TMS FOR THE TREATMENT OF INSOMNIA - UCLA Neuromodulation
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Semel Institute
APRIL 2021 / ISSUE 2
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:
Katharine G Marder, MD, Managing Editor
TMS Updates
TMS FOR THE TREATMENT OF INSOMNIA TMS for the Treatment of Insomnia
TMS for the Treatment of Depression
Emily Wood, MD, PhD reviewing Sun et al. Sleep Med 2021 Jan
in Parkinson's Disease
In this systematic review and meta-analysis, repetitive transcranial TMS Treatment of Comorbid
magnetic stimulation (rTMS) treatment was associated with improved
sleep outcomes when compared to sham rTMS or to other treatments.
Depression and Obsessive-
Compulsive Disorder
Insomnia is highly prevalent and is associated with negative physical and From the Archives: Priming Enhances
mental health outcomes, reduced quality of life, and an economic burden the Efficacy of Low-Frequency Right-
exceeding $100 billion USD annually. Cognitive behavioral therapy for sided Stimulation for Depression
insomnia (CBTi) is the first-line treatment, followed by pharmacological
treatments, but both techniques have limitations. Repetitive transcranial
Portable Devices
magnetic stimulation (rTMS) is a safe and non-invasive neuromodulation
Trigeminal Nerve Stimulation for
strategy that can be used to increase or decrease cortical excitability;
Pediatric ADHD
insomnia patients demonstrate abnormal cortical excitability. Might rTMS
have a role in the treatment of insomnia?
Innovative Technology
Researchers searched multiple English and Chinese language databases, Bimodal Acoustic and Electrical
including Cochrane, PubMed, and others for controlled trials (cont'd.) Somatosensory Stimulation for the
Treatment of Tinnitus
1
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involving adults with primary or comorbid Pulse numbers ranged between 800 and common side effect was mild headache;
insomnia who received active rTMS 2400, and total number of sessions varied this was more common with active rTMS
compared with sham rTMS, other treatment, between 7 and 30. Based on the included versus control groups. Differences in the
or no intervention. The primary outcomes treatment arms, three different comparisons occurrence of dizziness, nausea, and
were sleep parameters as assessed by the were made: rTMS versus sham TMS, rTMS fatigue were not significantly different.
Pittsburgh Sleep Quality Index (PSQI) and versus other treatment, and other treatment
Polysomnography (PSG). Secondary with and without adjunctive rTMS.
outcome measures included other sleep- Impact: When compared to sham
related scales, sleep parameters measured In all comparisons, rTMS was associated rTMS, other treatment alone, or as an
by actigraphy, and adverse events. with superior improvement in PSQI total adjunctive, rTMS was associated with
scores and greater improvement in stage 3 significantly improved sleep as
A total of 28 studies (with 2,357 adult and REM sleep on PSG. When compared to measured by decrease in PSQI total
participants) met inclusion criteria. All were sham TMS or as an adjunctive, active rTMS score and some PSG measures.
carried out in China and published between led to greater improvement in all seven Limitations of this analysis include
2012-2019. Twenty-one studies treated subscale scores on the PSQI (sleep latency, high heterogeneity, low quality of
patients with primary insomnia; the sleep disturbance, use of hypnotics, sleep some evidence, and limited external
remaining 7 studies treated patients with quality, sleep time, sleep efficiency, and validity (all included studies were
comorbid insomnia (with anxiety, daytime dysfunction). When compared to conducted in China). The results of
depression, stroke, or drug-dependency). other treatment, rTMS was associated only this analysis are consistent with those
Most trials stimulated the dorsolateral with improvement on PSQI subscale scores of one prior meta-analysis of rTMS for
prefrontal cortex (DLPFC) with frequencies for sleep latency, sleep disturbance, and insomnia, and together suggest that
ranging from 0.5 Hz to 20 Hz (most use of hypnotics. No severe adverse effects rTMS may be a safe and effective
commonly, right DLPFC at 1 Hz). related to rTMS were reported. The most option for insomnia as monotherapy or
as an adjunctive treatment.
Sun N, He Y, Wang Z, Zou W, Liu X. The effect of repetitive transcranial magnetic stimulation for insomnia: a systematic review and meta-
analysis. Sleep Med. 2021;77:226-237 doi:10.1016/j.sleep.2020.05.020
TMS FOR THE TREATMENT OF DEPRESSION IN PARKINSON'S DISEASE
Andrew K Corse, MD reviewing Hai-jiao et al. Int J Neuroscience 2020 Jan
This meta-analysis examining the use of repetitive transcranial magnetic stimulation in patients with Parkinson’s Disease
provides evidence that rTMS can improve depression, but not motor function or cognition.
Approximately 35% of Parkinson’s "Parkinson's Disease”, “transcranial Examination (MMSE), and the Montreal
Disease (PD) patients suffer from magnetic stimulation," and "depression." Cognitive Assessment (MoCA).
persistent and treatment-resistant Included studies were randomized,
depression. Repetitive transcranial double-blinded, and placebo-controlled, The authors found that rTMS led to
magnetic stimulation (rTMS) delivered to and involved subjects with clinical significantly greater reductions in BDI
the left dorsolateral prefrontal cortex diagnoses of both idiopathic Parkinson’s scores than sham-rTMS (SMD= -0.86; 95%
(DLPFC) has proven effective for the Disease and Major Depressive Disorder. CI: -1.29 to -0.43; p
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significant difference between rTMS and
Impact: This meta-analysis demonstrates that rTMS over the left DLPFC
sham-rTMS (SMD = -0.07, CI: -0.56 to
is superior to sham—but not to SSRIs—for the treatment of depression in
0.41; p=0.68). Another two studies
patients with Parkinson’s Disease. Although rTMS is not superior to
examined MoCA scores; again, there was
SSRIs, it is a valuable treatment option in PD patients, who are generally
no significant difference between rTMS elderly and therefore vulnerable to serious side effects from SSRIs,
and sham-rTMS groups (SMD=-0.29, 95% including falls, bleeding, and hyponatremia. Contrary to previous studies,
CI : -1.43 to 0.85; p=0.62). this meta-analysis did not demonstrate that rTMS led to significant
changes in motor or neurocognitive function. Additional studies with
Hai-jiao W, Ge T, Li-na Z, et al. The efficacy of repetitive
transcranial magnetic stimulation for Parkinson disease patients greater number of participants and more standardized stimulation
with depression. International Journal of Neuroscience. 2020;
130:1, 19-27, doi: 10.1080/00207454.2018.1495632.
parameters and follow-up periods are required.
TMS TREATMENT OF COMORBID DEPRESSION AND OBSESSIVE-COMPULSIVE DISORDER
Katharine G Marder, MD reviewing Tadayonnejad R et al. Brain Stimulation 2020 Oct 13
In this case series, excitatory transcranial magnetic stimulation of left dorsolateral prefrontal cortex followed by
inhibitory stimulation of supplementary motor area led to meaningful response in both depression and OCD symptoms.
Obsessive-compulsive disorder (OCD) different psychotropic medications and partial response (20-34% reduction in
and major depressive disorder (MDD) 2.4 courses of psychotherapy. YBOCS score). Five of seven
are frequently comorbid; this Participants received 36 TMS treatment participants showed a full response of
comorbidity is associated with lower sessions of excitatory treatment at left depressive symptoms (defined as a
quality of life and higher treatment- dorsolateral prefrontal cortex (LDLPFC) >50% reduction in IDS-SR score), and
resistance. TMS is established as an with either 3,000 pulses of 10 Hz or 600 the remaining two participants showed
effective treatment for both MDD and pulses of intermittent theta burst a partial response (30-50% reduction
OCD when the conditions occur stimulation at a goal intensity of 120% in IDS-SR score). There were no
independently. Can stimulating multiple motor threshold, followed by 1,200 adverse events leading to treatment
targets in a sequential fashion pulses of 1 Hz inhibitory TMS over the discontinuation.
effectively treat comorbid MDD and bilateral supplementary motor area
OCD? (SMA) at a goal intensity of 130% motor
Impact: This study suggests a
threshold.
sequential TMS treatment
Researchers retrospectively analyzed
protocol targeting both LDLPFC
treatment outcomes of seven patients Over the course of treatment, there were
and SMA can effectively treat
with refractory and comorbid MDD and significant decreases in average YBOCS comorbid MDD and OCD. The
OCD. The participants had severe scores (from 24.2 at baseline to 12.71, results from this retrospective
symptoms, with an average baseline 47% decrease, p=0.0013) and IDS-SR case series are promising, but
Yale-Brown Obsessive Compulsive scores (from 45.1 at baseline to 19.29, should be interpreted with
Scale (Y-BOCS) score of 24.2 and an 57% decrease, p=0.0017). Five of seven caution; a larger, prospective,
average baseline Inventory of participants showed a full response of sham-controlled study of this
Depressive Symptomatology Self- OCD symptoms (defined as >35%
novel treatment approach is
warranted.
Report (IDS-SR) score of 45.1. reduction in YBOCS score), and the
Participants had on average tried 6.8 remaining two participants showed a
Tadayonnejad, R, Wilson, AC, Corlier, J et al. Sequential multi-locus transcranial magnetic stimulation for treatment of obsessive-compulsive disorder with comorbid major depression: A case series. Brain
Stimulation. 2020; 13(6): 1600-1602. doi: 10.1016/j.brs.2020.10.003.
3Semel Institute
FROM THE ARCHIVES: PRIMING ENHANCES THE EFFICACY OF LOW-FREQUENCY
RIGHT-SIDED STIMULATION FOR DEPRESSION
Michael K. Leuchter, MD reviewing Fitzgerald PB et al. Journal of Clinical Psychopharmacology 2007 September 19
This study found that administering a brief "priming" stimulation protocol prior to 1 Hz stimulation increased the efficacy of
the 1 Hz treatment for reducing symptoms of depression. This study was the first to examine the clinical use of TMS priming
in depression, and set the foundation for its use in clinical practice.
When treating major depressive disorder participants) received priming stimulation group effect was observed). There was a
(MDD) with repetitive transcranial magnetic (6 Hz, 600 pulses, 25-second inter-train trend towards higher rates of clinical
stimulation (rTMS), both high-frequency interval, 10 minutes, 90% RMT) response in the active priming group
(excitatory) stimulation to the left immediately prior to each session of 1 Hz. compared to sham group (33% vs 14% of
dorsolateral prefrontal cortex (DLPFC) and The sham group (30 participants) received participants). Stimulation site discomfort
low-frequency (inhibitory) stimulation to the the same stimulation with the coil angled and mild headache occurred in both
right DLPFC have proven effective. There is away from the scalp. Partial responders groups, and were reported in greater
a pressing clinical need to enhance the (>20% improvement) could receive an numbers in the active group, though no
efficacy of these two treatment strategies. additional 10 treatment sessions. The statistical comparison was noted. One
Some research indicates that applying high- primary outcome was the change in the patient in the active group reported
frequency (excitatory) stimulation at a low- 10-item Montgomery-Asberg Depression nausea during a single session.
intensity immediately prior to low-frequency Rating Scale (MADRS) score; secondary
(inhibitory) stimulation can “prime” the outcomes included remission and Impact: This study demonstrated
neurons and enhance their response to the response rates, and change in the Brief that an active priming protocol
subsequent low-frequency (inhibitory) train. Psychiatric Rating Scale (BPRS), Beck administered prior to 1 Hz
Can “priming” the right DLPFC in this Depression inventory (BDI), CORE stimulation of the right DLPFC was
manner enhance the efficacy of low- Assessment of Psychomotor Change, superior to a sham priming protocol
frequency, right-sided rTMS for the Global Assessment of Functioning Scale in reducing depressive symptoms.
treatment of depression? (GAF), and Clinical Global Improvement
More broadly, this pivotal study
Scale (CGI) scores. Assessments were
supported the notion that “priming”
Researchers performed a randomized, collected at baseline, 2 weeks, and 4
double-blind, sham-controlled study weeks.
a target by delivering low-intensity,
comparing the efficacy of priming stimulation high-frequency stimulation prior to
to sham priming stimulation during a course There were significantly greater reductions low-frequency stimulation can
of low-frequency right-sided TMS treatment. in MADRS score in the verum priming enhance clinical benefit. This
60 participants with treatment-resistant group compared to the sham priming important result informed the
depression were randomized to two groups: group at both week 2 (21.7 vs 7.3 percent clinical use of priming prior to low-
a priming group and a sham priming group. change, p < 0.005) and at week 4 (30.5 vs
frequency rTMS and inspired
Both groups (all participants) received 10 13.2 percent change, p < 0.05).
research into the role of priming
sessions of 1 Hz rTMS treatment to the right Secondary outcomes demonstrated similar
stimulation in other rTMS treatment
DLPFC (900 pulses, continuous, 15 minutes, trends, except for the change in CORE
110% RMT). The priming group (30 scores (a time effect was noted, though no protocols.
Fitzgerald PB, Hoy K, McQueen S, et al. Priming Stimulation Enhances the Effectiveness of Low-Frequency Right Prefrontal Cortex Transcranial Magnetic Stimulation in Major Depression. J Clin Psychopharmacol.
2008;28(1):52-58. doi:10.1097/jcp.0b013e3181603f7c
TRIGEMINAL NERVE STIMULATION FOR PEDIATRIC ADHD
Katharine Marder, MD reviewing McGough et al. J Am Acad Child Adolesc Psychiatry 2019 Apr
In this randomized, double-blinded, sham-controlled trial, non-invasive electrical stimulation with a portable device was
superior to sham for reducing ADHD symptoms in pediatric patients.
While stimulant medications are the involved in ADHD, such as the nucleus produces an electrical current to stimulate
mainstay of ADHD treatment, many tractus solitarius, locus coeruleus, the trigeminal nerve via an adhesive
patients and families prefer non- reticular activating system, anterior electrode worn on the forehead. Can
pharmacological approaches due to cingulate, and insula. Trigeminal nerve trigeminal nerve stimulation provide
concerns about side effects or social stimulation is a non-invasive clinical benefit for ADHD?
stigma. The trigeminal nerve conveys neuromodulation treatment modality in
sensory information to brain regions which a small, portable stimulator Researchers performed a randomized,
4Semel Institute
double-blinded, sham-controlled trial in which In the first week, both groups demonstrated
children aged 8 to 12 years with ADHD by improvement (with greater improvement in Impact: This study demonstrates the
DSM-5 criteria (n=62) were randomized to the active TNS group). The active group safety and efficacy of TNS in the
receive active trigeminal nerve stimulation demonstrated gradual ongoing treatment of ADHD in this age group.
(rate of 120 Hz, pulse width of 250-μs, improvement for the remainder of the trial, The effect size is similar to that of
strength of 2 to 4 milli-Amperes, and duty while the sham group did not. A significant non-stimulant medications, and the
cycle of 30 seconds on/30 seconds off) or group-by-time interaction was found. The treatment is well tolerated and
sham stimulation via identical-appearing effect size of active treatment at week 4 accepted by patients and parents. The
stimulators (the Monarch eTNS System™, was 0.50, indicating a medium effect size. Monarch eTNS System™ has since
NeuroSigma, Inc., Los Angeles CA) for 8 The number-needed-to-treat for been FDA approved as monotherapy
hours nightly over a 4-week period, followed improvement on the CGI-I scale was 3. for ADHD in patients ages 7 to 12.
by one blinded week without intervention. Quantitative EEG demonstrated increased Further study is needed to determine
The primary outcome was change in the broadband power with active TNS. Power
whether this portable device has a
clinician completed ADHD-RS Total Score; changes in right frontal and frontal midline
role in treating patients in other age
secondary outcomes included clinician- regions were significantly associated with
groups or as an adjunct to
scored CGI-Improvement (CGI-I) and several decreases in ADHD-RS scores, particularly
psychotropic medication.
parent- and teacher-completed scales. for hyperactive and impulsive symptoms.
Scales were collected weekly over the 5 The active TNS group showed increased
week study period. Participants underwent weight and blood pressure, as well as McGough JJ, Sturm A, Cowen J, et al. Double-Blind, Sham-Controlled,
Pilot Study of Trigeminal Nerve Stimulation for Attention-
quantitative electroencephalography (EEG) fatigue, headache, increased appetite, and Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry.
at baseline and weeks 1 and 4. Participants temporary skin discoloration from patch 2019;58(4):403-411.e3. doi: 10.1016/j.jaac.2018.11.013.
were randomized to active treatment (n=32) removal. There were no serious adverse
or sham (n=30). events.
BIMODAL ACOUSTIC AND ELECTRICAL SOMATOSENSORY STIMULATION FOR THE
TREATMENT OF TINNITUS
Katharine G Marder, MD reviewing Conlon B et al. Sci Transl Med. 2020 Oct 7
Approximately 10-15% of the population In this study, researchers investigated participants experienced improvement. All
suffers from chronic tinnitus, or the bimodal stimulation with the Lenire device within-arm comparisons demonstrated highly
perception of sound in the absence of an (Neuromod Devices, Dublin, Ireland) for the significant decreases in TFI and THI scores,
external stimulus. The condition can be treatment of tinnitus. A small battery- with moderate to large effect sizes (ranging
debilitating, and no adequate treatment powered stimulator electrically stimulated from -0.77 to -0.92). There was not a
options are currently available. the tongue via a wired connection to a small significant difference between the arms during
Neuromodulation offers one promising array of 32 electrodes placed on the anterior the treatment phase. Arms 1 and 2 sustained
approach. Neuromodulation strategies dorsal surface of the tongue. The same benefits out to 12 months, while arm 3 did not;
generally apply a magnetic or electrical stimulator provided acoustic stimulation via this finding was consistent with the notion that
stimulus to the brain, for example by a Bluetooth connection to a set of more synchronized stimulation (as in Arms 1
stimulating a peripheral nerve or by applying headphones. 326 participants with chronic, and 2) drives greater plasticity and therapeutic
a magnetic field or an electric current to the subjective tinnitus were randomized 1:1:1 effect. Adverse effects included increase in
scalp, in order to modulate neuronal activity. into one of three treatment arms. Each arm tinnitus symptoms, discomfort in the head, ear,
Some strategies, including electrical paired sound and tongue stimulation with or mouth, and ulceration in the mouth. There
somatosensory stimulation, achieve different frequencies, inter-stimulus delays, were no serious adverse events.
nonspecific activation of widespread areas synchronization, and tone-to-tongue
of the brain. Paired stimulation is a mapping. The volume of acoustic stimulation Impact: This is one of the largest medical
neuromodulation approach that pairs broad and the intensity of electrical tongue device trials for the treatment of tinnitus, and
electrical stimulation with a targeted input in stimulation was customized to each demonstrates that bimodal neuromodulation is
order to achieve greater activation within a participant’s sensation thresholds. In each feasible, safe, tolerable, and likely effective for
selected group of neurons. Animal studies arm, patients used the device for 60 minutes the treatment of tinnitus. A significant limitation
and pilot human studies have shown that daily for 12 weeks. The primary outcome is the absence of a sham control. A sham-
pairing sound (the targeted input) with was within-arm and between-arm change in controlled study of this novel treatment
electrical somatosensory stimulation (the the Tinnitus Handicap Inventory (THI) and approach is warranted to provide definitive
broad input) can increase plasticity within Tinnitus Functional Index (TFI), where evidence of efficacy.
the auditory system and improve tinnitus scores range from 0 (least severe)
symptoms. More synchronized stimulation to 100 (highest severity). Conlon B, Langguth B, Hamilton C, et al. Bimodal neuromodulation
combining sound and tongue stimulation reduces tinnitus symptoms in a
appears to drive greater increases in large randomized clinical study. Sci Transl Med. 2020 Oct
plasticity. Depending on the arm, 74.7 to 88.8% of 7;12(564):eabb2830. doi: 10.1126/scitranslmed.abb2830. PMID: 33028707.
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