The Influence Coulson JM, Murphy K, Harris AD, Fjordorova M, Cockcroft JR , Wise RG.

1. The Influence of the Brain on the Control of Mean Arterial Pressure in Normal and Hypertensive Young Adults The Influence Coulson JM, Murphy K, Harris AD, Fjordorova M, Cockcroft JR, Wise RG.

2. Introduction • Primary hypertension is characterised by excessive sympathetic activity : • Increased SNS efferent activity in animal models of hypertension (Judy et al. 1979) • Increased systemic & regional noradrenaline turnover in hypertensive humans (Esler et al. 1989 and Goldstein 1983) • Increased sympathetic neuronal activity in hypertensive adults (Narkiewicz et al 2005) • Decreased parasympathetic activity in hypertensive adults (Langewitz et al 1994)

3. Introduction • Increased SNS activity may have a causal role in the pathogenesis of hypertension: • A hyperkinetic circulation & increased plasma noradrenaline precedes the onset of hypertension in young adults (Julius et al. 1991) • The magnitude of increased SNS activation is proportional to the severity of hypertension (Anderson et al. 1989 &Grassi et al. 2007) • The cause of this apparent imbalance in autonomic tone is not understood

6. Blood oxygen level dependent (BOLD) fMRI • CNS oxygen delivery to active brain regions is in excess of oxygen consumption (neurovascular coupling) (Roy and Sherrington 1890) • Oxyhaemoglobin is diamagnetic, exhibiting a lower magnetic susceptibility than paramagnetic deoxyhaemoglobin (Pauling and Coryell 1936) • Deoxyhaemoglobin can therefore be utilized as a natural contrast agent during MRI (Ogawa et al 1990) • A spatially localised increase in BOLD signal directly and monotonically reflects an increase in neural activity (Logothetis et al 2001) • BOLD signal correlates with changes in muscle sympathetic nervous activity (Macefield and Henderson 2010)

7. Aims • Identify regions of the human brain associated with the blood pressure response to voluntary isometric forearm contraction (IFC). • Identify a relationship between the BOLD signal associated with the blood pressure response to IFC and baseline mean arterial pressure.

8. Methods • 12 right-handed adults (6 female) volunteers • aged from 23 to 36 years • Resting MAP ranging from 73 – 113 mmHg • Blood pressure profiling study • Preformed IFC at 40% and 5% of their maximum grip strength for varying time intervals (11 - 180 seconds) • Beat to beat blood pressure response to IFC was obtained in during an out of the MRI scanner session and used to model the blood pressure response to isometric forearm contraction

9. Methods • BOLD fMRI study • Preformed IFC at 40% and 5% of their maximum grip strength for varying time intervals (11 - 180 seconds) within a 3-Tesla whole body MRI scanner (General Electric, US) • A continuous series of 170 fMRI image volumes (echo-planar images using BOLD contrast, scan time = 12m 39s) were collected for each run. • Each volume covered the entire brain and brainstem (57 slices, TR = 4385ms, TE = 25ms)  • Structural images were collected using a T1-weighted sequence • Each T1 scan was registered to the MNI152, an average T1 brain image constructed from 152 normal subjects at the Montreal Neurological Institute (MNI), Montreal, QC, Canada.

10. Results – baseline characteristics

11. Results – BP response to IFC

12. R b Z score a a b Z -44 mm (a) R cerebellum and (b) medullar e R R R d c Z 56 mm (d) sensory motor cortex Z -12 mm (e) medial frontal cortex Z 14 mm (c) R insular posterior cortex Group map (n = 12) showing brain areas where the BOLD response to FIC correlated with the blood pressure response. Significant regions are displayed with a threshold Z > 2.3, with a cluster probability threshold of p < 0.05.

13. The Brainstem BOLD response Correlation between MAP and brainstem BOLD signal change. Correlation coefficient = 0.61, p-value = 0.01

14. The Brainstem BOLD response * Comparison between baseline MAP and BMI BOLD signal change, (*)p-value < 0.05.

15. Discussion • Areas of the brain where BOLD signal change correlated with the modelled rise in blood pressure to IFC: • insular cortex • Medial Frontal Cortex • Sensory-motor cortex • Thalamus • Cerebella hemisphere • Brainstem

16. Discussion • First study to consider the effect of baseline blood pressure and BMI on blood pressure-associated BOLD signal changes. • Inverse relationship between baseline MAP and brainstem BOLD signal change • The output of the RVLM is believed to be tonic (Campos et al 2008) • May reflect that BOLD measures relative changes, rather than absolute changes, in neurovascular activity (Mathews and Jezzard 2004)

17. Limitations 1. Crossectional study 2. The effect of IFC may also potentially alter the BOLD signal by causing alterations in cerebral blood flow. 3. It was not possible to obtain blood pressure measurements on subjects during scanning sessions due to magnetic interference with the Finapres system. 4. intra-subject variability over time was therefore not specifically measured. 6. The conclusions concerning the relationship between BOLD signal change and baseline MAP are only valid over the range of the study population

18. WHRI Professor Cockcroft Mrs M.Munnery Mr I. Munnery CUBRIC Professor Richard Wise Professor Singh Dr. K. Murphy Dr. A. Harris Thanks to: Clinical Pharmacology Professor Routledge Dr. Krishna Dr. JP Thompson Dr. A Thomas • Cambridge University • Dr I. Wilkinson • Dr.C. McEniery