Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Abstract

Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed.

Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition.

Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores.

Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance.

Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

Keywords: Cognitive aging; neuroplasticity; transcranial magnetic stimulation; type 2 diabetes mellitus; verbal learning.

Fig. 1

Cortical reactivity and plasticity can be measured noninvasively in the human motor cortex using TMS. Reactivity refers to the average amplitude of MEPs elicited by single-pulse TMS, while plasticity is defined as the change in reactivity induced by iTBS. A) MR-guided TMS was applied to the left primary motor cortex and resulting MEPs were recorded from the right FDI muscle by surface EMG. B). The present study assessed TMS-iTBS measures of plasticity as well as paired pulse TMS measures of cortical inhibition and facilitation. After determining resting motor threshold (rMT), 50 single (unconditioned) monophasic TMS pulses were delivered, followed by three sets of 50 pulse-pairs to assess short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). After a break, rMT was reassessed and three sets of 30 biphasic pulses were delivered to measure baseline cortico-motor reactivity. The active motor threshold (aMT) was assessed and iTBS was applied. Cortico-motor reactivity was reassessed in six blocks of 30 pulses at 5, 10, 20, 30, 40, and 50 min post-iTBS. C) Example MEP traces from a single control subject (top) and T2DM patient (bottom) recorded at baseline (left) and 10 min after iTBS (right).

Fig. 2

Comparison of TMS-plasticity measures by group. Mean and standard error of the percent change in MEP amplitude are shown for each post-iTBS time-point. Pairwise comparisons between controls and T2DM for each time-point were made with Student’s t tests (*p < 0.05, **p < 0.01). 5–10 min after iTBS, the change in MEP amplitudes was significantly reduced in individuals with T2DM relative to controls.

Fig. 3

Relationship between cortico-motor plasticity and verbal learning. Pearson’s correlation coefficients were calculated separately for T2DM and control groups to assess the relationship between the change in MEP amplitude 10-min post-iTBS (x-axis) and performance (y-axis) on the Rey Auditory Verbal Learning Test (RAVLT) learning trials (% correct). T2DM participants whose MEPs increased following iTBS demonstrated better verbal learning performance than those whose MEPs remained unchanged or decreased.