Differential effects of amplitude-modulated transcranial focused ultrasound on excitatory and inhibitory neurons

Abstract

Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2°C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.

Ultrasound stimulation of the motor cortex during tonic muscle contraction

“…This is in sharp contrast to the lengthy silent periods from single-pulse TMS. This is also in contrast to a growing number of studies showing inhibitory effects by tUS [ 2 , 31 – 33 , 35 – 38 ].…”

“…TMS preferentially depolarizes axons [ 71 – 74 ]. While still early in investigation, tUS conversely has often been proposed to preferentially affect inhibitory neurons [ 2 , 35 – 38 ]—though this is certainly not universal [ 75 ]. If these assumptions are true, this could explain why tUS struggled to silence corticospinal output in these data.…”

“…Because of its physiological underpinnings, the cSP is in a unique position to be leveraged as an externally detectable phenomenon to better understand tUS effects on M1. Specifically, tUS has been proposed to preferentially affect inhibitory interneurons [ 2 , 32 , 35 – 38 ], feeding well into cSP’s existence as a interneuron-facilitated phenomenon. Additionally, since cSPs have been reported to occur without a preceding MEP [ 27 , 29 , 30 , 39 , 40 ], tUS’ apparent inability to instigate an MEP does not preclude its use to attempt induction of cSPs.…”

Ultrasound stimulation of the motor cortex during tonic muscle contraction

“…If this MEP-cSP dependency is true, this could suggest that cortical silent period is dependent on the recruitment of M1 motor units. TMS preferentially depolarizes axons (Lazzaro, Ziemann, & Lemon, 2008;Lefaucheur et al, 2014;McIntyre & Grill, 2002;Nowak & Bullier, 1998), while tUS has been proposed to preferentially affect inhibitory neurons (Kim et al, 2014;Legon et al, 2014;Nguyen et al, 2020;Plaksin et al, 2016;Rinaldi et al, 1991). If these assumptions are true, this could explain why tUS struggled to silence corticospinal output.…”

“…Because of its physiological underpinnings, the cSP is in a unique position to be leveraged as an externally detectable phenomenon to better understand tUS effects on M1. Specifically, tUS has been proposed to preferentially affect inhibitory interneurons (Kim et al, 2014;Legon et al, 2014;Nguyen, Berisha, Konofagou, & Dmochowski, 2020;Plaksin, Kimmel, & Shoham, 2016;Rinaldi, Jones, Reines, & Price, 1991), feeding well into cSP's existence as a interneuron-facilitated phenomenon. Additionally, since cSPs have been reported to occur without a preceding MEP (Cantello, Gianelli, Civardi, & Mutani, 1992;Classen & Benecke, 1995;Davey et al, 1994;Wassermann et al, 1993;Wolters et al, 2012), tUS' apparent inability to instigate an MEP does not preclude its use to attempt induction of cSPs.…”