Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates

Abstract

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2e0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for noninvasive deep brain stimulation.

Sustained Modulation of Deep Brain Circuits with Focused Ultrasonic Waves

“…for 18-31 minutes after a 20 second sonication of the frontal eye field. 26 Other studies have similarly shown changes in NHP behavior 27 , fMRI [21][22][23] or motor evoked potentials (MEP) in humans 28 that persist for minutes to hours following sonications with durations between 40 and 120 seconds. Thus, our measurement of lateralized behavioral changes adds considerable evidence to a growing consensus that ultrasound can induce durable and reversible changes in neuronal activity.…”

“…19,20 Proofs of concept of durable changes have been published. [21][22][23][24][25][26][27][28] However, the full strength of ultrasound-programmatic targeting of multiple deep brain regions to induce sustained and region-specific neuroplastic effects in awake subjects (Figure 1b)-has not yet been demonstrated. This demonstration is critical for effective and personalized treatments.…”

“…Transcranial low-intensity focused ultrasound can noninvasively modulate deep brain circuits with millimeter precision [9]. The effects on the target circuits can be either transient [10][11][12][13][14][15][16][17][18] or durable [19][20][21][22][23][24][25][26], depending on the stimulus duration.…”

Safety of Clinical Ultrasound Neuromodulation

“…While the evidence remains inconclusive and warrants further investigation, this conflicting evidence illustrates the importance of methodological choice (as well as proper controls) in experimental designs when investigating thermal and mechanical effects of ultrasound stimulation. One long-term study investigated stimulation effects in 2 macaques over 2 years (129 and 147 stimulation sessions, respectively; 0.5–7.8 W/cm 2 I SPPA in water, 10.1–156.7 mW/cm 2 I SPTA ) and found no signs of trauma on MRI scans or in behavioral analysis [ 52 ].…”

Effects of Anesthesia on Cerebral Blood Flow and Functional Connectivity of Nonhuman Primates

“…In addition, dexmedetomidine has been used widely as a sedative agent in fMRI and functional connectivity studies of rodents [ 60 , 140 ] by combining it with isoflurane and/or ketamine. These combinations of procedures were explored in a few studies of monkeys for fMRI [ 141 , 142 ] and functional connectivity [ 86 ], suggesting it may improve the detection sensitivity of BOLD signal in the monkey brain at 3T. In addition, ketamine is a racemic mixture of R- and S- ketamine and both showed suppression effects on fMRI signals in the brain.…”