Transcranial focused ultrasound modulates feedforward and feedback cortico-thalamo-cortical pathways by selectively activating excitatory neurons

Transcranial focused ultrasound stimulation (tFUS) is a promising neuromodulation technique capable of non-invasively modulating focal neuronal activities and neural circuits in both animals and humans. The cell-type selectivity of tFUS within targeted areas such as the somatosensory cortex (S1) during sonication has been shown to be parameter related. However, it remains unclear how tFUS affects neural circuits by changing the correlation between neurons and how to optimize the tFUS parameters to modulate neural pathways. In this study, multi-site intracranial recordings are used in anesthetized male rats to quantify the neuronal responses to tFUS stimulation recorded from S1 and posterior medial thalamic nucleus (POm) of cortico-thatlamo-cortical (CTC) pathway. Different tFUS parameters including ranges of pulse repetition frequencies (PRFs) and duty cycles (DCs) are tested. We find that when targeting at S1, only regular spiking units (RSUs) respond to specific tFUS parameters during sonication (DC: 6%-60% PRF: 1500Hz, 3000Hz and 4500Hz), and RSUs from the POm exhibit a synchronized response. The changes of directional correlation between S1 RSUs and POm RSUs indicate the activation of feedback modulation. Delayed responses and correlation changes were further observed at around 200ms post sonication from the neurons in S1 and POm, indicating feedforward modulation. Our results reveal that tFUS can modulate the feedback and feedforward CTC pathways by selectively activating cortical RSUs, and adjusting the tFUS parameters, particularly the PRF, to maximize cortical RSU activity could enhance the modulation of the CTC pathway. Significance Statement Previous work has shown that tFUS can selectively activate different neuron types and affect neural pathways. However, how tFUS affects neural circuits and how to optimize the tFUS parameters to modulate neural pathways remains unclear. Our work found that using specific PRFs (e.g., 1500Hz, 3000Hz) combined with particular duty cycles (e.g., 6% to 60%) induces higher targeted somatosensory excitatory neuronal response. By using multi-site recordings, we showed that the feedback and feedforward cortico-thalamo-cortical (CTC) pathways could be activated by the selective excitation of tFUS on excitatory neurons in the somatosensory cortex. We found that tuning the tFUS parameters, especially the PRFs, to maximize cortical excitatory neuronal activities could enhance the modulation of the CTC pathway.