technique a joué un rôle déterminant dans la réussite de la greffe chez la patiente.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. METHODS: Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2 mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. RESULTS: Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p < .0001) in three cases and electrographic seizures (3.83/h to 0/h, p < .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. SIGNIFICANCE: Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

Attributable Perioperative Cost of Frailty after Major, Elective Noncardiac Surgery: A Population-based Cohort Study.

BACKGROUND: Patients with frailty consistently experience higher rates of perioperative morbidity and mortality; however, costs attributable to frailty remain poorly defined. This study sought to identify older patients with and without frailty using a validated, multidimensional frailty index and estimated the attributable costs in the year after major, elective noncardiac surgery. METHODS: The authors conducted a retrospective population-based cohort study of all patients 66 yr or older having major, elective noncardiac surgery between April 1, 2012, and March 31, 2018, using linked health data obtained from an independent research institute (ICES) in Ontario, Canada. All data were collected using standard methods from the date of surgery to the end of 1-yr follow-up. The presence or absence of preoperative frailty was determined using a multidimensional frailty index. The primary outcome was total health system costs in the year after surgery using a validated patient-level costing method capturing direct and indirect costs. Secondary outcomes included costs to postoperative days 30 and 90 along with sensitivity analyses and evaluation of effect modifiers. RESULTS: Of 171,576 patients, 23,219 (13.5%) were identified with preoperative frailty. Unadjusted costs were higher among patients with frailty (ratio of means 1.79, 95% CI 1.76 to 1.83). After adjusting for confounders, an absolute cost increase of $11,828 Canadian dollar (ratio of means 1.53; 95% CI, 1.51 to 1.56) was attributable to frailty. This association was attenuated with additional control for comorbidities (ratio of means 1.24, 95% CI, 1.22 to 1.26). Among contributors to total costs, frailty was most strongly associated with increased postacute care costs. CONCLUSIONS: For patients with preoperative frailty having elective surgery, the authors estimate that attributable costs are increased 1.5-fold in the year after major, elective noncardiac surgery. These data inform resource allocation for patients with frailty.

Hospital-, anaesthetist-, and patient-level variation in peripheral nerve block utilisation for hip fracture surgery: a population-based cross-sectional study.

BACKGROUND: Unwarranted variation in anaesthesia practice is associated with adverse outcomes. Despite high-certainty evidence of benefit, a minority of hip fracture surgery patients receive a peripheral nerve block. Our objective was to estimate variation in peripheral nerve block use at the hospital, anaesthetist, and patient levels, while identifying predictors of peripheral nerve block use in hip fracture patients. METHODS: After protocol registration (https://osf.io/48bvp/), we conducted a population-based cross-sectional study using linked administrative data in Ontario, Canada. We included adults >65 yr of age having emergency hip fracture surgery from April 1, 2012 to March 31, 2018. Logistic mixed models were used to estimate the variation in peripheral nerve block use attributable to hospital-, anaesthetist-, and patient-level factors with use of peripheral nerve block, quantified using the variance partition coefficient and median odds ratio. Predictors of peripheral nerve block use were estimated and temporally validated. RESULTS: Of 50 950 patients, 9144 (18.5%) received a peripheral nerve block within 1 day of surgery. Patient-level factors accounted for 14% of variation, whereas 42% and 44% were attributable to the hospital and anaesthetist providing care, respectively. The median odds ratio for receiving a peripheral nerve block was 5.73 at the hospital level and 5.97 at the anaesthetist level. No patient factors had large associations with receipt of a peripheral nerve block (odds ratios significant at the 5% level ranged from 0.86 to 1.35). CONCLUSIONS: Patient factors explain the minimal variation in peripheral nerve block use for hip fracture surgery. Interventions to increase uptake of peripheral nerve blocks for hip fracture patients will likely need to focus on structures and processes at the hospital and anaesthetist levels.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

Demographic differences in Canadian medical students' motivation and confidence to promote physical activity.

BACKGROUND: Physical activity (PA) remains under prescribed by physicians. Motivation and confidence are clear drivers of frequency of promoting PA. Research shows demographic differences in physicians' preventive practices, yet none have included medical students who form habits during training. OBJECTIVES: Study objectives were to (i) examine how Canadian medical students' motivation to recommend PA to future patients differs according to six demographic variables (i.e. gender, ethnicity, year of study, university, proposed specialty and academic background) and (ii) examine how Canadian medical students' confidence to recommend PA to future patients differs according to these same demographic variables. METHODS: A cross-sectional design was used. First to fourth year medical students from three medical schools responded to an online survey (N = 221). RESULTS: Female participants were more motivated to counsel patients on PA and refer to an exercise specialist compared to males (P < 0.01). Second year students were more motivated to assess a patients' level of PA compared to third and fourth year students (P < 0.01). Students pursuing family medicine were more confident to assess and counsel compared to students pursuing paediatrics (P < 0.01). CONCLUSION: Given that motivation and confidence have a positive influence on frequency-promoting PA, these results suggest where future efforts should focus, to improve PA promotion in medical practice. Physical inactivity continues to be a major issue worldwide, and medical students as future physicians have a unique opportunity to enhance PA amongst the population.

Logging in: a comparative analysis of electronic health records versus anesthesia resident-driven logbooks.

PURPOSE: Resident logbooks (RLBs) documenting clinical case exposure are widespread in medical education despite evidence of poor accuracy. Electronic health records (e.g., anesthesia information management systems [AIMS]) may provide advantages for auditing longitudinal case exposure. We evaluated the agreement between AIMS and RLBs for tracking case exposure during anesthesiology residency. METHODS: We performed a historical cohort study with anesthesiology residents (2011-2018, all of whom used a RLB contemporaneously with AIMS) working in a multisite academic health sciences network. The primary outcome was total case-load logging; secondary outcomes were volumes for seven surgical specialties (general, gynecology, neuro, orthopedic, thoracic, urology, and vascular surgery). Correlation of case numbers tracked by AIMS vs RLB was assessed using Pearson correlation; agreement was determined using Bland-Altman plots and intraclass correlation coefficients (ICC). RESULTS: Data from 27 anesthesiology residents were collected. Overall, mean (standard deviation) case numbers were generally greater with AIMS vs RLB [649 (103) vs 583 (191); P = 0.049). Total case volumes between systems had moderate correlation (r = 0.50) and agreement (intraclass correlation coefficient [ICC], 0.42; 95% CI, 0.34 to 0.59). Bland-Altman plots showed variable agreement between AIMS and RLB data [mean (SD) bias = 66 (166) cases]. For general, gynecology, neuro, orthopedic, thoracic, urology, and vascular surgery, there was a range of poor to moderate agreement (ICC, 0.23-0.57) between AIMS and RLB. CONCLUSION: For anesthesiology resident case-logging, the number of cases logged in an AIMS was higher with lower variance compared with RLBs. Anesthesia information management systems vs RLB data showed low-moderate correlation and agreement. Given the additional time and resources required for RLBs, AIMS may be a superior method for tracking cases where available.

RéSUMé: OBJECTIF: Les logbooks des résidents documentant leur exposition à des cas cliniques sont répandus dans la formation médicale et ce, malgré des données probantes déplorant leur manque de précision. Les dossiers médicaux informatisés (par ex., les systèmes de gestion de l'information en anesthésie [SGIA]) pourraient présenter des avantages pour le contrôle de l'exposition longitudinale des résidents aux cas. Notre étude a évalué la concordance entre les SGIA et les logbooks pour l'exposition aux cas pendant la résidence en anesthésiologie. MéTHODE: Nous avons réalisé une étude de cohorte historique auprès de résidents en anesthésiologie (2011­2018, tous les résidents ayant utilisé un logbook simultanément aux SGIA) travaillant dans un réseau universitaire de sciences de la santé multisite. Le critère d'évaluation principal était l'enregistrement du nombre de cas total; les critères d'évaluation secondaires comprenaient les volumes pour sept spécialités chirurgicales (soit la chirurgie générale, gynécologique, orthopédique, thoracique, urologique, vasculaire et la neurochirurgie). La corrélation entre le nombre de cas enregistrés dans les SGIA vs les logbooks a été évaluée à l'aide d'une corrélation de Pearson; l'agrément a été déterminé à l'aide d'un graphique de Bland­Altman et de coefficients de corrélation intraclasse (CCI). RéSULTATS: Les données de 27 résidents en anesthésiologie ont été colligées. Globalement, les nombres de cas moyens (écart type) étaient en général plus élevés dans les SGIA que dans les logbooks [649 (103) vs 583 (191); P = 0,049). Les volumes de cas totaux entre les systèmes présentaient une corrélation (r = 0,50) et un agrément (coefficient de corrélation intraclasse [CCI], 0,42; IC 95 %, 0,34 à 0,59) modérés. Les graphiques de Bland­Altman ont démontré un agrément variable entre les données des SGIA et celles des logbooks [biais moyen (ÉT) = 66 (166) cas]. Pour les chirurgies générales, gynécologiques, orthopédiques, thoraciques, urologique, vasculaires et neurochirurgies, l'agrément allait de faible à modéré (CCI, 0,23-0,57) entre les SGIA et les logbooks. CONCLUSION: En ce qui a trait à l'enregistrement des cas des résidents en anesthésiologie, le nombre de cas enregistrés dans un SGIA était plus élevé et présentait une variance moindre que dans les logbooks. Les données des systèmes de gestion de l'information en anesthésie vs des logbooks ont affiché une corrélation et un agrément faible à modéré. Étant donné le temps et les ressources supplémentaires nécessaires pour compléter les logbooks, les SGIA pourraient constituer une méthode supérieure pour le suivi des cas, lorsqu'un tel système est disponible.

The effect of plasma osmolality and baroreceptor loading status on postexercise heat loss responses.

We examined the separate and combined effects of plasma osmolality and baroreceptor loading status on postexercise heat loss responses. Nine young males completed a 45-min treadmill exercise protocol at 58 ± 2% V̇o2 peak, followed by a 60-min recovery. On separate days, participants received 0.9% NaCl (ISO), 3.0% NaCl (HYP), or no infusion (natural recovery) throughout exercise. In two additional sessions (no infusion), lower-body negative (LBNP) or positive (LBPP) pressure was applied throughout the final 45 min of recovery. Local sweat rate (LSR; ventilated capsule: chest, forearm, upper back, forehead) and skin blood flow (SkBF; laser-Doppler flowmetry: forearm, upper back) were continuously measured. During HYP, upper back LSR was attenuated from end-exercise to 10 min of recovery by ∼0.35 ± 0.10 mg·min(-1)·cm(-2) and during the last 20 min of recovery by ∼0.13 ± 0.03 mg·min(-1)·cm(-2), while chest LSR was lower by 0.18 ± 0.06 mg·min(-1)·cm(-2) at 50 min of recovery compared with natural recovery (all P < 0.05). Forearm and forehead LSRs were not affected by plasma hyperosmolality during HYP (all P > 0.28), which suggests regional differences in the osmotic modulation of postexercise LSR. Furthermore, LBPP application attenuated LSR by ∼0.07-0.28 mg·min(-1)·cm(-2) during the last 30 min of recovery at all sites except the forehead compared with natural recovery (all P < 0.05). Relative to natural recovery, forearm and upper back SkBF were elevated during LBPP, ISO, and HYP by ∼6-10% by the end of recovery (all P < 0.05). We conclude that 1) hyperosmolality attenuates postexercise sweating heterogeneously among skin regions, and 2) baroreceptor loading modulates postexercise SkBF independently of changes in plasma osmolality without regional differences.

Phase-amplitude coupling and interlaminar synchrony are correlated in human neocortex.

One of the striking manifestations of neuronal population activity is that of rhythmic oscillations in the local field potential. It is thought that such oscillatory patterns, including phase-amplitude coupling (PAC) and inter-regional synchrony, may represent forms of local and long-range cortical computations, respectively. Although it has been speculated that these two oscillatory patterns are functionally related, and bind disparate cortical assemblies to one another at different timescales, there is little direct evidence to support this hypothesis. We have demonstrated recently that theta to high-gamma PAC and interlaminar phase coherence at theta frequencies can be generated in human cortical slices maintained in vitro. Here we show that not only do such oscillatory patterns exist within human temporal neocortex, but that the strength of one is related to the strength of the other. We demonstrate that at theta frequencies, metrics of temporal synchrony between superficial and deep cortical laminae (phase-dependent power correlations, and phase coherence) are correlated to the magnitude of intralaminar PAC between theta and high-gamma. Specifically, our results suggest that interlaminar communication within human temporal neocortex and local laminar excitability are linked to one another through a dependence mediated by theta oscillations. More generally, our results provide evidence for the hypothesis that theta oscillations may coordinate inter-areal excitability in the human brain.

Do nitric oxide synthase and cyclooxygenase contribute to the heat loss responses in older males exercising in the heat?

This study evaluated the separate and combined roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in forearm sweating and cutaneous vasodilatation in older adults during intermittent exercise in the heat. Twelve healthy older (62 ± 7 years) males performed two 30 min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C, 20% relative humidity). The exercise bouts were followed by 20 and 40 min of recovery, respectively. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) were evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (non-selective COX inhibitor), (3) 10 mm N(G) -nitro-l-arginine methyl ester (l-NAME; non-selective NOS inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. Sweating was not different between the four sites during either exercise bout (main effect P = 0.92) (average of last 5 min of second exercise, Control, 0.80 ± 0.06; ketorolac, 0.77 ± 0.09; l-NAME, 0.74 ± 0.07; ketorolac + l-NAME, 0.77 ± 0.09 mg min(-1) cm(-2) ). During both exercise bouts, relative to CVC evaluated at the Control site (average of last 5 min of second exercise, 69 ± 6%max), CVC was similar at the ketorolac site (P = 0.62; 66 ± 4%max) whereas it was attenuated to a similar extent at both the l-NAME (49 ± 8%max) and ketorolac + l-NAME (54 ± 8%max) sites (both P < 0.05). Thus, we demonstrate that NOS and COX are not functionally involved in forearm sweating whereas only NOS contributes to forearm cutaneous vasodilatation in older adults during intermittent exercise in the heat.

Cutaneous vascular and sweating responses to intradermal administration of ATP: a role for nitric oxide synthase and cyclooxygenase?

KEY POINTS: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation along with whether and how ATP increases sweating remains uncertain. Recent work has implicated nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine in the modulation of cutaneous vasodilatation and sweat production during both local (i.e. localized heating) and whole-body heat stress (i.e. exercise-induced heat stress). We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via NOS, COX and/or adenosine. We show that in humans in vivo, intradermal administration of ATP induces pronounced vasodilatation which is partially mediated by NOS, but neither COX nor adenosine influences ATP-mediated vasodilatation, and ATP alone does not induce an increase in sweating. These findings advance our basic physiological knowledge regarding control of skin blood flow and sweating, and provide insight into the mechanisms governing thermoeffector activity, which has major implications for whole-body heat exchange and therefore core temperature regulation in humans during heat stress. ABSTRACT: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation and whether and how ATP increases sweating remain uncertain. We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine-dependent mechanisms. Cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated at intradermal microdialysis forearm skin sites, each receiving pharmacological agents (two separate protocols). In Protocol 1 (n = 12), sites were perfused with: (1) lactated Ringer solution (Control), (2) 10 mm N(ω) -nitro-l-arginine (l-NNA, a NOS inhibitor), (3) 10 mm ketorolac (Ketorolac, a COX inhibitor) or (4) a combination of 10 mm l-NNA + 10 mm ketorolac (l-NNA + Ketorolac). In Protocol 2 (n = 8), sites were perfused with: (1) lactated Ringer solution (Control) or (2) 4 mm theophylline (Theophylline, an adenosine receptor inhibitor). At all sites, ATP was simultaneously perfused at 0.12, 1.2, 12, 120 and 1200 nm min(-1) (each for 20 min). Relative to CVC at the Control site with ATP infused at 120 nm min(-1) (71 ± 9% of max CVC), CVC at the Ketorolac site was comparable (64 ± 13% of max CVC, P = 0.407), but lower at l-NNA (51 ± 15% of max CVC, P = 0.040) and l-NNA + Ketorolac (51 ± 13% of max CVC, P = 0.049) sites. Conversely, across the four skin sites at any other ATP infusion rate (all P > 0.174), no differences in CVC were observed. Theophylline did not influence CVC at any ATP infusion rate (all P > 0.234). Furthermore, no ATP infusion rate elicited an increase in sweating from baseline at any skin site (all P > 0.235). We show that NOS, but neither COX nor adenosine receptors, modulates ATP-mediated cutaneous vasodilatation, whereas ATP does not directly increase sweating.

Muscle metaboreceptors modulate postexercise sweating, but not cutaneous blood flow, independent of baroreceptor loading status.

We examined whether sustained changes in baroreceptor loading status during prolonged postexercise recovery can alter the metaboreceptors' influence on heat loss. Thirteen young males performed a 1-min isometric handgrip exercise (IHG) at 60% maximal voluntary contraction followed by 2 min of forearm ischemia (to activate metaboreceptors) before and 15, 30, 45, and 60 min after a 15-min intense treadmill running exercise (>90% maximal heart rate) in the heat (35°C). This was repeated on three separate days with continuous lower body positive (LBPP, +40 mmHg), negative (LBNP, -20 mmHg), or no pressure (Control) from 13- to 65-min postexercise. Sweat rate (ventilated capsule; forearm, chest, upper back) and cutaneous vascular conductance (CVC; forearm, upper back) were measured. Relative to pre-IHG levels, sweating at all sites increased during IHG and remained elevated during ischemia at baseline and similarly at 30, 45, and 60 min postexercise (site average sweat rate increase during ischemia: Control, 0.13 ± 0.02; LBPP, 0.12 ± 0.02; LBNP, 0.15 ± 0.02 mg·min(-1)·cm(-2); all P < 0.01), but not at 15 min (all P > 0.10). LBPP and LBNP did not modulate the pattern of sweating to IHG and ischemia (all P > 0.05). At 15-min postexercise, forearm CVC was reduced from pre-IHG levels during both IHG and ischemia under LBNP only (ischemia: 3.9 ± 0.8% CVCmax; P < 0.02). Therefore, we show metaboreceptors increase postexercise sweating in the middle to late stages of recovery (30-60 min), independent of baroreceptor loading status and similarly between skin sites. In contrast, metaboreflex modulation of forearm but not upper back CVC occurs only in the early stages of recovery (15 min) and is dependent upon baroreceptor unloading.

The Influence of Arc-Flash and Fire-Resistant Clothing on Thermoregulation during Exercise in the Heat.

We evaluated the effect of arc-flash and fire-resistant (AFR) clothing ensembles (CE) on whole-body heat dissipation during work in the heat. On 10 occasions, 7 males performed four 15-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C), each separated by 15-min of recovery. Whole-body heat loss and metabolic heat production were measured by direct and indirect calorimetry, respectively. Body heat storage was calculated as the temporal summation of heat production and heat loss. Responses were compared in a semi-nude state and while wearing two CE styles: (1) single-piece (coveralls) and (2) two-piece (workpant + long-sleeve shirt). For group 1, there was one non-AFR single-piece CE (CE1STD) and three single-piece CE with AFR properties (CE2AFR, CE3AFR, CE4AFR). For group 2, there was one non-AFR two-piece CE (CE5STD) and four two-piece CE with AFR properties (CE6AFR, CE7AFR, CE8AFR, CE9AFR). The workpants for CE6AFR were not AFR-rated, while a cotton undershirt was also worn for conditions CE8AFR and CE9AFR and for all single-piece CE. Heat storage for all conditions (CE1STD: 328 ± 55, CE2AFR: 335 ± 87, CE3AFR: 309 ± 95, CE4AFR: 403 ± 104, CE5STD: 253 ± 78, CE6AFR: 268 ± 89, CE7AFR: 302 ± 70, CE8AFR: 360 ± 36, CE9AFR: 381 ± 99 kJ) was greater than the semi-nude state (160 ± 124 kJ) (all p ≤ 0.05). No differences were measured between single-piece uniforms (p = 0.273). Among the two-piece uniforms, heat storage was greater for CE8AFR and CE9AFR relative to CE5STD and CE6AFR (all p ≤ 0.05), but not CE7AFR (both p > 0.05). Differences between clothing styles were measured such that greater heat storage was observed in both CE1STD and CE2-4AFR relative to CE5STD. Further, heat storage was greater in CE2AFR and CE4AFR relative to CE6AFR, while it was greater in CE4AFR compared to CE7AFR. Body heat storage during work in the heat was not influenced by the use of AFR fabrics in the single- or two-piece uniforms albeit less heat was stored in the two-piece uniforms when no undershirt was worn. However, heat storage was comparable between clothing styles when an undershirt was worn with the two-piece uniform.

Adenosine receptor inhibition attenuates the suppression of postexercise cutaneous blood flow.

The time-dependent contributions of active vasodilation (e.g. nitric oxide) and noradrenergic vasoconstriction to the postexercise suppression of cutaneous perfusion despite persistent hyperthermia remain unknown. Moreover, adenosine receptors have been shown to mediate the decrease in cutaneous perfusion following passive heating. We examined the time-dependent modulation of nitric oxide synthase, noradrenergic vasoconstriction and adenosine receptors on postexercise cutaneous perfusion. Eight males performed 15 min of high-intensity (85% VO2 max) cycling followed by 60 min of recovery in temperate ambient conditions (25°C). Four microdialysis probes were inserted into the forearm skin and continuously infused with: (1) lactated Ringer solution (Control); (2) 10 mm N(G)-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase inhibitor); (3) 10 mm bretylium tosylate (BT; inhibitor of noradrenergic vasoconstriction); or (4) 4 mm theophylline (THEO; adenosine receptor inhibitor). Cutaneous vascular conductance (CVC) was expressed as a percentage of maximum and was calculated as perfusion units (laser Doppler) divided by mean arterial pressure. End-exercise CVC was similar in Control, THEO and BT (P > 0.1), but CVC with l-NAME (39 ± 4%) was lower than Control (59 ± 4%, P < 0.01). At 20 min of recovery, Control CVC (22 ± 3%) returned to baseline levels (19 ± 2%, P = 0.11). Relative to Control, CVC was reduced by l-NAME for the first 10 min of recovery whereas CVC was increased with BT for the first 30 min of recovery (P < 0.03). In contrast, CVC with THEO was elevated throughout the 60 min recovery period (P ≤ 0.01) compared to Control. We show that adenosine receptors appear to have a major role in postexercise cutaneous perfusion whereas nitric oxide synthase and noradrenergic vasoconstriction are involved only earlier during recovery.

Do metaboreceptors alter heat loss responses following dynamic exercise?

Metaboreceptor activation during passive heating is known to influence cutaneous vascular conductance (CVC) and sweat rate (SR). However, whether metaboreceptors modulate the suppression of heat loss following dynamic exercise remains unclear. On separate days, before and after 15 min of high-intensity treadmill running in the heat (35°C), eight males underwent either 1) no isometric handgrip exercise (IHG) or ischemia (CON), 2) 1 min IHG (60% of maximum, IHG), 3) 1 min IHG followed by 2 min of ischemia (IHG+OCC), 4) 2 min of ischemia (OCC), or 5) 1 min IHG followed by 2 min of ischemia with application of lower body negative pressure (IHG+LBNP). SR (ventilated capsule), cutaneous blood flow (Laser-Doppler), and mean arterial pressure (Finometer) were measured continuously before and after dynamic exercise. Following dynamic exercise, CVC was reduced with IHG exercise (P < 0.05) and remained attenuated with post-IHG ischemia during IHG+OCC relative to CON (39 ± 2 vs. 47 ± 6%, P < 0.05). Furthermore, the reduction in CVC was exacerbated by application of LBNP during post-IHG ischemia (35 ± 3%, P < 0.05) relative to IHG+OCC. SR increased during IHG exercise (P < 0.05) and remained elevated during post-IHG ischemia relative to CON following dynamic exercise (0.94 ± 0.15 vs. 0.53 ± 0.09 mg·min(-1)·cm(-2), P < 0.05). In contrast, application of LBNP during post-IHG ischemia had no effect on SR (0.93 ± 0.09 mg·min(-1)·cm(-2), P > 0.05) relative to post-IHG ischemia during IHG+OCC. We show that CVC is reduced and that SR is increased by metaboreceptor activation following dynamic exercise. In addition, we show that the metaboreflex-induced loading of the baroreceptors can influence the CVC response, but not the sweating response.

Adenosine receptor inhibition attenuates the decrease in cutaneous vascular conductance during whole-body cooling from hyperthermia.

Adenosine has both vasodilatory and vasoconstrictive properties, yet its influence on cutaneous vascular conductance (CVC) during whole-body cooling remains unknown. The present study evaluated the influence of adenosine on reflex cutaneous vasoconstriction. Four microdialysis probes were inserted into the dorsal forearm skin of eight subjects and infused with the following solutions: (i) lactated Ringer solution (CON); (ii) 4 mm theophylline (Theo), a non-selective adenosine receptor antagonist; (iii) 10 mm l-NAME, an inhibitor of nitric oxide synthase; and (iv) combined 4 mm theophylline and 10 mm l-NAME (Theo + l-NAME). Subjects subsequently donned a water-perfusion garment. Following a thermoneutral baseline period, the suit was perfused with water at 10°C for 20 min (Cooling 1). The suit was then perfused with water at 49°C for 45 min (Heating), followed by a second cooling period of 20 min using 10°C water (Cooling 2). Cutaneous blood flow (laser-Doppler) was measured over each microdialysis probe and used to calculate CVC as a percentage of the maximum determined by sodium nitroprusside infusion and local heating. Cutaneous vascular conductance was significantly elevated at the Theo site relative to CON following Cooling 1 (18 ± 6 versus 8 ± 2%; P = 0.01) and Cooling 2 (27 ± 11 versus 14 ± 5%; P = 0.022). Likewise, CVC at the Theo + l-NAME site remained greater compared with l-NAME after Cooling 1 (13 ± 4 versus 7 ± 3%; P = 0.030) and Cooling 2 (15 ± 3 versus 9 ± 2%; P = 0.009). The present findings demonstrate that non-selective antagonism of adenosine receptors attenuates the decrease in cutaneous vascular conductance during whole-body cooling from hyperthermia.

The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy.

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.