Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus

Abstract

Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30þ minutes after tFUS administration. In N ¼ 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.

Ultrasound Neuromodulation and Correlation Change in the Rat Somatosensory Cortex

“…The 100 Hz condition was significantly higher than all other conditions ( p < 1e-7), while the 50 Hz condition was significantly lower than all except the 10 Hz condition ( p < 1e-5). This interestingly appears to align with the previous hippocampus result of 50Hz causing LTD (Niu et al, 2022b)Here, we observe that in response to 50 Hz ultrasound stimulation, on average, the network undergoes a decrease in correlation. In about half of the cases these correlation changes appear to last for the remainder of the session time, although in others the change only lasts for 10-20 minutes much like the firing rate changes (Figure 4A-C).…”

“…Following our group’s previous work in the hippocampus examining the ability of ultrasound to induce plasticity changes(Niu et al, 2022b), we next examined whether ultrasound was capable of causing correlation changes in S1. Examining the changes in correlation induced between every pair of neurons in a session, it was observed that every frequency resulted in a significant average correlation change besides 10 Hz ( p < 1e-4) (Figure 4G).…”

“…Ultrasound stimulation was delivered at 5 different SRFs, i.e., 10 Hz, 50 Hz, 75 Hz, 100 Hz, and 125 Hz. 50 Hz stimulation was observed by our group to induce LTD in the rat hippocampus (Niu et al, 2022a), so this range of frequencies was chosen to further explore the parameter space and discover whether inducing LTP as well may be possible. In each animal, two ultrasound sessions and a sham session were performed in a random order before euthanasia.…”

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…The morphological formation of these neurons within the hippocampus leads to the further subfield classification of pyramidal cells in what is known as Cornu Ammonus (CA), divided into CA1, CA2, and CA3 [ 49 , 50 ]. These regions serve an important role in localizing KCNQ channel function in synaptic plasticity [ 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Within synaptic plasticity, two major models involved in the application of neural plasticity are long-term potentiation (LTP) and long-term depression (LTD) [ 59 ].…”

“…These regions serve an important role in localizing KCNQ channel function in synaptic plasticity [ 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Within synaptic plasticity, two major models involved in the application of neural plasticity are long-term potentiation (LTP) and long-term depression (LTD) [ 59 ]. These models are activity-dependent, and the literature establishes their role in namesake enhancement or reduction in synaptic efficiency.…”