Susceptibility of Primary Sensory Cortex to Spreading Depolarizations.

UNLABELLED: Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT: Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury.

Suppression of sex behavior by kappa opiates and stress steroids occurs via independent neuroendocrine pathways.

Endocannabinoids and their receptors are found throughout the brain of all vertebrates. By virtue of their wide distribution, endocannabinoids have the potential to affect many behaviors. Prior research has shown that cannabinoids inhibit courtship-clasping and mediate behavioral responses to stress in male rough-skinned newts, Taricha granulosa, and cannabinoid signaling is initiated by rapid actions of the steroid corticosterone (CORT) at its specific membrane receptor (mCR). This same mCR also recognizes κ-opioid receptor agonists and antagonists. Prior behavioral studies show that κ-opioid agonists suppress clasping behavior in a dose dependent manner. Combined, these studies suggest that κ-opioid agonists might suppress clasping behavior via the same pathway initiated by CORT: up-regulation of endocannabinoid signaling. We examined whether pretreatment with a CB1 antagonist, AM281, would block κ-opioid-mediated suppression of clasping. We found that the CB1 antagonist did not reverse κ-opioid-induced suppression of clasping, revealing that while endocannabinoids mediate CORT-induced suppression of clasping, endocannabinoids do not mediate the κ-opioid-induced suppression of clasping.

A comparison of Doppler, tissue Doppler imaging, and strain rate imaging in the assessment of postexercise left ventricular function.

Left ventricular (LV) function is characterized by contraction in the longitudinal, radial, and circumferential planes. Previous studies of postexercise changes in LV function have assessed global indices of LV function. The purpose of this study was to use 2-dimensional (2D) strain analysis to examine LV function following marathon running in the circumferential, radial, and longitudinal planes, and to compare these data with other global and regional indices of function. Fifteen (mean +/- SD: age, 32 +/- 7 years; stature, 1.76 +/- 0.08 m; body mass, 77.8 +/- 8.2 kg) competitors in the London Marathon were echocardiographically assessed pre- and postrace. 2D strain (ejection fraction (EF), Doppler (early (E) and late (A) trans-mitral filling), tissue Doppler imaging (TDI) (systolic (S') and early diastolic (E') wall-motion velocities); TDI-derived longitudinal strain (epsilon(TDI)), and systolic and diastolic strain rate (SR(TDI)); and 2D-derived peak circumferential, radial, and longitudinal strain (epsilon(2D)), and systolic and diastolic strain rate (SR(2D)) were examined. Differences pre- and postrace completion were assessed using paired tau tests, with alpha set at 0.01. All participants completed the marathon in a mean time of 213 +/- 41 min. A varied response was observed for measures of LV systolic and diastolic function following completion of the marathon (mean +/- SD): EF, 63 +/- 6 vs. 63 +/- 7% (p > 0.01); E:A, 1.70 +/- 0.37 vs. 1.17 +/- 0.37; E':A', 2.36 +/- 0.79 vs. 1.60 +/- 0.57 (p < 0.01); mean longitudinal epsilon(TDI), 19.1 +/- 5.1 vs. 17.5 +/- 4.2% (p < 0.01); mean longitudinal diastolic SR(TDI), 1.81 +/- 0.54 vs. 1.58 +/- 0.51 x s(-1) (p < 0.01); mean longitudinal systolic SR(2D), 0.73 +/- 0.21 vs. 0.97 +/- 0.22 x s(-1) (p < 0.01); mean longitudinal diastolic SR(2D), 0.94 +/- 0.34 vs. 1.01 +/- 0.23 x s(-1) (p > 0.01); mean radial systolic SR(2D), 1.20 +/- 0.15 vs. 1.45 +/- 0.32 x s(-1) (p < 0.01); mean radial diastolic SR(2D), 1.19 +/- 0.25 vs. 1.29 +/- 0.41 x s(-1) (p > 0.01); mean circumferential systolic SR(2D), -1.09 +/- 0.16 vs. -1.24 +/- 0.18 x s(-1) (p < 0.01); and mean circumferential diastolic SR(2D), -1.27 +/- 0.28 vs. -1.22 +/- 0.31 x s(-1) (p > 0.01). Marathon running promotes a varied echocardiographic response, with some functional parameters showing no change, some increasing, and some decreasing postexercise. This varied response likely reflects the complexities of cardiac function and highlights the need to adopt a multimodality approach when assessing cardiac function following exercise.

Changes in respiratory muscle and lung function following marathon running in man.

Respiratory muscle fatigue has been reported following short bouts of high-intensity exercise, and prolonged, moderate-intensity exercise, as evidenced by decrements in inspiratory and expiratory mouth pressures. However, links to functionally relevant outcomes such as breathing effort have been lacking. The present study examined dyspnoea and leg fatigue during a treadmill marathon in nine experienced runners. Maximal inspiratory and expiratory pressure, peak inspiratory and expiratory flow, forced vital capacity, and forced expiratory volume in one second were assessed before, immediately after, and four and 24 hours after a marathon. During the run, leg effort was rated higher than respiratory effort from 18 through 42 km (P < 0.05). Immediately after the marathon, there were significant decreases in maximal inspiratory pressure and peak inspiratory flow (from 118 +/- 20 cm H(2)O and 6.3 +/- 1.4 litres x s(-1) to 100 +/- 22 cm H(2)O and 4.9 +/- 1.5 litres x s(-1) respectively; P < 0.01), while expiratory function remained unchanged. Leg maximum voluntary contraction force was significantly lower post-marathon. Breathing effort correlated significantly with leg fatigue (r = 0.69), but not inspiratory muscle fatigue. Our results confirm that prolonged moderate-intensity exercise induces inspiratory muscle fatigue. Furthermore, they suggest that the relative intensity of inspiratory muscle work during exercise makes some contribution to leg fatigue.

Postexercise changes in left ventricular function: the evidence so far.

Whether prolonged exercise results in a transient depression in left ventricular (LV) function has been the focus of numerous studies since the 1960s. This review attempts to summarize the findings of this growing body of research. Understanding in this area has followed the advances in imaging techniques and specifically in echocardiographic technology. As such, the review focuses on evidence from the traditional echocardiographic technology (two-dimensional and Doppler measures), the more advanced technique of tissue Doppler imaging (TDI), and finally the assessment of myocardial strain and strain rate. Although many of the studies have adopted a similar cross-sectional pre- to postexercise design, there are often significant differences in terms of subject characteristics, exercise duration, and exercise modality. Accordingly, we draw together the common findings from this growing body of research in an attempt to reach a consensus regarding the influence of prolonged exercise on LV function.

Exercise-induced cardiac troponin T release: a meta-analysis.

PURPOSE: Cardiac troponin T (cTnT) is a highly specific marker of myocardial damage and used clinically in the diagnosis of acute myocardial infarction (AMI). Release of cTnT has been demonstrated in several small studies after endurance exercise. The purpose of this study was to explore, using a meta-analytic approach, the incidence of postexercise cTnT release after endurance exercise. METHODS: Articles identified via Pubmed, SportDiscus, and Embase (1997-2006) searches using the key words cardiac troponin T, cTnT, cardiac biomarkers, and exercise; a search of bibliographies; and consultation with experts in the field were entered into a random-effects meta-analysis. We identified 26 relevant studies (1120 cases). Age, gender, and body mass of participants, as well as exercise mode and duration, were explored as possible moderator variables with meta-regressions. RESULTS: Postexercise cTnT levels exceeded the assay detection limit in 47% of participants (95% CI = 39-56%). The detection of postexercise cTnT after cycling events was approximately half that of running events (27 vs 52%, P = 0.042). The detection of postexercise cTnT decreased slightly as event duration increased (P = 0.022) and mean body mass decreased (P = 0.0033). Postexercise detection of cTnT was not affected by age (P= 0.309) and was only slightly higher for studies with more males in the sample (P = 0.028). CONCLUSIONS: Exercise-induced cTnT release is apparent in almost half of the endurance athletes who have been studied to date. Relatively heavy individuals competing in shorter endurance events, primarily running marathons, are slightly more likely to demonstrate elevated cTnT postexercise than other athletes. These data are useful for clinicians evaluating athletes with cTnT elevations after competitive endurance exercise events.

Effect of preload augmentation on pulsed wave and tissue Doppler echocardiographic indices of diastolic function after a marathon.

BACKGROUND: The mechanisms underlying alterations in left ventricular diastolic function after a marathon are unknown and may be a consequence of a reduced preload. OBJECTIVE: We sought to assess the effect of preload augmentation through passive leg elevation (PLE) on echocardiographic indices of diastolic function after a marathon. METHODS: Fourteen trained participants (13 male) were echocardiographically assessed before and after a marathon in the supine position and during PLE. Diastolic function was measured via conventional Doppler, color M-mode, and tissue Doppler echocardiography. Early and late transmitral filling velocities (E and A, respectively), flow propagation velocity of early filling, and basal early and late left ventricular wall velocities (E' and A', respectively) were obtained. RESULTS: The E/A ratio, flow propagation velocity of early filling, and the E'/A' ratio decreased by 31%, 24%, and 32%, respectively (P < .05), after marathon running. Postrace PLE returned E to baseline and increased E/A compared with postrace supine (P < .05). However, E/A remained depressed compared with baseline as a result of the persistent elevation in A. Postrace PLE caused Vp to return to baseline; mean E' also increased (9%, P < .05), but did not return to resting levels. Mean A' was unaffected by postrace PLE, therefore, E'/A' was unchanged postrace despite PLE. CONCLUSION: Postexercise alterations in Doppler indices of diastolic function can be partially explained by a reduction in preload. However, data from tissue Doppler echocardiography indicate that there is an intrinsic impairment in myocardial relaxation after marathon running.

Impact of repeated prolonged exercise bouts on cardiac function and biomarkers.

PURPOSE: The present study examined the impact of repeated bouts of prolonged (< 60 min) exercise on left ventricular function and cardiac biomarkers. METHODS: Ten athletes completed a 15.3-mile hill run on three consecutive days and were assessed before, immediately after, 1 h after, and 20 h after each bout. Six of the athletes completed a fourth bout. Left ventricular (LV) function was examined echocardiographically using two-dimensional M-mode, Doppler, and flow propagation velocity (Vp). Venous blood samples were analyzed for cardiac biomarkers including cardiac troponin T (cTnT). RESULTS: Ejection fraction (EF) significantly decreased (P = 0.027) after the third exercise bout compared with baseline (mean +/- SD: 56.3 +/- 4.4 vs 51.3 +/- 5.9%), accompanied by a nonsignificant decrease in systolic blood pressure/end systolic volume (SBP/ESV) ratio. A sustained depression in systolic function 20 h after bout 3 also persisted in the subset who completed a fourth bout, yet this did not reach clinical levels. Significant (P < 0.01) reductions in early to late diastolic filling (E:A) ratio pre-to post-bout 1 (mean +/- SD: 1.9 +/- 0.5 vs 1.4 +/- 0.3) and pre- to post-bout 3(2.0 +/- 0.5 vs 1.3 +/- 0.4) normalized after each 20-h recovery period. A similar pattern of change was observed in Vp. Cardiac troponin T was elevated in four individuals 1 h after bout 1 (range: 0.013-0.125 microg.L(-1)) but was undetectable thereafter except in one athlete. CONCLUSION: Repeated bouts of prolonged exercise induce short-term reductions in diastolic filling and a cumulative decrease in systolic function, yet these alterations seem to have minimal clinical or functional impact. Elevated cTnT after the initial bout, but not thereafter, may represent an adaptive response to prolonged exercise.

Altered left ventricular diastolic filling following a marathon is a reproducible phenomenon.

The present study examined the reproducibility of alterations in left ventricular function and cardiac biomarkers in a cohort of athletes following two marathons, one year apart. Eight participants in the 2004 and 2005 London Marathons were tested pre- and post-race via echocardiography and humoral analysis. Reductions in diastolic filling, unrelated to loading or heart rate, following both marathons were reproducible within individuals, which may be a function of exercise duration. In contrast, exercise-induced cardiac troponin release was inconsistent.

Corticomotor excitability contributes to neuromuscular fatigue following marathon running in man.

It is unknown whether changes in corticomotor excitability follow prolonged exercise in healthy humans. Furthermore, the role of supraspinal fatigue in decrements of force production and voluntary activation following prolonged exercise has not been established. This study investigated peripheral and central fatigue after a marathon (42.2 km) on a treadmill. Isometric ankle dorsiflexion force and electromyographic responses of the tibialis anterior in response to magnetic stimulation of the peroneal nerve (PNMS) and the motor cortex (TMS) were measured before, immediately after, 4 and 24 h post-marathon (MAR) in nine volunteers (mean +/- s.d. completion time, 208 +/- 22 min). Maximal voluntary contraction decreased by 18 +/- 7% immediately after MAR (P = 0.009) and remained significantly decreased after 4 h. The amplitude of the evoked response to TMS, but not to PNMS, was depressed immediately post-MAR by 57 +/- 25% (P = 0.04). Potentiated resting twitch force was reduced in response to both TMS and PNMS post-MAR (71 +/- 8 and 35 +/- 2% decrease, P = 0.035 and 0.037, respectively), and voluntary activation was reduced to 61.9 +/- 18% immediately post-MAR (P < 0.05). All measures had returned to baseline values after 24 h. These results suggest that fatigue was attributable to both a disturbance of the contractile apparatus within the muscle and submaximal output from the motor cortex.

The effects of marathon running on expression of the complement regulatory proteins CD55 (DAF) and CD59 (MACIF) on red blood cells.

Exercise is known to result in the haemolysis of red blood cells (RBCs). Although mechanical stressors such as footstrike and an increased velocity of blood flow may be involved, the biological mechanisms that underpin RBC haemolysis remain elusive. RBCs are potentially susceptible to lysis by autologous complement activation. RBCs are protected from the lytic effects of complement by regulatory proteins (CRPs) bound to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. This study aimed to determine if marathon running would result in RBC haemolysis through a loss of membrane expression of the CRPs CD55 (decay accelerating factor) and CD59 (membrane attack complex inhibitory factor). Blood samples were obtained from 14 male runners before, within 30 min after, and 24 h after completion of the 2004 London Marathon. RBCs were assessed for cell surface CD55 and CD59 expression using indirect immunofluorescence assays and flow cytometry. No significant changes in the total RBC count, haematocrit or haemoglobin concentrations were found in response to running the marathon (P > 0.05). Blood bilirubin concentrations after the marathon were significantly greater than the pre-race values (P < 0.01). The relative fluorescent intensity (arbitrary units) of CD55 and CD59 expression on RBC membranes did not change in response to the marathon race (P > 0.05). In conclusion, marathon running did not alter the expression of CD55 or CD59 on RBCs, despite concomitant elevations in blood bilirubin concentrations. Consequently, any haemolysis of RBCs that occurred in response to the marathon was not likely due to a loss of membrane bound CRPs and subsequent cell lysis by autologous complement.

The impact of marathon running upon ventricular function as assessed by 2D, Doppler, and tissue-Doppler echocardiography.

The impact of prolonged exercise upon right ventricular (RV) function is poorly understood and to date no studies have utilized tissue-Doppler imaging (TDI). Thirty-five marathon runners (age range 18-50 years) volunteered for the study. Two-dimensional, pulsed Doppler, and TDI studies were performed one day before and immediately following race completion. Right and left ventricular (LV) longitudinal TDI myocardial velocities were acquired from the tricuspid annulus and mitral annulus, providing velocity data during systole (S'), early diastole (E'), and late diastole (A'). Transtricuspid and transmitral, early diastolic (E), and late diastolic (A) velocities and ratios were assessed using conventional pulsed-wave Doppler. RV and LV fractional area changes (FAC) were calculated from RV and LV end-diastolic and end-systolic areas recorded from 2D scans in a subsample (n = 23). RV myocardial velocities were unchanged pre-post race in S' (21.1 +/- 2.7 to 21.7 +/- 4.5 cm s(-1), P > 0.05), reduced in E' (23.3 +/- 3.5 to 19.9 +/- 5.3 cm s(-1), P < 0.05), increased in A' (19.1 +/- 3.6 to 23.7 +/- 6.8 cm s(-1), P < 0.05) with a resultant decline in E'/A' (1.28 +/- 0.36 to 0.94 +/- 0.45, P < 0.05). This pattern of data was mirrored in the LV. Similarly both pulsed-Doppler tricuspid and mitral E/A ratios decreased from pre- to postrace (P < 0.05). FAC for the RV and LV were unaltered postrace (P > 0.05). The impact of differing age, finishing time (173-330 min), hemodynamic loading and heart rate upon RV and LV function pre- to postrace was negligible. In conclusion, TDI and 2D data, for both the RV and LV demonstrated little change in systolic function after a marathon race. Conversely, a reduction in diastolic function was observed in both ventricles for which a mechanism has yet to be deduced.

Left ventricular function immediately following prolonged exercise: A meta-analysis.

PURPOSE: Evidence supporting cardiac fatigue following prolonged endurance exercise remains equivocal. The purpose of this meta-analysis was to quantify all data fulfilling the specified inclusion criteria, examining the short-term effect of prolonged endurance exercise on left ventricular function. METHODS: A random effects meta-analysis of the weighted mean change in ejection fraction (EF), systolic blood pressure/end systolic volume (SBP/ESV) ratio, and early-to-late diastolic filling (E/A) was conducted on 23 studies using the SE of the between-subjects SD. HR, SBP, and left ventricular internal diameter during diastole (LVIDd) were also analyzed. Studies were coded according to exercise duration and training status: moderate duration trained (MDt) and untrained (MDu), 60-150 min; long duration (LD), 166-430 min; and ultra duration (UD), 640-1440 min. Relationships were assessed via Pearson's product-moment correlation. RESULTS: A significant (P < 0.05) overall decrease in EF (mean, confidence interval (CI): -1.95%, -1.03 to -2.88%), SBP/ESV (mean, CI: -0.8, -0.63 to -0.97), and E/A (mean, CI: -0.45, -0.39 to -0.51) was observed. Only UD and MDu subgroups demonstrated a reduction in EF. All subgroups demonstrated significant (P < 0.05) decreases in E/A. Alterations in LVIDd and SBP were related to respective decreases in EF and SBP/ESV, but not to E/A. CONCLUSION: The decrease in EF and SBP/ESV observed in UD and MDu indicates a reduction in systolic function, partially explained by altered cardiac loading. A decrease in E/A in all subgroups, unrelated to changes in loading, suggests an intrinsic impairment of left ventricular relaxation. Future investigators should employ load-independent indices of cardiac function and attempt to uncover the mechanisms of this phenomenon.

Novel application of flow propagation velocity and ischaemia-modified albumin in analysis of postexercise cardiac function in man.

The present study employed novel echocardiographic tools and cardiac markers to obtain a greater understanding of the aetiology and time course of altered cardiac function and cardiac damage following prolonged exercise and, in particular, the possible role of transient ischaemia within these phenomena. Fourteen runners in the 2004 London Marathon were assessed pre-, immediately post-, 1 h post- and 24 h postcompletion of the race. Left ventricular function was examined echocardiographically using 2-D, M-mode, tissue Doppler imaging and flow propagation velocity (Vp). Venous blood samples were analysed for N-terminal pro-B-type natriuretic peptide (proBNP), cardiac troponin T (cTnT) and ischaemia-modified albumin (IMA). Left ventricular (LV) diastolic filling was altered on completion of the race, as indicated by significant decreases in mean early to late diastolic myocardial wave (E':A') ratio and Vp (from 1.82 +/- 0.9 to 1.32 +/- 0.32, and from 67.5 +/- 9.3 to 60.2 +/- 8.2 cm s(-1), respectively, P < 0.05), accompanied by an increase in proBNP (from 21.6 +/- 11 to 47.08 +/- 19.5 pg l(-1), P < 0.05). The observed reduction in LV diastolic filling following completion of a marathon, unrelated to changes in heart rate or loading parameters, indicates an intrinsically mediated change in diastolic filling. Exercise-induced elevations in cTnT in nine individuals (range, 0.023-0.37 microg l(-1)) were indicative of minor cardiac damage. A significant reduction in IMA was observed after the marathon (from 63.68 +/- 9.83 to 44.94 +/- 16.13 Um l(-1), P < 0.05), unrelated to the alterations in cardiac function, proBNP or cTnT. The absence of an elevation in IMA suggests that exercise-induced myocardial ischaemia did not occur and therefore could not explain the changes in cardiac function or biomarkers. Future studies in this area should investigate alternative diagnostic tools for the detection of transient ischaemia, and other potential mechanisms, in order to extend the understanding of this phenomenon.