The Trouble Interpreting fMRI Studies in Populations with Cerebrovascular Risk: The Use of a Subject-Specific Hemodynamic Response Function in a Study of Age, Vascular Risk, and Memory

Abstract

Functional magnetic resonance imaging (fMRI) is commonly used to investigate the neural bases of behavior ranging from basic cognitive mechanisms to aging to psychological disorders. However, the BOLD signal captured by fMRI is an indirect measure of neural function and is affected by many factors that are non-neural in origin. These non-neural factors, however, do affect brain vasculature such as the shape and timing of the hemodynamic response function (HRF) during task-evoked fMRI that, in turn, can cause inappropriate and/or misleading interpretations of fMRI differences between groups. In this study, we tested the proposition that vascular health risks, which often go unmeasured in neuroimaging studies, and aging interact to modify the shape and/or timing of the HRF (height, time-to-peak, width), which then affect the differences in patterns of brain activity in a task-evoked memory encoding paradigm. Adult participants (aged 20-74) answered questions about their health history and underwent two fMRI tasks: viewing of a flashing checkerboard using a slow event-related design and a paired associates memory encoding task during a fast event-related design. We found that aging and vascular risk had the largest impacts on the maximum peak value of the HRF. Using a subject-specific HRF resulted in an overall dampening of the estimated brain activity in both task-positive and task-negative regions due to a reduction in the inter-individual variance of that activity. Across three vascular risk factors, using a subject-specific HRF resulted in more consistent brain regions that reached significance and larger effect sizes compared with the canonical HRF. A slight advantage in the reliability of brain-behavior correlations also was found. The findings from this study have far reaching consequences for the interpretation of task-evoked fMRI activity, especially in populations known to experience alterations to brain vasculature including adults of all ages that have higher vascular risk, the majority of older adults, and people with neurocognitive disorders in which vasculature differences may play a role including dementia.\n\nHighlightsO_LIOlder age was associated with smaller maximum peak of the hemodynamic response.\nC_LIO_LIYounger and middle-aged adults with more vascular risk had higher HRF peaks.\nC_LIO_LIUsing a subject-specific HRF resulted in a \"dampening\" of brain activity.\nC_LIO_LIA subject-specific HRF resulted in more consistent aging and vascular risk effects.\nC_LI