Corticomotor Plasticity Predicts Clinical Efficacy of Combined Neuromodulation and Cognitive Training in Alzheimer's Disease

Anna-Katharine Brem, Riccardo Di Iorio, Peter J Fried, Albino J Oliveira-Maia, Camillo Marra, Paolo Profice, Davide Quaranta, Lukas Schilberg, Natasha J Atkinson, Erica E Seligson, Paolo Maria Rossini, Alvaro Pascual-Leone, Anna-Katharine Brem, Riccardo Di Iorio, Peter J Fried, Albino J Oliveira-Maia, Camillo Marra, Paolo Profice, Davide Quaranta, Lukas Schilberg, Natasha J Atkinson, Erica E Seligson, Paolo Maria Rossini, Alvaro Pascual-Leone

Abstract

Objective: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training for treatment of cognitive symptoms in patients with Alzheimer's disease (AD). A secondary objective was to analyze associations between brain plasticity and cognitive effects of treatment.

Methods: In this randomized, sham-controlled, multicenter clinical trial, 34 patients with AD were assigned to three experimental groups receiving 30 daily sessions of combinatory intervention. Participants in the real/real group (n = 16) received 10 Hz repetitive transcranial magnetic stimulation (rTMS) delivered separately to each of six cortical regions, interleaved with computerized cognitive training. Participants in the sham rTMS group (n = 18) received sham rTMS combined with either real (sham/real group, n = 10) or sham (sham/sham group, n = 8) cognitive training. Effects of treatment on neuropsychological (primary outcome) and neurophysiological function were compared between the 3 treatment groups. These, as well as imaging measures of brain atrophy, were compared at baseline to 14 healthy controls (HC).

Results: At baseline, patients with AD had worse cognition, cerebral atrophy, and TMS measures of cortico-motor reactivity, excitability, and plasticity than HC. The real/real group showed significant cognitive improvement compared to the sham/sham, but not the real/sham group. TMS-induced plasticity at baseline was predictive of post-intervention changes in cognition, and was modified across treatment, in association with changes of cognition.

Interpretation: Combined rTMS and cognitive training may improve the cognitive status of AD patients, with TMS-induced cortical plasticity at baseline serving as predictor of therapeutic outcome for this intervention, and potential mechanism of action.

Clinical trial registration: www.ClinicalTrials.gov, identifier NCT01504958.

Keywords: Alzheimer’s disease; clinical trial; cognitive training; combinatory intervention; plasticity; randomized controlled; transcranial magnetic stimulation.

Copyright © 2020 Brem, Di Iorio, Fried, Oliveira-Maia, Marra, Profice, Quaranta, Schilberg, Atkinson, Seligson, Rossini and Pascual-Leone.

Figures

FIGURE 1
FIGURE 1
CONSORT flowchart: Enrollment and study design. (A) Flow diagram of the enrollment process and final study participants analyzed. (B) Schematic representation of study design.
FIGURE 2
FIGURE 2
(A) Plasticity change at T5, T10, and on average at T5–30 (T mean) expressed as the mean ratios of single-pulse TMS-measured MEP amplitudes pre-post iTBS before the intervention. (B) Paired-pulse TMS-measures of short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI) in AD (before intervention) and HC. (C) (including Italian sample): Best individual score change (ratio post/pre) in ADAS-Cog after real/real (light grey), sham/sham (medium grey), and after combined real cognitive training with sham rTMS (black). (D) Average ADAS-Cog score at pre, post and follow-up in the three treatment groups. (E) Average ADCS-CGIC scores. A score of 4 (dotted line) is equivalent to no change from pre- to post-intervention, scores < 4 indicate improvement, scores > 4 indicate decline. Indicated values correspond to mean ± standard error (SE).
FIGURE 3
FIGURE 3
Relationship between TMS-driven measures and cognitive function (ADAS-Cog). Relationship at baseline (A–D) in AD and HC, or clinical response over time (ADAS-Cog ratio) in AD patients (E–H) treated with real or sham rTMS. Cortico-motor plasticity was expressed as the change of cortical reactivity from baseline to post-iTBS. Circles reflect data for individuals and lines are unadjusted regression lines for the specified groups. When adjusting for age, education and mean atrophy, significant associations were found between baseline ADAS-Cog and resting motor threshold [rMT – (A)], short-interval intracortical inhibition [SICI – (B)], long-interval intracortical inhibition [LICI – (C)] and mean plasticity from 5 to 30 min post-iTBS (D). However, in models adjusting for rTMS intervention (real vs. sham), mean plasticity (H), but not rMT (E), SICI (F), and LICI (G) was found to be a significant predictor of response.

References

    1. Ahmed M. A., Darwish E. S., Khedr E. M., El Serogy Y. M., Ali A. M. (2012). Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J. Neurol. 259 83–92. 10.1007/s00415-011-6128-4
    1. Alzheimer’s Association (2012). 2012 Alzheimer’s disease facts and figures. Alzheimers Dement. 8 131–168. 10.1016/j.jalz.2012.02.001
    1. Ballard C., Gauthier S., Corbett A., Brayne C., Aarsland D., Jones E. (2011). Alzheimer’s disease. Lancet 377 1019–1031. 10.1016/S0140-6736(10)61349-9
    1. Beekly D. L., Ramos E. M., Lee W. W., Deitrich W. D., Jacka M. E., Wu J., et al. (2007). The National Alzheimer’s coordinating center (NACC) database: the uniform data set. Alzheimer Dis. Assoc. Disord. 21 249–258. 10.1097/WAD.0b013e318142774e
    1. Belleville S., Clément F., Mellah S., Gilbert B., Fontaine F., Gauthier S. (2011). Training-related brain plasticity in subjects at risk of developing Alzheimer’s disease. Brain 134 1623–1634. 10.1093/brain/awr037
    1. Bentwich J., Dobronevsky E., Aichenbaum S., Shorer R., Peretz R., Khaigrekht M., et al. (2011). Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J. Neural. Transm. 118 463–471. 10.1007/s00702-010-0578-1
    1. Brem A.-K., Atkinson N. J., Seligson E. E., Pascual-Leone A. (2013). Differential pharmacological effects on brain reactivity and plasticity in Alzheimer’s disease. Front. Psychiatry 4:124. 10.3389/fpsyt.2013.00124
    1. Brem A.-K., Sensi S. L. (2018). Towards combinatorial approaches for preserving cognitive fitness in aging. Trends Neurosci. 41 885–897. 10.1016/j.tins.2018.09.009
    1. Buss S. S., Fried P. J., Pascual-Leone A. (2019). Therapeutic noninvasive brain stimulation in Alzheimer’s disease and related dementias. Curr. Opin. Neurol. 32 292–304. 10.1097/WCO.0000000000000669
    1. Chang W. H., Kim Y.-H., Yoo W.-K., Goo K.-H., Park C.-H., Kim S. T., et al. (2012). rTMS with motor training modulates cortico-basal ganglia-thalamocortical circuits in stroke patients. Restor. Neurol. Neurosci. 30 179–189. 10.3233/RNN-2012-110162
    1. Clare L., Woods R. T., Moniz Cook E. D., Orrell M., Spector A. (2003). Cognitive rehabilitation and cognitive training for early-stage Alzheimer’s disease and vascular dementia. Cochrane Database Syst. Rev. 2003:CD003260. 10.1002/14651858.CD003260
    1. Cooke S. F., Bliss T. V. P. (2006). Plasticity in the human central nervous system. Brain 129 1659–1673. 10.1093/brain/awl082
    1. Cotelli M., Calabria M., Manenti R., Rosini S., Zanetti O., Cappa S. F., et al. (2011). Improved language performance in Alzheimer disease following brain stimulation. J. Neurol. Neurosurg. Psychiatry 82 794–797. 10.1136/jnnp.2009.197848
    1. Di Lorenzo F., Ponzo V., Bonnì S., Motta C., Negrão Serra P. C., Bozzali M., et al. (2016). LTP-like cortical plasticity is disrupted in Alzheimer’s disease patients independently from age of onset. Ann. Neurol. 80 202–210. 10.1002/ana.24695
    1. Farzan F., Barr M. S., Levinson A. J., Chen R., Wong W., Fitzgerald P. B., et al. (2010). Reliability of long-interval cortical inhibition in healthy human subjects: a TMS-EEG study. J. Neurophysiol. 104 1339–1346. 10.1152/jn.00279.2010
    1. Ferreri F., Pauri F., Pasqualetti P., Fini R., Dal Forno G., Rossini P. M. (2003). Motor cortex excitability in Alzheimer’s disease: a transcranial magnetic stimulation study. Ann. Neurol. 53 102–108. 10.1002/ana.10416
    1. Freitas C., Mondragón-Llorca H., Pascual-Leone A. (2011). Noninvasive brain stimulation in Alzheimer’s disease: systematic review and perspectives for the future. Exp. Gerontol. 46 611–627. 10.1016/j.exger.2011.04.001
    1. Haffen E., Chopard G., Pretalli J.-B., Magnin E., Nicolier M., Monnin J., et al. (2012). A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease. Brain Stimul. 5 264–266. 10.1016/j.brs.2011.03.003
    1. Hill N. T. M., Mowszowski L., Naismith S. L., Chadwick V. L., Valenzuela M., Lampit A. (2017). Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis. Am. J. Psychiatry 174 329–340. 10.1176/appi.ajp.2016.16030360
    1. Huang Y.-Z., Chen R.-S., Rothwell J. C., Wen H.-Y. (2007). The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin. Neurophysiol. 118 1028–1032. 10.1016/j.clinph.2007.01.021
    1. Huang Y.-Z., Edwards M. J., Rounis E., Bhatia K. P., Rothwell J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron 45 201–206. 10.1016/j.neuron.2004.12.033
    1. Jacobs H. I. L., Van Boxtel M. P. J., Uylings H. B. M., Gronenschild E. H. B. M., Verhey F. R., Jolles J. (2011). Atrophy of the parietal lobe in preclinical dementia. Brain Cogn. 75 154–163. 10.1016/j.bandc.2010.11.003
    1. Kakuda W., Abo M., Watanabe S., Momosaki R., Hashimoto G., Nakayama Y., et al. (2013). High-frequency rTMS applied over bilateral leg motor areas combined with mobility training for gait disturbance after stroke: a preliminary study. Brain Inj. 27 1080–1086. 10.3109/02699052.2013.794973
    1. Kallio E.-L., Öhman H., Kautiainen H., Hietanen M., Pitkälä K. (2017). Cognitive Training Interventions for patients with Alzheimer’s disease: a systematic review. J. Alzheimers Dis. 56 1349–1372. 10.3233/JAD-160810
    1. Khedr E. M., Abo El-Fetoh N., Ali A. M., El-Hammady D. H., Khalifa H., Atta H., et al. (2014). Dual-hemisphere repetitive transcranial magnetic stimulation for rehabilitation of poststroke aphasia: a randomized, double-blind clinical trial. Neurorehab. Neural Re. 28 740–750. 10.1177/1545968314521009
    1. Kim C., Choi H. E., Jung H., Lee B.-J., Lee K. H., Lim Y.-J. (2014). Comparison of the Effects of 1 Hz and 20 Hz rTMS on Motor Recovery in Subacute Stroke Patients. Ann. Rehabil. Med. 38 585–591. 10.5535/arm.2014.38.5.585
    1. Koch G., Di Lorenzo F., Bonnì S., Ponzo V., Caltagirone C., Martorana A. (2012). Impaired LTP- but not LTD-like cortical plasticity in Alzheimer’s disease patients. J. Alzheimers Dis. 31 593–599. 10.3233/JAD-2012-120532
    1. Lee J., Choi B. H., Oh E., Sohn E. H., Lee A. Y. (2015). Treatment of Alzheimer’s disease with repetitive transcranial magnetic stimulation combined with cognitive training: a prospective, randomized, double-blind, placebo-controlled study. J. Clin. Neurol. 12 57–64.
    1. Liepert J., Bär K. J., Meske U., Weiller C. (2001). Motor cortex disinhibition in Alzheimer’s disease. Clin. Neurophysiol. 112 1436–1441. 10.1016/s1388-2457(01)00554-5
    1. Mattson M. P. (2004). Pathways towards and away from Alzheimer’s disease. Nature 430 631–639. 10.1038/nature02621
    1. McGirr A., Van den Eynde F., Tovar-Perdomo S., Fleck M. P. A., Berlim M. T. (2015). Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial. J. Affect. Disord. 173 216–220. 10.1016/j.jad.2014.10.068
    1. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. (1984). Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 34 939–944. 10.1212/wnl.34.7.939
    1. Mori F., Rossi S., Sancesario G., Codecà C., Mataluni G., Monteleone F., et al. (2011). Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis. Neuropsychopharmacology 36 559–568. 10.1038/npp.2010.187
    1. Oliveira-Maia A. J., Press D., Pascual-Leone A. (2017). Modulation of motor cortex excitability predicts antidepressant response to prefrontal cortex repetitive transcranial magnetic stimulation. Brain Stimul. 10 787–794. 10.1016/j.brs.2017.03.013
    1. Pallanti S., Di Rollo A., Antonini S., Cauli G., Hollander E., Quercioli L. (2012). Low-frequency rTMS over right dorsolateral prefrontal cortex in the treatment of resistant depression: cognitive improvement is independent from clinical response, resting motor threshold is related to clinical response. Neuropsychobiology 65 227–235. 10.1159/000336999
    1. Pascual-Leone A., Valls-Solé J., Wassermann E. M., Hallett M. (1994). Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117(Pt 4), 847–858. 10.1093/brain/117.4.847
    1. Preacher K. J., Hayes A. F. (2008). Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav. Res. Methods 40 879–891. 10.3758/brm.40.3.879
    1. Price C. J., Winterburn D., Giraud A. L., Moore C. J., Noppeney U. (2003). Cortical localisation of the visual and auditory word form areas: a reconsideration of the evidence. Brain Lang. 86 272–286. 10.1016/s0093-934x(02)00544-8
    1. Quan W. X., Zhu X. L., Qiao H., Zhang W. F., Tan S. P., Zhou D. F., et al. (2015). The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study. Neurosci. Lett. 584 197–201. 10.1016/j.neulet.2014.10.029
    1. Rabey J. M., Dobronevsky E. (2016). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: clinical experience. J. Neural Transm. 123 1449–1455. 10.1007/s00702-016-1606-6
    1. Rabey J. M., Dobronevsky E., Aichenbaum S., Gonen O., Marton R. G., Khaigrekht M. (2013). Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: a randomized, double-blind study. J. Neural. Transm. 120 813–819. 10.1007/s00702-012-0902-z
    1. Rogalsky C., Matchin W., Hickok G. (2008). Broca’s area, sentence comprehension, and working memory: an fMRI study. Front. Hum. Neurosci. 2:14. 10.3389/neuro.09.014.2008
    1. Rossi S., Hallett M., Rossini P. M., Pascual-Leone A. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. 120 2008–2039. 10.1016/j.clinph.2009.08.016
    1. Rossini P. M., Barker A. T., Berardelli A., Caramia M. D., Caruso G., Cracco R. Q., et al. (1994). Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr. Clin. Neurophysiol. 91 79–92. 10.1016/0013-4694(94)90029-9
    1. Rossini P. M., Burke D., Chen R., Cohen L. G., Daskalakis Z., Di Iorio R., et al. (2015). Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin. Neurophysiol. 126 1071–1107. 10.1016/j.clinph.2015.02.001
    1. Rusjan P. M., Barr M. S., Farzan F., Arenovich T., Maller J. J., Fitzgerald P. B., et al. (2010). Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. Hum. Brain Mapp. 31 1643–1652. 10.1002/hbm.20964
    1. Ryu S.-H., Katona C., Rive B., Livingston G. (2005). Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study. Am. J. Geriatr. Psychiatry 13 976–983. 10.1176/appi.ajgp.13.11.976
    1. Sajonz B., Kahnt T., Margulies D. S., Park S. Q., Wittmann A., Stoy M., et al. (2010). Delineating self-referential processing from episodic memory retrieval: common and dissociable networks. Neuroimage 50 1606–1617. 10.1016/j.neuroimage.2010.01.087
    1. Schrag A., Schott J. M. Alzheimer’s Disease Neuroimaging Initiative (2012). What is the clinically relevant change on the ADAS-Cog? J. Neurol. Neurosurg. Psychiatr. 83 171–173. 10.1136/jnnp-2011-300881
    1. Silvanto J., Pascual-Leone A. (2008). State-dependency of transcranial magnetic stimulation. Brain Topogr. 21 1–10. 10.1007/s10548-008-0067-0
    1. Udupa K., Ni Z., Gunraj C., Chen R. (2009). Interactions between short latency afferent inhibition and long interval intracortical inhibition. Exp. Brain Res. 199 177–183. 10.1007/s00221-009-1997-9
    1. Wagner T., Eden U., Fregni F., Valero-Cabre A., Ramos-Estebanez C., Pronio-Stelluto V., et al. (2008). Transcranial magnetic stimulation and brain atrophy: a computer-based human brain model study. Exp. Brain Res. 186 539–550. 10.1007/s00221-007-1258-8
    1. Wang M., Wong A. H., Liu F. (2012). Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res. 1476 154–163. 10.1016/j.brainres.2012.03.029
    1. Wang X., Mao Z., Ling Z., Yu X. (2019). Repetitive transcranial magnetic stimulation for cognitive impairment in Alzheimer’s disease: a meta-analysis of randomized controlled trials. J. Neurol. 267 791–801. 10.1007/s00415-019-09644-y
    1. Wobrock T., Guse B., Cordes J., Wölwer W., Winterer G., Gaebel W., et al. (2015). Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial. Biol. Psychiatry 77 979–988. 10.1016/j.biopsych.2014.10.009
    1. Yang Y.-R., Tseng C.-Y., Chiou S.-Y., Liao K.-K., Cheng S.-J., Lai K.-L., et al. (2013). Combination of rTMS and treadmill training modulates corticomotor inhibition and improves walking in Parkinson disease: a randomized trial. Neurorehabil. Neural. Repair. 27 79–86. 10.1177/1545968312451915

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir