817 Robotic Semi-Automated Transcranial Doppler Assessment of Cerebrovascular Autoregulation in Post Concussional Syndrome: Methodological Considerations

Introduction Post-concussive syndrome (PCS) refers to a constellation of physical, cognitive, and emotional symptoms after traumatic brain injury (TBI). Despite its incidence, the underlying mechanisms are unclear. We hypothesised that impaired cerebral autoregulation (CA) is a contributor. Method A prospective, observational study was integrated into outpatient clinics at a tertiary neurosurgical centre. Data points included: demographics, symptoms (Post-Concussion Symptom Scale [PCSS]), neuropsychological assessment (Cambridge Neuropsychological Test Automated-Battery [CANTAB]) and cerebrovascular metrics (Mxa co-efficient and the transient hyperaemic-response ratio [THRR]) - via transcranial Doppler (TCD), plethysmography and bespoke software (ICM+). Results 12 participants were recruited with 2 excluded after unsuccessful cerebrovascular TCD insonation. 10 participants (5 TBI patients, 5 healthy controls) were included in the analysis (median age 26.5, male:female 7:3). Median PCSS scores were 6/126 (TBI subgroup). Median CANTAB percentiles were 78 (healthy controls) and 25 (TBI). Mxa was calculated for 90% and THRR for 50% of participants. Median study time was 127.5 minutes and feedback (n = 6) highlighted the perceived acceptability of the study. Conclusions This pilot study has demonstrated a feasible and reproducible assessment of PCS and CA metrics (non-invasively) in a real-world setting. By scaling this methodology, we hope to test whether CA changes are correlated with symptomatic PCS in patients post-TBI.

Quantitative cardiovascular magnetic resonance myocardial perfusion mapping to assess hyperaemic response to adenosine stress

Aims Assessment of hyperaemia during adenosine stress cardiovascular magnetic resonance (CMR) remains a clinical challenge with lack of a gold-standard non-invasive clinical marker to confirm hyperaemic response. This study aimed to validate maximum stress myocardial blood flow (SMBF) measured using quantitative perfusion mapping for assessment of hyperaemic response and compare this to current clinical markers of adenosine stress. Methods and results Two hundred and eighteen subjects underwent adenosine stress CMR. A derivation cohort (22 volunteers) was used to identify a SMBF threshold value for hyperaemia. This was tested in a validation cohort (37 patients with suspected coronary artery disease) who underwent invasive coronary physiology assessment on the same day as CMR. A clinical cohort (159 patients) was used to compare SMBF to other physiological markers of hyperaemia [splenic switch-off (SSO), heart rate response (HRR), and blood pressure (BP) fall]. A minimum SMBF threshold of 1.43 mL/g/min was derived from volunteer scans. All patients in the coronary physiology cohort demonstrated regional maximum SMBF (SMBFmax) >1.43 mL/g/min and invasive evidence of hyperaemia. Of the clinical cohort, 93% had hyperaemia defined by perfusion mapping compared to 71% using SSO and 81% using HRR. There was no difference in SMBFmax in those with or without SSO (2.58 ± 0.89 vs. 2.54 ± 1.04 mL/g/min, P = 0.84) but those with HRR had significantly higher SMBFmax (2.66 1.86 mL/g/min, P < 0.001). HRR >15 bpm was superior to SSO in predicting adequate increase in SMBF (AUC 0.87 vs. 0.62, P < 0.001). Conclusion Adenosine-induced increase in myocardial blood flow is accurate for confirmation of hyperaemia during stress CMR studies and is superior to traditional, clinically used markers of adequate stress such as SSO and BP response.

Abnormal neurovascular coupling as a cause of excess cerebral vasodilation in familial migraine

Aims Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R mice) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these α2+/G301R mice also have increased cerebrovascular hyperaemic responses to these local metabolites leading to hyperperfusion in the affected part of the brain. Methods and results Neurovascular coupling was compared in α2+/G301R and matching wild-type (WT) mice using Laser Speckle Contrast Imaging. In brain slices, parenchymal arteriole diameter and intracellular calcium changes in neuronal tissue, astrocytic endfeet, and smooth muscle cells in response to neuronal excitation were assessed. Wall tension and smooth muscle membrane potential were measured in isolated middle cerebral arteries. Quantitative polymerase chain reaction, western blot, and immunohistochemistry were used to assess the molecular background underlying the functional changes. Whisker stimulation induced larger increase in blood perfusion, i.e. hyperaemic response, of the somatosensory cortex of α2+/G301R than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from α2+/G301R than WT mice. These hyperaemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (Kir). Relaxation to elevated bath K+ was larger in arteries from α2+/G301R compared to WT mice. This difference was endothelium-dependent. Endothelial Kir2.1 channel expression was higher in arteries from α2+/G301R mice. No sex difference in functional responses and Kir2.1 expression was found. Conclusion This study suggests that an abnormally high cerebrovascular hyperaemic response in α2+/G301R mice is a result of increased endothelial Kir2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack.

The Effect of Shear Force on Skin Viability in Patients with Type 2 Diabetes

Background. Shear is a major risk factor in the development of diabetic foot ulcers, but its effect on the skin of patients with type 2 diabetes mellitus (DM) remains to be elucidated. The aim was to determine skin responses to shear in DM patients with and without diabetic polyneuropathy (DNP). Methods. The forearm skin was loaded with 14.5 N shear (+2.4 kPa pressure) and with 3.5 kPa pressure for 30 minutes in 10 type 2 DM patients without DNP, 10 type 2 DM patients with DNP, and 10 healthy participants. A Sebutape collected IL-1α (measure of tissue damage). A laser Doppler flowmeter measured cutaneous blood cell flux (CBF) as a measure of the reactive hyperaemic skin response. Findings. Reactive hyperaemia and IL-1α release was significantly increased after shear loading in all three groups and was higher compared to the responses to pressure loading. The reactive hyperaemic response after shear loading was impaired in patients with type 2 DM compared to healthy participants but did not differ between patients with and without DNP. The reactive hyperaemic response was negatively correlated with the blood glucose level but did not correlate with the DNP severity score. Interpretation. Shear is important in the development of tissue damage, but the reparative responses to shear are impaired in patients with type 2 DM. DNP was not associated with altered skin responses, suggesting that the loss of protective sensation to sense shear to skin remains a key factor in the development of diabetic foot ulcers in patients with DNP.

Predicting Blood Flow Responses to Rhythmic Handgrip Exercise From One Second Isometric Contractions

The aim of this work was to predict blood flow responses to rhythmic handgrip exercise from one second isometric contractions. Seven healthy men were studied. Each subject performed a single 1 s handgrip contraction at 10 %, 20 % and 40 % of the maximum handgrip strength. We then repeatedly summed hyperaemic responses from single contractions to predict hyperaemic response to a prolonged bout of rhythmic exercise. There was similarity between steady state brachial blood flow velocity (BBV) extrapolated from single handgrip contractions and during 2 min of rhythmic exercise for 20 % (10.0±3.8 cm/s vs. 10.2±2.6 cm/s, r=0.93, p=0.003) and 40 % of maximum contractions (14.2±5.5 cm/s vs. 15.6±3.4 cm/s, r=0.88, p=0.009), but not for 10 % (7.5±4.1 cm/s vs. 5.7±3.3 cm/s, r=0.94, p=0.018). BBV progressively rose substantially higher during rhythmic contractions than peak BBV observed during single contractions at matched intensity. Respective peak BBV during single contractions and steady state BBV rhythmic contractions were 4.4±2.1 and 5.7±3.3 cm.s−1 at 10 % forearm strength (p=0.14), 5.6±2.4 and 10.2±2.8 cm.s−1 at 20 % (p=0.002), and 7.0±2.5 and 15.6±3.6 cm.s−1 at 40 % (p=0.003). In conclusion, there is similarity between the summated blood flow velocity calculated from a single 1 s muscle contraction and the steady state blood flow velocity response of rhythmic exercise.

A Comparison of Measures of Endothelial Function in Patients with Peripheral Arterial Disease and Age and Gender Matched Controls

This study compared flow-mediated dilatation (FMD), peripheral artery tonometry (PAT), and serum nitric oxide (NO) measures of endothelial function in patients with peripheral artery disease (PAD) against age/gender matched controls. 25 patients (mean age: 72.4 years, M : F 18 : 7) with established PAD and an age/gender matched group of 25 healthy controls (mean age: 72.4 years, M : F 18 : 7) were studied. Endothelial function was measured using the % FMD, reactive hyperemia index (RHI) using PAT and serum NO (μmol). Difference for each method between PAD and control patients and correlation between the methods were investigated. FMD and RHI were lower in patients with PAD (median FMD for PAD = 2.16% versus control = 3.77%,p=0.034and median RHI in PAD = 1.64 versus control = 1.92,p=0.005). NO levels were not significantly different between the groups (PAD median = 7.70 μmol, control median = 13.05 μmol,p=0.662). These results were obtained in elderly patients and cannot be extrapolated to younger individuals. FMD and PAT both demonstrated a lower hyperaemic response in patients with PAD; however, FMD results in PAD patients were unequivocally reduced whereas half the PAD patients had RHI values above the established threshold for endothelial dysfunction. This suggests that FMD is a more appropriate method for the measurement of NO-mediated endothelial function.