Default Mode Network Neuromodulation to Treat Depression via Non-Invasive Transcranial Focused Ultrasound: Acute and Sustained Effects
DOI: Pending DOI
Synopsis
Up to 50% of depressed individuals fail to respond to treatment, highlighting the need for mechanistically-derived treatments promoting sustained benefits. DMN hyperconnectivity, associated with repetitive negative thought (RNT) and depression symptoms, is a promising target for transcranial focused ultrasound (tFUS), a novel neuromodulation technique. This open-label trial assessed whether three weeks of tFUS targeting a major hub of the DMN decreases depression, RNT, and DMN connectivity in depressed participants. Depression and RNT decreased significantly after treatment, with sustained benefits lasting six months post-tFUS. DMN connectivity decreased acutely after treatment. These findings demonstrate tFUS as a fast-acting intervention with lasting benefits, while supporting the role of the DMN in depression.
Background
Fifty percent of individuals with Major Depressive Disorder (MDD) fail to respond to current treatments (1), highlighting a critical need for the development of novel treatments derived from a mechanistic understanding of the disorder, with the goal of producing meaningful and sustained benefits. A hallmark cognitive feature of depression is repetitive negative thought (RNT), a pattern of persistent, self-focused thinking linked to both depression symptom severity (2) and aberrant neural activity (3). Specifically, hyperconnectivity within the default mode network (DMN), a brain network implicated in self-referential processing (4), has been associated with both depression symptoms (5) and RNT (4), making this network an ideal target for treatment. Transcranial focused ultrasound (tFUS), a novel, non-invasive neuromodulation technique capable of precisely targeting cortical structures with fewer side effects compared to other techniques (e.g., Transcranial Magnetic Stimulation) (6, 7), holds promise as a tool for modulating DMN connectivity. This open-label pilot trial assessed whether tFUS targeting the DMN can decrease depression symptoms and RNT acutely and up to six months after treatment, as well as decrease DMN connectivity acutely, in individuals with MDD.
Methods
Twenty participants diagnosed with MDD were recruited for this study. Each participant completed up to eleven, ten-minute sessions of tFUS treatment targeting a major hub of the DMN, the left anterior medial prefrontal cortex. Before and after treatment, participants completed resting state functional magnetic resonance imaging and self-report assessments of depression and RNT via the Beck Depression Inventory-II (BDI-II) and the Perseverative Thinking Questionnaire (PTQ), respectively. Participants also completed the same self-report assessments one, three, and six months after completion of the acute treatment period. Two participants withdrew from the study due to time constraints and were excluded from analyses.
Results
Two linear mixed models examined BDI-II self-report depression and PTQ self-report RNT scores across all timepoints (baseline, Week 1, Week 3, 1-month, 3-month, 6-month follow-up). Depression symptom severity decreased significantly across the acute treatment period (baseline through week 3) and was sustained up to six months following tFUS treatment (p < .001). The largest reductions occurred during the acute phase, with scores stabilizing, though remaining significantly below baseline, across the 1-, 3-, and 6-month follow-up timepoints. Repetitive negative thought followed a similar pattern, with significant reductions emerging during acute treatment and persisting across the follow-up period (p < .001).
Two linear mixed models examined whether acute RNT and depression reduction predicted depression severity (BDI-II scores) across the three follow-up timepoints (1-month, 3-month, 6-month), and whether this relationship differed as a function of timepoint. Depression (BDI-II) and RNT (PTQ) reduction scores were calculated as a proportional change score ((baseline score − acute post-treatment score) / baseline score)). Greater acute RNT reduction significantly predicted lower depression severity at 1-month follow-up (p = .004), such that individuals with larger acute RNT reductions entered follow-up with lower depression scores. A significant interaction between acute RNT reduction and 3-month timepoint (p = .049) indicated that the advantage associated with greater acute RNT reduction attenuated at 3-month follow-up relative to 1-month. A trending interaction was observed at 6-month follow-up (p = .061). A similar relationship was observed for acute depression symptom reduction, with greater acute depression reduction predicting lower depression severity at 1-month follow-up (p = .003). Significant interactions between acute depression reduction and both 3-month (p = .012) and 6-month timepoints (p = .024) indicated that the advantage associated with greater acute depression reduction attenuated over time.
ROI-to-ROI connectivity (RRC) matrices were estimated characterizing the functional connectivity between each pair of regions among six ROIs that comprise the major hubs of subsystem A of the DMN: leftPFC (dorsal), leftPFC (medial), leftPCC, rightPFC (dorsal), rightPFC (medial), and rightPCC. Default Mode Network connectivity significantly decreased acutely after tFUS treatment between the leftPFC (medial) and leftPCC (pFDR = 0.003).
Discussion
Depression and RNT decreased significantly during the acute treatment period and remained significantly below baseline across 1-, 3-, and 6-month follow-up. These findings are consistent with previous psychotherapy and brain stimulation trials that demonstrate a pattern of large acute gains that stabilize, rather than deteriorate, over time (8, 9). Greater acute reductions in both RNT and depression symptoms predicted lower depression severity at 1-month follow-up, a finding that is consistent across antidepressant and brain stimulation treatments wherein early symptom improvement reliably predicts favorable longer-term outcomes (10, 11). While this predictive advantage attenuated at 3- and 6-month follow-up for both RNT and depression reduction, it reflects a narrowing of the gap between higher and lower acute responders rather than a deterioration in outcomes. Notably, greater acute RNT reduction predicted future depression severity, extending findings from literature demonstrating that acute changes in RNT are associated with acute changes in depression (7); further supporting the role of RNT in depression. tFUS also produced a significant acute decrease in DMN connectivity, aligning with findings from antidepressant (12) TMS (13) trials and supporting DMN hyperconnectivity as a viable treatment target. Given the open-label design and small sample size, future work with larger samples and a control group is required to validate findings. Despite these limitations, this study supports tFUS as a fast-acting intervention for MDD with lasting benefits, offering a promising alternative to existing treatments.
Disclosures
The author(s) declared that this work received funding from Openwater. Authors CB, PH, SO, SK and AA were employed by company Openwater. he funder had the following involvement in the study: supported the success of the study by ensuring the ultrasound equipment functioned properly, reviewed the manuscript, and provided expertise in describing the ultrasound technology.
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