Task-related fMRI BOLD response to hyperinsulinemia in healthy older adults

Abstract

Background: There is growing evidence to suggest that the brain is an important target for insulin action, and that states of insulin resistance may extend to the CNS with detrimental effects on cognitive functioning. Although the effect of systemic insulin resistance on peripheral organs is well-studied, the degree to which insulin impacts brain function in vivo remains unclear.

Methods: This randomized, single-blinded, 2-way-crossover, sham-controlled, pilot study determined the effects of hyperinsulinemia on fMRI brain activation during a 2-back working memory task in 9 healthy older adults (aged 57-79 years). Each participant underwent two clamp procedures (an insulin infusion and a saline placebo infusion, with normoglycemia maintained during both conditions), to examine the effects of hyperinsulinemia on task performance and associated blood-oxygen-level dependent (BOLD) signal using fMRI.

Results: Hyperinsulinemia (compared to saline control) was associated with an increase in both the spatial extent and relative strength of task-related BOLD signal during the 2-back task. Further, the degree of increased task-related activation in select brain regions correlated with greater systemic insulin sensitivity, as well as decreased reaction times and performance accuracy between experimental conditions.

Conclusion: Together, these findings provide evidence of insulin action in the CNS among older adults during periods of sustained cognitive demand, with the greatest effects noted for individuals with highest systemic insulin sensitivity.

Funding: This work was funded by the National Institutes of Health (5R21AG051958, 2016).

Keywords: Aging; Endocrinology; Insulin; Insulin signaling; Neuroimaging.

Figure 1. Spatial overlap of task-related fMRI activation for 2-back greater than 0-back trials during insulin and saline conditions analyzed separately.

(A) Conjunction map showing the spatial overlap from 1-sample group mean analyses of task-related activation for 2-back to 0-back trials for insulin and saline conditions analyzed separately (n = 9; P < 0.01, corrected). An expected pattern of task-related activation was observed across both conditions largely involving frontal and parietal regions, although the spatial extent of activation was 1.8 times larger during insulin compared with saline condition. (B) Results from each 2-back to 0-back contrast analyzed separately by experimental condition (insulin and saline) contributing to the conjunction map above, resampled onto the cortical surface for ease of viewing.

Figure 2. Brain areas showing significantly increased task-related fMRI activation during insulin compared to saline conditions, and regional associations with task performance and baseline insulin sensitivity.

(A) Cluster-based results of a 2-step higher-level analysis to evaluate average within-subject difference in 2-back to 0-back contrast between insulin and saline conditions (n = 9). First, subject-level repeated-measure analysis was performed to yield a single cope comparing blood oxygen level–dependent (BOLD) signal during the contrast of interest (2-back to 0-back) between insulin and saline runs. Next, each within-subject difference cope was entered into a single 1-sample group mean regression model to identify brain regions that consistently demonstrated a change in BOLD signal during the 2-back task between the insulin and saline conditions, such that the mean change in activation across all participants was significantly different from the null hypothesis of no change. Final Z-statistic maps were thresholded using clusters determined by Z > 2.3 (P < 0.01) and a corrected cluster significance threshold of P < 0.05. Significant differences in task-related BOLD signal were noted in bilateral inferior frontal, parahippocampal, precuneus, and thalamic regions, as well as lateralized clusters within right superior frontal, right supramarginal, and left middle frontal cortices. (B) Scatter plots demonstrating significant bivariate correlations between the degree of BOLD signal parameter estimate (PE) change during insulin compared with saline conditions and difference in RT on 2-back trials between conditions (n = 9; P < 0.05 for all). Colored outline around scatter plots corresponds to the matching cluster color from which its data were extracted. Clusters are described in greater detail in Table 4 (cluster 5, left fusiform/supramarginal gyrus; cluster 8, bilateral precuneus; cluster 9, right supramarginal/angular gyrus; and cluster 10, right inferior frontal cortex).

Figure 3. Scatter plot demonstrating a significant positive bivariate correlation between increased task-related activation during the insulin compared with saline clamp, quantified as a change in BOLD signal PE and hyperinsulinemic euglycemic clamp–insulin sensitivity index (HEC-ISI) within the bilateral precuneus (cluster 8); n = 9.

Figure 4. Overview of study procedures.

(A) Overview of study timeline for each experimental visit (insulin and saline clamp conditions) conducted within the Massachusetts General Hospital, Clinical Research Center (CRC). Each infusion condition was implemented following an overnight 12-hour fast. Study tasks (consisting of electroencephalography [EEG], cognitive testing, and functional MRI [fMRI]) commenced as soon as steady state was achieved. (B) Schematic of clamp setup. A continuous infusion of either insulin or saline was administered alongside a variable dextrose infusion to maintain normoglycemia, as indicated by 5-minute-interval blood glucose level checks. (C) Overview of N-back working memory task that was given during each fMRI session concurrently with infusion procedure. For the 2-back trials, participants were required to respond by button press if the letter presented was exactly the same as 2 stimuli before. For the 0-back control trials, participants were instructed to press a response button immediately upon seeing the letter X.