The Effect of Acute Hypoglycemia on Brain Function and Activation A Functional Magnetic Resonance Imaging Study J. Miranda Rosenthal, 1,2 Stephanie A. Amiel, 1 Lidia Ya ´gu ¨ ez, 2,3 Edward Bullmore, 2 David Hopkins, 1 Mark Evans, 1 Andrew Pernet, 1 Helen Reid, 1 Vincent Giampietro, 2 Chris M. Andrew, 2 John Suckling, 2 Andrew Simmons, 2,3 and Stephen C.R. Williams 2,3 The authors’ aim was to examine the regional anatomy of brain activation by cognitive tasks commonly used in hypoglycemia research and to assess the effect of acute hypoglycemia on these in healthy volunteers. Eight right-handed volunteers performed a set of cognitive tasks—finger tapping (FT), simple reaction time (SRT), and four-choice reaction time (4CRT)—twice during blood oxygen level– dependent (BOLD) functional mag- netic resonance imaging of the brain on two occasions. In study 1 (n  6), plasma glucose was maintained at euglycemia (5 mmol/l) throughout. In study 2 (n  6), plasma glucose was reduced to 2.5 mmol/l for the second set. Performance of the tasks resulted in specific group brain activation maps. During hypoglycemia, FT slowed (P  0.026), with decreased BOLD activation in right premotor cortex and supplementary motor area and left hippocampus and with increased BOLD activation in left cerebellum and right frontal pole. Although there was no significant change in SRT, BOLD activation was re- duced in right cerebellum and visual cortex. The 4CRT deteriorated (P  0.020), with reduction in BOLD acti- vation in motor and visual systems but increased BOLD signal in a large area of the left parietal association cortex, a region involved in planning. Hypoglycemia impairs simple brain functions and is associated with task-specific localized reductions in brain activation. For a task with greater cognitive load, the increased BOLD signal in planning areas is compatible with re- cruitment of brain regions in an attempt to limit dys- function. Further investigation of these mechanisms may help devise rational treatment strategies to limit cortical dysfunction during acute iatrogenic hypoglyce- mia. Diabetes 50:1618 –1626, 2001 T he brain is normally dependent on glucose for oxidative metabolism and function. Acute iatro- genic hypoglycemia, occurring as a result of insulin excess during the treatment of type 1 diabetes, can cause clinically significant cognitive impair- ment. In health, such hypoglycemic cognitive dysfunction does not occur. Endogenous counterregulatory mecha- nisms are activated in response to a small reduction in circulating glucose, preventing more profound hypoglyce- mia. In diabetes, the inability to reduce circulating insulin levels (1), the failure of glucagon responses (2), sometimes accompanied by defective autonomic and adrenergic re- sponses (3), can allow plasma glucose levels to fall low enough to result in detectable disturbance of cognitive function, ranging from a subtle slowing of reaction times (3) to coma (4). A variety of measures of cognitive function have been used in the investigation of the responses of the brain to acute hypoglycemia, and these show different susceptibil- ities to hypoglycemia. In health, autonomic activation occurs at arterialized plasma glucose of 3.0 –3.6 mmol/l (5–7). Choice reaction times (3,8) and performance of Stroop interference tests become slower at 3 mmol/l; short-term memory deteriorates at 2.5 mmol/l (9); and finger tapping, a simple motor task, slows at 2.3 mmol/l (10). The glucose level at which some brain functions alter, such as the activation of autonomic counterregula- tory responses (3,8,11–13) (a hypothalamic action [14]) or deterioration of the performance of the Stroop and mem- ory tests (10,11,13), may change according to prior expe- rience of hyper- or hypoglycemia, with higher or lower plasma glucose associated with the onset of change, re- spectively. Such changes may leave those diabetic patients with prior experience of hypoglycemia at high risk for severe hypoglycemia with no warning hypoglycemia un- awareness (15). Functional magnetic resonance imaging (fMRI) detects regional changes in brain oxygenation state during acti- vation by a task (16 –20). This allows exploration of phys- iological mechanisms underlying cognitive dysfunction during hypoglycemia. This study uses fMRI to test the hypothesis that different functional brain areas are in- volved in the performance of the different cognitive func- tions tests used in hypoglycemia research, and these will From the 1 Department of Medicine, Guy’s, King’s and St. Thomas’ School of Medicine; the 2 Institute of Psychiatry, King’s College; and 3 Maudsley Hospital, London, U.K. Address correspondence and reprint requests to Dr. Jane Miranda Rosenthal, Department of Diabetes, Endocrinology, and Internal Medicine, GKTSM, Denmark Hill Campus, Bessemer Road, London SE5 9PJ, U.K. E-mail: miranda.rosenthal@kcl.ac.uk. Received for publication 8 May 2000 and accepted in revised form 19 March 2001. AC-PC, anterior commisure–posterior commisure; 4CRT, four-choice reac- tion time; BOLD, blood oxygen level– dependent; fMRI, functional magnetic resonance imaging; FT, finger tapping; MR, magnetic resonance; SRT, simple reaction time; TE, echo time; TI, inversion time; TR, repetition time. 1618 DIABETES, VOL. 50, JULY 2001