Subthreshold Priming Associated with Improved Outcomes in rTMS for MDD - UCLA Neuromodulation
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Semel Institute
AUGUST 2021 / ISSUE 6
PULSE
A Monthly Update on Advances in Neuromodulation
Produced by the Neuromodulation Division of the Semel Institute at UCLA
Andrew F Leuchter, MD, Editor-in-Chief IN THIS ISSUE:
Collin M. Price, MD, Managing Editor
Subthreshold Priming Associated with Improved TMS Updates
Subthreshold Priming Associated
Outcomes in rTMS for MDD with Improved Outcomes in rTMS for
Joseph Kaizer, MD reviewing Lee JC et al. Brain Stim 2021 MDD
Acute Improvements Found with
In this retrospective review of patients who underwent iTBS priming rTMS for Cocaine Use Disorder
before undergoing rTMS, those who received subthreshold intensity
therapy showed superior clinical outcomes compared with those who rTMS May Be Less Affected by
received suprathreshold therapy. Borderline Personality Traits than
ECT
Repetitive Transcranial Magnetic Stimulation (rTMS) directed at the
dorsolateral prefrontal cortex (DLPFC) is an effective treatment for
Innovative Technology
major depressive disorder (MDD). When predicting the efficacy of
Improved Negative Symptoms in
rTMS, initial response to high-frequency left-sided (HFL) stimulation of
Schizophrenia with High-Frequency
the DLPFC is an important indicator of long-term outcomes. When
Transcranial Random Noise
patients show no early signs of benefiting from HFL stimulation of the
Stimulation
DLPFC, intermittent theta-burst stimulation priming (iTBS-P) can
improve clinical efficacy. However, it has yet to be determined how the
intensity of the priming stimulus and number of priming pulses affects
clinical outcomes. Are intensity and pulse number of iTBS-P before
rTMS associated with improved response?
1
Semel Institute
Researchers at UCLA conducted a pulse number (< or > 1200 pulses), using suprathreshold group (775 vs. 962,
retrospective review of 71 patients the mean for each across a participant’s p=0.022) and had significantly lower IDS-
diagnosed with MDD who received iTBS- priming sessions. A linear model was fit SR scores at treatment #30 (24.6 vs.
P augmentation after receiving at least to the data, with change in IDS-SR as the 32.6), though there was not a statistically
five sessions of HFL and showing little primary outcome variable, and intensity significant difference between groups in
clinical benefit. Weekly self-ratings on the (subthreshold or suprathreshold), number response (33% vs. 18%) or remission
Inventory of Depressive Symptomatology of pulses (1200), gender, age, (19% vs. 5%) rates. All patients offered
Self Report (IDS-SR) were obtained after and the number of iTBS-P treatments as iTBS-P elected to proceed with the
every five treatments to direct treatment predictors. augmentation strategy, and no subjects
parameters. All patients received a total were forced to discontinue therapy due to
of 30 HFL rTMS treatments to the left Fifty-nine participants (83%) received 10 adverse effects.
DLPFC. iTBS-P augmentation was or more sessions of HFL stimulation prior
Impact: The findings here suggest a
offered to most patients after 10 to being offered priming augmentation.
superior response to iTBS-priming of
treatments if IDS-SR scores indicated The mean number of iTBS-P sessions
rTMS treatment when exposed to
100% MT) and fewer pulses compared to the
Lee JC, Corlier J, Wilson AC, et al. Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder. Brain Stimul. 2021;14(4):1015-1021.
doi:10.1016/j.brs.2021.06.008
Acute Improvements Found with rTMS for Cocaine Use Disorder
Collin M. Price, MD reviewing Garza-Villarreal et al. Biol Psychiatry Cogn Neurosci Neuroimaging 2021
A 2-week randomized, double-blind, sham-controlled study of rTMS in cocaine use disorder yielded significant
reductions in cravings and impulsivity, though these effects were not fully maintained during a subsequent 6 month
open-label phase.
There are few effective treatments for year. The study designed involved two and included clinical outcomes as well as
most substance use disorders (SUD), with phases: an acute phase, which was a structural and functional magnetic
disorders associated with stimulants such double-blind, parallel-group, two-week resonance imaging (MRI) data. Primary
as cocaine proving particularly difficult to randomized controlled trial; and a outcomes measures were craving
treat. As repetitive transcranial magnetic maintenance phase, which was a 6- (measured via visual analog scale [VAS]
stimulation (rTMS) has shown month open-label trial. rTMS was and questionnaire) and cocaine-positive
effectiveness in a variety of psychiatric delivered at 100% of motor threshold to urine, with secondary outcomes
conditions, interest has grown in applying the left dorsolateral prefrontal cortex (l- including impulsivity, depression,
this novel treatment to SUD. Can the DLPFC). During the acute phase, anxiety, and sleep quality. A modified
addition of rTMS to standard treatment of treatments were given once-daily, 5 Timeline Followback method was used to
cocaine use disorder (CUD) improve days a week, for two weeks, with 5000 assess self-reported frequency and
treatment outcomes? pulses delivered per day at 5 Hz. During amount of cocaine use. MRI data was
the maintenance phase, similar used to analyze resting-state functional
Researchers recruited 44 participants who sessions were delivered two times per connectivity (rs-FC) between l-DLFPC
were identified as having high- week. Data were acquired at baseline, 2 and ventromedial prefrontal cortex
consumption of cocaine for at least one weeks, 3 months, and 6 months, (vmPFC).
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After the 2-week acute phase, active showed significant reductions from
Impact: This study provides RCT-level
rTMS was more effective than sham at baseline at 3 months, but not 6 months
evidence of effectiveness for 5-Hz rTMS to
reducing cravings based on VAS (pSemel Institute
Impact: ECT and rTMS are both effective treatment options for treatment-resistant depression.However, while the efficacy of ECT is
generally diminished in the presence of co-morbid BPD, this large-sample study suggests that rTMS has similar efficacy regardless
of the presence of BPD traits. This result, while not conclusive given its retrospective naturalistic nature, suggests that further study
may more conclusively demonstrate the efficacy of rTMS in depression with co-morbid BPD, and possibly other personality
disorders.
Ward HB, Yip A, Siddiqui R, Morales OG, Seiner SJ, Siddiqi SH. Borderline personality traits do not influence response to TMS. J Affect Disord. 2021;281:834-838. doi:10.1016/j.jad.2020.11.054
Improved Negative Symptoms in Schizophrenia with High-Frequency Transcranial
Random Noise Stimulation
Collin M. Price, MD reviewing Chang et al. J Psychiatr Res 2021
In a double-blind, randomized, sham-controlled study, high-frequency transcranial random noise stimulation targeted to the
prefrontal cortex led to significant improvements in the negative symptoms of schizophrenia. Effect sizes were large, and
improvements persisted up to one-month.
The negative symptoms associated with a 4x1 configuration, with the single anode group, at all timepoints (-17.11 % vs.
schizophrenia are notoriously difficult to placed over 10-10 EEG-position AF3 (left -1.68 % at end-of-treatment; -16.47 % vs.
treat, though various neuromodulatory lateral prefrontal cortex), while the four -0.10 at 1 week; and -16.82 % vs. -0.15
techniques have shown some promise in cathodes were placed over positions AF4, % at 1 month). The end-of-treatment
recent years. One such technique, high- F2, F6, and FC4 (right lateral prefrontal effect sizes for active hf-tRNS were large
frequency transcranial random noise cortex). Active hf-tRNS was delivered for PANSS-FSNS (Cohen’s d = 2.16) and
stimulation (hf-tRNS), utilizes alternating using a variable intensity between -1mA PANSS-Total (d=1.69). Active treatment
current stimulation delivered in a and 3mA, with a variable frequency also showed improvements in awareness
randomized pattern at varying intensities between 100 to 640 Hz, for 20min each of negative symptoms (d=1.37),
and frequencies. Such stimulation is treatment including a 15s ramp-in/ramp- subjective response to taking medication
hypothesized to optimize signal-to-noise out. Sham hf-tRNS involved 40s of 2mA (d=1.85), and extrapyramidal symptoms
ratios in affected neural networks, and stimulation followed by a 110microA, severity (d=1.26). Negative symptoms
has been shown to improve cognitive 15ms pulse delivered at a frequency of awareness showed persistent
tasks as well as symptoms of 1.81 Hz for 20min. The primary outcome improvements at 1 month. Blinding
schizophrenia in limited case reports. Can was the change over time in the PANSS assessments indicated adequate blinding,
hf-tRNS improve the negative symptoms Factor Score for Negative Symptoms and no significant difference was noted in
of schizophrenia in a randomized (PANSS-FSNS) between baseline and mean total side effect score.
controlled trial? end-of-treatment (10 sessions), one-week
follow-up, and one-month follow-up.
Researchers in Taipei, Taiwan recruited Response rates, tolerability, and cognitive Impact: This randomized, double-blind,
36 participants to take part in a measures were among the secondary sham-controlled study shows that hf-
randomized, double-blind, sham- outcome measures. Data were analyzed tRNS can provide rapid and enduring
controlled study of hf-tRNS. Participants in an intention-to-treat analysis, using improvements in the negative
were included if they carried a diagnosis Bonferroni correction for multiple symptoms of schizophrenia. Although
results were modest in absolute terms,
of schizophrenia or schizoaffective comparisons.
effect sizes were large. With a paucity
disorder, were stable on an antipsychotic,
of effective treatments for negative
and had a Positive and Negative Thirty-five participants completed the
symptoms in schizophrenia, positive
Syndrome Scale (PANSS)-Total 2h between each FSNS was significantly greater in the technology.
treatment. Five electrodes were placed in treatment group compared to the sham
Chang CC, Lin YY, Tzeng NS, Kao YC, Chang HA. Adjunct high-frequency transcranial random noise stimulation over the lateral prefrontal cortex improves negative symptoms of schizophrenia: A randomized, double-
blind, sham-controlled pilot study. J Psychiatr Res. 2021;132:151-160. doi:10.1016/j.jpsychires.2020.10.008
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