By Debra J. Stultz, MD
Transcranial Magnetic Stimulation (TMS) is now being studied for many disorders and various symptoms and has advanced into the treatment of sleep disorders and multiple disorders associated with insomnia, such as Restless Leg Syndrome, Parkinson’s, Chronic Pain, Anxiety, and Substance Abuse. As many of our treatment resistant, depressed patients have co-existing insomnia that may have preceded their depression or could put them at a risk of relapse, attention to this symptom may improve outcomes. In addition, those with insomnia as a primary disorder may be at risk to later develop depression and even an increased risk of suicidal ideation, as reported by Suh et al. 20131, based on their 6 year follow-up study that documented two or more episodes of insomnia in non-depressed patients increases the risk of both depression and suicidal ideation. There are reports demonstrating improvement in patients with primary insomnia when treated with TMS. While studies that include both findings on depression scales and insomnia scales may not always be able to separate their findings independent of each other, they do document the need to be aware of both symptoms. The majority of studies show at least some benefit for insomnia with TMS, but there have also been reports that failed to find improvement. Documented improvement on sleep scales such as the Insomnia Severity Index2, the Pittsburgh Sleep Quality Index3, the Athens Insomnia Scale4 the Parkinson’s Disease Sleep Scale5, the International RLS-Ratings Scale6 and the Epworth Sleepiness Scale7 have been demonstrated, as well as polysomnographic evidence on PSG studies and actigraphy results with rTMS treatment.
Documented PSG and EEG improvements have been noted with rTMS treatment. He et al. 20198 suggested that disturbed intracortical excitability was responsible for insomnia and that rTMS inhibits “the hyperarousal state of the cerebral cortex, affecting metabolic activity and sleep-related hormones, and promoting hippocampal neurogenesis”. Sanchez-Escandon et al. 20149 studied 10 patients with idiopathic insomnia and EEG abnormalities. After 10 days of 1 Hz TMS for 15 minutes (900 pulses) over the left frontal and frontal-central areas, they saw an improvement in total sleep time, sleep efficiency, sleep onset latency, total wake time, and wake time after sleep onset. Their study was based on the findings of Arana-Lechuga 2011 et al.10, that suggested EEG abnormalities of sharp-wave activity with phase inversion, spikes, and left frontal/frontal-central area sharp activity are found in those with Idiopathic Insomnia.
Jiang et al. 201311 reported rTMS improved both Slow Wave Sleep and REM sleep in their comparison of CBT, rTMS, and hypnotic agents. They reported that TMS had the lowest relapse rate and was a better option for insomnia than CBT. They studied 120 patients with chronic primary insomnia with 40 patients receiving rTMS, 40 patients receiving estazolam 2 mg, and 40 patients receiving cognitive-behavioral psychotherapy focused on sleep health education, relaxation training, stimulus control therapy, sleep restriction therapy, and cognitive therapy. The patients were treated with right dorsolateral prefrontal cortex TMS at a frequency of 1 Hz and a motor threshold of 80% daily for two weeks. They followed the Pittsburgh Sleep Quality Index, a PSG, serum cortisol, adrenocorticotropic hormone, highly sensitive thyrotropin, free T3, and free T4. The Pittsburgh Sleep Quality Index changed the most in the rTMS group. The relapse and recurrence rates 3 months after rTMS were significantly better (p<0.05), rTMS improved REM and NREM stage 3, and rTMS improved labs (p<0.05) over the other treatments. They reported “rTMS treatment is more advantageous than both medication and psychotherapy treatments in improving the sleep architecture. Further rTMS significantly decreased the body awakening level and provides a better long-term treatment effect”.
Pellicciari et al. 201312 used 10 daily bilateral rTMS treatments of 1 Hz over the right dorsolateral prefrontal cortex and subsequent 10 Hz TMS over the left DLPFC in 10 patients with resistant depression. They followed depression using the Hamilton Depression Rating Scale13 and sleep using spatial changes of EEG frequency bands during both NREM and REM sleep before and after rTMS. Treatment demonstrated topographical-specific decrease of the alpha activity during REM sleep over the L-DLPFC. They suggested “rTMS, and specifically the high frequency stimulation, can represent a relevant strategy in the modulation of hypoactivity syndrome, like in MDD and that the study of the microstructural sleep pattern represents a potential tool for understanding the neurophysiological mechanisms of the mood disorders and their possible regulation.” And they suggested, “the left frontal alpha frequency of the REM sleep as a state-dependent marker for depression and its remission.”
Song et al. 201914 studied 20 patients with Primary Insomnia (PI) using 1 Hz rTMS for 14 days monitoring the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and the Epworth Sleepiness Scale. They also conducted 20 minutes of TMS-EEG before and immediately after TMS. The PSQI, ISI, and ESS ratings showed significant improvements that were maintained for one month. EEG monitoring before treatment showed increased outflow in the left occipital region, the frontal mid-line, and the right posterior temporal area with inadequate outflow in the right central, right parietal, and right temporal area. After TMS treatment PI patients outflow in the left temporal region increased and the outflow in the frontal mid-line region decreased. Their conclusion was that “low frequency rTMS targeting the right posterior parietal cortex has significant positive effects on the treatment of PI that can last for at least one month and can reverse abnormal changes of time-varying EEG networks”.
TMS related improvement on various sleep scales have been documented by numerous reports. Li et al. 201315 studied 30 patients with major depressive disorder and 30 patients with major depressive disorder associated with insomnia while following the Montgomery-Asberg Depression Scale16 and the Pittsburgh Sleep Quality Index. Both groups improved with respect to the depression after 4 weeks of treatment. In those with insomnia, there were improvements in sleep efficiency, sleep onset latency, sleep quality and daytime functioning as based on the PSQI. Khurshid and Holbert 201517 using dTMS at 120% MT in a patient with treatment resistant depression and insomnia measured the Insomnia Severity Index and saw an improvement in insomnia as early as day 2-with significant improvement in insomnia by session 5. The patient’s insomnia symptoms improved before his depression. Tello et al. 201718 reported on 25 patients with chronic insomnia without depression in which they administered 20 sessions of 1 Hz rTMS at 110% MT for 1800 stimuli/day over the right dorsolateral prefrontal cortex and found 80% of the patients had a significant decrease in their Pittsburgh Sleep Quality Index with 32% relapsing rate at 6 months.
Khurshid and Holbert19 presented an abstract at the 2017 APA entitled “A New Approach to Treatment of Insomnia With Transcranial Magnetic Stimulation (TMS)” and using bi-frontal low-frequency TMS on 6 patients found a mean change in sleep duration on actigraphy of one hour, a mean change in ISI scores of 15%, and a mean change in sleep efficiency of 10%. Having an interest in both insomnia and mood, our team (Stultz et al. 201920) presented a poster in June 2019 at the SLEEP conference in San Antonia, Texas on a 6 month study of insomnia, depression, and TMS in 15 patients using the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. In those with initial insomnia we found significant reduction in insomnia with both scales after delivering dTMS to the left dorsolateral prefrontal cortex at 120% MT for an average of 27 treatments. Benefit was maintained at 6 months. We have also had a poster at the 2018 Clinical TMS Society meeting (Stultz et al. 201821) in which we studied 20 patients using the H1 coil at 18 Hz and an average of 29 treatments. We monitored weight change and depression scales in addition to the Insomnia Severity Index and the Pittsburgh Sleep Quality Index using the same TMS parameters as above to the left dorsolateral prefrontal cortex. The average ISI score improved from 11.5 to 8.25 and the average PSQI improved from 11.55 to a score of 8.25 showing statistically significant improvement using paired sample t-tests at the end of treatment.
Theta Burst Stimulation has also been studied with respect to insomnia. Mensen et al. 201422 calculated the effects of theta-burst stimulation on sleep and vigilance using both continuous and intermittent theta-burst protocols with inhibition or excitation of the left dorsolateral prefrontal cortex vs. the left dorsolateral associative visual cortex. They studied a Maintenance of Wakefulness Test23, the sleep onset latency, and a psychomotor vigilance task. Theta burst stimulation decreased latency to stage 2NREM sleep and improved sleep efficiency, but had no effects on sleep drive or psychomotor vigilance with either TBS type or location.
Reports of improvement in sleep while using TMS to treat other disorders such as Anxiety, Restless Legs Syndrome, Chronic Pain, and Substance Abuse have been described. With respect to anxiety, Ishida et al. 201814 studied 16 healthy patients who underwent one session of excitatory rTMS to either the right DLPFC or the left DLPFC. Their study used a M-BIT 24 hour autonomic nervous system monitor, salivary samples of cortisol and melatonin, and the Profile of Moods States Edition 2 (POMS2)24 mood assessment questionnaire to compare active vs. sham TMS as well as right vs. left. Measuring cortisol and melatonin levels, they revealed excitatory left DLPFC treatment is more effective than right and sham treatment in decreasing cortisol and increasing melatonin levels two days after treatment. Right DLPFC rTMS treatment had the most improvement in sleep quality with an increase in average time of sleep, decreased number of times eyes opened during sleep, and improved sympathetic activity in sleep. Huang et al. 201825 described right sided parietal cortex stimulation for comorbid generalized anxiety and insomnia at 1 Hz and 90% MT for 10 days showing improvement in the Hamilton Rating Scale for Anxiety26 as well as the Pittsburgh Sleep Quality Index in 36 patients with either sham or active rTMS. Diefenbach et al. 201927 while treating Generalized Anxiety with TMS measured the Insomnia Severity Index pretreatment, posttreatment, and at 3 months follow-up. Using low-frequency (1 Hz, 90% MT, 900 pulses) to the right dorsolateral prefrontal cortex, they documented elevated ISI scores pretreatment, subthreshold scores at posttreatment and non-clinical values at 3-months follow-up.
Restless Leg Syndrome is a significant source of insomnia and TMS has been used to treat RLS with beneficial results on sleep. Altunrende et al. 201428 studied patients with RLS monitoring the International RLS-rating scale6 using 10 sessions of high frequency rTMS over the supplementary motor area and documented improvement as compared to a sham group in 11 patients who received the active treatment as well as in 5 patients who initially received sham treatment and then switched to real treatment one month later. Lin et al. 201529 using 15 Hz TMS at 100% MT to 14 patients with RLS over the leg representation motor cortex area of the frontal lobe for a total of 14 sessions demonstrated improvement in the IRLS-RS scores and the PSQI with benefits lasting for at least 2 months. Sancehz-Escandon et al. 201730 used left primary motor cortex TMS in a patient with periodic limb movements and restless legs syndrome and followed the IRLS-RS and PSG findings using 1 Hz/1000 pulses per day. They documented improvement in total sleep time from 342 minutes to 474 minutes, increased sleep efficiency from 70 to 80%, decreased periodic limb movements, improvement in the IRLS, and the patient reported subjective improvement in their sleep.
Park et al. 201431 in studying lower back pain, depression, and insomnia used the Insomnia Severity Index and found improvements on insomnia from severe to sub threshold in two women with lower back pain, depression, and chronic insomnia. The author used TMS for 3 or 4 weeks, 5 days per week at 1 Hz and 100% MT over the left prefrontal cortex for 20 minutes delivering 1200 pulses per session.
There are a growing number of TMS studies on treating Parkinson’s Disorder symptoms and also sleep in those patients. Sleep fragmentation occurs in the majority of patients with Parkinson’s Disorder. Van Dijk et al. 200932 studied sleep using actigraphy and a pressure sensitive pad in 13 patients with Parkinson’s using 5 Hz rTMS over the motor or the parietal cortex. rTMS over the parietal, but not the motor cortex improved sleep fragmentation and sleep efficiency and decreased the average duration of nocturnal awakenings. Antczak et al. 201133 studied 11 patients (10 completed) using 15 Hz rTMS bilaterally over the primary motor areas at 120% MT. Using the Parkinson’s Disease Sleep Scale34 and PSG findings they found decreased NREM stage 1 and decreased nocturnal arousals as well as subjective improvement by patients report.
There has been much excitement these days about TMS treatment of substance abuse and Lin et al. 201935 studied sleep quality and mood in 105 male inpatients addicted to either heroin or methamphetamine after an abstinence period on average of 6 months. 40 patients received 10 Hz stimulation, 40 received sham TMS and 25 had no treatment. Following the Pittsburgh Sleep Quality Index, Self-rating Anxiety Scale36 and Self-rating Depression Scale37 both at onset of treatment and 6 weeks after intervention found improved sleep quality, depression and anxiety in dependent patients in early abstinence. This of course could be very beneficial in preventing future relapses.
TMS has even been studied with acupuncture for chronic insomnia by Zhang et al. 201835. They studied 78 patients divided into two treatment groups of TMS and acupuncture vs. acupuncture with sham TMS treatment studying the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, total sleep time, sleep onset latency, wakefulness after sleep onset, and sleep efficiency using sleep diaries and actigraphy. Both groups improved, but the control group improved more significantly.
Reports suggesting lack of benefit for insomnia with TMS have also been described. Rosenquist et al. 201338 completed a multicenter, sham-controlled trial for 6 weeks using TMS and evaluating the Hamilton Depression Scale (HAMD)13 and the Inventory of Depressive Symptoms-Self Report (IDS-SR)39. They reported at the end of the study there was a statistically significant improvement in both the HAMD sleep factor score and the IDS-SR sleep factor score seen in both sham and active treatment and suggested “TMS exerts no intrinsic effect upon sleep in patients with MDD”. In 2019 Rosenquist40 wrote a letter to the editor in response to the previously mentioned article by Huang et al.25 involving TMS and Generalized Anxiety and stated he felt the sleep improvement they documented as measured by the PSQI may not be independent of anxiety. Rosenquist declared in their initial 2013 study “the improvement in sleep factors was highly correlated with non-sleep related items on the HRSD, such that we could only conclude that TMS did not have an independent effect upon sleep”. Antczak et al. 201741 studied 13 patients with bipolar or unipolar depression using 10 Hz rTMS over the left dorsolateral prefrontal cortex for 20 sessions and using the Athens Insomnia Scale42, actigraphy, and a sleep diary reported rTMS did not improve the objective sleep quality in depression. Arias et al. 201043 using rTMS in 18 idiopathic Parkinson’s Disease patients (nine active and 9 sham) of 1 Hz over the vertex with 100 pulses for 10 days found no improvement in sleep based on the Parkinson’s Disease Sleep Scale and actigraphy. There was no effect on actigraphy and equally significant improvement with sham and real TMS on the Parkinson’s disease Sleep Scale. Kaur et al. 201944 in a recent study to evaluate sleep-wake, cognitive, and other clinical correlates with TMS treatment used TMS at 110% MT on the left dorsolateral prefrontal cortex for 20 sessions over 4 weeks and found improvement in depression, anxiety, cognitive flexibility, and verbal learning, but no effect on sleep-wake or cognitive measures.
While exciting evidence exists for the treatment of insomnia with TMS, variations in placement, intensity, number of treatments, co-existing disorders, and studies disputing the benefits make it difficult to make specific recommendations on how to administer TMS specifically for insomnia. There does appear to be great potential for growth in this area.
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