Cognitive and emotional effects of different patterns of

glucocorticoid replacement therapy in Addison's and Congenital

Adrenal Hyperplasia 

Chief Investigator	Institution	Dates	Funding Stream	Amount
Dr Georgina Russell	University of Bristol	01/11/2014 to 31/12/2017	Above and Beyond Spring 2014	£19,951

Summary

Steroid replacement therapy is a key aspect for treatment for Addison's and Congenital Adrenal Hyperplasia (CAH).  These patients have a mortality rate twice that of the background population and report significant morbidity especially from early morning mental and physical fatigue.  Despite our best attempts to mimic normal daily levels of cortisol in the blood, our current therapy fails to reproduce either the timing of the normal circadian rhythm of cortisol secretion or the hourly ultradian pattern of cortisol secretion critical for normal gene regulation, hormonal and behavioural activity.  Additionally, there is strong evidence for links between glucocorticoids and cognition. The short-lived rise in glucocorticoids during acute stress is associated with heightened cognitive ability whilst prolonged hypersecretion is associated with cognitive decline.

We have developed a novel, portable subcutaneous hydrocortisone pump that can reproduce a normal physiological pattern of cortisol closely replicating both circadian and ultradian rhythmicity.

There are currently no good objective measures of cognitive processing in patients on cortisol replacement.

We have designed and are validating in healthy volunteers a specially designed battery of psychological tasks. I should now like to see whether genuine physiological hormone replacement can improve the cognitive processing of our patients in comparison to standard treatment.

This project is part of a wider body of work looking at the cognitive, emotional, biochemical and metabolic effects of different patterns of glucocorticoid replacement therapy in patients with Addison's disease (AD) and congenital adrenal hyperplasia (CAH). The total anticipated N was 20 (12 AD and 8 CAH), for this project funding for scanning costs was granted for 17 patients. By end of study 12/17, 21 patients were recruited in total, 17 AD and 4 CAH. One patient dropped out after arm 1 due to personal reasons and felt that could not commit to the trial.

Recruitment has generally been challenging and I have had to extend the duration of the study and the recruitment radius to within 2 hours of Bristol. In addition there has been marked difficulty in engaging patients with CAH patients. The feedback I have received is that they are interested in the outcome of the trail but reluctant to take part. I have discussed this with collaborators on other projects and they too have found similar issues with patients with CAH so I do not think this is a study specific issue. On discussion with our data monitoring committee it was felt reasonable to over-recruit with AD patients.

Main findings

Differential resting state connectivity pathways between the dorsal striatum and Right Insula with default mode network (pump over pill) and an altered whole brain and region of interest response to fear in the task based fMRI (pill over pump). The project as a whole has shown improvements in quality of life and mood in the pump arm over standard care.

Impact

The fMRI responses seen under condition of fear in the pill arm are similar to changes seen in major depressive disorder and individuals at risk of depression. In particular the changes in the paracingulate gyrus and amygdala.

For resting state data, the findings in the pump arm are the reverse as seen in depression and fibromyalgia. Indeed, it is hypothesised that it is these structural changes that may underpin the behavioural responses seen.  These findings in combination with the mood and QoL data are very powerful and have major implications not only for replacement therapy, but also disease states associated with HPA axis dysfunction (depression) and patients on therapeutic dosages of glucocorticoids and heir experience of side-effects.

Larger grants

 

Project outputs

Papers

Currently being written ready for submission to Lancet diabetes and endocrinology

Oral presentation 

Subcutaneous pulsatile versus oral hydrocortisone replacement therapy on fMRI resting and task based emotional processing in Addison's Disease, British Endocrine Society, Brighton, 2019

Posters

• An fMRI study of emotion during pulsatile glucocorticoid replacement in adrenal insufficiency, British Neuroscience Association, Dublin, 2019
• An fMRI study of emotion during pulsatile glucocorticoid replacement in adrenal insufficiency, preliminary data, Bristol Brain Research Day, 2018

Research outputs

Trials. 2016 Jan 22;17:44. doi: 10.1186/s13063-016-1159-x. Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals: study protocol for a randomised controlled trial. Kalafatakis K,  Russell GM, Harmer CJ, Munafo MR, Marchant N, Wilson A, Brooks JC, Thai NJ, Ferguson SG, Stevenson K, Durant C, Schmidt K, Lightman SL. 

Higher Degrees

• Needham Cooper Charitable Trust PhD - Neurobehavioral evaluation of different systemic glucocorticoid dynamins in humans: approach under physiological conditions and adrenal insufficiency (passed 2018 - minor corrections).
• Wellcome Trust Neural Dynamics PhD program : from synapses to systems in health and disease - Stress effects on Brain Connectivity (on going)
• MRes, University of Bristol - Resting State Functional Connectivity Under Changing Cortisol Dynamics (distinction 2019)
• iBSc, Univeristy of Bristol - Investigating the importance of glucocorticoid dynamics on the functional connectivity of the hippocampus in relation to cognition and emotional processing - a resting-state fMRI study of patients with Addison's disease (distinction 2019)

Public dissemination

• Pituitary Foundation lecture 11 2019
• ADSHG 11 2018

Other project outcomes

Established academic connections with:

• Department of biological psychology, University of Bristol - Prof M Munafo, Prof I Gilchrist
• Department of psychiatry, University of Oxford - Prof Catherine Harmer
• Department of cognitive neurology, University of Oxford - Prof Masud Husain

Updated 23/01/2020