Local extracellular K+ in cortex regulates norepinephrine levels, network state, and behavioral output.

Extracellular potassium concentration ([K+]e) is known to increase as a function of arousal. [K+]e is also a potent modulator of transmitter release. Yet, it is not known whether [K+]e is involved in the neuromodulator release associated with behavioral transitions. We here show that manipulating [K+]e controls the local release of monoaminergic neuromodulators, including norepinephrine (NE), serotonin, and dopamine. Imposing a [K+]e increase is adequate to boost local NE levels, and conversely, lowering [K+]e can attenuate local NE. Electroencephalography analysis and behavioral assays revealed that manipulation of cortical [K+]e was sufficient to alter the sleep-wake cycle and behavior of mice. These observations point to the concept that NE levels in the cortex are not solely determined by subcortical release, but that local [K+]e dynamics have a strong impact on cortical NE. Thus, cortical [K+]e is an underappreciated regulator of behavioral transitions.

High-intensity training in patients with lacunar stroke: A one-year follow-up.

OBJECTIVES: Physical inactivity is a major risk factor for stroke. It is a challenge for patients to initiate and adhere to regular exercise post-stroke. Early initiation of home-based high-intensity interval training (HIIT) may engage patients in physical activity, improve cardiorespiratory fitness, and reduce risk of recurrent stroke. MATERIALS AND METHODS: Post-intervention follow-up of patients with lacunar stroke, randomized to three-months HIIT including weekly motivational calls, or usual care. At follow-up (six- and 12-months post-stroke), we investigated changes in cardiorespiratory fitness, physical activity, fatigue, depression, mental well-being, stress, cognition, cardiovascular function, and recurrent stroke. RESULTS: We included 71 patients of whom 59 patients (mean age: 63.9 ± 8.8 years) completed six- and 12-month follow-up. No change was detected in cardiorespiratory fitness between groups from baseline to 12-months follow-up. At six months, vigorous-intensity activity (median hours/week [interquartile range]) was maintained in the intervention group (baseline, 0[0;2]; post-intervention, 2[0;3]; six-month, 2[0;4]) and increased in the usual care group (baseline, 0[0;1]; post-intervention, 1[0;2]; six-month, 1[0;3]), with no difference between groups. Vigorous-intensity activity declined to baseline levels at 12-months in both groups. Secondary outcomes improved from baseline to 12-months with no significant differences between groups. Similar rate of recurrent stroke (n=3) occurred in each group with a three-month delay in the intervention group. CONCLUSIONS: Early initiated HIIT did not increase long-term cardiorespiratory fitness, but increased time spent doing vigorous-intensity activities post-stroke. Decline to baseline activity level at 12 months warrants identification of motivators to initiate and sustain physical activity post-stroke.

Cortex-wide Changes in Extracellular Potassium Ions Parallel Brain State Transitions in Awake Behaving Mice.

Brain state fluctuations modulate sensory processing, but the factors governing state-dependent neural activity remain unclear. Here, we tracked the dynamics of cortical extracellular K+ concentrations ([K+]o) during awake state transitions and manipulated [K+]o in slices, during visual processing, and during skilled motor execution. When mice transitioned from quiescence to locomotion, [K+]o increased by 0.6-1.0 mM in all cortical areas analyzed, and this preceded locomotion by 1 s. Emulating the state-dependent [K+]o increase in cortical slices caused neuronal depolarization and enhanced input-output transformation. In vivo, locomotion increased the gain of visually evoked responses in layer 2/3 of visual cortex; this effect was recreated by imposing a [K+]o increase. Elevating [K+]o in the motor cortex increased movement-induced neuronal spiking in layer 5 and improved motor performance. Thus, [K+]o increases in a cortex-wide state-dependent manner, and this [K+]o increase affects both sensory and motor processing through the dynamic modulation of neural activity.

Effect of Home-Based High-Intensity Interval Training in Patients With Lacunar Stroke: A Randomized Controlled Trial.

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training in improving cardiorespiratory fitness in patients with cardiovascular disease, but is it safe, feasible and effective in patients with stroke? We investigated feasibility and effect of early, home-based HIIT in patients with lacunar stroke combined with usual care vs. usual care, only. Methods: Patients with minor stroke (severity: 55/58 point on the Scandinavian Stroke Scale) were randomized to HIIT or usual care in a randomized, controlled trial. We measured the following outcomes at baseline and post-intervention: cardiorespiratory fitness monitored as power output from the Graded Cycling Test with Talk Test (GCT-TT; primary outcome), physical activity, fatigue, depression, well-being, stress, cognition, endothelial function, blood pressure, body mass index, and biomarkers. Results: We included 71 patients (mean age 63.7 ± 9.2), 49 men, 31 in intervention group. Home-based HIIT was feasible with no reported adverse events in relation to the intervention. No significant change between the groups in GCT-TT power output was detected (p = 0.90). The change in time spent on vigorous-intensity activity was 2 h/week and 0.6 h/week, intervention and usual care, respectively (p = 0.045). There were no significant differences between groups in the remaining secondary outcomes. Conclusion: HIIT was feasible and safe in patients with lacunar stroke. Patients can engage early in home-based HIIT when involved in choosing exercise modality and guided by weekly motivational phone calls. Within 3 months, HIIT did, however, not yield effect on cardiorespiratory fitness. We await further evaluation of long-term effects of this intervention on continued regular physical exercise and cardiovascular event. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT02731235.

Self-Reported Physical Activity and Cardiovascular Disease Risk Factors in Patients with Lacunar Stroke.

BACKGROUND: Physical inactivity is a major modifiable risk factor for stroke. The aim was to explore if stroke patients admitted with lacunar stroke adhere to the international recommendations on physical activity prestroke (≥150 minutes of moderate-intensity activity, or ≥75 minutes of vigorous-intensity activity, or an equivalent combination). Further, to assess association between prestroke physical activity and cardiovascular disease (CVD) risk factors. METHODS: A cross-sectional study, including patients with lacunar stroke according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Data collected included prestroke physical activity using the self-reported Physical Activity Scale. Cardiorespiratory fitness was estimated as the power output from the Graded Cycling Test with Talk Test and sociodemographic factors including age, sex, education, and CVD risk factors including pre-existing diabetes, history of hypertension, body mass index, and lipids were assessed. RESULTS: We included 19 women and 52 men (mean age 64 years). Overall, 79% of the recruited patients adhered to the physical activity recommendations prestroke, but only 35% did vigorous-intensity activity. Prestroke physical activity was associated with a history of hypertension. CONCLUSIONS: A high proportion of the lacunar stroke patients reported to adhere to the recommendations on physical activity prestroke; however, only one third engaged in vigorous-intensity activity. Studies are warranted to investigate if vigorous-intensity activity is effective as secondary prevention in patients with a lacunar stroke.

Home-based aerobic exercise in patients with lacunar stroke: Design of the HITPALS randomized controlled trial.

BACKGROUND: The effects of physical exercise in patients with lacunar stroke, seem promising in secondary prevention and only few studies have investigated the effect of high-intensity interval training in patients with lacunar stroke. This study will be investigating whether high-intensity interval training improves cardiovascular fitness as well as cognitive- and endothelial function and potentially attenuating the risk of recurrent stroke. METHODS: A randomized controlled trial evaluating 12 weeks of home-based, high-intensity interval training compared with usual care. The intervention group will be exercising 15 min a day, 5 days a week, for 12 weeks. Outcomes will be evaluated at baseline, three, six and twelve months post-stroke with 'The Graded Cycling Test with Talk Test' as the primary outcome registered as power output in Watts. Additionally, an annually register-based follow-up will be performed for 5 years from date of inclusion with a composite endpoint of cardiovascular disease or death. Secondary outcomes will be: physical activity, endothelial response, mental well-being, cognition, mood, fatigue, stress, and MRI scan. DISCUSSION: This study is going to show if early initiated home-based high-intensity interval training is feasible and effective in patients with lacunar stroke. A self-chosen aerobic exercise modality allows a realistic implementation of practice, together with greater chance of long-term adherence. A limitation of the study is that recruitment bias cannot be ruled out, as there may be a preferential enrolment of patients who are self-motivated to engage in exercise.

Voluntary running enhances glymphatic influx in awake behaving, young mice.

Vascular pathology and protein accumulation contribute to cognitive decline, whereas exercise can slow vascular degeneration and improve cognitive function. Recent investigations suggest that glymphatic clearance measured in aged mice while anesthetized is enhanced following exercise. We predicted that exercise would also stimulate glymphatic activity in awake, young mice with higher baseline glymphatic function. Therefore, we assessed glymphatic function in young female C57BL/6J mice following five weeks voluntary wheel running and in sedentary mice. The active mice ran a mean distance of 6km daily. We injected fluorescent tracers in cisterna magna of awake behaving mice and in ketamine/xylazine anesthetized mice, and later assessed tracer distribution in coronal brain sections. Voluntary exercise consistently increased CSF influx during wakefulness, primarily in the hypothalamus and ventral parts of the cortex, but also in the middle cerebral artery territory. While glymphatic activity was higher under ketamine/xylazine anesthesia, we saw a decrease in glymphatic function during running in awake mice after five weeks of wheel running. In summary, daily running increases CSF flux in widespread areas of the mouse brain, which may contribute to the pro-cognitive effects of exercise.

Sulforhodamine 101, a widely used astrocyte marker, can induce cortical seizure-like activity at concentrations commonly used.

Sulforhodamine 101 (SR101) is a preferential astrocyte marker widely used in 2-photon microscopy experiments. Here we show, that topical loading of two commonly used SR101 concentrations, 100 µM and 250 µM when incubated for 10 min, can induce seizure-like local field potential (LFP) activity in both anaesthetized and awake mouse sensori-motor cortex. This cortical seizure-like activity develops in less than ten minutes following topical loading, and when applied longer, these neuronal discharges reliably evoke contra-lateral hindlimb muscle contractions. Short duration (<1 min) incubation of 100 µM and 250 µM SR101 or application of lower concentrations 25 µM and 50 µM of SR101, incubated for 30 and 20 min, respectively, did not induce abnormal LFP activity in sensori-motor cortex, but did label astrocytes, and may thus be considered more appropriate concentrations for in vivo astrocyte labeling. In addition to label astrocytes SR101 may, at 100 µM and 250 µM, induce abnormal neuronal activity and interfere with cortical circuit activity. SR101 concentration of 50 µM or lower did not induce abnormal neuronal activity. We advocate that, to label astrocytes with SR101, concentrations no higher than 50 µM should be used for in vivo experiments.

Cortical involvement in anticipatory postural reactions in man.

All movements are accompanied by postural reactions which ensure that the balance of the body is maintained. It has not been resolved that to what extent the primary motor cortex and corticospinal tract are involved in the control of these reactions. Here, we investigated the contribution of the corticospinal tract to the activation of the soleus (SOL) muscle in standing human subjects (n=10) in relation to voluntary heel raise, anticipatory postural activation of the soleus muscle when the subject pulled a handle and to reflex activation of the soleus muscle when the subject was suddenly pulled forward by an external perturbation. SOL motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) increased significantly in relation to rest -75 ms prior to the onset of EMG in the heel-raise and handle-pull tasks. The short-latency facilitation of the soleus H-reflex evoked by TMS increased similarly, suggesting that the increased MEP size prior to movement was caused at least partly by increased excitability of corticospinal tract cells with monosynaptic projections to SOL motoneurones. Changes in spinal motoneuronal excitability could be ruled out since there was no significant increase of the SOL H-reflex until immediately prior to EMG onset for any of the tasks. Tibialis anterior MEPs were unaltered prior to the onset of SOL EMG activity in the handle-pull task, suggesting that the MEP facilitation was specific for the SOL muscle. No significant increase of the MEPs was observed prior to EMG onset for the external perturbation. These data suggest that the primary motor cortex is involved in activating the SOL muscle as part of an anticipatory postural reaction.