ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This case-control study compared resting-state functional connectivity (rs-fc) of the brain between patients with autoimmune Addison’s disease (AAD) and healthy controls. The results suggest that AAD affects the baseline functional organization of the brain and that current treatment strategies of AAD may be a risk factor.

Comment: Autoimmune Addison disease (AAD) is a form of primary adrenal insufficiency (PAI), in which autoimmune adrenal cortex destruction results in chronic glucocorticoid (GC) and mineralocorticoid (MC) deficiency that require life-long replacement treatment at the lowest dose possible to prevent negative side effects from cortisol overdosing (1). These side-effects offer scientists a pathophysiologic insight into the widespread effects of cortisol, which affect many physiologic systems. In the CNS, brain widely expresses both GC and MC receptors, and cortisol can affect both the anatomical structure and the functional activity and connectivity (FC) of the brain on a short-term and long-term basis (2). The relation between cortisol-related metabolic changes and direct effects on neuronal excitability and changes in rs connectivity signal are unclear. Neurobiology of chronic insomnia is linked to hypothalamic-pituitary-adrenal-axis dysregulation, and in particular, alterations in circadian and ultradian cortisol rhythmicity, which affect many cognitive and affective processes, including long-term memory, working memory, and emotional regulation, particularly in response to stressful situations (3). Stress system activation is tightly connected to Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks’ activation, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression-to-activation response of the CEN, all adaptive changes favoring proper decisions and survival (4).

In this study, patients with AAD had increased rs-fc within 3 major networks, namely the orbitofrontal cortex (OFC), the posterior DMN and the medial visual network, while being on a relatively higher GC replacement dose was associated with stronger rs-fc in a small part of the OFC network. These changes are associated with regions (particularly the OFC) that show the strongest reduction in volume in patients with AAD (5). In patients with CAH, stronger rs-fc in the precuneus compared to healthy controls has been observed, while in patients with Cushing disease increases in rs-fc in several networks, including the posterior cingulate cortex/precuneus and the prefrontal cortex, the subgenual ACC-DMN and the medial temporal (right parahippocampal gyrus) and medial prefrontal cortex have been described, even following remission (6-8).

The networks that showed group differences were the OFC and the DMN. The OFC (or ventromedial prefrontal cortex) is mostly known for containing a high density of GC receptors, and is involved in many higher- order cognitive processes, such as motivation and emotion regulation, processing reward-related information needed for emotional and social behavior, but also shaping autonomic and endocrine responses, including stress (9-11). The DMN is involved in a wide variety of tasks, while it is typically deactivated during most stimulus-driven cognitive tasks – and during acute stress (4). It is hypothesized that DMN provides the functional infrastructure for integrating past, present and future events related to the self (12).

In conclusion, patients with AAD have stronger rs-fc in several brain networks, partly correlating with GC replacement dose. Further studies are needed to determine if these changes predispose individuals to problems with cognition and mood later in life or if they are part of a compensation mechanism. Both psychologic and brain health need to be considered when optimizing replacement therapy, while GC replacement therapy that mimics normal cortisol secretion should be preferred.

References: 1. Husebye ES, Pearce SH, Krone NP, Kampe O. Adrenal insufficiency. Lancet. 2021; 397(10274): 613-29.2. Joels M. Corticosteroids and the brain. J Endocrinol. 2018; 238(3): R121-R30.3. Vargas I, Vgontzas AN, Abelson JL, Faghih RT, Morales KH, Perlis ML. Altered ultradian cortisol rhythmicity as a potential neurobiologic substrate for chronic insomnia. Sleep Med Rev. 2018; 41: 234-43.4. Paltoglou G, Stefanaki C, Chrousos GP. Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review. Curr Neuropharmacol. 2024; 22(5): 976-89.5. Van’t Westeinde A, Padilla N, Siqueiros Sanchez M, Fletcher-Sandersjoo S, Kampe O, Bensing S, et al. Brain structure in autoimmune Addison’s disease. Cereb Cortex. 2023; 33(8): 4915-26.6. Messina V, Van’t Westeinde A, Padilla N, Lajic S. Changes in resting-state functional connectivity in patients with congenital adrenal hyperplasia. Neuroimage Clin. 2022; 35: 103081.7. Jiang H, He NY, Sun YH, Jian FF, Bian LG, Shen JK, et al. Altered spontaneous brain activity in Cushing’s disease: a resting-state functional MRI study. Clin Endocrinol (Oxf). 2017; 86(3): 367-76.8. Stomby A, Salami A, Dahlqvist P, Evang JA, Ryberg M, Bollerslev J, et al. Elevated resting-state connectivity in the medial temporal lobe and the prefrontal cortex among patients with Cushing’s syndrome in remission. Eur J Endocrinol. 2019; 180(5): 329-38.9. Kringelbach ML, Rolls ET. The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol. 2004; 72(5): 341-72.10. Maier SU, Makwana AB, Hare TA. Acute Stress Impairs Self-Control in Goal-Directed Choice by Altering Multiple Functional Connections within the Brain’s Decision Circuits. Neuron. 2015; 87(3): 621-31.11. Diorio D, Viau V, Meaney MJ. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci. 1993; 13(9): 3839-47.12. Buckner RL, Carroll DC. Self-projection and the brain. Trends Cogn Sci. 2007; 11(2): 49-57.