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BACKGROUND
Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility...
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Citations
... With an advantageous side effect profile over medication, response rates have been estimated to be as high as 25-35% [5,8]. Unfortunately, rTMS is burdened by several limitations that decreases accessibility, such as high equipment costs, complexity of technical operation, and the need for daily sessions over several weeks [9]. This reinforces the need for careful patient selection to maximize treatment outcomes and avoid futile treatment courses. ...
Treatment resistant depression is challenging because patients who fail their initial treatments often do not respond to subsequent trials and their course of illness is frequently marked by chronic depression. Repetitive transcranial magnetic stimulation (rTMS) is a well-established treatment alternative, but there are several limitations that decreases accessibility. Identifying biomarkers that can help clinicians to reliably predict response to rTMS is therefore necessary. Allostatic load (AL), which represents the ‘wear and tear’ on the body and brain which accumulates as an individual is exposed to chronic stress could be an interesting staging model for TRD and help predict rTMS treatment response. We propose an open study which aims to test whether patients with a lower pre-treatment AL will have a stronger antidepressant response to 4 week-rTMS treatment. We will also assess the relation between healthy lifestyle behaviors, AL, and rTMS treatment response. Blood samples for AL parameters will be collected before the treatment. The AL indices will summarize neuroendocrine (cortisol, Dehydroepiandrosterone), immune (CRP, fibrinogen, ferritin), metabolic (glycosylated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, uric acid, body mass index, waist circumference), and cardiovascular (heart rate, systolic and diastolic blood pressure) functioning. Mood assessment (Montgomery-Åsberg Depression Rating Scale and Inventory of Depressive symptomatology) will be measured before the treatment and at two-week intervals up to 4 weeks. With the help of different lifestyle questionnaires, a healthy lifestyle index (i.e., a single score based on lifestyle factors) will be created. We will use linear and logistic regressions to assess AL in relation to changes in mood score. Hierarchical regression will be done in order to assess the association between AL, healthy lifestyle index and mood score. Long-lasting and unsuccessful antidepressant trials may increase the chance of not responding to future trials of antidepressants and it can therefore increase treatment resistance. It is essential to identify reliable biomarkers that can predict treatment responses.
... With an advantageous side effect profile over medication, response and remission rates have been estimated to be as high as 40-60% and 25-35%, respectively, in recent meta-analyses . Unfortunately, rTMS is burdened by several limitations that decreases accessibility (Miron et al., 2021a(Miron et al., , 2021b(Miron et al., , 2020: equipment costs are high, technical operation complex, and treatment courses lengthy, requiring daily sessions over several weeks. This reinforces the need for careful patient selection to maximize treatment outcomes and avoid futile treatment courses. ...
... The use of HRV for response prediction to rTMS in MDD has not been well studied. We therefore assessed the role of pre-treatment (baseline) resting HRV in MDD participants who received an accelerated rTMS (arTMS) course of 1 Hz stimulation delivered to the right DLPFC over a 5-day period (Miron et al., 2021a). We hypothesized that higher pre-treatment HRV would be associated with greater improvement. ...
... We conducted a prospective, single-arm, open-label feasibility study in N = 30 participants; complete methods are described elsewhere (Miron et al., 2021a). In brief, adult outpatients age 18-85 were included for study participation if they 1) had a Mini International Neuropsychiatric Interview (MINI) confirmed MDD diagnosis (single or recurrent episode) and 2) maintained a stable medication regimen from 4 weeks before treatment start to the end of the study. ...
BACKGROUND
Major depressive disorder (MDD) is now the first cause of disability worldwide. So far, no validated and scalable biomarker has been identified to help with response prediction to antidepressant treatment. Cardiac biomarkers such as heart rate variability (HRV) have been studied in MDD, but few studies have examined its potential use for outcome prediction to repetitive transcranial magnetic stimulation (rTMS).
OBJECTIVE
We recorded pre-treatment HRV in MDD participants prior to an rTMS course. We hypothesized that higher pre-treatment HRV would be correlated with better clinical outcomes.
METHODS
HRV was recorded as part of a single-arm, open-label rTMS feasibility study. Pre-treatment HRV was assessed in N = 30 MDD participants before they underwent a one-week (5 days, 8 daily sessions, 40 sessions total) accelerated rTMS (arTMS) course using a low-frequency 1 Hz course (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex at 120% of the resting motor threshold. Clinical outcomes were captured using the Beck Depression Inventory-II (BDI-II). We tested for an association between pre-treatment HRV and clinical outcomes on the BDI-II using a linear mixed effects model.
RESULTS
Although average BDI-II score significantly changed over time, these changes were not significantly associated with pre-treatment HRV (p = 0.60). This finding remained when adjusting for age, sex, and HR, individually and collectively.
CONCLUSION
The current study did not find a relationship between pre-treatment HRV and response to low frequency rTMS. Other approaches using cardiac biomarkers may have potential for response prediction.
... Given that increased number of pulses has been associated with increased response in 1 Hz rTMS in some studies (Marcelo T Marcelo T M T Berlim et al., 2012), it may be advantageous to increase the number of pulses within the same time frame (e.g., 600 pulses in 10 min). We recently reported on such a protocol with some degree of success (Miron et al., 2021). Still, our limited effectiveness could be seen as in opposition to our message of increased scalability. ...
Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation
(rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS
techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and
custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per
session), delivered on the most affordable FDA-approved device. MDD participants received an initial
accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of
daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II
(BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course.
No serious adverse events occurred, and all patients reported manageable pain levels. Response and
remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course.
Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our
protocol will require further improvements, some of the concepts we introduced here could help guide the
design of future trials aiming at increasing accessibility to rTMS.
This study was initiated to establish whether spatio-spectral Eigen-modes of EEG brain waves can be described by an Acoustic Quantum Code of Resonant Coherence, as found by us earlier in a spectrum of animate and inanimate systems. Presently available EEG-and MEG recordings were analyzed as to their peak frequencies in relation to our Quantum Code coherence values. Both the EEG-and MEG studies of healthy persons exhibited quantum coherence of EEG peaks with mean quantum coherence of 0.95 (an average of 90-100% showed coherent peak values), while in patient groups with various mental disorders, a significant decrease of coherence correlation was found. ADHD subjects show a moderate change in peak coherence, being in the range of 1.0 to 0.83, while during epileptic seizures the degree of peak coherence is reduced to a range of 0.94 to 0.75. Depressed patients have EEG peaks with a consistently lower coherence values than healthy persons: 0.77-0.88, while autistic persons show an even lower coherence of 0.50 till 0.75. Patients with severe psychiatric disorders, such as depression, show a coherence of only 0.49-0.61. The importance of EEG brain coherence for conscious states was demonstrated in patients under anaesthesia that exhibited a very low coherence level of about 0.25. The graded loss of brain EEG coherence combined with alterations in Phi based EEG wave separation, can therefore be of value for differentiation in severity and nature of neurological disorders. The value of our frequency algorithm was also shown for trans-cranial therapy: the presently chosen frequencies of rTMS therapy in clinical practice correspond very well with the values of our algorithm. Of interest, the Acoustic Quantum Code pattern was also shown to describe neuronal microtubular (MT) wave frequencies, as measured in vitro by others. MT oscillations were claimed by Hameroff and Penrose to be instrumental in the creation of brain consciousness through alignment with gravity fluctuation at the Planck scale. Our results on brain EEG coherence are therefore discussed in relation to the current models for understanding the nature of (self)-consciousness. We regard the potential relation between neuronal coherence/decoherence balance and conscious states as a central mechanism for producing quantum entanglement in the brain as related to long-distance neuro-communication and brain binding. As postulated earlier, consciousness can be modelled by a 5D brain-associated, toroidal workspace, that provides quality control and monitoring of integral brain function, according to holographic principles and was earlier framed as the "Event Horizon Brain". Consciousness, in this concept, requires photon/phonon mediated and resonant communication with this field-receptive holographic workspace, seen as associated with but not reducible to the human brain. The related brain supervening role of the event horizon workspace requires the collective conscious and unconscious states and realizes a total holographic modality of consciousness that enables effective predictive coding. This 5D, scale invariant, memory workspace, therefore, can be instrumental in the manifestation of Psi phenomena and experiences of cosmic consciousness. At the sub-atomic level, gravity guided quantum tunnelling and coherence of micro-tubular oscillations may produce neuronal entanglement. The latter represents a dominant factor in long distance neural information transfer and functional brain binding. The resulting synchronization of neural network frequencies is likely reflected in the abovementioned brain coherency of EEG peaks, as well as in various mental states that promote feelings of mental wholeness in meditation and psycho-drug therapy. 2
Background
Accelerated transcranial magnetic stimulation (aTMS) is an emerging delivery schedule of repetitive TMS (rTMS). TMS is “accelerated” by applying two or more stimulation sessions within a day. This three-part review comprehensively reports the safety/tolerability, efficacy, and stimulation parameters affecting response across disorders.
Methods
We used the PubMed database to identify studies administering aTMS, which we defined as applying at least two rTMS sessions within one day.
Results
Our targeted literature search identified 85 aTMS studies across 18 diagnostic and healthy control groups published from July 2001 to June 2022. Excluding overlapping populations, 63 studies delivered 43,873 aTMS sessions using low frequency, high frequency, and theta burst stimulation in 1543 participants. Regarding safety, aTMS studies had similar seizure and side effect incidence rates to those reported for once daily rTMS. One seizure was reported from aTMS (0.0023% of aTMS sessions, compared with 0.0075% in once daily rTMS). The most common side effects were acute headache (28.4%), fatigue (8.6%), and scalp discomfort (8.3%), with all others under 5%. We evaluated aTMS efficacy in 23 depression studies (the condition with the most studies), finding an average response rate of 42.4% and remission rate of 28.4% (range = 0–90.5% for both). Regarding parameters, aTMS studies ranged from 2 to 10 sessions per day over 2–30 treatment days, 10–640 min between sessions, and a total of 9–104 total accelerated TMS sessions per participant (including tapering sessions). Qualitatively, response rate tends to be higher with an increasing number of sessions per day, total sessions, and total pulses.
Discussion
The literature to date suggests that aTMS is safe and well-tolerated across conditions. Taken together, these early studies suggest potential effectiveness even in highly treatment refractory conditions with the added potential to reduce patient burden while also expediting response time. Future studies are warranted to systematically investigate how key aTMS parameters affect treatment outcome and durability.
