Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Background: Low intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively.Objective/Hypothesis: We sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region.Methods: In this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC).Results: tFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity.Conclusion: We demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

This study intended to evaluate a possible therapeutic effect among patients with treatment-refractory generalized anxiety disorder (trGAD) by using transcranial focused ultrasound (tfUS) to modulate amygdalar activity. Twenty-five participants with severe trGAD as outlined in the DSM-V were recruited from Los Angeles neurology and psychiatry clinics. All participants completed eight weekly 10-min tfUS sessions targeting the right amygdala. Functional and structural neuroimaging were used to navigate individual targets. Outcome measures including the Hamilton Anxiety Inventory (HAM-A, primary outcome) and Beck Anxiety Inventory (BAI) were collected at baseline and protocol completion. Upon study completion, participants were asked to report perceived change in clinical status using the Patient Global Impression - Improvement (PGI-I) scale. Data was collected from May 2020 through January 2023. All participants were able to tolerate treatment without notable side effects. No adverse events were reported. A Wilcoxon Signed-Rank Test was conducted to compare pre- and post-tfUS measures of anxiety. tfUS resulted in a significant decrease in anxiety as measured by the HAM-A (W = -3.69, p < 0.001, pre-post-Δ = -12.64 ± 12.51) and the BAI (W = -3.94, p < 0.001, pre-post-Δ = -12.88 ± 10.42). Sixteen (16) of twenty-five (25) total participants indicated clinically significant benefit on PGI-I scores at completion. This study provides preliminary evidence supporting the safety and efficacy of tfUS as a clinical intervention. These results warrant further investigation of tfUS as a therapeutic intervention for anxiety and other psychiatric and neurological disorders. NCT04250441.

Recent evidence suggests the aging process is accelerated by HIV. Degradation of white matter (WM) has been independently associated with HIV and healthy aging. Thus, WM may be vulnerable to joint effects of HIV and aging. Diffusion‐weighted imaging (DWI) was conducted with HIV‐seropositive (n = 72) and HIV‐seronegative (n = 34) adults. DWI data underwent tractography, which was parcellated into 18 WM tracts of interest (TOIs). Functional Analysis of Diffusion Tensor Tract Statistics (FADTTS) regression was conducted assessing the joint effect of advanced age and HIV on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along TOI fibers. In addition to main effects of age and HIV on WM microstructure, the interactive effect of age and HIV was significantly related to lower FA and higher MD, AD, and RD across all TOIs. The location of findings was consistent with the clinical presentation of HIV‐associated neurocognitive disorders. While older age is related to poorer WM microstructure, its detrimental effect on WM is stronger among HIV+ relative to HIV− individuals. Loss of WM integrity in the context of advancing age may place HIV+ individuals at increased risk for brain and cognitive compromise.