Changes in hemodynamic response function components reveal specific changes in neurovascular coupling in type 2 diabetes

Abstract

Type 2 Diabetes Mellitus (T2DM) is a metabolic disease that leads to multiple vascular complications with concomitant changes in human neurophysiology, which may lead to long-term cognitive impairment, and dementia. Early impairments of neurovascular coupling can be studied using event-related functional magnetic resonance imaging (fMRI) designs. Here, we aimed to characterize the changes in the hemodynamic response function (HRF) in T2DM to probe components from the initial dip to late undershoot. We investigated whether the HRF morphology is altered throughout the brain in T2DM, by extracting several parameters of the fMRI response profiles in 141 participants (64 patients with T2DM and 77 healthy controls) performing a visual motion discrimination task. Overall, the patients revealed significantly different HRFs, which extended to all brain regions, suggesting that this is a general phenomenon. The HRF in T2DM was found to be more sluggish, with a higher peak latency and lower peak amplitude, relative slope to peak, and area under the curve. It also showed a pronounced initial dip, suggesting that the initial avidity for oxygen is not compensated for, and an absent or less prominent but longer undershoot. Most HRF parameters showed a higher dispersion and variability in T2DM. In sum, we provide a definite demonstration of an impaired hemodynamic response function in the early stages of T2DM, following a previous suggestion of impaired neurovascular coupling. The quantitative demonstration of a significantly altered HRF morphology in separate response phases suggests an alteration of distinct physiological mechanisms related to neurovascular coupling, which should be considered in the future to potentially halt the deterioration of the brain function in T2DM.

Keywords: BOLD signal; brain imaging; cerebral hemodynamics; diabetes; fMRI; hemodynamic response function; neurovascular coupling.

FIGURE 1

Graphical representation of the stimuli and experimental protocols of block and event-related designs.

FIGURE 2

HRF parameters calculated on the HRF curves. Note that the HRF third positive section curve area is not depicted in this representation of a standard HRF but was observed in cases of altered HRF in T2DM.

FIGURE 3

Functional maps generated from RFX GLM analysis of the fMRI response to any stimulation condition during the block design experiment for controls and T2DM patients. The map is corrected for multiple comparisons (p_Bonferroni < 0.05). One can see significant positive signal change (yellow/red) and negative signal change (blue) in several clusters, which are further described in Tables 2, 3. We used these ROIs to extract the fMRI BOLD signal for further analysis of the HRF in each group. SAG, sagittal; TRA, transverse; COR, coronal; A, anterior; P, posterior; R, right; L, left.

FIGURE 4

Grand average and grand median HRF curves in the ROIs with positive signal change. Solid and dashed thick lines represent the average/median for each condition, and the shaded areas represent the standard deviation/interquartile range.

FIGURE 5

Average HRF curves in each ROI with positive signal change. Solid and dashed thick lines represent the average for each condition, and the shaded areas represent the standard deviation.

FIGURE 6

Grand average and grand median HRF curves in the ROIs with negative signal change. Solid and dashed thick lines represent the average/median for each condition, and the shaded areas represent the standard deviation/interquartile range.