Voluntary control of corticomuscular coherence through neurofeedback: a proof-of-principle study in healthy subjects.

Corticomuscular coherence (CMC) relates to synchronization between activity in the motor cortex and the muscle activity. The strength of CMC can be affected by motor behavior. In a proof-of-principle study, we examined whether independent of motor output parameters, healthy subjects are able to voluntarily modulate CMC in a neurofeedback paradigm. Subjects received visual online feedback of their instantaneous CMC strength, which was calculated between an optimized spatial projection of multichannel electroencephalography (EEG) and electromyography (EMG) in an individually defined target frequency range. The neurofeedback training consisted of either increasing or decreasing CMC strength using a self-chosen mental strategy while performing a simple motor task. Evaluation of instantaneous coherence showed that CMC strength was significantly larger when subjects had to increase than when to decrease CMC; this difference between the two task conditions did not depend on motor performance. The exclusion of confounding factors such as motor performance, attention and task complexity in study design provides evidence that subjects were able to voluntarily modify CMC independent of motor output parameters. Additional analysis further strengthened the assumption that the subjects' response was specifically shaped by the neurofeedback. In perspective, we suggest that CMC-based neurofeedback could provide a therapeutic approach in clinical conditions, such as motor stroke, where CMC is altered.

The effect of midazolam on cerebral endothelial (P-selectin and ICAM-1) adhesion molecule expression during hypoxia-reperfusion injury in vitro.

BACKGROUND AND OBJECTIVE: Hypoxia-reperfusion injury is an important determinant of secondary brain injury. In the acute phase of cerebral reperfusion, pro-inflammatory events enhance expression of cerebral endothelial (intercellular adhesion molecule-1 and P-selectin) adhesion molecules, which play an important role in brain hypoxia-reperfusion injury. Midazolam is the most commonly used sedative in patients with brain injury. The objective of this investigation was to examine the effect of midazolam on the expression of cerebral endothelial intercellular adhesion molecule-1 and P-selectin during hypoxia-reperfusion injury in vitro. METHODS: The up-regulation of mouse cerebral endothelial cells intercellular adhesion molecule-1 and P-selectin was assessed following hypoxia-reoxygenation (hypoxia-reperfusion). Cells were pre-treated with three different concentrations of midazolam (0, 5 and 50 microg mL(-1)) prior to hypoxia. Flow cytometry was used to estimate adhesion molecule expression mean channel fluorescence. Data are presented as mean +/- SD. RESULTS: Mouse cerebral endothelial cell intercellular adhesion molecule-1 and P-selectin expression was greater after exposure to hypoxia-reoxygenation compared to normoxia (mean channel fluorescence) 241 +/- 12 vs. 140 +/- 7 and 120 +/- 14 vs. 46 +/- 7, respectively, P < 0.05. Intercellular adhesion molecule-1 and P-selectin expression was decreased by midazolam (5 microg mL(-1)) pre-incubation compared to control, mean channel fluorescence 184 +/- 10 vs. 241 +/- 12 and 51 +/- 7 vs. 120 +/- 14, respectively, P < 0.05. Midazolam at 50 microg mL(-1) had the same effect as 5 microg mL(-1). CONCLUSION: Pre-treatment with midazolam diminishes increased expression of cerebral endothelial intercellular adhesion molecule-1 and P-selectin expression following hypoxia-reoxygenation.

Contemporary referral of patients from community care to cardiology lack diagnostic and clinical detail.

The quantity of referrals to secondary care is increasing. That the quality of medical referrals is decreasing is a common allegation yet has rarely been assessed. We report a time-limited, cross-sectional survey evaluating cardiological referral information quality. Referral letters (n = 218, excluding direct access pro formas) from GPs to the Cardiology Department at City Hospital, Birmingham, were collated and analysed over 2 months. A subset (n = 49) of these patients completed questionnaires assessing their knowledge and patient communication of the referral. Information quality was poor (length, diagnosis, expectation, prior treatment and investigation) with almost half of all letters containing only outline symptomatic complaints without diagnosis. The majority of patients referred had not been investigated or treated in any way before referral. Despite lack of understanding of the reason for referral, typically the majority of patients expressed themselves as satisfied with the process. Given most referrals are seen as appropriate, information exchange between secondary and primary care is crucial. By contrast, the standard of even basic clinical assessment communicated between primary care and secondary care was severely limited. The reason(s) why medical assessment is lacking are unclear but must be explored to give more support to primary care to complete basic medical task particularly if investment is to flow into this source.

Effect of midazolam on in vitro cerebral endothelial ICAM-1 expression induced by astrocyte-conditioned medium.

BACKGROUND AND OBJECTIVE: Astrocytes exposed to hypoxia produce pro-inflammatory cytokines and upregulate intercellular adhesion molecule-1 on cerebral endothelium. This study investigated the effects of midazolam on this response. METHODS: Mouse astrocytes were exposed to 4 h of hypoxia and 24 h of reoxygenation. Astrocyte-conditioned medium were applied to mouse cerebral endothelial cell cultures for 4 h and 24 h in normoxia. Endothelial cells were pre-incubated for 1 h with midazolam (0, 5, 50 microg L-1). Flow cytometry was used to estimate endothelial ICAM-1 expression. IL-1beta concentrations were measured with ELISA. Repeated comparisons were made using ANOVA and post hoc Tukey Test as appropriate. Data are mean (SD). RESULTS: Mouse cerebral endothelial cell ICAM-1 expression was greater after 24 h exposure to hypoxia-reoxygenation astrocyte-conditioned medium compared to normoxic astrocyte-conditioned medium (mean channel flouresence 112.5 (9.5) vs. 81.5 (7.5), P = 0.01). ICAM-1 expression was decreased by midazolam (5 microg L(-1)) compared to control (mean channel flouresence 81.35 (7.5) vs. 112.5 (9.5), P = 0.01). Supernatant IL-1beta concentrations (pg mL(1)) in astrocytes exposed to hypoxia-reoxygenation were greater than those exposed to normoxia (16.41 (2.35) vs. 10.5 (2.13), P = 0.01). CONCLUSION: We conclude that decreased cerebral endothelial ICAM-1 expression in response to activated glial cell compartment by midazolam may decrease post ischaemic brain inflammation and secondary brain injury.

Plasma concentrations of nitric oxide products and cognitive dysfunction following coronary artery bypass surgery.

BACKGROUND AND OBJECTIVE: Prospective longitudinal studies now indicate that cognitive dysfunction following coronary artery bypass surgery (CABG) is both common and persistent. This dysfunction is due in part to the inflammatory response and cerebral ischaemia-reperfusion, with nitric oxide (NO) as an important mediator of both. We hypothesized that a clinically significant association exists between plasma concentrations of nitrate/nitrite (NO3-/NO2-) and cognitive dysfunction after CABG. METHODS: Cognitive assessment was performed on 36 adult patients the day before CABG, on the fourth postoperative day and 3 months postoperatively. Patient spouses (n = 10) were also studied. RESULTS: A new cognitive deficit was present in 22/36 (62%) 4 days postoperatively and in 16/35 (49%) of patients, 3 months postoperatively. Patients who had cognitive dysfunction 3 months postoperatively were more likely to have cognitive dysfunction and increased plasma NO3-/NO2- concentrations compared to the non-deficit group preoperatively (22.6 (9.2) vs. 27.6 (8.4)) (P = 0.002). Plasma NOx (NO3- plus NO2-) concentrations were greater in patients with cognitive dysfunction 3 months postoperatively, 2 h (24.2 (6.3) vs. 19.1 (5.2)) (P = 0.002), and 12 h postoperatively (24.8 (7.6) vs. 18.8 (5.6)) (P = 0.001). There was, however, a time course similarity in NOx elevations for both deficit and non-deficit groups. CONCLUSIONS: Perioperative plasma NOx concentrations do not serve as an effective biomarker of cognitive deficit after CABG.

Effect of aprotinin on in vitro cerebral endothelial ICAM-1 expression induced by astrocyte-conditioned medium.

BACKGROUND AND OBJECTIVE: Aprotinin administration may decrease the incidence of stroke associated with coronary artery bypass surgery by an unknown mechanism. Astrocytes exposed to hypoxia produce proinflammatory cytokines and upregulate intercellular adhesion molecule (ICAM)-1 on cerebral endothelium. This study investigated the effects of aprotinin on cerebral endothelial activation by hypoxic astrocytes in vitro. METHODS: Mouse astrocytes were exposed to hypoxia in an anaerobic chamber for 4 h followed by reoxygenation for 24 h. Astrocyte-conditioned medium (ACM) collected from mouse astrocytes subjected to hypoxia/reoxygenation (HR) or normoxia were applied to mouse cerebral endothelial cell (MCEC) cultures for 4 and 24 h in normoxia. Endothelial cells were preincubated for 1 h with aprotinin (1600 KIU mL(-1)) prior to exposure to ACM. Flow cytometry was used to estimate endothelial ICAM-1 expression. Interleukin (IL)-1beta space concentrations in ACM were estimated with enzyme-linked immunosorbent assay (ELISA). Repeated comparisons were made using analysis of variance (ANOVA) and post hoc Tukey test as appropriate. P < 0.05 was considered significant. Data is presented as mean (standard deviation, SD). RESULTS: MCEC ICAM-1 expression was greater after 24 h exposure to HR-ACM compared to normoxic-ACM (mean channel flouresence (MCF) 107.5 (4.5) vs. 74.3 (4.5), respectively, P < 0.001). ICAM-1 expression was decreased by aprotinin preincubation compared to control (MCF 91.0 (1.1) vs. 107.5 (2.1), P = 0.006). Supernatant IL-1beta concentrations in astrocytes exposed to HR were greater than those exposed to normoxia (7.1 (0.2) vs. 4.1 (0.2), P = 0.01). CONCLUSIONS: This may be a neuroprotective mechanism associated with aprotinin administration.

S100beta and nitric oxide product concentrations following cerebral aneurysm clipping in patients with subarachnoid haemorrhage: a pilot study.

OBJECTIVE: The objective of this investigation was to determine the efficacy of S100beta and nitric oxide product (nitrate and nitrite [NOx]) concentrations as markers of brain injury following cerebral aneurysm clipping in patients with spontaneous subarachnoid haemorrhage. METHODS: Fifteen patients with spontaneous subarachnoid haemorrhage were studied. Blood samples were obtained for estimation of serum S100beta (microg/L) and nitric oxide product (nitrate and nitrite [NOx]) (microM) concentrations immediately preoperatively (baseline) and then 10 minutes, 2, 6 and 12 hr postoperatively and daily thereafter for five days. Neurological outcome was assessed three months after surgery by the Glasgow Outcome Scale (GOS) (poor outcome, grade 1 - 3 and good outcome as grade 4 - 5). Data were analysed using the Mann-Whitney-U-test. RESULTS: S100beta concentrations were greater at two hours postoperatively compared to baseline (0.33 +/- 0.16 vs 0.25 +/- 0.04)(P = 0.02). S100beta concentrations were similar in good and poor neurological outcome groups as defined by GOS at three months. NOx concentrations were less at 12 hours postoperatively compared to baseline (9.81 +/- 3.25 vs 12.74 +/- 2.9)(P = 0.03). NOx concentrations were greater on the fourth and fifth postoperative days compared to baseline (t0) (17.22 +/- 7.9, 12.74 +/- 2.9 vs 9.81 +/- 3.25) (P < 0.05). NOx concentrations were greater in patients with a poor neurological outcome (n = 4) compared to the good outcome group (n = 11) (24.7 +/- 4.9 vs. 11.3 +/- 3.3)(P = 0.04). CONCLUSIONS: S100beta and NOx concentrations increase after cerebral aneurysm clipping in patients with spontaneous SAH. Increased nitric oxide product concentrations were associated with subsequent poor neurological outcome.

The effect of lidocaine on in vitro neutrophil and endothelial adhesion molecule expression induced by plasma obtained during tourniquet-induced ischaemia and reperfusion.

BACKGROUND: Changes in neutrophil and endothelial adhesion molecule expression occur during perioperative ischaemia and reperfusion (I/R) injury. We investigated the effects of lidocaine on neutrophil-independent changes in neutrophil and endothelial adhesion molecule expression associated with tourniquet-induced I/R. METHODS: Plasma was obtained from venous blood samples (tourniquet arm) taken before (baseline), during, 15 min, 2 and 24 h following tourniquet release in seven patients undergoing elective upper limb surgery with tourniquet application. Isolated neutrophils from healthy volunteers (n = 7) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1) for 1 h, and then incubated with I/R plasma for 2 h. Human umbilical vein endothelial cells (HUVECs) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1)) for 1 h, and then incubated with the plasma for 4 h. Adhesion molecule expression was estimated using flow cytometry. Data were analysed using ANOVA and post hoc Student-Newman-Keuls tests. RESULTS: I/R plasma (withdrawn 15 min following tourniquet release) increased isolated neutrophil CD11b (P = 0.03), CD18 (P = 0.01) and endothelial intercellular adhesion molecule-1 (ICAM-1) (P = 0.008) expression compared to baseline. CD11b, CD18 and ICAM-1 expression on lidocaine (0.005 mg mL(-1)) treated neutrophils was similar to control. CD11b (P < 0.001), CD18 (P = 0.03) and ICAM-1 (P = 0.002) expression on lidocaine (0.05 mg mL(-1)) treated neutrophils and HUVECs was less than that on controls. CONCLUSION: Increased in vitro neutrophil and endothelial cell adhesion molecule expression on exposure to plasma obtained during the early reperfusion phase is diminished by lidocaine at greater than clinically relevant plasma concentrations.

Dose-response and onset/offset characteristics of rapacuronium.

BACKGROUND: A rigorous study of the dose-response relation of rapacuronium has, to our knowledge, yet to be performed. In addition, there is little information available regarding the onset or offset profile of rapacuronium when administered in subparalyzing doses. These issues necessitate further study. METHODS: Forty-seven adult patients, American Society Anesthesiologists physical status I or II, were studied. Tracheal intubation was accomplished without muscle relaxants. Anesthesia was maintained with use of nitrous oxide, propofol, and alfentanil. The electromyogram of the first dorsal interosseous muscle was measured using a monitor. Single stimuli at 0.10 Hz were administered. A single dose of rapacuronium was administered. After log-dose or logit transformation of the data, the best-fit line of regression was determined using the method of least squares. For each subject, the authors estimated the 50% effective dose (ED50) and 95% effective dose (ED95) from the Hill equation using the slope obtained from regression analysis. The onset times to 50 and 90% of peak effect were estimated in a subset of 10 individuals in which peak twitch depression decreased to the range of 90-99%. RESULTS: The calculated ED50 and ED95 values for rapacuronium were 0.39 +/- 0.08 (SD) and 0.75 +/- 0.16 mg/kg, respectively. After a single ED95 dose, 90% of the drug's peak effect was evident in 77 +/- 17 s. After this dose, rapacuronium has a clinical duration of 6.1 +/- 1.1 min. CONCLUSIONS: The authors found the ED95 of rapacuronium to be substantially less than suggested by previous estimates. Rapacuronium has an onset profile that is not different from that previously reported for succinylcholine. The rate of spontaneous recovery was faster after rapacuronium than the authors previously observed after mivacurium administration but was slower than after succinylcholine, using an identical protocol.