Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβplaques and brain rhythms in 5×FAD mice

Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.

Therapeutic potential of neuromodulation for demyelinating diseases

Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons.Currently,several different techniques have been developed-or are currently being investigated–to treat a wide variety of neurological and neuropsychiatric disorders.Recently,in vivo and in vitro studies have revealed that neuromodulation can also induce myelination,meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy.These findings come on the heels of a paradigm shift in the view of myelin's role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation.In the present review,we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activitydependent myelination.We also highlight several considerations for neuromodulatory techniques,including the need for further research into spatiotemporal precision,dosage,and the safety and efficacy of transcranial focused ultrasound stimulation,an emerging neuromodulation technology.As the field of neuromodulation continues to evolve,it could potentially bring forth methods for the treatment of demyelinating diseases,and as such,further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.