Transcranial magnetic stimulation for the treatment of anxiety disorder

Figures & data

Figure 1 Flow diagram of the papers selected in our study, following PRISMA statement guidelines.

Table 1 Patients with anxiety disorders, according to DSM 5

Author/Year	Patient/Sham group	Diagnosis	Study design	Target	# of rTMS sessions	Frequency	Pulses per session	Stimulation intensity	NP tests	Relevant results following treatment	Tolerability and safety	Sustained effect of response
Zhang, 2019^Citation37	117 rTMS	Mood or Anxiety Disorders	RCT	Left DLPFC	10	10 Hz	2400	120% of RMT	HAMA	All the age groups showed significant improvements in clinical symptoms	No safety or tolerability concerns were identified	Yes for adolescents, but not in adults
Lu R, 2018^Citation38	28 rTMS	GAD	Open-label	Right DLPFC + left DLPFC	10	1 Hz	750	80% of RMT	HRSA	In this study, low-frequency rTMS which was successively delivered to right and left DLPFC effectively alleviated anxiety symptoms in GAD patients	All patients tolerated rTMS well without any adverse effects	Yes
Dilkov D, 2017^Citation33	9 rTMS/12 sham	GAD	RCT	Right DLPFC	25	20 Hz	3600	110% of RMT	HRSA	Participants receiving rTMS showed clinically significant decrease in reported anxiety symptoms.	One participant in the active group had seizure; transient dizziness was reported in three patients	Yes
Diefenbach GJ, 2016^Citation35	13 rTMS/12 sham	GAD	RCT	Right DLPFC	30	1 Hz	900	90% of RMT	HRSA; DASS	ANOVA demonstrated significant group x time interaction for the primary and secondary outcomes with the gains maintained only in the rTMS group at follow-up.	No seizures occurred; mild adverse effects were reported and was similar in rTMS and sham groups	Yes
White D and Tavakoli S, 2015^Citation5	13 rTMS	Comorbid MDD and GAD	Open-label, pilot study	Right DLPFC + left DLPFC	2436	1Hz (right side)+10hz (left side)	1000	NR	GAD-7	Paired T-test comparing baseline to final scores showed a markedly significant difference for both GAD-7 and the HDRS-21, suggesting a decrease of 65% and 75% in depression and anxiety, respectively.	NR	Not applicable
Mantovani A, 2013^Citation34	12 rTMS/13 sham	PD and comorbid MDD	RCT. Two phases: Phase I 4-week double-blind followed by Phase II (optional) 4-week open-label	Right DLPFC	Phase I: 20; Phase II: 20	1Hz	1800	110% of RMT	PDSS; HRSA-14	Repeated-measures ANOVA revealed a significant time by group interaction with PDSS, with greater reduction in active group.	No seizures were reported. None of the patients reported significant side effects	Yes
Prasko J, 2007^Citation36	7 rTMS/8 sham	PD or PD with agoraphobia	RCT	Right DLPFC	10	1 Hz	1800	110% of RMT	HRSA; BAI; PDSS	No statistical difference between groups were observed after treatment.	No seizures, headaches, neurological and cognitive decline occurred	Not applicable

Abbreviations: BAI, Beck Anxiety Inventory; DASS, Depression Anxiety Stress Scales; DLPFC, Dorsolateral Prefrontal Cortex; GAD, Generalized Anxiety Disorder; GAD-7, Generalized Anxiety Disorder scale; HAMA, Hamilton Rating Scale for Anxiety; HRSA, Hamilton Rating Scale for Anxiety; MDD, major depressive disorder; NP, neuropsychological; NR, Not Reported; PD, Panic Disorder; PDSS, Panic Disorder Severity Scale; RCT, Randomized Controlled Trial; RMT, Resting Motor Threshold; rTMS, repetitive Transcranial Magnetic Stimulation.

Table 2 Anxiety symptoms, from neurological and psychiatric disorders

Author/Year	Patient/Sham group	Diagnosis	Study design	Target	# of rTMS sessions	Frequency	Pulses per session	Stimulation intensity	Anxiety questionnaire	Primary outcome	Relevant results following treatment	Tolerability and safety	Sustained effect of response
Kaur M, 2019^Citation39	16 rTMS	Mood disorders	Open-label	Left DLPFC	20	10 Hz	NR	110% of RMT	Anxiety subscale of the HDRS	To determine whether sleep–wake disturbance, cognition or depression chronicity are associated with rTMS outcome in young depressed adults	Show reduced depressive and anxiety symptoms and no cognitive deterioration	NR	Yes
Lin H, 2018^Citation40	7 rTMS	Thalamic pain	Open-label	Motor cortex	10	10 Hz	1000	90% of RMT	HAMA	To evaluate the analgesic lasting effect to treat thalamic pain	High-frequency rTMS can provide long-term pain relief in patients with thalamic pain	All patients tolerated rTMS well with out any adverse effects	No
Reyes-Lopez. J, 2018^Citation41	29 rTMS	Borderline	RCT	Right DLPFC + left DLPFC	15	5 Hz or 1 Hz	900 or 1500	100% of RMT	HRSA	To evaluate clinical improvement in patients with BPD after application of rTMS	HAM-A scores reduced after rTMS treatment. Both protocols produced global improvement in severity and symptoms of BPD, particularly in impulsiveness, affective instability, and anger	NR	Yes
Durmaz O, 2017^Citation42	36 rTMS	MDD	Open-label	Left DLPFC	15	20 Hz	1000	110% of RMT	HRSA	To evaluate the efficacy of rTMS in patients with treatment-resistant major depression	The findings suggested that comorbid anxiety symptoms, particularly somatic anxiety, could predict the response to rTMS in treatment-resistant major depressive disorder	Headache in eight patients, dizziness in four patients, and lacrimation in three patients. Only one patient dropped out of the study due to side effects or intolerance	Yes
Noh TS, 2017^Citation43	17 rTMS	Tinnitus	RCT	Left auditory cortex (AC) and left DLPFC or only the left DLPFC	4	1 Hz	2000 or 3000	110% of RMT	STAI	We evaluated treatment outcomes following single-site rTMS in the DLPFC and dual-site rTMS in the AC and DLPFC	Group 1 exhibited significant improvements in scores on the STAI for both state anxiety and trait anxiety at 12 weeks posttreatment. Group 2 showed an improvement in only the STAI-X2 score at 12 weeks posttreatment.	NR	No
Tovar-Perdomo S, 2017^Citation44	24 rTMS	MDD	Open-label, pilot study	Left DLPFC	20	10 Hz	3000	120% of RMT	BAI	To explore the effects of a course of accelerated high-frequency rTMS on two neurocognitive domains in patients with MDD	Depression and anxiety scores significantly improved from pre-post HF-rTMS treatment.	The absence of practice effects in our longitudinal design raises the possibility that rTMS may also have cognitive side effects which, like antidepressant effects, may recede and reveal cognitive improvements after treatment cessation and sustained recovery	No
Elbeh KAM, 2016^Citation6	30 rTMS/15 sham	OCD	RCT	Right DLPFC + left DLPFC	10	1 Hz or 10 Hz	200 or 500	100% of RMT	HRSA	To evaluate the impact of different frequencies of rTMS in OCD	1 Hz rTMS over the right DLPFC has medium-term effect on obsessive-compulsive symptoms and anxiety	All patients tolerated rTMS well without any adverse effects except for two patients in the active stimulation group who experienced transient headache that disappeared with in a few hours	Yes
Malavera A, 2016^Citation45	27 rTMS/27 sham	Pain	RCT	Primary Motor Cortex contralateral to the amputated leg	10	10 Hz	1200	90% of RMT	Zung Self-Rating Anxiety Scale	The score change in the Visual Analogue Scale for pain	No statistically significant between-group difference was found when comparing the absolute scores of the depression and anxiety scales at day 15 or day 30	Some patients experienced minor adverse effects such as headache, neck pain, and sleepiness without significant differences between groups	Yes
Bilici S, 2015^Citation46	45 rTMS/30 sham	Tinnitus	RCT	Left temporoparietal region	10	1 Hz or 10 Hz	600 or 900	110% of RMT	BAS	To compare the effects of rTMS and paroxetine on tinnitus in terms of effectiveness and medium-term results	The positive effects that were observed might reflect a relationship between tinnitus and auditory cortex areas related to emotions	In the 10 Hz TMS treatment group, two patients complained of neck and shoulder stiffness, which disappeared in 2 days without any medical treatment; two patients had jaw fasciculation, which continued for 1 hr; and one patient had a headache for 1 day. One patient in the 1 Hz rTMS group had mild jaw pain for 2 days. All patients in the paroxetine-treated group were asked to report possible side effects of the drug. Among those, three had cephalalgia, two had gastrointestinal disorders, and one had sexual dysfunction; all these side effects were mild-to-moderate in intensity and did not delay the therapy	Yes
Lin YC, 2015^Citation47	14 rTMS	RLS	Open-label	Motor cortex area of the frontal lobe	14	15 Hz	600	100% of RMT	HRSA	To investigate whether rTMS could have any beneficial effects in restless legs syndrome	rTMS can markedly alleviate the motor system symptoms, sleep disturbances, and anxiety in RLS patients	No adverse effects were observed during stimulation or after treatment, and all patients showed good compliance	Yes
Oznur T, 2014^Citation48	20 rTMS	PTSD	Open-label	Right DLPFC	20	1 Hz	NR	80% of RMT	BAI	To examine the effectiveness of rTMS in patients with treatment-resistant posttraumatic stress disorder	The effectiveness of rTMS on the anxiety and depression scores in the patients was not determined in this study	NR	No
Diefenbach GJ, 2013^Citation49	32 rTMS	MDD	Open-label	Left DLPFC	31	10 Hz	3000–5000	80 at 130% of RMT	Anxiety/somatization subscale of the HDRS	To determine if anxious depression is associated with attenuated response to rTMS	Both depression and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects	NR	Yes
Pretalli JB, 2012^Citation50	75 rTMS	MDD	RCT	Left DLPFC	10	10 Hz	NR	95% of RMT	HAMD anxiety subscale (items 9, 10, 11, and 15); Tyrer scale for anxiety; STAI	To investigate whether or not RMT changes during the treatment of resistant depression	These RMT changes influenced the outcome of the 10 sessions concerning the severity of depressive and anxiety symptoms	Only mild side-effects were reported (pain at the site of the coil placement or headache)	Yes
Sun W, 2012^Citation51	60 rTMS	Focal epilepsy	RCT	Epileptogenic focus	10	0.5 Hz	1500	90% or 20% of RMT	SCL-90	To evaluate the therapeutic effect of low-frequency rTMS on patients with refractory partial epilepsy	All the subscale scores of somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, paranoid ideation and psychoticism in group 1 was lower than that of group 2 when evaluated at the end of follow-up period	The most common adverse events were mild or moderate headache and tinnitus. Adverse events occurred more often in group one patients who received “90% rMT” rTMS	Yes
Watts BV, 2012^Citation21	10 rTMS/10 sham	PTSD	RCT	Right DLPFC	10	1 Hz	NR	90% of RMT	STAI	This study seeks to examine the efficacy of rTMS for PTSD	Anxiety symptoms showed improvement with rTMS, but those improvements were not statistically significant compared with sham	NR	Yes
Berlim MT, 2011^Citation52	15 rTMS	MDD	Open-label	Left DLPFC	20	10 Hz	3000	120% of RMT	HRSA; BAI	To address an augmenting strategy in subjects with chronic, severely treatment-resistant MDD	Clinically meaningful improvements in anxious and depressive symptoms	Only one of the 15 participants withdrew from the study at week 1 because of lack of tolerability (ie, severe scalp pain)	Yes
Boggio PS, 2010^Citation53	20 rTMS/10 sham	PTSD	RCT	Right DLPFC or left DLPFC	10	20 Hz	1600	80% of RMT	HRSA	To investigate the efficacy of rTMS for the relief of posttraumatic stress disorder (PTSD)-associated symptoms	Right rTMS generated a significant improvement in the measure of anxiety at days 5 and 10 while left rTMS did not	There were no seizures and only mild adverse effects, such as mild headache, neck pain, sleepiness, and dizziness were reported similarly in the 3 groups of treatment	Yes
Epstein CM, 2007^Citation54	14 rTMS	Parkinson disease	Open-label	Left DLPFC	10	10 Hz	1000	110% of RMT	HRSA	To investigate about rTMS as a potential treatment for depression in PD and for the movement disorder of PD	Open rTMS treatment of PD patients with treatment-resistant depression was followed by highly significant improvement in mood scores and anxiety ratings	There were no seizures and no complaints of headache or neurological deterioration	Yes
Passard A, 2007^Citation55	15 rTMS/15 sham	Fibromyalgia	RCT	Left primary motor cortex	10	10 Hz	2000	80% of RMT	Hospital Anxiety Scale	To assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia	The analgesic effects were observed from the fifth stimulation onwards and were not related to changes in mood or anxiety.	Minor and transient side effects were reported during the stimulation period only. Nine patients reported headaches: four in the active-stimulation group and five in the sham stimulation group. These headaches, reported after only 1 of the 10 daily sessions, were mild and transient in all cases. Other side effects included nausea after the fifth session in one patient in the active-treatment group. Two patients reported transient tinnitus and one patient reported mild dizziness after one sham-stimulation session	Yes
Rossi S, 2007^Citation56	14 rTMS	Tinnitus	Open-label	Left temporoparietal region	5	1 Hz	1200	120% of RMT	HRSA	To assess about rTMS on chronic tinnitus in which also eventual mood changes are monitored	In patients with chronic tinnitus, psychiatric comorbidity as mood or anxiety disorders are relevant and may partly found their functional counterpart in the activation of higher-order processing	The majority of patients did not complain of side effects due to rTMS, a part a slight transient headache on the stimulation site, which however did not require pharmacological treatment. About 30% of patients complained of tongue paraesthesia occurring during the active rTMS. Most of patients reported a transient worsening of their tinnitus in the first two–three days of active rTMS. Two male patients, one receiving active rTMS and one sham rTMS as first intervention, dropped ut from the study for this reason	Yes
Cohen H, 2004^Citation57	18 rTMS/6 sham	PTSD	RCT	Right DLPFC	10	1 Hz or 10 Hz	NR	80% of RMT	HRSA	To evaluate the therapeutic effects of two different frequencies of active rTMS of PTSD patients	Active 10-Hz rTMS, relative to 1-Hz treatment and sham, significantly reduced Hamilton anxiety scale scores but not Hamilton depression scale scores	Headache was the main side effect reported, regardless of stimulation group. It was reported by 14 patients: eight patients reported headache after one rTMS treatment, five patients reported it after two sessions, and one (receiving sham treatment) reported it after three sessions. In most cases, this side effect was reported several hours after the stimulation or on the following morning. Only four patients reported headache immediately after the stimulation. In three cases, headache was a symptom before the study. However, the total number of headaches after treatment was 21. Two patients receiving high-frequency rTMS reported neck pain and muscular contraction in the area. Another patient receiving high-frequency treatment reported an exacerbation of previously existing dizziness. One patient in the group receiving slow-frequency rTMS and one patient from the high-frequency group developed a manic episode; in both cases, this occurred after the third session of rTMS. One patient reported a mild rage attack, probably related to the stimulation. Although we did not use earplugs, only two patients reported ear discomfort, which lasted less than 1 min	Yes
Loo CK, 2003^Citation58	18 rTMS	MDD	RCT	Left DLPFC	NR	15 Hz or 1 Hz	NR	90% of RMT	7-item scale	To understand further the mechanisms of action of high- and low-frequency rTMS by examining their acute effects on regional cerebral blood flow (rCBF) in depressed patients	Anxiety scores did not differ between the 15 Hz and 1 Hz groups. rTMS can produce functional changes in areas of the brain involved in mood control, including changes tending toward correction of deficits associated with depression	NR	Yes
Münchau A, 2002^Citation59	12 rTMS	GTS	Open-label	Left premotor	6	1 Hz	1200	80% of RMT	Hospital Anxiety Scale	To study whether rTMS targeted to left motor and premotor cortex can improve tics in GTS	There was no significant improvement of symptoms after any of the rTMS conditions as assessed	One patient reported mild headache after premotor rTMS. Two patients reported excessive tiredness after both premotor and motor rTMS lasting for about 1 day	Yes
George MS, 2000^Citation60	20 rTMS/10 sham	MDD	RCT	Left prefrontal cortex	10	5 Hz or 20 Hz	NR	100% of RMT	HRSA	To conduct a study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham	Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the BDI as well as the HARS than did those who received sham	Two subjects with average MTs (60% and 70% of machine output) elected to stop the study because of the pain of stimulation. One subject tried for 2 consecutive days, whereas the other decided to stop after only 2 mins of the first session. Ten subjects reported mild headaches following at least one session (beginning immediately after to 3 hrs after rTMS), which were relieved by acetaminophen	Yes
Rollnik JD, 2000^Citation61	6 rTMS/6 sham	Schizophrenia	RCT	Left DLPFC	10	20 Hz	800	80% of RMT	STAI	To investigate the therapeutic efficacy of rTMS in schizophrenic patients with acute exacerbation of their psychosis	STAI, BDI, and NCT scores tended to improve during active rTMS and to worsen during sham stimulation, but the observed changes were not significant.	NR	Yes

Abbreviations: STAI, State-Trait Anxiety Inventory; HRSA, Hamilton Rating Scale for Anxiety; BAI, Beck Anxiety Inventory; HAMA, Hamilton Rating Scale for Anxiety; RMT, Resting Motor Threshold; rTMS, repetitive Transcranial Magnetic Stimulation; DLPFC, dorsolateral prefrontal cortex; MDD, major depressive disorder; PTSD, Post Traumatic Stress Disorder; RLS, Restless Legs Syndrome; OCD, Obsessive Compulsive Disorder.

Table 3 Symptoms of anxiety present in neurological disorders

Primary pathology	Number of studies
Pain	3 (Lin et al, 2018^Citation40 Malavera et al, 2016^Citation45 Passard et al, 2007^Citation55)
Restless Legs Syndrome	1 (Lin et al, 2015^Citation47)
Focal epilepsy	1 (Sun W, 2012^Citation51)
Parkinson’s disease	1 (Epstein et al, 2007^Citation54)
Gilles de la Tourette Syndrome	1 (Münchau et al, 2002^Citation59)

Table 4 Symptoms of anxiety present in psychiatric disorders

Primary pathology	Number of studies
Borderline	1 (Reyes-Lopez. J et al,2018^Citation41)
MDD	8 (Kaur et al, 2019^Citation39 Durmaz et al, 2017^Citation42 Tovar-Perdomo et al, 2017^Citation44 Diefenbach et al, 2013^Citation49 Pretalli et al, 2012^Citation50 Berlim et al, 2011^Citation52 Loo et al, 2003^Citation58 George et al, 2000^Citation60)
Tinnitus	3 (Noh et al, 2017^Citation43 Bilici et al, 2015^Citation46 Rossi et al, 2007^Citation56)
Obsessive Compulsive Disorder	1 (Elbeh et al, 2016^Citation6)
Post Traumatic Stress Disorder	4 (Oznur et al, 2014^Citation48 Watts et al, 2012^Citation21 Boggio et al, 2010^Citation53 Cohen et al, 2004^Citation57)
Schizophrenia	1 (Rollnik et al, 2000^Citation61)

Abbreviation: MDD, major depressive disorder.

Table 5 Anxiety scales found in papers

Anxiety questionnaire papers	Number of citations
HRSA	15
BAI	4
STAI	4
Hospital Anxiety Scale	2
PDSS	2
Anxiety/somatization subscale of the HDRS	2
HAMA	2
7-item scale	1
BAS	1
DASS	1
GAD-7	1
HAMD anxiety subscale (items 9, 10, 11 and 15)	1
SCL-90	1
Tyrer scale for anxiety	1
Zung Self-Rating Anxiety Scale	1

Abbreviations: HRSA, Hamilton Rating Scale for Anxiety; BAI, Beck Anxiety Inventory; STAI, State-Trait Anxiety Inventory; PDSS, Panic Disorder Severity Scale; HAMA, Hamilton Rating Scale for Anxiety; DASS, Depression Anxiety Stress Scales; GAD, Generalized Anxiety Disorder.

Table 6 Side effects of rTMS found in papers

Side effects	Frequency in papers
Dizziness	4
Pain and stiffness in the neck and shoulder	2
Ringing in the ear	3
Drowsiness	2
Tearing	1
Regression in cognitive improvement during treatment	1
Neck pain	1
Fasciculation and mandibular pain	1
Gastrointestinal disorders	1
Sexual dysfunction	1
Muscle contraction	1
Rage attack	1
Ear discomfort	1
Excessive fatigue	1

Zhang T, Zhu J, Xu L, et al. Add-on rTMS for the acute treatment of depressive symptoms is probably more effective in adolescents than in adults: evidence from real-world clinical practice. Brain Stimul. 2019;12(1):103–109. doi:10.1016/j.brs.2018.09.00730237010

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Lu R, Zhang C, Liu Y, Wang L, Chen X, Zhou X. The effect of bilateral low-frequency rTMS over dorsolateral prefrontal cortex on serum brain-derived neurotropic factor and serotonin in patients with generalized anxiety disorder. Neurosci Lett. 2018;684:67–71. doi:10.1016/j.neulet.2018.07.00830008380

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Diefenbach GJ, Bragdon LB, Zertuche L, et al. Repetitive transcranial magnetic stimulation for generalised anxiety disorder: a pilot randomised, double-blind, sham-controlled trial. Br J Psychiatry. 2016;209(3):222–228. doi:10.1192/bjp.bp.115.16820327198484

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White D, Tavakoli S. Repetitive transcranial magnetic stimulation for treatment of major depressive disorder with comorbid generalized anxiety disorder. Ann Clin Psychiatry. 2015;27(3):192–196.26247218

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Mantovani A, Aly M, Dagan Y, Allart A, Lisanby SH. Randomized sham controlled trial of repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex for the treatment of panic disorder with comorbid major depression. J Affect Disord. 2013;144(1–2):153–159. doi:10.1016/j.jad.2012.05.03822858212

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Kaur M, Naismith SL, Lagopoulos J, et al. Sleep-wake, cognitive and clinical correlates of treatment outcome with repetitive transcranial magnetic stimulation for young adults with depression. Psychiatry Res. 2019;271:335–342. doi:10.1016/j.psychres.2018.12.00230529316

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Lin H, Li W, Ni J, Wang Y. Clinical study of repetitive transcranial magnetic stimulation of the motor cortex for thalamic pain. Medicine. 2018;97(27):e11235.29979386

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Epstein CM, Evatt ML, Funk A, et al. An open study of repetitive transcranial magnetic stimulation in treatment-resistant depression with Parkinson’s disease. Clin Neurophysiol. 2007;118(10):2189–2194. doi:10.1016/j.clinph.2007.07.01017714987

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Passard A, Attal N, Benadhira R, et al. Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain. 2007;130(10):2661–2670. doi:10.1093/brain/awm18917872930

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