Online Effects of Transcranial Direct Current Stimulation in Real Time on Human Prefrontal and Striatal Metabolites

  • Antoine Hone-Blanchet
    Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale, Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec, Faculté de médecine, Université Laval, Quebec City, Quebec, Canada
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  • Richard A. Edden
    Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland

    F.M. Kirby Center for Functional Brain Imaging, Baltimore, Maryland
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  • Shirley Fecteau
    Address correspondence to Shirley Fecteau, Ph.D., Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale, Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec, Faculté de médecine, Université Laval, 2325 rue de l’Université, Quebec City, Quebec G1V 0A6, Canada.
    Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale, Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec, Faculté de médecine, Université Laval, Quebec City, Quebec, Canada

    Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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Published:November 19, 2015DOI:



      Studies have reported that transcranial direct current stimulation (tDCS) can modulate human behaviors, symptoms, and neural activity; however, the neural effects during stimulation are unknown. Most studies compared the effects of tDCS before and after stimulation. The objective of our study was to measure the neurobiological effect of a single tDCS dose during stimulation.


      We conducted an online and offline protocol combining tDCS and magnetic resonance spectroscopy (MRS) in 17 healthy participants. We applied anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) and cathodal tDCS over the right DLPFC for 30 minutes, one of the most common montages used with tDCS. We collected MRS measurements in the left DLPFC and left striatum during tDCS and an additional MRS measurement in the left DLPFC immediately after the end of stimulation.


      During stimulation, active tDCS, as compared with sham tDCS, elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine but did not induce significant differences in prefrontal or striatal gamma-aminobutyric acid level. Immediately after stimulation, active tDCS, as compared with sham tDCS, did not significantly induce differences in glutamate + glutamine, N-acetylaspartate, or gamma-aminobutyric acid levels in the left DLPFC.


      These observations indicate that tDCS over the DLPFC has fast excitatory effects, acting on prefrontal and striatal transmissions, and these effects are short lived. One may postulate that repeated sessions of tDCS might induce similar longer lasting effects of elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine levels, which may contribute to its behavioral and clinical effects.


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        • Nihonsugi T.
        • Ihara A.
        • Haruno M.
        Selective increase of intention-based economic decisions by noninvasive brain stimulation to the dorsolateral prefrontal cortex.
        J Neurosci. 2015; 35: 3412-3419
        • Metuki N.
        • Sela T.
        • Lavidor M.
        Enhancing cognitive control components of insight problems solving by anodal tDCS of the left dorsolateral prefrontal cortex.
        Brain Stimul. 2012; 5: 110-115
        • Zaehle T.
        • Sandmann P.
        • Thorne J.D.
        • Jäncke L.
        • Herrmann C.S.
        Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: Combined behavioural and electrophysiological evidence.
        BMC Neurosci. 2011; 12: 2
        • Horvath J.C.
        • Forte J.D.
        • Carter O.
        Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review.
        Neuropsychologia. 2015; 66: 213-236
        • Horvath J.C.
        • Forte J.D.
        • Carter O.
        Quantitative review finds no evidence of cognitive effects in healthy populations from single-session transcranial direct current stimulation (tDCS).
        Brain Stimul. 2015; 8: 535-550
        • Stagg C.J.
        • Best J.G.
        • Stephenson M.C.
        • O’Shea J.
        • Wylezinska M.
        • Kincses Z.T.
        • et al.
        Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation.
        J Neurosci. 2009; 29: 5202-5206
        • George M.S.
        • Aston-Jones G.
        Noninvasive techniques for probing neurocircuitry and treating illness: Vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).
        Neuropsychopharmacology. 2012; 35: 301-316
        • Brunoni A.R.
        • Nitsche M.A.
        • Bolognini N.
        • Bikson M.
        • Wagner T.
        • Merabet L.
        • et al.
        Clinical research with transcranial direct current stimulation (tDCS): Challenges and future directions.
        Brain Stimul. 2012; 5: 175-195
        • Brunoni A.R.
        • Valiengo L.
        • Baccaro A.
        • Zañao T.A.
        • de Oliveira J.F.
        • Goulart A.
        • et al.
        The sertraline vs electrical current therapy for treating depression clinical study.
        JAMA Psychiatry. 2013; 70: 383-391
        • Loo C.
        • Alonzo A.
        • Martin D.
        • Mitchell P.B.
        • Galvez V.
        • Sachdev P.
        Transcranial direct current stimulation for depression: 3-week, randomized, sham-controlled trial.
        Br J Psychiatry. 2012; 200: 52-59
        • Brunelin J.
        • Mondino M.
        • Gassab L.
        • Haesebaert F.
        • Gaha L.
        • Suaud-Chagny M.F.
        • et al.
        Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia.
        Am J Psychiatry. 2012; 169: 719-724
        • Jansen J.M.
        • Daams J.G.
        • Koeter M.W.J.
        • Veltman D.J.
        • van den Brink W.
        • Goudriaan A.E.
        Effects of non-invasive neurostimulation on craving: A meta-analysis.
        Neurosci Biobehav Rev. 2013; 37: 2472-2480
        • Liebetanz D.
        • Nitsche M.A.
        • Tergau F.
        • Paulus W.
        Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability.
        Brain. 2002; 125: 2238-2247
        • Nitsche M.A.
        • Liebetanz D.
        • Schlitterlau A.
        • Henschkle U.
        • Fricke K.
        • Fromman K.
        • et al.
        GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans.
        Eur J Neurosci. 2004; 19: 2720-2726
        • Urenjak J.
        • Williams S.R.
        • Gadian D.G.
        • Noble M.
        Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types.
        J Neurosci. 1993; 13: 981-989
        • Moffett J.R.
        • Ross B.
        • Arun P.
        • Madhavarao C.N.
        • Namboodiri A.M.
        N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology.
        Prog Neurobiol. 2007; 81: 89-131
        • Kelley A.E.
        Memory and addiction: Shared neural circuitry and molecular mechanisms.
        Neuron. 2004; 44: 161-179
        • Gandiga P.C.
        • Hummel F.C.
        • Cohen L.
        Transcranial DC stimulation (tDCS): A tool for double-blind sham-controlled clinical studies in brain stimulation.
        Clin Neurophysiol. 2006; 117: 845-850
        • Nitsche M.
        • Paulus W.
        Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans.
        Neurology. 2001; 57: 1899-1901
        • Mescher M.
        • Merkle H.
        • Kirsch J.
        • Garwood M.
        Simultaneous in vivo spectral editing and water suppression.
        NMR Biomed. 1998; 11: 266-272
        • Puts N.A.
        • Edden R.A.
        In vivo magnetic resonance spectroscopy of GABA: A methodological review.
        Prog Nucl Magn Reson Spectrosc. 2012; 60: 29-41
        • Mullins P.G.
        • McGonigle D.J.
        • O’Gorman R.L.
        • Puts N.A.
        • Vidyasagar R.
        • Evans C.J.
        • et al.
        Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA.
        Neuroimage. 2014; 86: 43-52
        • Wilson M.
        • Reynolds G.
        • Kauppinen R.A.
        • Arvanatis T.N.
        • Peet A.C.
        A constrained least-squares approach to the automated quantitation of in vivo 1H magnetic resonance spectroscopy data.
        Magn Reson Med. 2011; 65: 1-12
        • Edden R.A.
        • Puts N.A.
        • Harris A.D.
        • Barker P.B.
        • Evans C.J.
        Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid-edited MR spectroscopy spectra.
        J Magn Reson Imaging. 2013; 40: 1445-1452
        • Harris A.J.
        • Puts N.A.
        • Edden R.A.
        Tissue correction for GABA-edited MRS: Considerations of voxel composition, tissue segmentation and tissue relaxation.
        J Magn Reson Imaging. 2015; 42: 1431-1440
        • Nitsche M.A.
        • Jaussi W.
        • Liebetanz D.
        • Lang N.
        • Tergau F.
        • Paulus W.
        Consolidation of human motor cortical neuroplasticity by D-cycloserine.
        Neuropsychopharmacology. 2004; 29: 1573-1578
        • Van der Graaf M.
        In vivo magnetic resonance spectroscopy: Basic methodology and clinical applications.
        Eur Biophys J. 2010; 39: 527-540
        • Gruber S.
        • Frey R.
        • Mlyranick V.
        • Stadlbauer A.
        • Heiden A.
        • Kasper S.
        • et al.
        Quantification of metabolic differences in the brain of depressive patients and controls obtained by 1H-MRS at 3 Tesla.
        Invest Radiol. 2003; 38: 403-410
        • Mondino M.
        • Brunelin J.
        • Poulet E.
        N-acetyl-aspartate level is decreased in the prefrontal cortex in subjects at-risk for schizophrenia.
        Front Psychiatry. 2013; 4: 1-6
        • Steen R.G.
        • Hamer R.M.
        • Lieberman J.A.
        Measurements of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: A systematic review and meta-analysis.
        Neuropsychopharmacology. 2005; 30: 1949-1962
        • Kronenberg G.
        • Ende G.
        • Alm B.
        • Deuschle M.
        • Heuser I.
        • Colla M.
        Increased NAA and reduced choline levels in the anterior cingulum following chronic methyphenidate.
        Eur Arch Psychiatry Clin Neurosci. 2008; 258: 446-450
        • Wiguna T.
        • Guerrero A.
        • Wibisono S.
        • Sastroasmoro S.
        Effect of 12-week administration of 20-mg long-acting methylphenidate on Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr rations in the prefrontal cortices on school-age children in Indonesia: a study using 1H resonance spectroscopy (MRS).
        Clin Neuropharmacol. 2012; 35: 81-85
        • Ertugrul A.
        • Volkan-Salanci B.
        • Basar K.
        • Oguz K.K.
        • Demir B.
        • Ergun E.L.
        • et al.
        The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: Relationship with treatment response.
        Psychiatry Res. 2009; 174: 121-129
        • Fregni F.
        • Potvin K.
        • Dasilva D.
        • Wang X.
        • Lenkinski R.E.
        • Freedman S.D.
        • Pascual-Leone A.
        Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain.
        Eur J Pain. 2011; 15: 53-60
        • Clarke V.P.
        • Coffman B.A.
        • Trumbo M.C.
        • Gasparovic C.
        Transcranial direct current stimulation (tDCS) produces localized and specific alterations in neurochemistry: A 1H magnetic resonance spectroscopy study.
        Neurosci Lett. 2011; 500: 67-71
        • Kalivas P.W.
        • Duffy P.
        • Barry J.
        Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes.
        J Pharmacol Exp Ther. 1989; 251: 378-387
        • Shepherd G.M.G.
        Corticostriatal connectivity and its role in disease.
        Nat Rev Neurosci. 2013; 14: 278-291
        • Koob G.
        • Volkow N.D.
        Neurocircuitry of addiction.
        Neuropsychopharmacology. 2009; 35: 217-238
        • Fornito A.
        • Zalesky A.
        • Pantelis C.
        • Bullmore E.T.
        Schizophrenia, neuroimaging and connectomics.
        Neuroimage. 2012; 4: 2296-2314
        • Foerde K.
        • Poldrack R.A.
        • Khan B.J.
        • Bookheimer S.Y.
        • Bilder R.M.
        • Guthrie D.
        • et al.
        Selective corticostriatal dysfunction in schizophrenia: Examination of motor and cognitive skill learning.
        Neuropsychology. 2008; 22: 100-109
        • Hasler G.
        • van der Veen J.W.
        • Tumonis T.
        • Meyers N.
        • Shen J.
        • Drevets W.C.
        Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy.
        Arch Gen Psychiatry. 2007; 64: 193-200
        • Abdallah C.G.
        • Jiang L.
        • De Feyter H.M.
        • Fasula M.
        • Krystal J.H.
        • Rothman D.L.
        • et al.
        Glutamate metabolism in major depressive disorder.
        Am J Psychiatry. 2014; 171: 1320-1327

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