Background and aim: Hypertension is the leading modifiable risk factor for the development of cardiovascular-related cerebral events (including ischaemic stroke and cerebral small-vessel disease)[i]. Hypertensive humans have lower cerebral blood flow compared with normotensives, which may contribute to the pathophysiology of the disease, particularly grey matter loss[ii][iii]. Lower cerebral blood flow may trigger reflex activation of sympathetic nerve activity (SNA); a hallmark of essential hypertension[iv]. The level of SNA may therefore reflect the likelihood and severity of cerebral events occurring in hypertensive individuals. Here we sought to investigate the association between cerebral tissue volumes (grey and/or white matter; GM, WM) and the level of SNA in hypertensive vs. normotensive humans. Methodology:Muscle SNA (MSNA) was measured using peroneal microneurography in 16 healthy, normotensive individuals, and in 25 otherwise healthy, patients with hypertension (treated and uncontrolled mixture) [(mean age: 42±4 and 54±2 years respectively, p<0.001) (mean BMI: 23.9±2 and 29±1 respectively, p<0.001)]. Tissue volumes were measured using T1-weighted 3T-Magnetic Resonance (FSPGR) Imaging of the brain. Total GM and WM volumes were established using automated segmentation software (FIRST, FSL) and normalised as a % of total intracranial volume. Comparisons of age, BMI and blood pressures between the normotensive and hypertensive cohorts were analysed using an unpaired student’s T-test. Associations between MSNA and cerebral tissue volumes were analysed using non-linear multivariate regression, controlling for age and BMI. Values are Mean ± S.E.M. Results: Office systolic blood pressure (SBP) and mean arterial pressure (MAP) were higher in hypertensives (134mmHg±2 and 100mmHg±2 respectively,) vs. normotensives (122mmHg±2 and 92mmHg±2 respectively) (p<0.01). In hypertensive, but not normotensive men, MSNA incidence (bursts/100 heart beats) and frequency (bursts/minute) were both negatively correlated with the ratio of GM to WM (p=0.002, r=0.001 and p=0.009, r=0.002 respectively). In normotensive and hypertensive women, no significant relationship between MSNA and cerebral tissue volume could be established (p>0.05). Conclusions and interpretations: In hypertensive men, MSNA levels negatively correlate with the ratio of GM to WM volume. This is not observed in normotensive men. Interestingly, this relationship appears to be sex-specific. We suggest that lower cerebral blood flow in hypertensive men may cause GM loss and subsequent reflex elevations in MSNA in order to aid perfusion. It is therefore possible that the level of MSNA reflects the severity of disease progression, and target organ damage in males with essential hypertension. Those with higher MSNA may therefore have a cerebral-vascular component driving their hypertension.