Title: Accelerated Theta Burst rTMS Treatment of Depression: A Case Report
Authors: Kyle Jiganti, OMS3; Dr. Kris Peterson, MD; Jerry DeVore, PhD
Background
The goal of our study was to demonstrate the clinical replicability of the Stanford Neuromodulation Therapy (SNT) in treating treatment resistant depression, and to maintain this effect with continued theta burst treatments.
Methods
One patient (identified as Case Study 1 or CS-1) with treatment resistant Major Depressive Disorder (MDD) who had minimal response to 44 treatments of repetitive transcranial magnetic stimulation (rTMS) was recruited to participate in the accelerated theta burst protocol. Her MADRS, PHQ-9 and GAD-7 were recorded pretreatment, each day of treatment, and each week following completion of the SNT protocol. Location of the treatment area, the dorsolateral prefrontal cortex (DLPFC), was found using the EEG measurements marked on a 10-20 cap. One week prior to treatment an EEG was obtained using a 19 channel recorder (Neurofield Q21). The rTMS machine used was the MagVenture Magpro. The patient was treated with 900 trains of intermittent theta burst stimulation (iTBS) at 90% of her motor threshold (aprox. 10 minutes) 50 minutes apart, 10 times per day for 5 days, totalling 50 sessions. Repeat EEG was completed one week post treatment. The patient continued weekly maintenance treatment sessions of 900 trains of iTBS TMS for 8 weeks post treatment in order to maintain treatment effect.
Results
Initial and post MADRS scores were 46 and 12, respectively. 6 weeks out the MADRS score was 11. Initial PHQ-9 and GAD-7 scores were 19 and 16, respectively. 6 weeks out PHQ-9 was 12 and GAD-7 was 9. EEG results initially showed frontal slowing in the 8 and 9Hz frequency bins, greater than 2 standard deviations (SD) for 9Hz and greater than 3 SD in the 8Hz bin. At post treatment the 8Hz bins were within normal limits and the 9Hz bins showed fewer 10/20 sites above normal.
Conclusions
The SNT protocol with continued weekly maintenance treatments is applicable in a clinical setting to treat TMS resistant MDD and maintain effect. EEG findings help to support the clinical and self reported observations reflected in the MADRS, PHQ-9 and GAD-7 scores.
I am one of the judges for your case, it was very interesting, but I was wondering why you think the intensive (10x/day x 5 days) treatment would have a different effect when she had failed the previous treatment regimen (5x/week for 36 sessions)?
Excellent question Dr Callan. I will not be able to give an exact justification for this, but can make inferences based on our current understanding of the new protocol, TMS and basic neuroscience. The original 2020 SNT study included TMS non-responders as well as TMS naive subjects (1). They included in their analysis the gradual increase in scores of previous TMS patients compared to the naive patients following the 5 day protocol (Slide 4, 1:50). This is part of the reason why we wanted to continue maintenance treatment with our patient.
Neurologically, the justification for shorter intervals between treatment is to cause more consistent activation in these brain regions. Previous studies have found that cortical activation persists following short iTBS sessions, and that multiple sessions per day is correlated with clinical improvement (2). An important caveat is that duration of stimulation and spacing is important. Once cortical activation is achieved, persistent stimulation is not warranted, much like starting an engine and keeping the key turned. Once this activation occurs, it strongly persists for 10 minutes following cessation of stimulation, and fades by 47 minutes (3). As this activation is occurring, perineuronal nets will surround the synapses to strengthen these new connections, a process which takes 40-90 minutes (4). Our goal then is to activate this pathway, let it run, and allow it to create strengthened connections. Therefore, patients who fail traditional protocols may have been unable to have this lasting activation that is required to create sufficient connections between the DLPFC and the ACC. Further studies are attempting to answer this question more precisely, but for now it is not exactly known.
Increasing the dose of an SSRI is appropriate management if a patient is initially non-responsive. We see this as (somewhat) analogous.
1.
Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M., Cherian, K., Tischler, C., … & Williams, N. R. (2020). Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. American Journal of Psychiatry, 177(8), 716-726.
2.
Goldsworthy, M. R., Pitcher, J. B., & Ridding, M. C. (2012). The application of spaced theta burst protocols induces long‐lasting neuroplastic changes in the human motor cortex. European Journal of Neuroscience, 35(1), 125-134.
3.
Thomson, A. C., de Graaf, T. A., Kenis, G., Rutten, B. P., Schuhmann, T., & Sack, A. T. (2019). No additive meta plasticity effects of accelerated iTBS with short inter-session intervals. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 12(5), 1301-1303.
4.
Smolen, P., Zhang, Y., & Byrne, J. H. (2016). The right time to learn: mechanisms and optimization of spaced learning. Nature Reviews Neuroscience, 17(2), 77-88.
Judge: How would you design a randomized clinical trial with a placebo to test the efficacy of this treatment? Why did the MADRs score improve (clinician score) but the patient score did not improve? Is there any bias in this result?
Dr. Novak, you bring up some interesting points. Current standard for placebo in TMS is with sham treatments. Because the magnetic field is being applied deep to the skull, superficial nerves are also hit, causing a sensation like getting tapped on the head (moderately hard). Sham coils are designed in a way that reproduces this sensation, but the magnetic field does not penetrate past the skull to illicit cortical excitation.
A randomized clinical trial would consist of patients with a current diagnosis of treatment resistant major depressive disorder being randomized to a sham and active group. Patients would still receive EEGs pre and post treatment. By looking at the EEG and behavioral results from this study we would be able to determine if this treatment is efficacious against the sham treatment. The limitations, however, are finding a homogenous group of patients that don’t have confounding factors such as other psychiatric diagnoses and medication regimens.
Because we are doing the MADRS there is inherent bias. Ideally the MADRS is performed by trained individuals that you can hire for your study, but we did not have access to this service. The difference in the scores could be due to the fact that the MADRS is a qualitative metric while the PHQ9 and GAD7 are quantitative, asking how often you feel symptoms, not the severity to which you experience them. However, a closer look at our data indeed shows a significant difference.
The patient continues maintenance treatment to this day, 5 months after the 5 day protocol, with her MADRS, PHQ9 and GAD7 scores on 3/31/22 being 17, 10 and 9, respectively. While these scores are not remission, they are on average persistently lower than her pre accelerated treatment scores. For her initial, 44 session treatment course, her average scores were PHQ9: 21.6 (stdv: 1.6) and GAD7: 18.1 (stdv: 2.4) while her average, post accelerated TMS protocol scores are PHQ9: 12.5 (2.6) and GAD7: 9.2 (stdv: 2.6). Running a paired T-test for both PHQ9 and GAD7, pre and post treatment, yields P<0.001. Unfortunately I am unable to run a T-test on MADRS as we do not have multiple pre-treatment data points.
I greatly appreciate your critique as the way I initially presented the data makes it seem like the change in PHQ9 and GAD7 were not statistically significant.
Novack* I apologize for neglecting to add the silent c. Or is it the K that is silent? Food for thought.
Judge: What are the implications of this case for rural health and healthcare technology?
Jennifer that is an interesting question. At this clinic, and others where I have worked, it is not abnormal to see patients who drive over an hour each way to their daily TMS appointments. Commuting like this can be difficult, especially for those with barriers to transportation. A 5 day commitment for this protocol with once weekly follow ups would be easier for patients living further from a TMS clinic. Additionally, several companies are working on devices that can be taken home. The possible application of this is that a patient completes the accelerated TMS protocol in the office and is able to continue maintenance treatment from their home without having to commute.
One clinic I’ve worked with has explored the idea of a mobile TMS clinic, which would be able to travel to more rural areas to provide this care.
It will still be some time before TMS is more readily available in rural areas, but interventions such as these will confer a better outcome, and ideally a decreased burden of time on the patient before an effect is recognized (usually around visit ~18 with the traditional protocol, which is ~4 weeks of treatment).
Thank you for the thought provoking question!