Abstract
In the absence of effective therapies for dementia and its precursors, enhancing neuroplasticity by means of non-invasive brain stimulation such as anodal transcranial direct current stimulation (atDCS) might be a promising approach to counteract or delay the onset of cognitive decline, but effect sizes have been moderate so far. Previous reports indicate that increasing serotonin levels may enhance atDCS-induced neuroplasticity. However, evidence for serotonergic modulation of atDCS effects on memory is still lacking. Here, we conducted a double-blind, randomized, sham-/placebo-controlled trial to investigate the impact of a selective serotonin reuptake inhibitor (SSRI; single dose of 20 mg citalopram) and atDCS over the right temporoparietal cortex (1 mA, 20 min) on memory formation. Twenty young and 20 older subjects completed an object-location learning task in each of the four conditions: sham+placebo, sham+SSRI, atDCS+placebo, and atDCS+SSRI. Outcome measures were performance in immediate (primary outcome) and delayed cued recall. While we found an SSRI effect, but no statistically significant effect of atDCS on immediate recall scores, young and older adults benefited most from the combined application (comparisons: atDCS+SSRI>atDCS+placebo and atDCS+SSRI>sham+placebo). Thus, our data provide evidence that atDCS improves memory formation if serotonergic neurotransmission is enhanced simultaneously. Further studies are needed to assess whether these findings extend to clinical populations with memory impairment and translate into clinically relevant improvements after long-term serotonergic enhancement and repeated stimulation.
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References
Anguera JA, Boccanfuso J, Rintoul JL, Al-Hashimi O, Faraji F, Janowich J et al (2013). Video game training enhances cognitive control in older adults. Nature 501: 97–101.
Barbas D, DesGroseillers L, Castellucci VF, Carew TJ, Marinesco S (2003). Multiple serotonergic mechanisms contributing to sensitization in aplysia: evidence of diverse serotonin receptor subtypes. Learn Mem 10: 373–386.
Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000). Citalopram—a review of pharmacological and clinical effects. J Psychiatry Neurosci 25: 241–254.
Boggio PS, Khoury LP, Martins DC, Martins OE, de Macedo EC, Fregni F (2009). Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J Neurol Neurosurg Psychiatry 80: 444–447.
Butters MA, Becker JT, Nebes RD, Zmuda MD, Mulsant BH, Pollock BG et al (2000). Changes in cognitive functioning following treatment of late-life depression. Am J Psychiatry 157: 1949–1954.
Butters MA, Whyte EM, Nebes RD, Begley AE, Dew MA, Mulsant BH et al (2004). The nature and determinants of neuropsychological functioning in late-life depression. Arch Gen Psychiatry 61: 587–595.
Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C et al (2011). Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 10: 123–130.
Coffman BA, Clark VP, Parasuraman R (2014). Battery powered thought: enhancement of attention, learning, and memory in healthy adults using transcranial direct current stimulation. Neuroimage 85: 895–908.
Cohen Kadosh R, Soskic S, Iuculano T, Kanai R, Walsh V (2010). Modulating neuronal activity produces specific and long-lasting changes in numerical competence. Curr Biol 20: 2016–2020.
Doraiswamy PM, Krishnan KRR, Oxman T, Jenkyn LR, Coffey DJ, Burt T et al (2003). Does antidepressant therapy improve cognition in elderly depressed patients? J Gerontol A Biol Sci Med Sci 58: 1137–1144.
Ferrucci R, Mameli F, Guidi I, Mrakic-Sposta S, Vergari M, Marceglia S et al (2008). Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology 71: 493–498.
Floel A (2014). tDCS-enhanced motor and cognitive function in neurological diseases. Neuroimage 85: 934–947.
Floel A, Meinzer M, Kirstein R, Nijhof S, Deppe M, Knecht S et al (2011). Short-term anomia training and electrical brain stimulation. Stroke 42: 2065–2067.
Floel A, Rosser N, Michka O, Knecht S, Breitenstein C (2008). Noninvasive brain stimulation improves language learning. J Cogn Neurosci 20: 1415–1422.
Floel A, Suttorp W, Kohl O, Kurten J, Lohmann H, Breitenstein C et al (2012). Non-invasive brain stimulation improves object-location learning in the elderly. Neurobiol Aging 33: 1682–1689.
Foehring RC, Lorenzon NM (1999). Neuromodulation, development and synaptic plasticity. Can J Exp Psychol 53: 45–61.
Fregni F, Nitsche MA, Loo CK, Brunoni AR, Marangolo P, Leite J et al (2015). Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel. Clin Res Regul Aff 32: 22–35.
Gandiga PC, Hummel FC, Cohen LG (2006). Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 117: 845–850.
Horvath JC, Forte JD, Carter O (2015a). 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 66: 213–236.
Horvath JC, Forte JD, Carter O (2015b). Quantitative review finds no evidence of cognitive effects in healthy populations from single-session transcranial direct current stimulation (tDCS). Brain Stimul 8: 535–550.
Invernizzi R, Velasco C, Bramante M, Longo A, Samanin R (1997). Effect of 5-HT1A receptor antagonists on citalopram-induced increase in extracellular serotonin in the frontal cortex, striatum and dorsal hippocampus. Neuropharmacology 36: 467–473.
Jacobs BL, Fornal CA (1997). Serotonin and motor activity. Curr Opin Neurobiol 7: 820–825.
Johnson PC (2014). Extension of Nakagawa & Schielzeth's R2 GLMM to random slopes models. Methods Ecol Evol 5: 944–946.
Jonassen R, Chelnokova O, Harmer C, Leknes S, Landro NI (2015). A single dose of antidepressant alters eye-gaze patterns across face stimuli in healthy women. Psychopharmacology 232: 953–958.
Klaassens BL, van Gorsel HC, Khalili-Mahani N, van der Grond J, Wyman BT, Whitcher B et al (2015). Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity. Neuroimage 122: 440–450.
Kulzow N, Kerti L, Witte VA, Kopp U, Breitenstein C, Floel A (2014). An object location memory paradigm for older adults with and without mild cognitive impairment. J Neurosci Methods 237: 16–25.
Kulzow N, Witte AV, Kerti L, Grittner U, Schuchardt JP, Hahn A et al (2016). Impact of omega-3 fatty acid supplementation on memory functions in healthy older adults. J Alzheimers Dis 51: 713–725.
Kuo HI, Paulus W, Batsikadze G, Jamil A, Kuo MF, Nitsche MA (2016). Chronic enhancement of serotonin facilitates excitatory transcranial direct current stimulation-induced neuroplasticity. Neuropsychopharmacology 41: 1223–1230.
Kuo MF, Paulus W, Nitsche MA (2008). Boosting focally-induced brain plasticity by dopamine. Cereb Cortex 18: 648–651.
Liebetanz D, Nitsche MA, Tergau F, Paulus W (2002). Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain 125: 2238–2247.
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010). Alzheimer's disease: clinical trials and drug development. Lancet Neurol 9: 702–716.
Meinzer M, Darkow R, Lindenberg R, Floel A (2016). Electrical stimulation of the motor cortex enhances treatment outcome in post-stroke aphasia. Brain 139: 1152–1163.
Meinzer M, Jahnigen S, Copland DA, Darkow R, Grittner U, Avirame K et al (2014). Transcranial direct current stimulation over multiple days improves learning and maintenance of a novel vocabulary. Cortex 50: 137–147.
Meinzer M, Lindenberg R, Antonenko D, Flaisch T, Floel A (2013). Anodal transcranial direct current stimulation temporarily reverses age-associated cognitive decline and functional brain activity changes. J Neurosci 33: 12470–12478.
Miniussi C, Harris JA, Ruzzoli M (2013). Modelling non-invasive brain stimulation in cognitive neuroscience. Neurosci Biobehav Rev 37: 1702–1712.
Nakagawa S, Schielzeth H (2013). A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol 4: 133–142.
Nebes RD, Pollock BG, Houck PR, Butters MA, Mulsant BH, Zmuda MD et al (2003). Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine. J Psychiatr Res 37: 99–108.
Nitsche MA, Doemkes S, Karakose T, Antal A, Liebetanz D, Lang N et al (2007). Shaping the effects of transcranial direct current stimulation of the human motor cortex. J Neurophysiol 97: 3109–3117.
Nitsche MA, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W (2004). Consolidation of human motor cortical neuroplasticity by d-cycloserine. Neuropsychopharmacology 29: 1573–1578.
Nitsche MA, Kuo MF, Karrasch R, Wachter B, Liebetanz D, Paulus W (2009). Serotonin affects transcranial direct current-induced neuroplasticity in humans. Biol Psychiatry 66: 503–508.
Oldfield RC (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9: 97–113.
Outhred T, Das P, Felmingham KL, Bryant RA, Nathan PJ, Malhi GS et al (2014). Impact of acute administration of escitalopram on the processing of emotional and neutral images: a randomized crossover fMRI study of healthy women. J Psychiatry Neurosci 39: 267–275.
Poreisz C, Boros K, Antal A, Paulus W (2007). Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull 72: 208–214.
Postma A, Kessels RPC, van Asselen M (2008). How the brain remembers and forgets where things are: the neurocognition of object-location memory. Neurosci Biobehav Rev 32: 1339–1345.
Prehn K, Floel A (2015). Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS. Front Cell Neurosci 9: 355.
Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E et al (2009). Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc Natl Acad Sci USA 106: 1590–1595.
Savaskan E, Muller SE, Bohringer A, Schulz A, Schachinger H (2008). Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients. Int J Neuropsychopharmacol 11: 381–388.
Shin YI, Foerster Á, Nitsche MA (2015). Transcranial direct current stimulation (tDCS) - application in neuropsychology. Neuropsychologia 69: 154–175.
Siepmann T, Penzlin AI, Kepplinger J, Illigens BM, Weidner K, Reichmann H et al (2015). Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence. Brain Behav 5: e00373.
Sommer T, Rose M, Weiller C, Buchel C (2005). Contributions of occipital, parietal and parahippocampal cortex to encoding of object-location associations. Neuropsychologia 43: 732–743.
Stern RA, Arruda JE, Hooper CR, Wolfner GD, Morey CE (1997). Visual analogue mood scales to measure internal mood state in neurologically impaired patients: description and initial validity evidence. Aphasiology 11: 59–71.
Takahashi E, Ohki K, Kim DS (2008). Dissociated pathways for successful memory retrieval from the human parietal cortex: anatomical and functional connectivity analyses. Cereb Cortex 18: 1771–1778.
van Asselen M, Kessels RPC, Kappelle LJ, Postma A (2008). Categorical and coordinate spatial representations within object-location memory. Cortex 44: 249–256.
Verbeke G, Molenberghs G (2000) Linear Mixed Models for Longitudinal Data. Springer: New York.
Williams E (1949). Experimental designs balanced for the estimation of residual effects of treatments. Aust J Sci Res 2: 149–168.
Acknowledgements
We would like to thank Nadine Külzow for help with programming the LOCATO task, Regina Schlieder for administrative support, and two anonymous reviewers for their helpful comments.
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Prehn, K., Stengl, H., Grittner, U. et al. Effects of Anodal Transcranial Direct Current Stimulation and Serotonergic Enhancement on Memory Performance in Young and Older Adults. Neuropsychopharmacol 42, 551–561 (2017). https://doi.org/10.1038/npp.2016.170
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DOI: https://doi.org/10.1038/npp.2016.170
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