This article describes an emerging non-invasive neuromodulatory technology, called low intensity focused ultrasound (LIFU). This technology is potentially paradigm shifting as it can deliver non-invasive and reversible deep brain neuromodulation through acoustic sonication, at millimeter precision. Low intensity focused ultrasound's spatial precision, yet non-invasive nature sets it apart from current technologies, such as transcranial magnetic or electrical stimulation and deep brain stimulation. Additionally, its reversible effects allow for the causal study of deep brain regions implicated in psychiatric illness. Studies to date have demonstrated that LIFU can safely modulate human brain activity at cortical and subcortical levels. Due to its novelty, most researchers and clinicians are not aware of the potential applications and promise of this technique, underscoring the need for foundational papers to introduce the community to LIFU. This mini-review and synthesis of recent advances examines several key papers on LIFU administered to humans, describes the population under study, parameters used, and relevant findings that may guide future research. We conclude with a concise overview of some of the more pressing questions to date, considerations when interpreting new data from an emerging field, and highlight the opportunities and challenges in this exciting new area of study.

/pdf/low-intensity-focused-ultrasound-for-non-invasive-and-2nxgsdvk.pdf

Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation—A Paradigm Shift in Psychiatric Research

Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD) and shows promise for posttraumatic stress disorder (PTSD), yet effectiveness varies. Electroencephalography (EEG) can identify rTMS-associated brain changes. EEG oscillations are often examined using averaging approaches that mask finer time-scale dynamics. Recent advances show some brain oscillations emerge as transient increases in power, a phenomenon termed "Spectral Events," and that event characteristics correspond with cognitive functions. We applied Spectral Event analyses to identify potential EEG biomarkers of effective rTMS treatment. Resting 8-electrode EEG was collected from 23 patients with MDD and PTSD before and after 5 Hz rTMS targeting the left dorsolateral prefrontal cortex. Using an open-source toolbox ( https://github.com/jonescompneurolab/SpectralEvents ), we quantified event features and tested for treatment associated changes. Spectral Events in delta/theta (1-6 Hz), alpha (7-14 Hz), and beta (15-29 Hz) bands occurred in all patients. rTMS-induced improvement in comorbid MDD PTSD were associated with pre- to post-treatment changes in fronto-central electrode beta event features, including frontal beta event frequency spans and durations, and central beta event maxima power. Furthermore, frontal pre-treatment beta event duration correlated negatively with MDD symptom improvement. Beta events may provide new biomarkers of clinical response and advance the understanding of rTMS. 

/pdf/fronto-central-resting-state-15-29-hz-transient-beta-events-2qhotin9.pdf

Fronto-central resting-state 15-29 Hz transient beta events change with therapeutic transcranial magnetic stimulation for posttraumatic stress disorder and major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD) and shows promise for posttraumatic stress disorder (PTSD), yet effectiveness varies. Electroencephalography (EEG) can identify rTMS-associated brain changes. EEG oscillations are often examined using averaging approaches that mask finer time-scale dynamics. Recent advances show some brain oscillations emerge as transient increases in power, a phenomenon termed "Spectral Events," and that event characteristics correspond with cognitive functions. We applied Spectral Event analyses to identify potential EEG biomarkers of effective rTMS treatment. Resting 8-electrode EEG was collected from 23 patients with MDD and PTSD before and after 5Hz rTMS targeting the left dorsolateral prefrontal cortex. Using an open-source toolbox (https://github.com/jonescompneurolab/SpectralEvents), we quantified event features and tested for treatment associated changes. Spectral Events in delta/theta (1-6 Hz), alpha (7-14 Hz), and beta (15-29 Hz) bands occurred in all patients. rTMS-induced improvement in comorbid MDD PTSD were associated with pre- to post-treatment changes in fronto-central electrode beta event features, including frontal beta event frequency spans and durations, and central beta event maxima power. Furthermore, frontal pre-treatment beta event duration correlated negatively with MDD symptom improvement. Beta events may provide new biomarkers of clinical response and advance the understanding of rTMS.

/pdf/fronto-central-resting-state-15-29hz-transient-beta-events-90ovi09x.pdf

Fronto-central resting-state 15-29Hz transient beta events change with therapeutic transcranial magnetic stimulation for posttraumatic stress disorder and major depressive disorder

Abstract Background: Two commonly used forms of repetitive transcranial magnetic stimulation (rTMS) were recently shown to be equivalent for the treatment of treatment-resistant depression (TRD): high-frequency stimulation (10 Hz), a protocol that lasts between 19-38 minutes, and intermittent Theta-Burst Stimulation (iTBS), a protocol that can be delivered in just 3 minutes. Intermittent TBS offers significant advantages to patients and clinics and has thus become a default treatment in many clinics. However, it is unclear whether iTBS treatment offers the same benefits as standard 10 Hz rTMS for comorbid symptoms, such as post-traumatic-stress-disorder (PTSD). Methods: In this retrospective case series, we analyzed treatment outcomes in Veterans from the VA San Diego Healthcare system (VASDHS) who received 10 Hz (n = 47) or iTBS (n = 51) rTMS treatments for TRD between the dates of Jan 2017 to June 2022. We compared outcomes between these two stimulation protocols used between these dates on symptoms of depression (using changes in the patient health questionnaire-9, or PHQ-9) and PTSD (using changes in the PTSD Checklist for DSM-5, or PCL-5). We hypothesized that there would be no differences in treatment outcomes between 10 Hz and iTBS protocols for either depression (confirming prior RCT) or PTSD. Results: We found that both types of stimulation showed a clinically meaningful reduction in symptoms with no difference in outcomes based on the type of stimulation. The mean reduction on the PHQ-9 scale was 5.8 +/- 0.93 (p <0.001, n = 47) in Veterans receiving 10 Hz stimulation and 6.6 +/- 0.71 (p < 0.001, n = 51) in the Veterans receiving iTBS. There were no difference between stimulation protocols (p = 0.5). The mean reduction on the PCL-5 symptom scale was 8.1 +/- 2.1 in Veterans receiving 10 Hz stimulation (p <0.001, n =47) and -13.2 +/- 2.4 the Veterans receiving iTBS (p <0.001, n = 51). This difference was not significant (p=0.11) and had a small effect size (eta^2 = 0.026). Follow-up analyses restricting the sample in various ways did not meaningfully change these results. Conclusions: While limited by small sample size, non-blinded and pseudo-randomized assignment, our data suggests that iTBS can be expected to have similar if not slightly greater reductions in PTSD symptoms compared with 10 Hz stimulation. Our findings pave the way for further research trials to validate and optimize iTBS for PTSD symptoms.

/pdf/effectiveness-of-theta-burst-versus-high-frequency-1hvjadg6.pdf

Effectiveness of theta burst versus high frequency repetitive transcranial magnetic stimulation in reducing symptoms of post-traumatic stress disorder in Veterans with depression: a retrospective case series.

Multiple lines of evidence demonstrate that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may improve clinical outcomes in patients with schizophrenia (SCZ). However, the efficacy of HF-rTMS on psychiatric symptoms remains unknown in veterans with SCZ. This study aimed to investigate whether HF-rTMS was beneficial in alleviating the clinical symptoms in veterans with SCZ. Forty-seven long-term hospitalized veterans with SCZ were randomly allocated to receive neuronavigated 10 Hz rTMS or sham stimulation over the left dorsolateral prefrontal cortex once daily for four consecutive weeks. Symptoms were assessed by using the Positive and Negative Syndrome Scale at baseline and at the end of week 4. We also collected easily available routine biochemical markers including blood sugar, lipid profiles, hormone, and blood cell counts, considering that these markers may potentially be used to predict the outcomes of rTMS treatment. We found that there was a significant interaction effect of time and group on the positive symptoms. Compared with the sham group, the positive factor score of veterans with SCZ was significantly decreased after treatment in the real rTMS group. Interestingly, the improvement of positive symptoms from baseline to 4-week follow-up was significantly associated with the whole white blood cells (WBC) counts at baseline in the real rTMS group, and baseline WBC counts were predictive of the symptom improvement after rTMS treatment. Our findings indicate that add-on 10 Hz rTMS is beneficial for clinical symptoms in veterans with SCZ. In addition, the baseline WBC counts were predictive of the outcomes after treatment. Clinical trial registration clinicaltrials.gov, identifier NCT03774927.

/pdf/repetitive-transcranial-magnetic-stimulation-for-psychiatric-1zsaby4k.pdf

Repetitive transcranial magnetic stimulation for psychiatric symptoms in long-term hospitalized veterans with schizophrenia: A randomized double-blind controlled trial

Prefrontal transcranial magnetic stimulation for depression in US military veterans - A naturalistic cohort study in the veterans health administration.

Jerome A. Yesavage

Papers

Prefrontal transcranial magnetic stimulation for depression in US military veterans - A naturalistic cohort study in the veterans health administration.