Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer's disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Our review briefly outlines some of the proposed neurobiological mechanisms of TMS benefits in AD, with particular emphasis on the modulatory effects on excitatory/inhibitory balance. On the basis of converging evidence from multiple fields, we caution that TMS therapeutic protocols established in young adults may have unexpected detrimental effects in older individuals or in the brain compromised by AD pathology. Our review surveys clinical studies of TMS in AD alongside basic research as a guide for moving this important area of work forward toward effective treatment development.

Objective. The temporal spacing or distribution of stimulation pulses in therapeutic neurostimulation waveforms—referred to here as the Temporal Pattern (TP)—has emerged as an important parameter for tuning the response to deep-brain stimulation and intracortical microstimulation (ICMS). While it has long been assumed that modulating the TP of ICMS may be effective by altering the rate coding of the neural response, it is unclear how it alters the neural response at the network level. The present study is designed to elucidate the neural response to TP at the network level. Approach. We use in vivo two-photon imaging of mice expressing the calcium sensor Thy1-GCaMP or the glutamate sensor hSyn-iGluSnFr to examine the layer II/III neural response to ICMS with different TPs. We study the neuronal calcium and glutamate response to TPs with the same average frequency (10 Hz) and same total charge injection, but varying degrees of bursting. We also investigate one control pattern with an average frequency of 100 Hz and 10X the charge injection. Main Results. Stimulation trains with the same average frequency and same total charge injection but distinct TPs recruit distinct sets of neurons. More than half (60% of 309 cells) of neurons prefer one TP over the other. Despite their distinct spatial recruitment patterns, cells exhibit similar ability to follow 30 s trains of both TPs without failing, and they exhibit similar levels of glutamate release during stimulation. Both neuronal calcium and glutamate release entrain to the bursting TP pattern, with a ∼21-fold increase in relative power at the frequency of bursting. Bursting also results in a statistically significant elevation in the correlation between somatic calcium activity and neuropil activity, which we explore as a metric for inhibitory-excitatory tone. Interestingly, soma-neuropil correlation during the bursting pattern is a statistically significant predictor of cell preference for TP, which exposes a key link between TP and inhibitory-excitatory tone. Finally, using mesoscale imaging, we show that both TPs result in distal inhibition during stimulation, which reveals complex spatial and temporal interactions between TP and inhibitory-excitatory tone in ICMS. Significance. Our results may ultimately suggest that TP is a valuable parameter space to modulate inhibitory-excitatory tone and to recruit distinct network activity in ICMS. This presents a broader mechanism of action than rate coding, as previously thought. By implicating these additional mechanisms, TP may have broader utility in the clinic and should be pursued to expand the efficacy of ICMS therapies.

Electrical stimulation has been critical in the development of an understanding of brain function and disease. Despite its widespread use and obvious clinical potential, the mechanisms governing stimulation in the cortex remain largely unexplored in the context of pulse parameters. Modeling studies have suggested that modulation of stimulation pulse waveform may be able to control the probability of neuronal activation to selectively stimulate either cell bodies or passing fibers depending on the leading polarity. Thus, asymmetric waveforms with equal charge per phase (i.e., increasing the leading phase duration and proportionately decreasing the amplitude) may be able to activate a more spatially localized or distributed population of neurons if the leading phase is cathodic or anodic, respectively. Here, we use two‐photon and mesoscale calcium imaging of GCaMP6s expressed in excitatory pyramidal neurons of male mice to investigate the role of pulse polarity and waveform asymmetry on the spatiotemporal properties of direct neuronal activation with 10‐Hz electrical stimulation. We demonstrate that increasing cathodic asymmetry effectively reduces neuronal activation and results in a more spatially localized subpopulation of activated neurons without sacrificing the density of activated neurons around the electrode. Conversely, increasing anodic asymmetry increases the spatial spread of activation and highly resembles spatiotemporal calcium activity induced by conventional symmetric cathodic stimulation. These results suggest that stimulation polarity and asymmetry can be used to modulate the spatiotemporal dynamics of neuronal activity thus increasing the effective parameter space of electrical stimulation to restore sensation and study circuit dynamics.