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Research Paper
Open Access

Effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders: a meta-analysis of sham or behaviour-controlled studies

Alessandra Vergallito, Alessia Gallucci, Alberto Pisoni, Mariacristina Punzi, Gabriele Caselli, Giovanni M. Ruggiero, Sandra Sassaroli and Leonor J. Romero Lauro
J Psychiatry Neurosci November 09, 2021 46 (6) E592-E614; DOI: https://doi.org/10.1503/jpn.210050
Alessandra Vergallito
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Alessia Gallucci
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Alberto Pisoni
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Mariacristina Punzi
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Gabriele Caselli
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Giovanni M. Ruggiero
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Sandra Sassaroli
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Leonor J. Romero Lauro
From the Department of Psychology, University of Milano Bicocca, Milan, Italy (Vergallito, Pisoni, Punzi, Romero Lauro); the Neuromi, Milan, Italy (Vergallito, Gallucci, Pisoni, Romero Lauro); the Department of Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy (Gallucci); the Studi Cognitivi, Milan, Italy (Caselli, Ruggiero, Sassaroli); and the Faculty of Psychology, Sigmund Freud University, Milan, Italy (Caseli, Ruggiero, Sassaroli)
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Figures

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  • Figure 1
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    Figure 1

    Flow chart of study selection. rTMS = repetitive transcranial magnetic stimulation; tDCS = transcranial direct current stimulation.

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    Figure 2

    Type of stimulation and target regions in included studies. Red dots indicate excitatory stimulation protocols (i.e., anodal tDCS, iTBS and high-frequency rTMS); blue dots indicate inhibitory stimulation (i.e., cathodal tDCS and low-frequency rTMS). The size of the dots correspond to the number of studies that applied an excitatory or inhibitory protocol over a specific region: 5 studies applied inhibitory stimulation protocols over the right dorsolateral prefrontal cortex, 3 studies applied excitatory stimulation protocols over the left dorsolateral prefrontal cortex, 1 study applied an excitatory stimulation protocol over the right dorsolateral prefrontal cortex, 1 study applied an inhibitory stimulation protocol over the right posterior parietal cortex, and 1 study applied an excitatory stimulation protocol over the ventromedial prefrontal cortex. Brain images were obtained from www.nitrc.org. iTBS = intermittent theta burst stimulation; rTMS = repetitive transcranial magnetic stimulation; tDCS = transcranial direct current stimulation.

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    Figure 3

    Forest plot of the effect size of noninvasive brain stimulation on continuous specific anxiety questionnaire scores. CI = confidence interval.

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    Figure 4

    Baujat plot of study distribution in terms of heterogeneity for continuous specific anxiety questionnaire scores. On visual inspection, study 8119 seemed to contribute most to the statistical heterogeneity of the included studies.

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    Figure 5

    Publication bias assessed by funnel plot for continuous specific anxiety questionnaire scores.

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    Figure 6

    Forest plot of the effect size of noninvasive brain stimulation on continuous general anxiety questionnaire scores. CI = confidence interval.

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    Figure 7

    Baujat plot of study distribution in terms of heterogeneity for continuous general anxiety questionnaire scores. On visual inspection, study 387 seemed to contribute most to the statistical heterogeneity of the included studies.

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    Figure 8

    Publication bias assessed by funnel plot for continuous general anxiety questionnaire scores.

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    Figure 9

    Forest plot of the effect size of noninvasive brain stimulation on continuous depression questionnaire scores. CI = confidence interval.

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    Figure 10

    Baujat plot of study distribution in terms of heterogeneity for continuous depression questionnaire scores. On visual inspection, study 287 seemed to contribute most to the statistical heterogeneity of the included studies.

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    Figure 11

    Publication bias assessed by funnel plot for continuous depression questionnaire scores.

Tables

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    Table 1

    Summary of study characteristics used for quantitative analysis

    SampleOutcome measures
    NIBSControl
    StudyTypeNo. patientsTypeNo. patientsNo. sessionsTarget regionProtocol typeBlindingSpecific anxietyGeneral anxietyDepression
    De Lima et al.86 (2019)tDCS15Sham155Left dlPFCExcitatoryDouble-blindLippHAM-ABDI
    Deppermann et al.115 (2014)iTBS20Sham2115Left dlPFCExcitatoryDouble-blindPASHAM-ANR
    Diefenbach et al.116 (2016)rTMS9Sham1010Right dlPFCInhibitoryDouble-blindPSWQHAM-AHAM-D
    Dilkov et al.87 (2017)rTMS15Sham2225Right dlPFCExcitatoryDouble-blindNRHAM-AHAM-D
    Herrmann et al.117 (2017)rTMS20Sham192vmPFCExcitatoryDouble-blindAQ anxietyNRNR
    Huang et al.118 (2018)rTMS18Sham1810Right PPCInhibitoryDouble-blindPSQIHAM-AHAM-D
    Mantovani et al.119 (2013)rTMS11Sham1020Right dlPFCInhibitoryDouble-blindPDSSHAM-AHAM-D
    Movahed et al.120 (2018)tDCS6Sham610Right dlPFCInhibitorySingle-blindPSWQHAM-AHAM-D
    Nasiri et al.121 (2020)tDCS13UP1510Right dlPFCInhibitoryDouble-blindGAD-Q-IVBAIBDI
    Notzon et al.88 (2015)iTBS20Sham201Left dlPFCExcitatorySingle-blindSPQNRNR
    Prasko et al.122 (2007)rTMS7Sham810Right dlPFCInhibitoryDouble-blindPDSSHAM-ANR
    • AQ anxiety = Acrophobia Questionnaire anxiety subscale; BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; dlPFC = left dorsolateral prefrontal cortex; GAD-Q-IV = Generalized Anxiety Disorder Questionnaire-IV; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; iTBS = intermittent theta burst stimulation; Lipp = Lipp Inventory of Stress Symptoms for Adults; NIBS = noninvasive brain stimulation; NR = not reported; PAS = Panic and Agoraphobia Scale; PDSS = Panic Disorder Severity Scale; PPC = posterior parietal cortex; PSQI = Pittsburgh Sleep Quality Index; PSWQ = Penn State Worry Questionnaire; rTMS = repetitive transcranial magnetic stimulation; SPQ = Spider Phobia Questionnaire; tDCS = transcranial direct current stimulation; UP = unified protocol; vmPFC = ventromedial prefrontal cortex.

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    Table 2

    Risk of bias among included studies

    Cochrane Items
    Selection biasPerformance biasDetection biasAttrition biasReporting bias
    StudyRandom sequence generationAllocation concealmentBlinding of participants and personnelBlinding of outcome assessmentIncomplete outcome dataSelective reportingOtherNo. of high, %*
    De Lima et al.86 (2019)LowLowLowLowLowLowLow0
    Deppermann et al.115 (2014)HighLowLowLowUnsureLowLow14.29
    Diefenbach et al.116 (2016)HighLowLowLowLowLowLow14.29
    Dilkov et al.87 (2017)LowLowLowLowHighLowLow14.29
    Herrmann et al.117 (2017)HighLowLowLowLowLowLow14.29
    Huang et al.118 (2018)HighLowLowLowLowLowLow14.29
    Mantovani et al.119 (2013)HighLowLowLowLowLowLow14.29
    Movahed et al.120 (2018)HighLowHighHighLowLowLow42.86
    Nasiri et al.121 (2020)HighHighLowLowLowHighLow42.86
    Notzon et al.88 (2015)HighLowHighHighUnsureLowLow42.86
    Prasko et al.122 (2007)HighLowLowLowLowLowLow14.29
    • ↵* We calculated a percentage for each study, as the quotient of the number of “High” ratings and the total number of relevant items. The lower the percentage, the lower the overall risk of bias.

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    Table 3

    Summary of participant characteristics from the included studies

    StimulationControl
    AuthorAge, yrM/FEducationAge, yrM/FEducationDiagnosisRecruitment
    De Lima et al.86 (2019)32.07 ± 6.55/102 elementary, 9 secondary, 4 university29 ± 5.056/92 elementary, 7 secondary, 6 universityGADTwo outpatient clinics
    Deppermann et al.115 (2014)37.6 (range 19–63)9/13*12.1 ± 1.7 yr36.3 (range 22–56)8/14*12.4 ± 2.0 yrPD ± agoraphobiaOutpatient clinics, advertisements, internet, information sent to local physicians
    Diefenbach et al.116 (2016)44.00 ± 11.951/812 yr (high school diploma)44.58 ± 14.753/712 yr (high school diploma)GADOutpatient clinic, advertisements, internet, community flyers, physician referral, media coverage
    Dilkov et al.87 (2017)34 ± 79/6NR38 ± 1011/11NRGAD2 mood disorder centres: Canada and Bulgaria
    Herrmann et al.117 (2017)43.2 ± 12.67/13NR46.6 ± 13.76/13NRSPAdvertisements in local newspapers
    Huang et al.118 (2018)44.94 ± 11.649/9NR45.22 ± 10.859/9NRGAD + insomniaNeurology outpatient clinic
    Mantovani et al.119 (2013)40.2 ± 104/8†NR39.87 ± 13.38/5†NRPD + MDDNR
    Movahed et al.120 (2018)NRNRNRNRNRNRGADNR
    Nasiri et al.121 (2020)20.23 ± 2.893/10NR21.53 ± 3.564/11NRGAD + MDDUniversity announcements
    Notzon et al.88 (2015)25.85 ± 7.6520‡11.30 ± 3.91 yr27.02 ± 9.2320‡11.34 ± 3.51 yrSPLocal advertisements
    Prasko et al.122 (2007)33.7 ± 9.21/65 elementary, 1 secondary, 1 university33.8 ± 12.23/51 elementary, 6 secondary, 1 universityPDNR
    • F = female; GAD = generalized anxiety disorder; M = male; MDD = major depressive disorder; NR = not reported; PD = panic disorder; SP = specific phobia. Values are mean ± standard deviation or n, unless otherwise specified.

    • ↵* The number of males and females was based on the original number of participants included in the study reported in Deppermann et al.110 (2017). Three participants did not complete the study (2 from the stimulation group and 1 from the sham group), but their sex was not reported by the authors.

    • ↵† The number of males and females was based on the original number of participants included in the study. Four participants did not complete the study (1 from the stimulation group and 3 from the sham group).

    • ↵‡ Participant sex in the stimulation and sham groups were not specified; we have reported the total number of patients from the authors’ data set.

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    Table 4

    Inclusion and exclusion criteria for the included studies

    StudyInclusion criteriaExclusion criteria
    De Lima et al.86 (2019)GAD diagnosis (DSM-5)
    Age 20–30 yr
    Psychotherapy or hospitalization indication from the psychiatrist at the beginning of the study
    Deppermann et al.115 (2014)Age 18–65 yr
    PD with or without agoraphobia (DSM-IV-TR)
    Severe somatic disorders
    Diefenbach et al.116 (2016)Age > 18 yr
    GAD as principal or coprincipal disorder
    HAM-A and HAM-D cut-off
    Unstable medical/psychiatric condition (e.g., thyroid disease, suicidality)
    Current PTSD
    Substance use disorder
    Lifetime bipolar, psychotic, developmental or obsessive–compulsive disorder
    Concurrent psychotherapy
    Dilkov et al.87 (2017)Age 18–65 yr
    GAD primary diagnosis (DSM-IV)
    Diagnosis of psychotic disorder, bipolar disorder I, MDD or substance/alcohol dependence in the 6 months before the study
    Severe axis II disorder
    Suicidal
    Severe or unstable medical conditions
    ECT treatment in the previous 3 mo
    TMS treatment in the previous 6 mo
    Herrmann et al.117 (2017)Specific phobia (acrophobia) diagnosis (DSM-IV)
    Subjective motivation to do something about their fear (at least 3 on a scale of 0–10; extreme motivation)
    Motion sickness with 3D movies < 4 (scale of 0–10)
    Heights treatment in the previous 6 mo
    Concurrent involvement in psycho-or pharmacotherapy
    Huang et al.118 (2018)Age 18–65 yr
    GAD primary diagnosis (DSM-IV)
    Insomnia for at least 3 months
    History of psychiatric diseases except GAD
    Concurrent psychotherapy or counselling
    Mantovani et al.119 (2013)Age 18–65 yr
    PD and MDD primary diagnosis (DSM-IV-TR)
    Current episode duration of at least a month
    Residual panic attack and MDD symptoms despite medication
    Stable medication for 4 wk
    Stable psychotherapy for 3 mo
    Suicide risk
    History of bipolar disorder, psychotic disorder or substance dependance/abuse in the previous year
    Movahed et al.120 (2018)Age 18–55 yr
    GAD diagnosis (DSM-5)
    5 points or higher on the 7-item GAD scale
    Previous mental illness
    Current physical illness
    Current psychological or pharmacological medication
    Nasiri et al.121 (2020)Age 18–40 yr
    GAD primary diagnosis (DSM-5)
    Comorbid MDD diagnosis (DSM-5)
    No medication use
    Speaks Persian fluently
    Ability to participate in all assessment and treatment sessions
    Need for immediate medical/therapeutic intervention
    Received no more than 8 sessions of CBT-based intervention within the last 5 yr
    Psychiatric disorder/substance abuse
    Current diagnosis of mental disorders
    Opposition to collaboration at any point in research
    Suicidality
    History of other psychological treatment
    Notzon et al.88 (2015)Age 18–65 yr
    Spider phobia (DSM-IV-TR)
    At least 16 on the SPQ
    Severe somatic disorder
    History of psychiatric disorders except for specific phobia
    Psychiatric or psychotropic medication
    Prasko et al.122 (2007)ICD-10 PD with or without agoraphobia
    Nonresponders to SRIs (at least 6 wk)
    Age 18–45 yr
    MDD
    Suicidality
    HAM-D score > 16
    Organic psychiatric disorder
    History of psychotic disorder in history
    Abuse of alcohol or other drugs
    Serious somatic disease
    Using nonprescribed medication
    • CBT = cognitive behavioural therapy; DSM = Diagnostic and Statistical Manual of Mental Disorders; ECT = electroconvulsive therapy; GAD = generalized anxiety disorder; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; MDD = major depressive disorder; NR = not reported; PD = panic disorder; PTSD = posttraumatic stress disorder; SP = specific phobia; SPQ = Spider Phobia Questionnaire; SRI = serotonin reuptake inhibitor; TMS = transcranial magnetic stimulation; TR = text revision.

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    Table 5

    Summary of stimulation protocols details, treatment strategies and associated therapies

    StudyIntensityDurationCoil/electrode positiontDCS referenceSham procedurePsychological interventionTreatment strategyMedication
    De Lima et al.86 (2019)2 mA
    Electrode size 5 × 7
    20 minF3FP230 sNot allowedMonotherapyStable doses
    Deppermann et al.115 (2014)15 Hz
    80% rMT
    3 min; 18 trains of 2 sF3–90° from skullPsychoeducation, 3 group sessionsMonotherapyStable doses for 3 wk
    Diefenbach et al.116 (2016)1 Hz
    90% rMT
    15 min; 900 pulses per sessionIndividual structural MRI: x, y, z = 42, 36, 32 (MNI)–Sham coilNot allowedMonotherapyStable doses for 3 mo or stable benzodiazepines for 2 wk
    Dilkov et al.87 (2017)20 Hz
    110% rMT
    20 trains, 9 s per train; 51 s intertrain interval5 cm rostral to motor cortex–90° from skull, same intensityAllowedMonotherapyStable doses for 6 mo or no medications for at least 2 wk
    Herrmann et al.117 (2017)10 Hz
    100% rMT
    40 trains of 4 s (1560 pulses; intertrain interval 26 sFPZ–Sham coilVirtual reality exposureAugmentationNot allowed
    Huang et al.118 (2018)1 Hz
    90% rMT
    3 trains of 500 pulses; intertrial interval 10 minP4–Sham coilNot allowedMonotherapyStable doses for 3 mo
    Mantovani et al.119 (2013)1 Hz
    110% rMT
    30 min5 cm anterior to motor cortex–Sham coilAllowedMonotherapyStable doses for 4 wk or no medication for 6–8 wk before
    Movahed et al.120 (2018)2 mA
    Electrode size NR
    20 minF4Left deltoidNRNot allowedMonotherapyNot allowed
    Nasiri et al.121 (2020)2 mA
    Electrode size 5 × 5
    30 minF4Left deltoidF3UP 12 sessionsMonotherapyNot allowed
    Notzon et al.88 (2015)15 Hz
    80% rMT
    3 min; 18 trains of 2 sF3–90° from skullVirtual reality exposureAugmentationNot allowed
    Prasko et al.122 (2007)1 Hz
    110% rMT
    30 min5 cm rostral to motor cortex–90° from skull, same intensityNRMonotherapyStable doses
    • EEG = electroencephalogram; F3 = 10–20 EEG position corresponding to the left dorsolateral prefrontal cortex; F4 = 10–20 EEG position corresponding to the right dorsolateral prefrontal cortex; FP2 = 10–20 EEG position corresponding to the supraorbital region; FPZ = 10–20 EEG position corresponding to the ventromedial prefrontal cortex; MNI = Montreal Neurological Institute; NR = not reported; P4 = 10–20 EEG position corresponding to the right posterior parietal cortex; rMT = resting motor threshold; UP = unified protocol.

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    Table 6

    Summary of stimulation protocol, statistical analyses, main results and additional groups and measures (part 1 of 2)

    StudyProtocolFollow-upStatistical analysisReported resultsAdditional groupsAdditional pre/post measures
    De Lima et al.86 (2019)5 consecutive days1 wkANOVA repeated-measuresAnxiety and depression symptoms did not differ between real and sham tDCS. Physical symptoms of stress were reduced at the end of treatment and at follow-up in the tDCS group v. the sham groupNoneAnxiety: BAI Global evaluation: PANAS
    Deppermann et al.115 (2014)5 daily sessions; 3 wkNRANOVA repeated-measuresNo differences in real v. sham rTMS. Both groups showed improvement in anxiety symptoms post-iTBS v. baselineHealthy controls; only for fNIRSPhysiological: CAQ Brain activation: fNIRS Cognitive: verbal fluency
    Diefenbach et al.116 (2016)5 daily sessions; 6 wk3 mo, 6 mo (only a subset not included in statistical analysis)ANOVA repeated- measures; planned contrastsAnxiety symptoms improved in post- v. pre- measurements in rTMS and sham groups that persisted at 3 mo follow-up only in the rTMS group. Worry and depressive symptoms improved only in the rTMS group at the end of treatment and at 3 mo follow-up. Brain activation increased after rTMS and tended to decrease after shamNoneAnxiety/mood: DASS-DEP Brain activation: fMRI during gambling task
    Dilkov et al.87 (2017)6 wk; 5 sessions/wk for the first 4 wk; during the wk 5, sessions reduced to 3 times/wk; during wk 6, sessions reduced to 2 times/wk2 wk and 6 wk after the end of treatmentANOVA repeated-measuresAnxiety and depressive symptoms improved in the stimulation v. sham condition at the end of treatment and the 2 follow-upsNoneGlobal evaluation: CGI
    Herrmann et al.117 (2017)2 sessions3 moANOVA repeated-measures; t test2 sessions of rTMS reduced anxiety and avoidance ratings compared to the sham groupNoneAnxiety: AQ-avoidance subscale; BAT
    Huang et al.118 (2018)10 consecutive days2 wk, 1 moANOVA repeated- measuresAnxiety, insomnia and depressive symptoms improved in the rTMS group v. the sham group at the end of treatment and the 2 follow-upsNoneNR
    Mantovani et al.119 (2013)5 d/wk; 4 wk double- blind + 4 weeks real*1, 3 and 6 moANOVA repeated- measures; t test4 weeks rTMS v. sham: improvement in panic symptoms but not depression. 8 weeks of rTMS v. pre- treatment: improvement in panic and depressive symptoms, global assessment, and social adjustmentNoneAnxiety: PDSS, PDSS-SR Mood: BDI; ZUNG-SAS Global evaluation: CGI; PGI; SASS
    Movahed et al.120 (2018)4 wk2 moANOVA repeated- measuresWorry, anxiety and depression scores were reduced after cathodal tDCS and pharmacotherapy v. sham tDCS. Pharmacotherapy was stronger than tDCS in reducing worry; tDCS was stronger in reducing depression. Anxiety symptoms did not differ after cathodal tDCS compared to pharmacotherapyPharmacotherapyNR
    Nasiri et al.121 (2020)10 daily sessions; 2 wk3 moMANCOVAWorry, anxiety and anxiety sensitivity improved after UP + tDCS v. UP alone at the end of treatment and at follow-upWaiting listAnxiety: ASI; IUS; PSWQ
    Notzon et al.88 (2015)Single sessionNRANOVA repeated- measuresiTBS increased sympathetic activity during the spider scene in both phobic and healthy participantsHealthy controls (real and sham)Anxiety: FSQ; ASI Global evaluation: IPQ; SUDS; DS Physiological: HR; SCL Brain activation: fNIRS
    Prasko et al.122 (2007)5 daily sessions; 2 wk2 wkNonparametric repeated- measures ANOVAAnxiety symptoms and psychopathology global scores improved after both real and sham rTMSNoneAnxiety: BAI Global evaluation: CGI
    • ANOVA = analysis of variance; AQ = Acrophobia Questionnaire; ASI = Anxiety Sensitivity Index; BAI = Beck Anxiety Inventory; BAT = Behavioral Avoidance Test; BDI = Beck Depression Inventory; CAQ = Cardiac Anxiety Questionnaire; CGI = Clinical Global Impression Scale; DASS-DEP = Depression-Anxiety Scales Depression Subscale; DS = Disgust Scale; fMRI = functional magnetic resonance imaging; fNIRS = functional near-infrared spectroscopy; FSQ = Fear of Spiders Questionnaire; HR = heart rate; IPQ = Igroup Presence Questionnaire; iTBS = intermittent theta burst stimulation; IUS = Intolerance of Uncertainty Scale; MANCOVA = multivariate analysis of covariance; NR = not reported; PANAS = Positive and Negative Affect Schedule; PDSS(−SR) = Panic Disorder Severity Scale (self-report); PGI = Patient Global Impression; PSWQ = Penn State Worry Questionnaire; rTMS = repetitive transcranial magnetic stimulation; SASS = Self-reported Social Adaptation Scale; SCL = skin conductance level; SUDS = Subjective Units of Discomfort Scale; tDCS = transcranial direct current stimulation; UP = unified protocol; ZUNG-SAS= Zung-Self Administered Scale.

    • ↵* In our analysis, we included data for the baseline and the first 4 weeks of rTMS treatment.

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    Table 7

    Summary of the results of the 3 meta-analyses

    ComparisonNo. of studiesEffect size summary (95% confidence interval)ZQ testI2 (%)Influence testEgger’s testKendall’s rank test
    Specific anxiety9−0.4858 (−0.8319 to −0.1398)−2.7517
    p = 0.006
    17.6384
    p = 0.040
    48.98None−1.2078
    p = 0.23
    −0.2889
    p = 0.29
    General anxiety90.8139 (−1.4484 to −0.1794)−2.5142
    p = 0.012
    41.0326
    p < 0.001
    80.50Dilkov et al.87 (2017)−0.3108
    p = 0.76
    −0.1667
    p = 0.61
    General anxiety*8−0.5684 (−1.0626 to −0.0742)−2.2541
    p = 0.024
    19.5887
    p = 0.007
    64.27None−0.1009
    p = 0.92
    −0.1429
    p = 0.72
    Depression7−0.9822 (−1.6177 to −0.3468)−3.0297
    p = 0.002
    23.4602
    p < 0.001
    74.42Dilkov et al.87 (2017)−0.9869
    p = 0.32
    −0.1429
    p = 0.77
    Depression*6−0.6433 (−0.9786 to −0.3081)−3.7616
    p < 0.001
    3.8846
    p = 0.57
    –None−0.7960
    p = 0.43
    −0.0667
    p > 0.99
    • ↵* Indicates results after outlier removal.

    • View popup
    Table 8:

    Results of the moderation analysis for specific and general anxiety scores and depression scores

    ModeratorSMD (95% CI)zpQ1
    Specific anxiety measure
     Session number−0.0414 (−0.1038 to 0.0209)−1.30190.191.6950
     Technique−0.2827 (−0.7443 to 0.1788)−1.20060.231.4415
     Target region−0.4963 (−1.2778 to 0.2852)−1.24470.211.5493
     Protocol type−0.4965 (−1.1366 to 0.1435)−1.52050.132.3118
    General anxiety measure
     Session number−0.0723 (−0.1811 to 0.0364)−1.30390.191.7001
     Technique−0.1830 (−1.2449 to 0.8790)−0.33770.740.1140
     Target region−0.8212 (−2.2992 to 0.6568)−1.08900.281.1858
     Protocol type0.2243 (−1.2106 to 1.6592)0.30640.760.0939
    Depression measure
     Session number−0.0777 (−0.1634 to 0.0080)−1.77600.076*3.1542
     Technique0.5794 (−0.7260 to 1.8847)0.86990.380.7567
     Target region−0.6709 (−2.9417 to 1.5998)−0.57910.560.3354
     Protocol type0.8540 (−0.5639 to 2.2718)1.18050.241.3935
     Comorbidity0.9563 (−0.3677 to 2.2803)1.41570.162.0042
    • CI = confidence interval; dlPFC = dorsolateral prefrontal cortex; iTBS = intermittent theta burst stimulation; rTMS = repetitive transcranial magnetic stimulation; SMD = standardized mean difference (effect size); tDCS = transcranial direct current stimulation. The applied technique (iTBS, rTMS, tDCS), target region (left vs. right dlPFC) and protocol type (excitatory v. inhibitory) moderators were categorical variables; session number was a numerical variable. For the depression outcome measure only, we computed whether the presence of comorbid depression influenced the outcome of the scores. z = z score associated with the SMD value; p = p value associated with the z score in the same row.

    • ↵* p < 0.10.

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Journal of Psychiatry and Neuroscience: 46 (6)
J Psychiatry Neurosci
Vol. 46, Issue 6
21 Dec 2021
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Effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders: a meta-analysis of sham or behaviour-controlled studies
Alessandra Vergallito, Alessia Gallucci, Alberto Pisoni, Mariacristina Punzi, Gabriele Caselli, Giovanni M. Ruggiero, Sandra Sassaroli, Leonor J. Romero Lauro
J Psychiatry Neurosci Nov 2021, 46 (6) E592-E614; DOI: 10.1503/jpn.210050

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Effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders: a meta-analysis of sham or behaviour-controlled studies
Alessandra Vergallito, Alessia Gallucci, Alberto Pisoni, Mariacristina Punzi, Gabriele Caselli, Giovanni M. Ruggiero, Sandra Sassaroli, Leonor J. Romero Lauro
J Psychiatry Neurosci Nov 2021, 46 (6) E592-E614; DOI: 10.1503/jpn.210050
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