Monkey Ultrasound for Brain Neuromodulation: Advances in Research

Researchers are exploring ultrasound as a tool for neuromodulation, offering a noninvasive way to influence brain activity. Studies in monkeys have demonstrated how focused ultrasound can alter neural responses, potentially opening new paths for treating neurological disorders or enhancing brain function. Unlike electrical or pharmacological methods, ultrasound provides precise spatial targeting without requiring implants or systemic drug effects.

Advances in this field have refined techniques for directing ultrasound to specific brain regions and understanding its effects on neural circuits. Scientists are investigating optimal stimulation parameters and assessing how it influences brain connectivity and sensory processing.

Physical Interactions Between Ultrasound And Neural Tissue

Ultrasound interacts with neural tissue through mechanical pressure waves that propagate through biological structures, influencing cellular and subcellular processes. When focused ultrasound is applied to the brain, it generates oscillations in the surrounding medium, leading to localized mechanical effects such as acoustic radiation force and microcavitation. These forces modulate neuronal excitability by altering membrane permeability, ion channel activity, and synaptic transmission. Studies using macaques have shown that low-intensity focused ultrasound (LIFU) can induce transient changes in neuronal firing rates, directly influencing neural signaling pathways.

The biophysical mechanisms involve both direct and indirect interactions with neural elements. Direct effects occur when ultrasound waves displace neuronal membranes, altering ion flux and action potential generation. Indirect effects arise from interactions with glial cells and the extracellular matrix, modifying neurotransmitter release and local field potentials. Research has shown that ultrasound can influence calcium dynamics, a process essential for synaptic plasticity and long-term neural modulation. In primate studies, targeted ultrasound has been observed to enhance or suppress activity in cortical and subcortical regions depending on the applied parameters.

Thermal effects, though present, are minimized in neuromodulation by using pulsed rather than continuous ultrasound. Even at low intensities, ultrasound can cause slight temperature elevations, which may contribute to neuronal excitability changes. However, controlled experiments confirm that neuromodulation occurs independently of significant thermal shifts, reinforcing the idea that mechanical interactions primarily drive ultrasound-induced neural modulation. In macaque experiments, precise temperature monitoring has shown that functional changes in brain activity can be achieved without exceeding safe thermal thresholds, ensuring ultrasound remains a viable noninvasive tool.

Targeting Sensory Regions For Acoustic Stimulation

Directing ultrasound to sensory regions requires precise spatial targeting to ensure stimulation reaches intended circuits without unintended effects. Research in nonhuman primates has shown that LIFU can selectively modulate activity in sensory cortices, including the primary somatosensory and auditory areas. By calibrating the focal point of the ultrasound beam, researchers have influenced neural responses in a controlled manner, allowing modulation of sensory perception and processing. This precision is valuable for studying sensory integration and manipulating external stimuli through targeted neuromodulation.

Experiments with macaques have shown that ultrasound applied to the somatosensory cortex alters tactile perception and neural encoding of touch-related stimuli. When directed at the primary somatosensory cortex (S1), researchers observed shifts in neuronal firing patterns corresponding to changes in the animals’ ability to detect vibrotactile stimuli. Functional imaging and electrophysiological recordings confirmed that ultrasound could enhance or suppress activity in specific cortical columns, suggesting a fine-tuned mechanism for modulating somatosensory processing. These findings have implications for treating sensory dysfunction conditions such as neuropathic pain or sensory processing disorders.

The auditory cortex has also been a focus of ultrasound neuromodulation research, with studies indicating that stimulation can alter auditory perception and processing. In macaques, ultrasound delivered to the primary auditory cortex (A1) has been shown to modulate frequency tuning properties of neurons, temporarily shifting auditory discrimination abilities. The ability to noninvasively influence auditory cortical activity suggests possible therapeutic applications for tinnitus and auditory processing disorders. Researchers have noted that ultrasound can induce excitatory or inhibitory effects depending on pulse parameters, underscoring the need to optimize stimulation protocols.

Temporal Patterns Of Neural Response

The timing of neural activity following ultrasound stimulation plays a fundamental role in its effects on brain function. Studies in nonhuman primates have shown that neural responses vary based on pulse duration, repetition rate, and the intrinsic dynamics of the targeted brain region. Electrophysiological recordings indicate that ultrasound induces both immediate changes in neuronal firing and delayed effects persisting beyond stimulation. These variations suggest ultrasound influences not only direct mechanical interactions with neural membranes but also network-level adaptations over time.

Short bursts of ultrasound typically elicit rapid firing rate modulations within milliseconds of stimulation onset. In macaques, neurons in the targeted region exhibit transient increases or decreases in spiking activity based on applied parameters. This immediate response likely results from mechanical perturbations affecting ion channel conformation and synaptic efficacy. Beyond these acute effects, prolonged or repeated ultrasound exposure leads to sustained changes in neural excitability. Some studies report alterations in local field potentials persisting for minutes post-stimulation, suggesting ultrasound may induce plasticity-like effects in cortical circuits.

One hypothesis is that ultrasound influences synaptic strength through calcium-mediated signaling, temporarily shifting excitability beyond the initial stimulus window. Functional imaging in primates has shown that ultrasound-triggered activity spreads to interconnected brain regions, further supporting the idea that temporal dynamics are shaped by network-wide interactions. These findings highlight ultrasound’s potential to engage broader neural systems, relevant for cognitive and sensorimotor function applications.

Frequencies And Pulse Configurations In Research

The effectiveness of ultrasound neuromodulation depends on selecting appropriate frequencies and pulse configurations, which determine how mechanical energy interacts with neural tissue. Research on nonhuman primates has explored frequencies between 250 kHz and 1 MHz, with lower frequencies offering deeper penetration and higher frequencies providing finer spatial resolution. Studies have found that frequencies around 500 kHz balance these factors, enabling precise targeting of cortical and subcortical regions without excessive attenuation or scattering. Some frequency ranges favor excitatory responses, while others promote inhibition.

Pulse configurations also shape neural effects. Ultrasound can be delivered continuously or in pulses, with pulsed modes preferred for neuromodulation to minimize thermal accumulation while maintaining effective mechanical stimulation. Pulse repetition frequency (PRF) and duty cycle influence the duration and intensity of neural engagement. Experiments with macaques show lower PRFs (e.g., 100 Hz) produce more sustained neuromodulatory effects, while higher PRFs (e.g., 1 kHz) generate rapid but transient changes in neuronal activity. Individual pulse durations, typically 0.3 to 10 milliseconds, further refine responses, with longer pulses leading to more prolonged excitability changes.

Observations In Brain Network Connectivity

Ultrasound neuromodulation affects localized neural activity and broader brain network connectivity. Research in nonhuman primates shows that stimulating specific cortical or subcortical regions with focused ultrasound induces changes in distant but functionally connected areas. This suggests ultrasound can modulate entire neural circuits rather than isolated neurons, making it a promising tool for investigating and treating disorders involving disrupted connectivity, such as depression or epilepsy. Functional MRI (fMRI) studies in macaques reveal that ultrasound stimulation of the thalamus alters activity in cortical areas associated with sensory processing and cognition.

The nature of connectivity changes depends on factors including frequency, intensity, and pulse duration. Some studies show brief ultrasound exposures enhance synchronization between brain regions, while prolonged stimulation may disrupt connectivity patterns, potentially offering therapeutic effects for pathological hyperconnectivity. Electrophysiological recordings indicate ultrasound-induced connectivity changes persist for minutes post-stimulation, suggesting effects involve adaptive plasticity rather than being purely transient. These findings open avenues for using ultrasound to reshape dysfunctional neural networks in neuropsychiatric and neurological disorders.

Noninvasive Imaging Paired With Ultrasound

Pairing ultrasound neuromodulation with noninvasive imaging has provided deeper insights into how brain activity is influenced at local and network levels. Functional MRI (fMRI) has been particularly useful in mapping ultrasound effects across the brain, allowing researchers to visualize changes in blood oxygenation and connectivity patterns in real time. Studies in macaques show that ultrasound applied to the prefrontal cortex induces widespread neural alterations detectable through fMRI, offering insight into how targeted stimulation influences cognitive and executive functions. Integrating ultrasound with fMRI has also helped differentiate direct neuromodulatory effects from secondary hemodynamic changes.

Electroencephalography (EEG) and magnetoencephalography (MEG) have further expanded the ability to measure neural responses with high temporal resolution. EEG recordings in primates show ultrasound stimulation alters oscillatory activity, particularly in the alpha and gamma frequency bands, which are associated with sensory processing and attention. MEG studies corroborate these findings, demonstrating that ultrasound can modulate neural synchrony similarly to transcranial magnetic stimulation (TMS) but with greater spatial precision. Combining ultrasound with these imaging modalities enhances optimization of stimulation parameters, paving the way for more targeted neuromodulation strategies.