Brain Activation During Working Memory is Altered in Patients With Type 1 Diabetes During Hypoglycemia

Discussion

This study demonstrates that patients with type 1 diabetes show a different pattern of brain activation in response to a WMT than do nondiabetic control subjects during hypoglycemia. Specifically, we found that for patients with type 1 diabetes during hypoglycemia, WMT-related activation responses were increased in several cortical regions, including the parietal and frontal cortices, hippocampus, and cerebellum. Task-induced deactivations, typically observed in the DMN during cognitive effort, were significantly suppressed during hypoglycemia in bilateral medial-frontal and posterior cingulate cortices for type 1 diabetic patients compared with control subjects. Activation and deactivation patterns were similar across groups during euglycemia. Behavioral performance on the WMT was similar across groups and conditions. Finally, HbA_1c was inversely correlated with WMT activation during hypoglycemia in the right parahippocampal gyrus and amygdala, two areas that have been reported to activate in memory-disordered populations as a form of compensatory recruitment.^[30–32]

The regional BOLD activations we observed in response to the WMT were compatible with those found in other fMRI studies of similar WMTs.^{[5,26,33–35]} Although the main regions that help govern working memory are the dorsolateral and medial prefrontal cortices and anterior cingulate cortex, other regions, such as the parietal lobe^[36] and cerebellum,^[37] are known to play supplementary roles. These regions were activated more in type 1 diabetic patients than in control subjects during hypoglycemia, suggesting that supplementary brain regions may have been recruited to help preserve cognitive performance. The failure to suppress activation in the DMN also is consistent with an interpretation that type 1 diabetic patients need to recruit more brain resources for cognitive preservation.^[11] Similar patterns of increased activation and decreased deactivation have been observed with mild cognitive impairment^[30] and in older individuals at risk for Alzheimer's disease,^[38] suggesting, in these cases, a compensatory response to accumulating pathology.

Cognitive performance was not altered by hypoglycemia in either subject group. Although some studies have shown similar results for less challenging WMTs,^[39] others have shown severe impairment during hypoglycemia for highly challenging WMTs involving reasoning.^[2] Of importance, a number of studies have used the same Sternberg WMT used here to evaluate differences in brain activation patterns across different populations.^[40,41] In our study, different brain activation patterns, despite similar cognitive performance across groups, suggest unique strategies of brain recruitment used across groups to augment performance during the glycemic challenge.

Our results showing hyperactivation of brain regions in type 1 diabetic patients with low HbA_1c and hypoactivation in patients with higher HbA_1c could reflect upregulation of glucose transport in the brain, as seen in patients with good glycemic control.^[42,43] Type 1 diabetic patients may engage more brain regions to maintain the same performance to compensate for cerebral inefficiency attributed to reduced brain resources.^[44] These results also are consistent with the patterns observed in many physiologic systems in which a period of compensatory hyperfunction precedes functional decline and ultimate organ-system failure.

In an earlier report from our group, we demonstrated that type 1 diabetic patients showed reduced gray-matter density in the parahippocampal gyrus associated with higher HbA_1c.^[45] One possible explanation may be that gray-matter loss in this temporal region prevents its participation in the brain's response to moderate acute hypoglycemia. Wessels et al.^[46] also observed abnormal brain activity patterns in patients with diabetes retinopathy, which is more likely to be associated with elevated HbA_1c levels. However, our studies differed in both design and data analytic methodology, making a direct comparison difficult.

The differences in the hypoglycemic BOLD response between patients and control subjects found in this study may be attributed to a variety of mechanisms, including preservation of global brain glucose uptake in diabetes as a result of adaptation to hypoglycemia,^[12,47] differences in neurovascular coupling, resting cerebral blood flow, neuronal activity linked to oxidative metabolism, increased brain glycogen stores,^[48] or a tendency to use nonglucose substrates to support higher neuronal activity.^[49] In addition, changes in brain glucose transport or metabolism, resulting in increased brain glucose levels, might occur as a result of recurrent hypoglycemia. We reported such a finding along with accompanying increases in glutamate that were correlated with decreases in memory and executive function.^[16] It may follow that abnormal glutamate metabolism contributed to altered neurovascular coupling in patients in our study. Although these adaptive mechanisms in type 1 diabetes may in the short-term allow compensation for altered brain activity patterns during a hypoglycemic challenge, they may presage long-term maladaptive or adverse consequences.

Although our study demonstrates greater activation during hypoglycemia in type 1 diabetes along with reduced deactivation of the DMN, the small sample size may limit the implications of our results. However, the regional BOLD activations we observed in response to the WMT were compatible with regional activations found in other fMRI studies of similar WMTs.^{[5,26,33–35]} The reductions in BOLD response observed during hypoglycemia were also compatible with other reports showing reduced brain BOLD activation in primary or association cortex in response to sensory, motor, or cognitive tasks in nondiabetic subjects.^{[11,12,14,47]} Also, this study was unable to resolve whether the alterations in brain activation were secondary to chronic hyperglycemia or recurrent hypoglycemia. Future studies can help resolve this issue.

In summary, patients with type 1 diabetes activate more brain regions than control subjects during hypoglycemia by maintaining activity from euglycemia to hypoglycemia in task-relevant regions and by failing to suppress activation in the DMN. This suggests that type 1 diabetic patients may need to recruit more brain resources to preserve cognitive performance. The pattern of hyperactivation of both the DMN and task-relevant regions is consistent with findings in disease states with impaired cognition, such as mild cognitive impairment and Alzheimer's disease.^[38] There has been persistent concern about the consequences of recurrent hypoglycemia on brain structure and cognitive function. There are minimal long-term effects of recurrent hypoglycemia on cognition into middle age,^[50] but it is not clear whether this resiliency will last throughout the aging process. Future research should evaluate our findings as an early manifestation and warning of future clinically relevant cognitive decline. This research may guide the development of treatment regimens to enhance symptom recognition or to stabilize the neurochemical response to hypoglycemia to reduce the impact of glucodeprivation on cognitive function.

Diabetes. 2011;60(12):3256-3264. © 2011