This systematic review aims to evaluate the current evidence regarding the efficacy and safety of LITUS neuromodulation for AD.
Searches were conducted across five databases from inception to May 18, 2024. To systematically and comprehensively search the relevant literature, we summarize the stimulation protocols (stimulus waveform parameters, stimulation frequency and duration, brain targeting and focusing strategies), neuromodulatory effects (neuropsychological tests, electrophysiological recordings, neuroimaging, and histological and biochemical analyses), underlying mechanisms, and safety of LITUS applications in both human and animal research.
A total of 7 human studies and 11 animal studies were identified. Animal studies commonly utilized fundamental frequencies ranging from 0.3 to 3.3 MHz, with the majority employing frequencies of ≤1 MHz. Stimulation frequency varied, occurring multiple times a day to twice a week, and the total duration of stimulation in human studies ranged from 3 days to 5 weeks. In contrast, animal studies had total stimulation durations ranging from 1 hour to 2 months, with individual treatment sessions lasting from 2 minutes to 2 hours. In human studies, the targeted brain regions included the bilateral frontal and lateral parietal cortices, as well as the extended precuneus cortex. In animal studies, stimulation primarily focused on the hippocampus, cortical areas, or both, utilizing stereotaxic apparatus and mouse brain coordinates. On the behavioral front, studies on LITUS demonstrated significant improvements in cognitive, learning, and memory functions in both humans and animals. LITUS was found to reduce phase-amplitude coupling between delta-epsilon, delta-gamma, and theta-gamma frequency bands, increase epsilon band power, decrease interneuron spike firing rate, and lessen theta-band phase-locked angle deviation with neuronal spikes. Neuroimaging results indicated that LITUS enhanced activation and functional connectivity in the hippocampus, parahippocampal cortex, parietal cortex, and precuneus in patients with mild AD. Histological and biological outcomes revealed notable findings, including the induction of Aβ load reduction, suppression of inflammatory responses, facilitation of neurogenesis, and modulation of antioxidant responses. Potential underlying mechanisms of LITUS neuromodulation include increased cell membrane permeability, neoangiogenesis, anti-inflammatory effects, and modulation of brain rhythms. While no adverse effects were reported in controlled animal studies included in our review, reversible headaches, nausea, and vomiting were reported in a few human subjects.
LITUS has demonstrated positive effects on cognitive-related neuropsychological outcomes, modulates electrophysiological parameters, and influences disease-specific changes, anti-inflammatory responses, neurogenesis, and antioxidant processes, all without major side effects. Future studies are warranted to further elucidate the underlying mechanisms by which LITUS exerts its effects and to identify optimal stimulation parameters and time windows for its application in Alzheimer’s disease (AD) patients.
Overall, LITUS represents a promising tool with the potential to transform our approach to the treatment of AD.
Alzheimer’s disease
neuromodulation
