Closed-loop Geoptimaliseerde rTMS voor depressie
Gerandomiseerde, cross-over, placebo-gecontroleerde studie om doelbetrokkenheid en dosisrespons van geoptimaliseerde closed-loop rTMS voor medicatieresistente depressie te bepalen
Targeted and individualized treatments for mental health disorders are critically needed. Repetitive transcranial magnetic stimulation (rTMS) represents the front-line of new and innovative approaches to normalizing dysfunctional brain networks in those with mental illness. rTMS is FDA-approved for depression and obsessive-compulsive disorder with clinical trials underway for PTSD and addiction, among others. However, remission rates are suboptimal and ideal stimulation parameters are unknown. We recently completed a randomized, double blind clinical trial and a depression severity biomarker that predicts clinical outcome. The overarching goal of this study is to develop the first broadly generalizable platform for real-time biomarker monitoring and personalized rTMS treatment. We plan to recruit patients with medication-resistant depression and in perform a four-phase, cross-over, double-blind, placebo-controlled trial to 1) identify how standard and optimized rTMS patterns engage the depression severity biomarker, and 2) determine the dose-response of these rTMS patterns. Findings from this study will provide the basis for a double-blind, randomized clinical trial comparing rTMS optimized to the individual against standard rTMS.
Studie Overzicht
Toestand
Conditie
Interventie / Behandeling
Gedetailleerde beschrijving
Nearly 50% of all Americans will suffer from a mental health disorder during their lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), are increasingly used to normalize dysfunctional brain circuits in these disorders. Mechanistically, rTMS is thought to work by changing the synaptic strength of neurons, referred to as brain plasticity. Despite the variety of disorders targeted and significant between-patient heterogeneity, rTMS is currently applied in a manner that is one-size-fits-all (without any individual optimization of the stimulation pattern) and open-loop (fixed schedule of stimulation pattern, with no measurement or adjustment during rTMS). We believe that the response rate of rTMS for depression, which is at present <50%, can be improved through personalized brain stimulation that enhances target engagement and maximizes plasticity. To personalize brain stimulation, one must (1) measure and monitor brain changes in real-time; (2) determine the optimal stimulation patterns for inducing brain changes; (3) develop adaptive treatments to drive desired changes on an individual patient-specific level over time. Such personalization of brain stimulation will increase our mechanistic understanding of brain plasticity to improve efficacy in non-responders to standard treatments.
The primary goals of my research program are to (1) discover brain biomarkers that predict progression to clinical remission, and (2) develop closed-loop treatment algorithms that optimize these biomarkers and improve clinical outcomes. We will focus on depression as it is the leading cause of disability worldwide and and medications are ineffective or not tolerated for close to half of these patients. Leveraging my previous work, we propose three stages of development of personalized brain stimulation using single pulses of TMS combined with electroencephalography (TMS-EEG) to generate a causal measurement of brain state that can easily be translated to the clinic. The TMS-EEG depression severity biomarker that I recently discovered occurs 30 milliseconds after administering a TMS test pulse (p30) in the fronto-parietal network (FPN), a region implicated in depression. The degree of suppression of this p30 signal predicted clinical outcome in depressed patients following rTMS treatment. Additionally, a single stimulation session was sufficient to suppress the p30 during and for 30 minutes after stimulation. This work indicates that p30 suppression can be monitored in real-time and has the potential to support empiric treatment optimization.
Findings from this study will provide the basis for a double-blind, randomized clinical trial of closed-loop rTMS against standard rTMS.
Studietype
Inschrijving (Werkelijk)
Fase
- Fase 1
Contacten en locaties
Studie Locaties
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California
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Stanford, California, Verenigde Staten, 94305
- Stanford University
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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
Inclusion Criteria:
- Men and women, ages 18 to 65
- Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales
- Right-handed
- No current or history of neurological disorders
- No seizure disorder or risk of seizures
- No use of PRN medication within 48 hours of the scheduled study appointment
Exclusion Criteria:
- Those with a contraindication for MRIs (e.g. implanted metal)
- Any unstable medical condition
- History of head trauma with loss of consciousness
- History of seizures
- Neurological or uncontrolled medical disease
- Active substance abuse
- Diagnosis of psychotic or bipolar disorder
- A prior history of ECT or rTMS failure
- Currently taking medications that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, lithium)
- Currently pregnant or breastfeeding
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Fundamentele wetenschap
- Toewijzing: Niet-gerandomiseerd
- Interventioneel model: Crossover-opdracht
- Masker: Enkel
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Experimenteel: Personalized rTMS
Participants received personalized rTMS using MRI-guided neuronavigation to target the dorsolateral prefrontal cortex (dlPFC). Intermittent theta burst stimulation (iTBS) consisted of 600 pulses delivered over approximately 3.5 minutes at 110% of the participant's resting motor threshold. Participants were monitored throughout each stimulation session for adverse events and side effects. |
Delivers patterned magnetic stimulation using MRI-guided neuronavigation. |
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Experimenteel: Sham rTMS
Participants may receive sham rTMS using MRI-guided neuronavigation in a crossover design. Sham stimulation was designed to mimic active stimulation while maintaining participant blinding. Participants were monitored throughout each stimulation session for adverse events and side effects. |
Delivers placebo magnetic stimulation |
Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
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Change in Early-local TMS-evoked Potential (EL-TEP)
Tijdsspanne: Baseline: ~1 hour before first intervention; Pre-intervention: ~1-15 min before first TBS; Post-intervention: ~1-15 min after last TBS, ~100 min after first TBS.
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TMS-EEG was used to measure the peak-to-peak amplitude of the TMS-evoked potential between 20-60 milliseconds after single TMS pulses in the left frontoparietal region. Changes in the TMS-evoked EEG response were quantified in decibels (dB) relative to baseline. Measurements were obtained before and after the rTMS intervention to assess neurophysiologic changes associated with target engagement. |
Baseline: ~1 hour before first intervention; Pre-intervention: ~1-15 min before first TBS; Post-intervention: ~1-15 min after last TBS, ~100 min after first TBS.
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Medewerkers en onderzoekers
Sponsor
Medewerkers
Studie record data
Bestudeer belangrijke data
Studie start (Werkelijk)
Primaire voltooiing (Werkelijk)
Studie voltooiing (Werkelijk)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Werkelijk)
Updates van studierecords
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Laatste update ingediend die voldeed aan QC-criteria
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Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- 60980-1
- R01MH126639 (Subsidie/contract van de Amerikaanse NIH)
Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
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