Hippocampal Alteration in Methamphetamine Misuse

An estimated 2.5 million adults in the United States will use methamphetamine (MA) this year and 1.6 million will meet the criteria for MA use disorder, mostly in western and midwestern states. The national societal and economic burden of MA use is estimated to be greater than $40 billion. The cost to the individual user’s health is also dire. MA misuse is associated with physical health concerns such as cardiac arrhythmia and stroke, mental health concerns such as depression and psychosis, and cognitive health concerns broadly including impairments in attention, decision making, and memory. MA-associated memory deficits are ubiquitous, particularly hippocampal-dependent memory, and yet MA-associated brain structure changes in the human hippocampus remain under investigated and poorly understood. Findings to date have used MRI-derived volume measures to assess hippocampal integrity with MA misuse and results have been inconsistent. There are several reasons that may account for these inconsistencies. First, volume is a gross measure of large-scale changes that is not sufficiently sensitive to measure microstructural changes that may occur with MA misuse. Second, the hippocampus is a heterogenous structure with dissociable subfields that each support different aspects of memory function. Magnetic resonance elastography (MRE) is an emerging tool for acquiring noninvasive measures of the mechanical properties of biological tissue. By doing so, MRE provides a measure of microstructural tissue health with sufficient resolution to assess the whole hippocampus, as well as the individual hippocampal subfields. The work proposed in the present application will (1) assess disruptions in the microstructural integrity of the hippocampus and identify impairments in its specific subfields with MA misuse and (2) to determine the impact of these MA-induced structural disruptions on hippocampal-dependent memory. To address these aims, MRI/MRE scans, as well as a diverse cognitive battery of hippocampaldependent memory tasks will be collected from MA users and a group of matched, non-substance using comparison participants. We expect that MRE-derived measures of microstructural integrity will differ between the groups with the MA group showing reduced integrity. We also expect that, based on findings form preclinical rodent studies, the dentate gyrus subfield will be most strongly affected and that the MA group will be impaired on tasks of hippocampal-dependent broadly, but the deficit will be largest for tasks that depend critically on relational information supported by the dentate gyrus. This work will establish MRE as a useful tool for measuring changes in hippocampal integrity associated with MA misuse forming a critical foundation for the identification of quantitative/diagnostic biomarkers for behavioral dysfunction in this population. This long-term goal of this project is to lay the groundwork for future investigations tracking brain changes associated with prolonged use, effective interventions, and recovery more broadly.