Noninvasive modulation of essential tremor with focused ultrasonic waves.

Objective: Transcranial focused low-intensity ultrasound has the potential to noninvasively modulate confined regions deep inside the human brain, which could provide a new tool for causal interrogation of circuit function in humans. However, it has been unclear whether the approach is potent enough to modulate behavior.Approach: To test this, we applied low-intensity ultrasound to a deep brain thalamic target, the ventral intermediate nucleus, in three patients with essential tremor.Main results: Brief, 15 s stimulations of the target at 10% duty cycle with low-intensity ultrasound, repeated less than 30 times over a period of 90 min, nearly abolished tremor (98% and 97% tremor amplitude reduction) in 2 out of 3 patients. The effect was observed within seconds of the stimulation onset and increased with ultrasound exposure time. The effect gradually vanished following the stimulation, suggesting that the stimulation was safe with no harmful long-term consequences detected.Significance: This result demonstrates that low-intensity focused ultrasound can robustly modulate deep brain regions in humans with notable effects on overt motor behavior.

Device for Multifocal Delivery of Ultrasound Into Deep Brain Regions in Humans.

Low-intensity focused ultrasound provides the means to noninvasively stimulate or release drugs in specified deep brain targets. However, successful clinical translations require hardware that maximizes acoustic transmission through the skull, enables flexible electronic steering, and provides accurate and reproducible targeting while minimizing the use of MRI. We have developed a device that addresses these practical requirements. The device delivers ultrasound through the temporal and parietal skull windows, which minimize the attenuation and distortions of the ultrasound by the skull. The device consists of 252 independently controlled elements, which provides the ability to modulate multiple deep brain targets at a high spatiotemporal resolution, without the need to move the device or the subject. And finally, the device uses a mechanical registration method that enables accurate deep brain targeting both inside and outside of the MRI. Using this method, a single MRI scan is necessary for accurate targeting; repeated subsequent treatments can be performed reproducibly in an MRI-free manner. We validated these functions by transiently modulating specific deep brain regions in two patients with treatment-resistant depression.

Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report.

BACKGROUND: Severe forms of depression have been linked to hyperactivity of the subcallosal cingulate cortex. The ability to stimulate the subcallosal cingulate cortex or associated circuits noninvasively and directly would maximize the number of patients who could receive treatment. To this end, we have developed an ultrasound-based device for effective noninvasive modulation of deep brain circuits. Here we describe an application of this tool to an individual with treatment-resistant depression. CASE PRESENTATION: A 30-year-old Caucasian woman with severe treatment-resistant non-psychotic depression was recruited into a clinical study approved by the Institutional Review Board of the University of Utah. The patient had a history of electroconvulsive therapy with full remission but without sustained benefit. Magnetic resonance imaging was used to coregister the ultrasound device to the subject's brain anatomy and to evaluate neural responses to stimulation. Brief, 30-millisecond pulses of low-intensity ultrasound delivered into the subcallosal cingulate cortex target every 4 seconds caused a robust decrease in functional magnetic resonance imaging blood-oxygen-level-dependent activity within the target. Following repeated stimulation of three anterior cingulate targets, the patient's depressive symptoms resolved within 24 hours of the stimulation. The patient remained in remission for at least 44 days afterwards. CONCLUSIONS: This case illustrates the potential for ultrasonic neuromodulation to precisely engage deep neural circuits and to trigger a durable therapeutic reset of those circuits. Trial registration ClinicalTrials.gov, NCT05301036. Registered 29 March 2022, https://clinicaltrials.gov/ct2/show/NCT05301036.

Multifrequency-based sharpening of focal volume.

Systems that emit electromagnetic or sonic waves for diagnostic or interventional applications often have constraints on the size of their aperture, and thus produce an elongated focus in the axial dimension. This extended depth of focus limits imaging resolution and spatial specificity of the delivered energy. Here, we have developed a method that substantially minimizes the depth of focus. The method superimposes beams of distinct frequencies in space and time to create constructive interference at target and amplify deconstructive interference everywhere else, thus sharpening the focus. The method does not require labeling of targets or other manipulations of the medium. Using simulations, we found that the method tightens the depth of focus even for systems with a narrow bandwidth. Moreover, we implemented the method in ultrasonic hardware and found that a 46.1% frequency fractional bandwidth provides an average 7.4-fold reduction in the focal volume of the resulting beams. This method can be readily applied to sharpen the focus of interventional systems and is expected to also improve the axial resolution of existing imaging systems.

Acoustic properties across the human skull.

Transcranial ultrasound is emerging as a noninvasive tool for targeted treatments of brain disorders. Transcranial ultrasound has been used for remotely mediated surgeries, transient opening of the blood-brain barrier, local drug delivery, and neuromodulation. However, all applications have been limited by the severe attenuation and phase distortion of ultrasound by the skull. Here, we characterized the dependence of the aberrations on specific anatomical segments of the skull. In particular, we measured ultrasound propagation properties throughout the perimeter of intact human skulls at 500 kHz. We found that the parietal bone provides substantially higher transmission (average pressure transmission 31 ± 7%) and smaller phase distortion (242 ± 44 degrees) than frontal (13 ± 2%, 425 ± 47 degrees) and occipital bone regions (16 ± 4%, 416 ± 35 degrees). In addition, we found that across skull regions, transmission strongly anti-correlated (R=-0.79) and phase distortion correlated (R=0.85) with skull thickness. This information guides the design, positioning, and skull correction functionality of next-generation devices for effective, safe, and reproducible transcranial focused ultrasound therapies.

Effective Ultrasonic Stimulation in Human Peripheral Nervous System.

OBJECTIVE: Low-intensity ultrasound can stimulate excitable cells in a noninvasive and targeted manner, but which parameters are effective has remained elusive. This question has been difficult to answer because differences in transducers and parameters-frequency in particular-lead to profound differences in the stimulated tissue volumes. The objective of this study is to control for these differences and evaluate which ultrasound parameters are effective in stimulating excitable cells. METHODS: Here, we stimulated the human peripheral nervous system using a single transducer operating in a range of frequencies, and matched the stimulated volumes with an acoustic aperture. RESULTS: We found that low frequencies (300 kHz) are substantially more effective in generating tactile and nociceptive responses in humans compared to high frequencies (900 kHz). The strong effect of ultrasound frequency was observed for all pressures tested, for continuous and pulsed stimuli, and for tactile and nociceptive responses. CONCLUSION: This prominent effect may be explained by a mechanical force associated with ultrasound. The effect is not due to heating, which would be weaker at the low frequency. SIGNIFICANCE: This controlled study reveals that ultrasonic stimulation of excitable cells is stronger at lower frequencies, which guides the choice of transducer hardware for effective ultrasonic stimulation of the peripheral nervous system in humans.

Schleswig: medieval leprosy on the boundary between Germany and Denmark.

Leprosy was a well-recognized and dreaded disease in medieval Europe. The disease is reported to have reached Germany with the Roman invasion and it was present in Scandinavia in the first centuries AD. This paper estimates and analyzes the frequency of leprosy among adult people buried in one of five medieval cemeteries in the city of Schleswig. Seven different dichotomous osteological lesions indicative of leprosy were analyzed, and it was possible to score at least one of these conditions on 350 adult skeletons (aged 15 or older). The scores were transformed to a statistic indicating the likelihood that the person to whom the skeleton belonged suffered from leprosy. It was found that the frequency of leprosy in the five cemeteries varied between 9 and 44%. Four of the five cemeteries showed frequencies ranging from 35 and 44% and with no statistically significant differences among them. The fifth cemetery showed a significantly lower frequency of leprosy (9%). The distribution of female age at death does not appear to be affected by leprosy status. This means that females experienced a considerably elevated risk of dying once they had contracted leprosy as the disease usually has a mid-adulthood age of onset. In four of the five cemeteries males with leprosy died in higher ages than men without leprosy--in two of the cemeteries the difference was statistically significant. This indicates that leprosy usually added less to the risk of dying among men than among women in medieval Schleswig.