Kate D. Fitzgerald

Current efforts to establish anatomically precise and causal deep brain circuit-symptom relationships to predict surgical responses require the insertion of intracranial electrodes. In the present study (ClinicalTrials.gov NCT05697172) we examined whether low-intensity focused ultrasound (LIFU; FDA Q220192) could modulate the white matter tracts in the anterior limb of the internal capsule (ALIC), a common surgical target for the treatment of refractory depression. We based our human study on the in vitro observation that ultrasound attenuates conduction in myelinated axons by operating mechanosensitive potassium channels in nodes of Ranvier. We employed a cross-over, randomized, sham-controlled, double-blind design to establish the ability of LIFU (80 s; 0.5 MHz; estimated peak tissue energy 2.26 Watt/cm²; 10% duty cycle) to engage a target in the ALIC in 21 patients with Major Depressive Disorder. Targets were defined as the area with highest density of thalamo-prefrontal probabilistic tractography streamlines. We measured changes in magnetic resonance functional connectivity, repetitive mentation, emotional state, and cardiac autonomic output. Compared with sham stimulation, active LIFU produced a functional disconnection of gray matter hubs connected by the sonicated tracts (d = −1.55; p < 0.001), an increase in positive emotion (d = 0.6; p = 0.04), and decreased cardiac sympathovagal balance (d = −0.57; p = 0.01). The observation that LIFU engages deep white matter tracts related to depression symptoms paves the way for rigorously investigating (1) mechanistic definitions of brain circuit-symptom relationships, (2) noninvasive, reversible, and anatomically precise probing of such circuits before surgery, and (3) potential use as a new therapy for depression.

Pediatric anxiety disorders and post-traumatic stress disorder (PTSD) are associated with elevated threat sensitivity and impaired emotion regulation, accompanied by dysfunction in the neural circuits involved in these processes. Despite established treatments like cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors, many children do not achieve remission, underscoring the importance of understanding the neurobiological underpinnings of these disorders. This review synthesizes current research on the neural predictors of treatment response and the neurofunctional changes associated with treatment in pediatric anxiety and PTSD during threat and reward processing. Several key findings emerged. First, enhanced threat/safety discrimination in the amygdala predicted better outcomes of pediatric anxiety and PTSD treatments. Second, differences in pretreatment activation within the lateral prefrontal and dorsal anterior cingulate cortices predicted treatment response, likely reflecting baseline executive control differences. Third, post-CBT decreases in activation in default mode, visuo-attentional, and sensorimotor areas may support treatment-related increases in task engagement. Finally, functional connectivity between the amygdala and other limbic, prefrontal, and default mode network nodes predicts treatment response in anxiety and PTSD, highlighting its potential as a biomarker for therapeutic efficacy. Understanding these neurofunctional markers could lead to more targeted interventions, optimizing treatment planning and potentially leading to the development of “pretreatment” strategies to enhance the efficacy of existing treatments. This review highlights the necessity for future research to establish more direct links between neuroimaging findings and clinical outcomes to facilitate the translation of these findings into clinical practice.

Major depressive disorder has a point prevalence of 5% of the world population and is the main cause of disability, with up to a third of patients not responding to first-line treatments. Surgical neuromodulation is offered to only an anecdotal proportion of these patients, because while these methods are curative in some individuals, the proportion of responders rarely exceeds 50%. Recent efforts to establish reliable brain circuit-symptom relationships and thus predict response have involved mapping with multiple intracranial electrodes, but the impracticality of this approach currently prevents its application at scale. In the present study ( ClinicalTrials.gov identifier NCT05697172 ; FDA Q220192) we begin to address this gap by leveraging low-intensity focused ultrasound (LIFU), a novel noninvasive technique, to modulate the anterior limb of the internal capsule, which is an established surgical deep white matter target for depression. We based our study on burgeoning in vitro evidence that LIFU attenuates axonal conduction by operating mechanosensitive channels in nodes of Ranvier. Compared with sham stimulus, active LIFU produced a functional disconnection of gray matter hubs reached by the sonicated axonal tracts, an increase in positive emotion, and top-down effects on the cardiovascular autonomic balance. Our results using LIFU of deep-brain white matter tracts in humans open three potential avenues to understand the mechanisms and improve the outcome of depression, namely attaining a personalized definition of brain circuit-symptom relationships, serving as a noninvasive probe for neuromodulation before irreversible procedures in a “try before you buy” approach, and ultimately emerging as a therapeutic intervention itself.

Subclinical symptoms of obsessive–compulsive disorder (i.e., obsessive compulsive symptoms, or “OCS”) cause functional impairment, including for youth without full-syndrome OCD. Further, despite high rates of OCS in youth with anxiety disorders, knowledge of OCS in the context of specific anxiety disorders is limited. The present study seeks to: (1) compare OCS in pediatric patients with anxiety disorders and healthy youth, (2) determine which categorical anxiety disorder(s) associate most with OCS, and (3) determine relationships between OCS with anxiety severity and impairment. Data on OCS, anxiety, and functional impairment were collected from 153 youth with anxiety disorders and 45 healthy controls, ages 7–17 years (M = 11.84, SD = 3.17). Findings indicated that patients had significantly more OCS than healthy controls. Among patients, GAD was a significant predictor of OCS as well as OCD risk. These results suggest that OCS should be a primary diagnostic and treatment consideration for youth who present in clinical settings with GAD.