publications
Researching the future of brain-based mental health care
Wave supports and contributes to a growing body of scientific research exploring the future of brain-based mental health care.
Our research library includes both independent publications and Wave-sponsored clinical studies focused on advancing the science of personalized neuromodulation and improving our understanding of how individualized brain-based interventions may support mental health outcomes.
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Alpha peak frequency-based Brainmarker-I as a method to stratify to pharmacotherapy and brain stimulation treatments in depression
Date published
December 2023
Publication
Nature Mental Health
Authors
Helena T. S. Voetterl, Alexander T. Sack, Sebastian Olbrich, Sven Stuiver, Renee Rouwhorst, Amourie Prentice, Diego A. Pizzagalli, Nikita van der Vinne, Jeroen A. van Waarde, Martin Brunovsky, Iris van Oostrom, Ben Reitsma, Johan Fekkes, Hanneke van Dijk, Martijn Arns
Key Takeaways
- Developed Brainmarker-I, an age- and sex-normalized EEG biomarker based on the individual alpha frequency, to stratify patients between depression treatments.
- Validated in blinded, out-of-sample analyses across roughly 600 patients: sertraline (N=240), rTMS discovery and validation (N=196, N=39), and ECT (N=41, N=51).
- Biomarker-guided stratification to brain stimulation improved remission from 53% to 65% (number needed to treat = 9).
- Independent demonstration that a single EEG-derived alpha measure can direct individual patients to the right treatment — personalization operating at the point of care.
Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury
Date published
August 2023
Publication
Brain
Authors
Woodrow RE, Winzeck S, Luppi AI, Kelleher-Unger IR, Spindler LRB, Wilson JTL, Newcombe VFJ, Coles JP, CENTER-TBI MRI Substudy Participants and Investigators, Menon DK, Stamatakis EA
Key Takeaways
- CENTER-TBI substudy: 108 mild TBI patients with normal CT versus 76 controls; 47% of the mTBI cohort showed incomplete recovery six months post-injury.
- Despite absent structural changes, acute thalamic functional hyperconnectivity differentiated patients who went on to develop chronic post-concussive symptoms.
- Emotional and cognitive symptoms mapped to thalamic connectivity changes in serotonergic and noradrenergic systems respectively — network-level pathophysiology invisible to structural imaging.
- Supports the network-disruption model of mTBI and the case for functional, network-based measurement and precision treatment.
Enhancing cognitive performance with repetitive transcranial magnetic stimulation at human individual alpha frequency
Date published
March 2023
Publication
European Journal of Neuroscience
Authors
Klimesch W, Sauseng P, Gerloff C
Key Takeaways
- Foundational experiment: rTMS delivered at each subject's individual upper alpha frequency (IAF+1 Hz) over frontal and parietal sites, versus sham and control frequencies (IAF−3 Hz and fixed 20 Hz).
- IAF-tuned stimulation enhanced mental-rotation task performance and, concomitantly, the extent of task-related alpha desynchronization.
- Control frequencies did not produce the effect — the benefit is specific to the individually calibrated rate.
- The original demonstration that stimulating at a person's own alpha frequency, rather than a universal rate, enhances brain function.
Daily prefrontal closed-loop repetitive transcranial magnetic stimulation (rTMS) produces progressive EEG quasi-alpha phase entrainment in depressed adults
Date published
March 2022
Publication
Brain Stimulation
Authors
Faller J, Doose J, Sun X, McIntosh JR, Saber GT, Lin Y, Teves JB, Blankenship A, Huffman S, Goldman RI, George MS, Brown TR, Sajda P
Key Takeaways
- Double-blind study of a closed-loop system delivering EEG-triggered rTMS synchronized to each depressed patient's prefrontal quasi-alpha rhythm (6–13 Hz), daily over six weeks.
- Synchronized patients developed strong, progressive phase entrainment at the stimulation site and in distal regions; entrainment phase shifted toward optimal engagement of the anterior cingulate cortex.
- Patients receiving identical rTMS without EEG synchronization showed no such entrainment.
- Entrainment built over days and weeks — evidence that timing stimulation to the patient's own rhythm drives neuroplastic change that fixed, unsynchronized stimulation misses.
Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial
Date published
February 2022
Publication
American Journal of Psychiatry
Authors
Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR
Key Takeaways
- Double-blind, randomized, sham-controlled trial of Stanford Neuromodulation Therapy: accelerated high-dose iTBS with individualized fMRI-guided targeting of each patient's DLPFC-subgenual cingulate circuit; 29 treatment-resistant depression patients (14 active, 15 sham).
- Mean MADRS reduction at four weeks: 52.5% with active treatment versus 11.1% with sham.
- Landmark precedent that individualizing treatment — here the spatial target — transforms the efficacy of the same underlying TMS hardware.
- Complementary to MeRT's approach: SNT personalizes where to stimulate; MeRT personalizes the pulse frequency delivered. Both reject one-size-fits-all protocols.
Novel method for identification of individualized resonant frequencies for treatment of Major Depressive Disorder (MDD) using repetitive Transcranial Magnetic Stimulation (rTMS): A proof-of-concept study
Date published
September 2021
Publication
Brain Stimulation
Authors
Leuchter AF, Wilson AC, Vince-Cruz N, Corlier J
Key Takeaways
- Proof-of-concept in 35 patients with depression: an rTMS-EEG 'interrogation' paradigm probed 71 stimulation frequencies from 3–17 Hz to locate each individual brain's resonant frequencies.
- Resonance measures were significantly associated with baseline symptom severity (p<0.0004) and with clinical improvement after ten 10 Hz treatments (p=0.04).
- Patients whose brains ranked 10 Hz highly as a resonant frequency had better outcomes from 10 Hz treatment.
- Direct experimental support for identifying individualized treatment frequencies rather than assuming one universal rate — the premise MeRT operationalizes at scale.
Frequency- and Area-Specific Phase Entrainment of Intrinsic Cortical Oscillations by Repetitive Transcranial Magnetic Stimulation
Date published
March 2021
Publication
Frontiers in Human Neuroscience
Authors
Okazaki YO, Nakagawa Y, Mizuno Y, Hanakawa T, Kitajo K
Key Takeaways
- Combined TMS-EEG study applying single-pulse and rhythmic TMS at 5, 11, and 23 Hz over motor and visual cortex.
- Each cortical area entrained best near its own natural frequency (motor ~21 Hz; visual ~8 Hz); entrainment outlasted stimulation and propagated through large-scale networks at the corresponding frequency.
- Mechanistic basis for frequency-matching: stimulation moves network dynamics most effectively when its rate matches the target circuit's intrinsic rhythm.
- The authors propose such frequency-tuned rTMS 'could be used to treat clinical symptoms associated with impaired oscillations and synchrony.'
Individual alpha frequency proximity associated with repetitive transcranial magnetic stimulation outcome: An independent replication study from the ICON-DB consortium
Date published
February 2021
Publication
Clinical Neurophysiology
Authors
Roelofs CL, Krepel N, Corlier J, Carpenter LL, Fitzgerald PB, Daskalakis ZJ, Tendolkar I, Wilson A, Downar J, Bailey NW, Blumberger DM, Vila-Rodriguez F, Leuchter AF, Arns M
Key Takeaways
- Independent multi-site replication by the international ICON-DB consortium: 153 patients with major depressive disorder (59 treated with 10 Hz left-DLPFC rTMS, 94 with 1 Hz right-DLPFC).
- Replicated the core finding: distance between individual alpha frequency and 10 Hz correlated negatively with symptom improvement — only in the 10 Hz group.
- Curve fitting revealed a quadratic association peaking at IAF = 10 Hz: the closer the brain's rhythm to the stimulation rate, the better the outcome, in a nonlinear fashion.
- Replication across independent sites and datasets makes frequency-to-rhythm proximity one of the better-replicated predictive biomarkers in TMS.