Transcranial Random Noise Stimulation for the Acute Treatment of Depression: A Randomized Controlled Trial

Stevan Nikolin, Angelo Alonzo, Donel Martin, Veronica Gálvez, Sara Buten, Rohan Taylor, James Goldstein, Cristal Oxley, Dusan Hadzi-Pavlovic, Colleen K Loo, Stevan Nikolin, Angelo Alonzo, Donel Martin, Veronica Gálvez, Sara Buten, Rohan Taylor, James Goldstein, Cristal Oxley, Dusan Hadzi-Pavlovic, Colleen K Loo

Abstract

Background: Transcranial electrical stimulation has broad potential as a treatment for depression. Transcranial random noise stimulation, which delivers randomly fluctuating current intensities, may have greater cortical excitatory effects compared with other forms of transcranial electrical stimulation. We therefore aimed to investigate the antidepressant efficacy of transcranial random noise stimulation.

Methods: Depressed participants were randomly assigned by computer number generator to receive 20 sessions of either active or sham transcranial random noise stimulation over 4 weeks in a double-blinded, parallel group randomized-controlled trial. Transcranial random noise stimulation was delivered for 30 minutes with a direct current offset of 2 mA and a random noise range of 2 mA. Primary analyses assessed changes in depression severity using the Montgomery-Asperg Depression Rating Scale. Neuroplasticity, neuropsychological, and safety outcomes were analyzed as secondary measures.

Results: Sixty-nine participants were randomized, of which 3 discontinued treatment early, leaving 66 (sham n = 34, active n = 32) for per-protocol analysis. Depression severity scores reduced in both groups (Montgomery-Asperg Depression Rating Scale reduction in sham = 7.0 [95% CI = 5.0-8.9]; and active = 5.2 [95% CI = 3.2-7.3]). However, there were no differences between active and sham groups in the reduction of depressive symptoms or the number of participants meeting response (sham = 14.7%; active = 3.1%) and remission criteria (sham = 5.9%; active = 0%). Erythema, paresthesia, fatigue, and dizziness/light-headedness occurred more frequently in the active transcranial random noise stimulation group. Neuroplasticity, neuropsychological, and acute cognitive effects were comparable between groups.

Conclusion: Our results do not support the use of transcranial random noise stimulation with the current stimulation parameters as a therapeutic intervention for the treatment of depression.

Clinical trial registration at clinicaltrials: gov/NCT01792414.

© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Mood scores. Graph showing Montgomery-Asberg Depression Rating Scale (MADRS) scores (estimated marginal means ± SD) across rating time points, including the sham-controlled phase (from baseline to 4 weeks), open-label phase (from 4–8 weeks), and 1-month follow-up assessment following the final taper session. Dotted lines indicate sham transcranial random noise stimulation (tRNS) sessions delivered during the sham-controlled phase.

References

    1. Abe T, Miyaguchi S, Otsuru N, Onishi H (2019) The effect of transcranial random noise stimulation on corticospinal excitability and motor performance. Neurosci Lett 705:138–142.
    1. Ambrus GG, Paulus W, Antal A (2010) Cutaneous perception thresholds of electrical stimulation methods: comparison of tDCS and tRNS. Clin Neurophysiol 121:1908–1914.
    1. Beck AT, Steer RA, Brown GK (1996) Manual for beck Depression Inventory-II. San Antonio, TX: The Psychological Corporation.
    1. Bennabi D, Nicolier M, Monnin J, Tio G, Pazart L, Vandel P, Haffen E (2015) Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram. Clin Neurophysiol 126:1185–1189.
    1. Bikson M, et al. (2016) Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul 9:641–661.
    1. Blumberger DM, Tran LC, Fitzgerald PB, Hoy KE, Daskalakis ZJ (2012) A randomized double-blind sham-controlled study of transcranial direct current stimulation for treatment-resistant major depression. Front Psychiatry 3:74.
    1. Broadbent DE, Cooper PF, FitzGerald P, Parkes KR (1982) The Cognitive Failures Questionnaire (CFQ) and its correlates. Br J Clin Psychol 21:1–16.
    1. Brunoni AR, Amadera J, Berbel B, Volz MS, Rizzerio BG, Fregni F (2011) A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol 14:1133–1145.
    1. Brunoni AR, Valiengo L, Baccaro A, Zanão TA, de Oliveira JF, Goulart A, Boggio PS, Lotufo PA, Benseñor IM, Fregni F (2013a) The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 70:383–391.
    1. Brunoni AR, Ferrucci R, Bortolomasi M, Scelzo E, Boggio PS, Fregni F, Dell’Osso B, Giacopuzzi M, Altamura AC, Priori A (2013b) Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the major depressive episode: findings from a naturalistic study. Eur Psychiatry 28:356–361.
    1. Brunoni AR, Moffa AH, Fregni F, Palm U, Padberg F, Blumberger DM, Daskalakis ZJ, Bennabi D, Haffen E, Alonzo A, Loo CK (2016) Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br J Psychiatry 208:522–531.
    1. Brunoni AR, Moffa AH, Sampaio-Junior B, Borrione L, Moreno ML, Fernandes RA, Veronezi BP, Nogueira BS, Aparicio LVM, Razza LB, Chamorro R, Tort LC, Fraguas R, Lotufo PA, Gattaz WF, Fregni F, Benseñor IM; ELECT-TDCS Investigators (2017) Trial of electrical direct-current therapy versus escitalopram for depression. N Engl J Med 376:2523–2533.
    1. Castrén E, Hen R (2013) Neuronal plasticity and antidepressant actions. Trends Neurosci 36:259–267.
    1. Chaieb L, Antal A, Paulus W (2015) Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive. Front Neurosci 9:125.
    1. Chan HN, Alonzo A, Martin DM, Player M, Mitchell PB, Sachdev P, Loo CK (2012) Treatment of major depressive disorder by transcranial random noise stimulation: case report of a novel treatment. Biol Psychiatry 72:e9–e10.
    1. Contemori G, Trotter Y, Cottereau BR, Maniglia M (2019) tRNS boosts perceptual learning in peripheral vision. Neuropsychologia 125:129–136.
    1. Curatolo M, La Bianca G, Cosentino G, Baschi R, Salemi G, Talotta R, Romano M, Triolo G, De Tommaso M, Fierro B, Brighina F (2017) Motor cortex tRNS improves pain, affective and cognitive impairment in patients with fibromyalgia: preliminary results of a randomised sham-controlled trial. Clin Exp Rheumatol 35(Suppl 105):100–105.
    1. Delis DC, Kramer JH, Kaplan E, Ober BA (2000) California Verbal Learning Test. 2nd ed. San Antonio, TX: The Psychological Corporation.
    1. Delis DC, Kaplan E, Kramer JH (2001) Delis-Kaplan Executive Function System (D-KEFS). San Antonio, TX: The Psychological Corporation.
    1. Duman RS, Aghajanian GK, Sanacora G, Krystal JH (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238–249.
    1. Endicott J, Nee J, Harrison W, Blumenthal R (1993) Quality of life enjoyment and satisfaction questionnaire: a new measure. Psychopharmacol Bull 29:321–326.
    1. Fekadu A, Wooderson S, Donaldson C, Markopoulou K, Masterson B, Poon L, Cleare AJ (2009) A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry 70:177–184.
    1. Fertonani A, Pirulli C, Miniussi C (2011) Random noise stimulation improves neuroplasticity in perceptual learning. J Neurosci 31:15416–15423.
    1. Fonteneau C, Mondino M, Arns M, Baeken C, Bikson M, Brunoni AR, Burke MJ, Neuvonen T, Padberg F, Pascual-Leone A, Poulet E, Ruffini G, Santarnecchi E, Sauvaget A, Schellhorn K, Suaud-Chagny MF, Palm U, Brunelin J (2019) Sham tDCS: a hidden source of variability? Reflections for further blinded, controlled trials. Brain Stimul 12:668–673.
    1. Ghin F, Pavan A, Contillo A, Mather G (2018) The effects of high-frequency transcranial random noise stimulation (hf-tRNS) on global motion processing: an equivalent noise approach. Brain Stimul 11:1263–1275.
    1. Goto Y, Yang CR, Otani S (2010) Functional and dysfunctional synaptic plasticity in prefrontal cortex: roles in psychiatric disorders. Biol Psychiatry 67:199–207.
    1. Guarienti F, Caumo W, Shiozawa P, Cordeiro Q, Boggio PS, Benseñor IM, Lotufo PA, Bikson M, Brunoni AR (2015) Reducing transcranial direct current stimulation-induced erythema with skin pretreatment: considerations for sham-controlled clinical trials. Neuromodulation 18:261–265.
    1. Guy W. (1976) ECDEU assessment manual for psychopharmacology. Rockville, MD: U.S. Department of Health, Education, and Welfare.
    1. Haesebaert F, Mondino M, Saoud M, Poulet E, Brunelin J (2014) Efficacy and safety of fronto-temporal transcranial random noise stimulation (tRNS) in drug-free patients with schizophrenia: a case study. Schizophr Res 159:251–252.
    1. Haq AU, Sitzmann AF, Goldman ML, Maixner DF, Mickey BJ (2015) Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors. J Clin Psychiatry 76:1374–1384.
    1. Hayward KS, Brauer SG, Ruddy KL, Lloyd D, Carson RG (2017) Repetitive reaching training combined with transcranial random noise stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series. J Neuroeng Rehabil 14:46.
    1. Ho KA, Taylor JL, Loo CK (2015) Comparison of the effects of transcranial random noise stimulation and transcranial direct current stimulation on motor cortical excitability. J Ect 31:67–72.
    1. Inukai Y, Saito K, Sasaki R, Tsuiki S, Miyaguchi S, Kojima S, Masaki M, Otsuru N, Onishi H (2016) Comparison of three non-invasive transcranial electrical stimulation methods for increasing cortical excitability. Front Hum Neurosci 10:668.
    1. Jooss A, Haberbosch L, Köhn A, Rönnefarth M, Bathe-Peters R, Kozarzewski L, Fleischmann R, Scholz M, Schmidt S, Brandt SA (2019) Motor task-dependent dissociated effects of transcranial random noise stimulation in a finger-tapping task versus a Go/No-Go task on corticospinal excitability and task performance. Front Neurosci 13:161.
    1. Kreuzer PM, Vielsmeier V, Poeppl TB, Langguth B (2017) A case report on red ear syndrome with tinnitus successfully treated with transcranial random noise stimulation. Pain Physician 20:E199–E205.
    1. Kuhn M, Mainberger F, Feige B, Maier JG, Wirminghaus M, Limbach L, Mall V, Jung NH, Reis J, Klöppel S, Normann C, Nissen C (2016) State-dependent partial occlusion of cortical LTP-like plasticity in major depression. Neuropsychopharmacology 41:1521–1529.
    1. Liu W, Ge T, Leng Y, Pan Z, Fan J, Yang W, Cui R (2017) The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural Plast 2017:6871089.
    1. Loo CK, Sachdev P, Martin D, Pigot M, Alonzo A, Malhi GS, Lagopoulos J, Mitchell P (2010) A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression. Int J Neuropsychopharmacol 13:61–69.
    1. Loo CK, Alonzo A, Martin D, Mitchell PB, Galvez V, Sachdev P (2012) Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry 200:52–59.
    1. Loo CK, Husain MM, McDonald WM, Aaronson S, O’Reardon JP, Alonzo A, Weickert CS, Martin DM, McClintock SM, Mohan A, Lisanby SH; International Consortium of Research in tDCS (ICRT) (2018) International randomized-controlled trial of transcranial direct current stimulation in depression. Brain Stimul 11:125–133.
    1. Mammarella N, Di Domenico A, Palumbo R, Fairfield B (2017) Self-generation and positivity effects following transcranial random noise stimulation in medial prefrontal cortex: a reality monitoring task in older adults. Cortex 91:186–196.
    1. Mancuso M, Abbruzzese L, Canova S, Landi G, Rossi S, Santarnecchi E (2017) Transcranial random noise stimulation does not improve behavioral and neurophysiological measures in patients with subacute vegetative-unresponsive wakefulness state (VS-UWS). Front Hum Neurosci 11:524.
    1. McFadden JL, Borckardt JJ, George MS, Beam W (2011) Reducing procedural pain and discomfort associated with transcranial direct current stimulation. Brain Stimul 4:38–42.
    1. Moffa AH, Brunoni AR, Fregni F, Palm U, Padberg F, Blumberger DM, Daskalakis ZJ, Bennabi D, Haffen E, Alonzo A, Loo CK (2017) Safety and acceptability of transcranial direct current stimulation for the acute treatment of major depressive episodes: analysis of individual patient data. J Affect Disord 221:1–5.
    1. Moliadze V, Fritzsche G, Antal A (2014) Comparing the efficacy of excitatory transcranial stimulation methods measuring motor evoked potentials. Neural Plast 2014:837141.
    1. Montagne B, Kessels RP, De Haan EH, Perrett DI (2007) The emotion recognition task: a paradigm to measure the perception of facial emotional expressions at different intensities. Percept Mot Skills 104:589–598.
    1. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389.
    1. Moss F, Ward LM, Sannita WG (2004) Stochastic resonance and sensory information processing: a tutorial and review of application. Clin Neurophysiol 115:267–281.
    1. Mutz J, Edgcumbe DR, Brunoni AR, Fu CHY (2018) Efficacy and acceptability of non-invasive brain stimulation for the treatment of adult unipolar and bipolar depression: a systematic review and meta-analysis of randomised sham-controlled trials. Neurosci Biobehav Rev 92:291–303.
    1. Nikolin S, Huggins C, Martin D, Alonzo A, Loo CK (2018) Safety of repeated sessions of transcranial direct current stimulation: a systematic review. Brain Stimul 11:278–288.
    1. Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A (2008) Transcranial direct current stimulation: state of the art 2008. Brain Stimul 1:206–223.
    1. Nitsche MA, Paulus W (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57:1899–1901.
    1. Noda Y, Zomorrodi R, Vila-Rodriguez F, Downar J, Farzan F, Cash RFH, Rajji TK, Daskalakis ZJ, Blumberger DM (2018) Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation. Depress Anxiety 35:448–456.
    1. Palm U, Schiller C, Fintescu Z, Obermeier M, Keeser D, Reisinger E, Pogarell O, Nitsche MA, Möller HJ, Padberg F (2012) Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study. Brain Stimul 5:242–251.
    1. Palm U, Chalah MA, Padberg F, Al-Ani T, Abdellaoui M, Sorel M, Dimitri D, Créange A, Lefaucheur JP, Ayache SS (2016) Effects of transcranial random noise stimulation (tRNS) on affect, pain and attention in multiple sclerosis. Restor Neurol Neurosci 34:189–199.
    1. Pavan A, Ghin F, Contillo A, Milesi C, Campana G, Mather G (2019) Modulatory mechanisms underlying high-frequency transcranial random noise stimulation (hf-tRNS): a combined stochastic resonance and equivalent noise approach. Brain Stimul 12:967–977.
    1. Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88–109.
    1. Player MJ, Taylor JL, Alonzo A, Loo CK (2012) Paired associative stimulation increases motor cortex excitability more effectively than theta-burst stimulation. Clin Neurophysiol 123:2220–2226.
    1. Player MJ, Taylor JL, Weickert CS, Alonzo A, Sachdev P, Martin D, Mitchell PB, Loo CK (2013) Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology 38:2101–2108.
    1. Player MJ, Taylor JL, Weickert CS, Alonzo A, Sachdev PS, Martin D, Mitchell PB, Loo CK (2014) Increase in PAS-induced neuroplasticity after a treatment course of transcranial direct current stimulation for depression. J Affect Disord 167:140–147.
    1. Popescu T, Krause B, Terhune DB, Twose O, Page T, Humphreys G, Cohen Kadosh R (2016) Transcranial random noise stimulation mitigates increased difficulty in an arithmetic learning task. Neuropsychologia 81:255–264.
    1. Rufener KS, Ruhnau P, Heinze HJ, Zaehle T (2017) Transcranial random noise stimulation (tRNS) shapes the processing of rapidly changing auditory information. Front Cell Neurosci 11:162.
    1. Rufener KS, Geyer U, Janitzky K, Heinze HJ, Zaehle T (2018) Modulating auditory selective attention by non-invasive brain stimulation: differential effects of transcutaneous vagal nerve stimulation and transcranial random noise stimulation. Eur J Neurosci 48:2301–2309.
    1. Ruff RM, Allen CC (1996) Ruff 2 and 7 selective attention test professional manual. Odessa, FL: Psychological Assessment Resources, Inc.
    1. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M; STAR*D Study Team (2006a) Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354:1231–1242.
    1. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006b) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917.
    1. Salemi G, Vazzoler G, Ragonese P, Bianchi A, Cosentino G, Croce G, Gangitano M, Portera E, Realmuto S, Fierro B, Brighina F (2019) Application of tRNS to improve multiple sclerosis fatigue: a pilot, single-blind, sham-controlled study. J Neural Transm (Vienna) 126:795–799.
    1. Sampaio-Junior B, Tortella G, Borrione L, Moffa AH, Machado-Vieira R, Cretaz E, Fernandes da Silva A, Fraguas R, Aparício LV, Klein I, Lafer B, Goerigk S, Benseñor IM, Lotufo PA, Gattaz WF, Brunoni AR (2018) Efficacy and safety of transcranial direct current stimulation as an add-on treatment for bipolar depression: a randomized clinical trial. JAMA Psychiatry 75:158–166.
    1. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809.
    1. Schulz KF, Altman DG, Moher D; CONSORT Group (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 8:18.
    1. Shalev N, De Wandel L, Dockree P, Demeyere N, Chechlacz M (2018) Beyond time and space: the effect of a lateralized sustained attention task and brain stimulation on spatial and selective attention. Cortex 107:131–147.
    1. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33;quiz 34–57.
    1. Smith A. (1991) Symbol digit modalities test. Los Angeles, CA: Western Psychological Services.
    1. Snowball A, Tachtsidis I, Popescu T, Thompson J, Delazer M, Zamarian L, Zhu T, Cohen Kadosh R (2013) Long-term enhancement of brain function and cognition using cognitive training and brain stimulation. Curr Biol 23:987–992.
    1. Szymkowicz SM, McLaren ME, Suryadevara U, Woods AJ (2016) Transcranial direct current stimulation use in the treatment of neuropsychiatric disorders: a brief review. Psychiatr Ann 46:642–646.
    1. Terney D, Chaieb L, Moliadze V, Antal A, Paulus W (2008) Increasing human brain excitability by transcranial high-frequency random noise stimulation. J Neurosci 28:14147–14155.
    1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M; STAR*D Study Team (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40.
    1. Tyler SC, Contò F, Battelli L (2018) Rapid improvement on a temporal attention task within a single session of high-frequency transcranial random noise stimulation. J Cogn Neurosci 30:656–666.
    1. van der Groen O, Tang MF, Wenderoth N, Mattingley JB (2018) Stochastic resonance enhances the rate of evidence accumulation during combined brain stimulation and perceptual decision-making. Plos Comput Biol 14:e1006301.
    1. van der Groen O, Wenderoth N (2017) Random noise stimulation of the cortex: stochastic resonance enhances central mechanisms of perception. Brain Stimul 10:e4.
    1. Vanneste S, Fregni F, De Ridder D (2013) Head-to-head comparison of transcranial random noise stimulation, transcranial AC stimulation, and transcranial DC stimulation for tinnitus. Front Psychiatry 4:158.
    1. Wechsler D. (2008) Wechsler adult intelligence scale. 4th ed. San Antonio, TX: Pearson.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever