Evolution and resolution of human brain perfusion responses to the stress of induced hypoglycemia

The relationship between the human brain response to acute stress and subjective, behavioural and physiological responses is poorly understood. We have examined the human cerebral response to the intense interoceptive stressor of hypoglycemia, controlling plasma glucose at either normal fasting concentrations (5 mmol/l, n = 7) or at hypoglycemia (2.7 mmol/l, n = 10) for 1 h in healthy volunteers. Hypoglycemia was associated with symptomatic responses, counterregulatory neuroendocrine responses and a sequential pattern of brain regional engagement, mapped as changes in relative cerebral perfusion using [15O]-H2O water positron emission tomography. The early cerebral response comprised activation bilaterally in anterior cingulate cortex (ACC) and thalamic pulvinar, with deactivation in posterior parahippocampal gyrus. Later responses (> 20 min) engaged bilateral anterior insula, ventral striatum and pituitary. Following resolution of hypoglycemia, the majority of responses returned to baseline, save persistent engagement of the ACC and sustained elevation of growth hormone and cortisol. Catecholamine responses correlated with increased perfusion in pulvinar and medial thalamus, ACC and pituitary, while growth hormone and cortisol responses showed no correlation with thalamic activation but did show additional correlation with the hypothalamus and ventral striatum bilaterally. These data demonstrate complex dynamic responses to the stressor of hypoglycemia that would be expected to drive physiological and behavioural changes to remedy the state. Further, these data show that sustained stress and its aftermath engage distinct sets of brain regions, providing a neural substrate for adaptive or ‘allostasic’ responses to stressors.

Research highlights► Using water positron emission tomography, and induced hypoglycemia as the stressor, we demonstrate the evolution over time of the brain's response to an acute stress in man. ► We show early activation of anterior cingulate (ACC) and orbitofrontal cortices and thalamic pulvinar (with deactivation in hippocampus and posterior parahippocampal gyrus), followed by new engagement of anterior insula, ventral striatum and pituitary as the hypoglycemia was sustained. Subjective awareness of stress and elevations in catecholamines correlated with these changes. ► After resolution of the hypoglycemia, there remained persistent engagement of the ACC, with sustained elevation of growth hormone and cortisol. There was deactivation in pulvinar and medial thalamus. ► These dynamic responses show the distinct sets of brain regions engaged by sustained stress and its aftermath, and provide a neural substrate for adaptive or ‘allostasic’ responses to stressors.