Background : Patients with primary adrenal insufficiency (PAI) describe significant impairments in quality of life. Current replacement regimes are non-physiological. Animal studies indicate that pulsatile presentation of endogenous glucocorticoids is critical for normal transcriptional and behavioural responses. Healthy volunteer work also shows that pattern of glucocorticoid presentation alters cognitive and emotional processing.
Objective: To assess the effects of glucocorticoid presentation on cognition and emotional processing in patients with PAI
Methods: The Pulses study (ISRCTN67193733) was a 6-week Double-blind placebo control cross over trial of standard three-time daily oral hydrocortisone to continuous pulsatile subcutaneous in PAI secondary to Addisons (AD) and Congenital Adrenal Hyperplasia (CAH) (N=21, AD 17/CAH 4). Secondary outcome measures of resting state and task based (Facial Expression Recognition Task FERT) functional magnetic resonance imaging (fMRI) are discussed. Whole brain and region of interest (ROI) analysis based on known cortisol sensitivity and involvement in emotional processing was performed. Washout range 6 weeks-1 year. Total daily dose of hydrocortisone was the same on both arms (range 2040 mg).
Results: Righthanded N=13 female AD only; fsl analysis detected differential activation between treatment arms. Task based whole brain analysis under fearful condition Middle Frontal Gyrus, Precentral Gyrus, Superior Frontal Gyrus, Supplementary Motor Cortex, Anterior Cingulate Gyrus and Paracingulate Gyrus. ROI analysis under fearful condition insula and amygdala. Resting state fMRI ROI analysis dorsal striatum and insula.
Conclusions: The Pulses trial confirms safety and tolerability of subcutaneous hydrocortisone pump treatment. No subjects dropped out due to trial related issues. fMRI detected differentially activated executive control regions that are important in cognitive and emotional processing. This gives an early indicator that cortisol dynamics impact on cognition and emotional processing and should be considered in glucocorticoid based therapeutics.