Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment.

Mild cognitive impairment (MCI) during aging is often a harbinger of Alzheimer's disease, and, therefore, early intervention to preserve cognitive abilities before the MCI symptoms become medically refractory is particularly critical. Functional MRI­guided transcranial magnetic stimulation is a promising approach for modulating hippocampal functional connectivity and enhancing memory in healthy adults. Here, we extend these previous findings to individuals with MCI and leverage theta burst stimulation (TBS) and white matter tractography derived from diffusion-weighted MRI to target the hippocampus. Our preliminary findings suggested that TBS could be used to improve associative memory performance and increase resting-state functional connectivity of the hippocampus and other brain regions, including the occipital fusiform, frontal orbital cortex, putamen, posterior parahippocampal gyrus, and temporal pole, along the inferior longitudinal fasciculus in MCI. Although the sample size is small, these results shed light on how TBS propagates from the superficial cortex around the parietal lobe to the hippocampus.

Association Between Responsiveness to Transcranial Magnetic Stimulation and Interhemispheric Functional Connectivity of Sensorimotor Cortex in Older Adults.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic technique, and is believed to accomplish its effect by influencing the stimulated and remotely connected areas. However, responsiveness to rTMS shows high interindividual variability, and this intersubject variability is particularly high in older adults. It remains unclear whether baseline resting-state functional connectivity (rsFC) contributes to this variability in older adults. The aims of this study are to (1) examine rTMS effects over the primary motor cortex (M1) in older adults, and (2) identify baseline network properties that may contribute to the interindividual variability. Methods: We tested response to intermittent theta burst stimulation (iTBS), an effective rTMS protocol, over M1 by using both electromyography and resting-state functional magnetic resonance imaging in older adults. Outcome measures included motor-evoked potential (MEP) elicited by single-pulse transcranial magnetic stimulation and rsFC before and after an iTBS session. Results: iTBS significantly increased MEP amplitudes and rsFC between the stimulation site, sensorimotor cortex, and supplementary motor area (SMA) in older adults. iTBS-induced changes in MEP amplitude were positively correlated with increases in interhemispheric rsFC after iTBS. Furthermore, older adults with lower baseline interhemispheric rsFC between sensorimotor cortex and SMA exhibited stronger MEP response after iTBS. Discussion: Findings of the study suggest that different levels of interhemispheric communication during resting state might contribute to the response heterogeneity to iTBS in older adults. Interhemispheric rsFC may have great potential serving as a useful marker for predicting iTBS responsiveness in older adults. ClinicalTrials.gov ID: 1707654427 Impact statement Factors contributing to interindividual variability of the responsive to repetitive transcranial magnetic stimulation (rTMS) in older adults remain poorly understood. In this study, we examined the effects of rTMS over the primary motor cortex in older adults, and found that response to rTMS is associated with prestimulation interhemispheric connectivity in the sensorimotor and premotor areas. Findings of the study have great potential to be translated into a connectivity-based strategy for identification of responders for rTMS in older adults.

Transcranial magnetic stimulation reveals diminished homoeostatic metaplasticity in cognitively impaired adults.

Homoeostatic metaplasticity is a neuroprotective physiological feature that counterbalances Hebbian forms of plasticity to prevent network destabilization and hyperexcitability. Recent animal models highlight dysfunctional homoeostatic metaplasticity in the pathogenesis of Alzheimer's disease. However, the association between homoeostatic metaplasticity and cognitive status has not been systematically characterized in either demented or non-demented human populations, and the potential value of homoeostatic metaplasticity as an early biomarker of cognitive impairment has not been explored in humans. Here, we report that, through pre-conditioning the synaptic activity prior to non-invasive brain stimulation, the association between homoeostatic metaplasticity and cognitive status could be established in a population of non-demented human subjects (older adults across cognitive spectrums; all within the non-demented range). All participants (n = 40; age range, 65-74, 47.5% female) underwent a standardized neuropsychological battery, magnetic resonance imaging and a transcranial magnetic stimulation protocol. Specifically, we sampled motor-evoked potentials with an input/output curve immediately before and after repetitive transcranial magnetic stimulation to assess neural plasticity with two experimental paradigms: one with voluntary muscle contraction (i.e. modulated synaptic activity history) to deliberately introduce homoeostatic interference, and one without to serve as a control condition. From comparing neuroplastic responses across these experimental paradigms and across cohorts grouped by cognitive status, we found that (i) homoeostatic metaplasticity is diminished in our cohort of cognitively impaired older adults and (ii) this neuroprotective feature remains intact in cognitively normal participants. This novel finding suggests that (i) future studies should expand their scope beyond just Hebbian forms of plasticity that are traditionally assessed when using non-invasive brain stimulation to investigate cognitive ageing and (ii) the potential value of homoeostatic metaplasticity in serving as a biomarker for cognitive impairment should be further explored.