Lennart Verhagen

Subject-specific simulations of wave propagation are commonly used to plan and report acoustic and thermal exposure during transcranial ultrasound (TUS) interventions. Their accuracy depends on acoustic and thermal tissue property assumptions, including sound speed, density, and attenuation. Reported property measurements vary widely across the literature, precluding consensus point estimates for simulation. How this property uncertainty affects estimated exposure has not been quantified. We compile literature-based bounds for seven acoustic and thermal properties of skull and brain tissue and assess their individual impact on simulated intensity and temperature rise using two independent simulation platforms (PRESTUS/k-Wave and BabelBrain). Variations in skull attenuation and absorption produced the largest outcome uncertainty: peak intensity in the brain varied roughly threefold across the reported range of skull attenuation alone, while absorption most strongly affected temperature rise within the skull. The direction of each parameter’s effect was consistent across platforms and, with one exception, across skull thickness. This allowed bounds to be combined into setups that bracket transmission and temperature rise. Compared to these extremes, default property sets of three simulation toolboxes (k-Plan, BabelBrain, PRESTUS) yielded similar brain intensity but divergent skull heating, driven mainly by differing assumptions on skull absorption and heat capacity. These results indicate that uncertainty in skull acoustic properties is a major source of variability in TUS exposure estimates, and that refined measurements of these properties, together with explicit reporting of exposure uncertainty, are needed to support safe, effective, and reproducible transcranial ultrasound planning.

Conflict monitoring and error processing are fundamental mechanisms underlying cognitive control and adaptive behavior and have been consistently associated with increased activity in the anterior midcingulate cortex (aMCC). Here, we used transcranial ultrasound stimulation (TUS), an emerging technique that enables non-invasive, deep, and focal neuromodulation, and EEG to investigate the causal role of the aMCC in cognitive control. Our findings demonstrate that TUS of aMCC improved performance, modulated the relationship between conflict monitoring and the stimulus-locked N2, and strengthened the suppression of distracting flankers as revealed by drift-diffusion model analyses. This suggests that TUS of aMCC enhances proactive control. Interestingly, TUS did not affect the error-related negativity as a measure of error monitoring. Finally, the TUS effects were observed during early compared with later task blocks corroborating previous findings which suggested that TUS effects are temporally dynamic and characterized by a limited post-stimulation window. HIGHLIGHTS: aMCC-TUS and PCC-TUS both increase behavioral accuracy during the early stages of task performance. aMCC-TUS transiently reduces the effect of incongruence on the stimulus-locked N2 suggesting reduced response conflict. Exploratory DDM analyses suggest that aMCC-TUS improves suppression of conflict- inducing distractors. aMCC thus selectively enhances proactive control, thereby reducing response conflict. TUS effects show a transient temporal profile, peaking 17–27 minutes after stimulation and declining after ∼37 minutes.

Here, we resolve the long-standing but unconfirmed hypothesis that the human amygdala is essential for rapidly acquiring cued-conditioned threat responses. We provide causal evidence for the amygdala’s contribution to forming threat memories that are resistant to extinction. Using transcranial ultrasound stimulation (TUS), a noninvasive technique that modulates deep brain structures with high spatial and temporal precision, we targeted the bilateral amygdala during Pavlovian threat conditioning in healthy adults. Linear mixed-effects models and computational modeling of trial-level skin conductance responses revealed that amygdala-TUS (experiment I, n = 25), but not hippocampus-TUS (experiment II, n = 25), selectively slowed initial threat acquisition, augmented subsequent extinction, and modulated declarative memory of retrospective threat probability. These findings demonstrate that the human amygdala drives an emotional learning state—learning fast, forgetting slow. Our study shows the potential of TUS for targeted neuromodulation of human deep brain structures implicated in conditions such as posttraumatic stress disorder, where pathological threat memories persist despite therapy.

A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise ultrasound stimulation protocol targeting the frontal eye fields — a well-characterized circuit critical for saccadic eye movements. We demonstrate that ultrasonic stimulation induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish ultrasound stimulation as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted transcranial ultrasonic stimulation applications in neuroscience and clinical settings.

Transcranial ultrasonic stimulation (TUS) redefines what is possible with non-invasive neuromodulation by oaering unparalleled spatial precision and flexible targeting capabilities. However, peripheral confounds pose a significant challenge to reliably implementing this technology. While auditory confounds during TUS have been studied extensively, the somatosensory confound has been overlooked thus far. It will become increasingly vital to quantify and manage this confound as the field shifts towards higher doses, more compact stimulation devices, and more frequent stimulation through the temple where co-stimulation is more pronounced. Here, we provide a systematic characterisation of somatosensory co-stimulation during TUS. We also identify the conditions under which this confound can be mitigated most eaectively by mapping the confound-parameter space. Specifically, we investigate dose-response eaects, pulse shaping characteristics, and transducer-specific parameters. We demonstrate that somatosensory confounds can be mitigated by avoiding near-field intensity peaks in the scalp, spreading energy across a greater area of the scalp, ramping the pulse envelope, and delivering equivalent doses via longer, lower-intensity pulses rather than shorter, higher-intensity pulses. Additionally, higher pulse repetition frequencies and fundamental frequencies reduce somatosensory eaects. Through our systematic mapping of the parameter space, we also find preliminary evidence that particle displacement (strain) may be a primary biophysical driving force behind peripheral somatosensory co-stimulation. This study provides actionable strategies to minimise somatosensory confounds, which will support the thorough experimental control required to unlock the full potential of TUS for scientific research and clinical interventions. Highlights: - Tactile, thermal, and even painful somatosensory confounds may occur during TUS. - Confounds can be mitigated via pulse shaping & transducer-specific parameters. - Valid and replicable TUS research requires control for peripheral confounds. - Particle displacement may be a primary driving force for somatosensory confounds.

Summary: A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation (TUS) offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise TUS protocol targeting the frontal eye fields (FEFs) — a well-characterized circuit critical for saccadic eye movements. We demonstrate that TUS induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish TUS as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted TUS applications in neuroscience and clinical settings. Highlights: Focused ultrasound modulates saccades with high spatial and temporal precision Inhibitory circuits in the frontal eye fields shape choice computations GABA levels predict individual variability in ultrasound-induced behavioral changes Ultrasound can be used to probe fast neural dynamics and individual differences