Transcranial and pulsed focused ultrasound that activates brain can accelerate remyelination in a mouse model of multiple sclerosis

Abstract

BackgroundMultiple sclerosis (MS) impacts approximately 400,000 in the United States and is the leading cause of disability among young to middle aged people in the developed world. Characteristic of this disease, myelin within generally focal volumes of brain tissue wastes away under an autoimmune assault, either inexorably or through a cycle of demyelination and remyelination. This centrally located damage produces central and peripheral symptoms tied to the portion of brain within the MS lesion site. Interestingly, Gibson and colleagues noted that optical activation of transgenically tagged central neurons increased the thickness of the myelin sheath around those neurons. Since ultrasound, delivered transcranially, can also activate brain focally, we hypothesized that ultrasound stimulation that followed the temporal pattern of Gibson et al. applied to MS lesions in a mouse model might either decelerate the demyelination phase or accelerate its remyelination phase.MethodsWe created a temporal pattern of ultrasound delivery that conformed to that of Gibson et al. and capable of activating mouse brain. We then applied ultrasound, transcranially, following that temporal pattern to separate cohorts of a mouse model of multiple sclerosis, using three different ultrasound carrier frequencies (0.625 MHz, 1.09 MHz, 2.0 MHz), during each of the demyelinating and remyelinating phases. After identifying the most promising protocol and MS brain state through qualitative analysis of myelin content, we performed additional studies for that condition then assayed for change in myelin content via quantitative analysis.ResultsWe identified one ultrasound protocol that significantly accelerated remyelination, without damage, as demonstrated with histological analysis.ConclusionMRI-guided focused ultrasound systems exist that can, in principle, deliver the ultrasound protocol we successfully tested here. In addition, MRI, as the clinical gold standard, can readily identify MS lesions. Given the relatively low intensity values of our ultrasound protocol – close to FDA limits – we anticipate that future success with this approach to MS therapy as tested using more realistic MS mouse models may one day translate to clinical trials that help address this devastating disease.

Therapeutic Potential of Ultrasound Neuromodulation in Decreasing Neuropathic Pain: Clinical and Experimental Evidence

“…Mathematical modeling suggests that LIFUS may activate sodium, calcium, and potassium channels [ 85 ], and might produce action potentials in neurons [ 85 ]. The application of a mechanical force improves electrical transmission through a damaged axon, which might be associated with nerve regenerating [ 75 ] and remyelinating [ 86 ] effects elicited by FUS.…”

“…Also, LIFUS (360-760 mW/cm 2 ) activates the cerebral cortex as measured by c-Fos expression [ 91 , 92 ] (Fig. 2 ) and electroencephalography [ 86 ]. Further studies agree with this excitatory effect [ 24 , 85 , 93 ].…”

Repeated Application of Transcranial Diagnostic Ultrasound Towards the Visual Cortex Induced Illusory Visual Percepts in Healthy Participants

“…Subject Response Rate Sliding Window Analysis A binary coding system was applied to the participant response of observed percepts at each trial (Fry et al, 1955;Velling and Shklyaruk, 1988;Tyler et al, 2008;Tufail et al, 2010;Min et al, 2011;Yoo et al, 2011aYoo et al, ,b, 2018Kim et al, 2012Kim et al, , 2014Deffieux et al, 2013;King et al, 2013;Younan et al, 2013;Mehić et al, 2014;Kamimura et al, 2016;Lee et al, 2016b;Monti et al, 2016;Ye et al, 2016;Airan et al, 2017;Wattiez et al, 2017;Olmstead et al, 2018), using ''1'' to signify a reported percept report and ''0'' for none. The data series was smoothed by passing it through different sliding windows where the average response rate was calculated for bins of four, five, eight, or 10 consecutive trials.…”

“…For example, stimulation of the thalamus of anesthetized rats can reduce the time required for them to recover from the anesthesia (Yoo et al, 2011b), while thalamic stimulation of a recently comatose patient produced significant clinical improvement (Monti et al, 2016). Our group has successfully applied nDU to a mouse model of multiple sclerosis, thereby demonstrating accelerated remyelination in mice (Olmstead et al, 2018); another group showed a reduction of acute epileptic seizure activity in rats (Min et al, 2011). Also, nDU application to the thalamus of swine inhibited down-stream sensory evoked potentials (Dallapiazza et al, 2018) with a variety of potential uses.…”

Can Enhancing Neuronal Activity Improve Myelin Repair in Multiple Sclerosis?

“…Epidural electrical stimulation after spinal cord injury also enhanced remyelination and increased OL differentiation and survival ( Li et al, 2020 ). Likewise, brain activation using 20 Hz ultrasound bursts increased remyelination after cuprizone demyelination in mice ( Olmstead et al, 2018 ) and voluntary exercise immediately after lysolecithin lesions of the spinal cord white matter increased OPC proliferation, differentiation and remyelination ( Jensen et al, 2018 ). Notably, pairing voluntary exercise with the pro-myelinating drug clemastine showed an additive effect in increasing myelin repair ( Jensen et al, 2018 ).…”