Transcranial Magnetic Stimulation and Constraint Induced Language Therapy for Alzheimer Disease

NCT04482179 | Completed Phase 1 Results DMC

• 2 other identifiers: 831532R01DC016800-01A1
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Impaired verbal communication is a cardinal symptom of Alzheimer Disease (AD) and the source of enormous distress and disability. Effective therapies for this deficit are lacking. In light of the emerging literature demonstrating that Transcranial Magnetic Stimulation (TMS) improves general cognition in subjects with Alzheimer Disease (AD), the investigators propose to study the effectiveness of TMS as a therapy for impaired verbal communication. The hypothesis to be tested is that TMS combined with Constraint Induced Language Therapy (CILT) improves verbal communication more than sham TMS and CILT. A second aim is to use state-of-the-art neuroimaging to understand the mechanisms underlying any beneficial effect of the treatment.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (1)

• Change in WAB-AQ Score

  The primary outcome measure will be the change in score on the Western Aphasia Battery Aphasia Quotient (WAB-AQ), a score assessing overall aphasia recovery. Scores can range from 0-100, with higher scores representing better outcomes. 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. A score of 93 or higher is considered recovered.

  12 weeks post-treatment

Secondary Outcomes (1)

• Change in Percentage of Items Correct on the PNT

  12 weeks post-treatment

Study Arms (2)

Active TMS

ACTIVE COMPARATOR

There will be 10 TMS sessions over 2 consecutive weeks in which 30 two-second stimulation trains of 10 Hz TMS will be delivered every 30 seconds to the left inferior pars triangularis and to the left posterior superior left temporal gyrus. Each TMS treatment session will be immediately followed by a 60-90 minute session of Constrained Induced Language Therapy (CILT).

Device: Active TMS; Behavioral: CILT

Sham TMS

SHAM COMPARATOR

There will be 10 TMS sessions over 2 consecutive weeks in which 30 two-second stimulation trains of 10 Hz sham TMS will be delivered every 30 seconds to the left inferior pars triangularis and to the left posterior superior left temporal gyrus. Sham TMS will be administered with a sham TMS coil that looks and sounds like the active coil but does not generate a magnetic field. Each TMS treatment session will be immediately followed by a 60-90 minute session of Constrained Induced Language Therapy (CILT).

Behavioral: CILT; Device: Sham TMS

Interventions

Active TMS DEVICE

Active TMS will be delivered at 100% motor threshold

Active TMS

CILT BEHAVIORAL

60-90 minutes of CILT will be administered during each treatment session

Also known as: Constraint Induced Language Therapy

Active TMS; Sham TMS

Sham TMS DEVICE

Sham TMS will be administered

Sham TMS

Eligibility Criteria

• Age: 60 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of mild-moderate AD as defined by the National Institute of Aging - Alzheimer's Disease and Related Disorders Association criteria
• Mild-moderate cognitive impairment, indicated by Mini-Mental Status Exam (MMSE) scores between 23 and 15 inclusive
• Must be right handed as defined by the Edinburgh Handedness Inventory
• Must be a native English speaker
• Must be able to understand the nature of the study, and give informed consent

You may not qualify if:

• History of stroke
• History of seizure
• History of any other significant neurologic disease (e.g., ALS)
• Significant depression as defined by the Geriatric Depression Scale.
• Any significant medical disorder that, in the view of the investigators, could threaten the subject's ability to complete the study (e.g., cancer, significant cardiac disease)
• Any contraindications to TMS, including uncontrolled seizures, previous brain surgery, and history of tinnitus

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Deafness and Other Communication Disorders (NIDCD): collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (47)

• Hamilton RH, Chrysikou EG, Coslett B. Mechanisms of aphasia recovery after stroke and the role of noninvasive brain stimulation. Brain Lang. 2011 Jul;118(1-2):40-50. doi: 10.1016/j.bandl.2011.02.005. Epub 2011 Apr 2.

  PMID: 21459427 BACKGROUND

• Medina J, Norise C, Faseyitan O, Coslett HB, Turkeltaub PE, Hamilton RH. Finding the Right Words: Transcranial Magnetic Stimulation Improves Discourse Productivity in Non-fluent Aphasia After Stroke. Aphasiology. 2012 Sep 1;26(9):1153-1168. doi: 10.1080/02687038.2012.710316. Epub 2012 Aug 29.

  PMID: 23280015 BACKGROUND

• Seniow J, Waldowski K, Lesniak M, Iwanski S, Czepiel W, Czlonkowska A. Transcranial magnetic stimulation combined with speech and language training in early aphasia rehabilitation: a randomized double-blind controlled pilot study. Top Stroke Rehabil. 2013 May-Jun;20(3):250-61. doi: 10.1310/tsr2003-250.

  PMID: 23841973 BACKGROUND

• Silvanto J, Muggleton N, Walsh V. State-dependency in brain stimulation studies of perception and cognition. Trends Cogn Sci. 2008 Dec;12(12):447-54. doi: 10.1016/j.tics.2008.09.004. Epub 2008 Oct 24.

  PMID: 18951833 BACKGROUND

• Ayache SS, Farhat WH, Zouari HG, Hosseini H, Mylius V, Lefaucheur JP. Stroke rehabilitation using noninvasive cortical stimulation: motor deficit. Expert Rev Neurother. 2012 Aug;12(8):949-72. doi: 10.1586/ern.12.83.

  PMID: 23002939 BACKGROUND

• Kakuda W, Abo M, Shimizu M, Sasanuma J, Okamoto T, Yokoi A, Taguchi K, Mitani S, Harashima H, Urushidani N, Urashima M; NEURO Investigators. A multi-center study on low-frequency rTMS combined with intensive occupational therapy for upper limb hemiparesis in post-stroke patients. J Neuroeng Rehabil. 2012 Jan 20;9(1):4. doi: 10.1186/1743-0003-9-4.

  PMID: 22264239 BACKGROUND

• Koganemaru S, Mima T, Thabit MN, Ikkaku T, Shimada K, Kanematsu M, Takahashi K, Fawi G, Takahashi R, Fukuyama H, Domen K. Recovery of upper-limb function due to enhanced use-dependent plasticity in chronic stroke patients. Brain. 2010 Nov;133(11):3373-84. doi: 10.1093/brain/awq193. Epub 2010 Aug 5.

  PMID: 20688810 BACKGROUND

• Shewan CM, Kertesz A. Reliability and validity characteristics of the Western Aphasia Battery (WAB). J Speech Hear Disord. 1980 Aug;45(3):308-24. doi: 10.1044/jshd.4503.308.

  PMID: 7412225 BACKGROUND

• Mirman D, Chen Q, Zhang Y, Wang Z, Faseyitan OK, Coslett HB, Schwartz MF. Neural organization of spoken language revealed by lesion-symptom mapping. Nat Commun. 2015 Apr 16;6:6762. doi: 10.1038/ncomms7762.

  PMID: 25879574 BACKGROUND

• Howard, D., & Patterson, K. E. (1992). The Pyramids and Palm Trees Test: A Test of Semantic Access from Words and Pictures. Thames Valley Test Company

  BACKGROUND

• Nicholas LE, Brookshire RH. A system for quantifying the informativeness and efficiency of the connected speech of adults with aphasia. J Speech Hear Res. 1993 Apr;36(2):338-50. doi: 10.1044/jshr.3602.338.

  PMID: 8487525 BACKGROUND

• Foygel, D., & Dell, G. S. (2000). Models of impaired lexical access in speech production. Journal of Memory and Language, 43(2), 182-216.

  BACKGROUND

• Pulvermuller F, Neininger B, Elbert T, Mohr B, Rockstroh B, Koebbel P, Taub E. Constraint-induced therapy of chronic aphasia after stroke. Stroke. 2001 Jul;32(7):1621-6. doi: 10.1161/01.str.32.7.1621.

  PMID: 11441210 BACKGROUND

• Medaglia JD, Huang W, Segarra S, Olm C, Gee J, Grossman M, Ribeiro A, McMillan CT, Bassett DS. Brain network efficiency is influenced by the pathologic source of corticobasal syndrome. Neurology. 2017 Sep 26;89(13):1373-1381. doi: 10.1212/WNL.0000000000004324. Epub 2017 Aug 4.

  PMID: 28779011 BACKGROUND

• Ahmed MA, Darwish ES, Khedr EM, El Serogy YM, Ali AM. Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia. J Neurol. 2012 Jan;259(1):83-92. doi: 10.1007/s00415-011-6128-4. Epub 2011 Jun 14.

  PMID: 21671144 BACKGROUND

• Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, Khaigrekht M, Marton RG, Rabey JM. 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 (Vienna). 2011 Mar;118(3):463-71. doi: 10.1007/s00702-010-0578-1. Epub 2011 Jan 19.

  PMID: 21246222 BACKGROUND

• Brem, A. K., Schilberg, L., Freitas, C., Atkinson, N., Seligson, E., & Pascual-Leone, A. (2013). Effects of cognitive training and rTMS in Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 9(4), P664.

  BACKGROUND

• Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Andrews-Hanna JR, Sperling RA, Johnson KA. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci. 2009 Feb 11;29(6):1860-73. doi: 10.1523/JNEUROSCI.5062-08.2009.

  PMID: 19211893 BACKGROUND

• Cheng CPW, Wong CSM, Lee KK, Chan APK, Yeung JWF, Chan WC. Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2018 Jan;33(1):e1-e13. doi: 10.1002/gps.4726. Epub 2017 May 11.

  PMID: 28493371 BACKGROUND

• Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, Cappa SF, Miniussi C. Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):794-7. doi: 10.1136/jnnp.2009.197848. Epub 2010 Jun 23.

  PMID: 20574108 BACKGROUND

• Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, Miniussi C. Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol. 2006 Nov;63(11):1602-4. doi: 10.1001/archneur.63.11.1602.

  PMID: 17101829 BACKGROUND

• Deters KD, Nho K, Risacher SL, Kim S, Ramanan VK, Crane PK, Apostolova LG, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative. Genome-wide association study of language performance in Alzheimer's disease. Brain Lang. 2017 Sep;172:22-29. doi: 10.1016/j.bandl.2017.04.008. Epub 2017 May 31.

  PMID: 28577822 BACKGROUND

• Drumond Marra HL, Myczkowski ML, Maia Memoria C, Arnaut D, Leite Ribeiro P, Sardinha Mansur CG, Lancelote Alberto R, Boura Bellini B, Alves Fernandes da Silva A, Tortella G, Ciampi de Andrade D, Teixeira MJ, Forlenza OV, Marcolin MA. Transcranial Magnetic Stimulation to Address Mild Cognitive Impairment in the Elderly: A Randomized Controlled Study. Behav Neurol. 2015;2015:287843. doi: 10.1155/2015/287843. Epub 2015 Jun 16.

  PMID: 26160997 BACKGROUND

• Engels MM, Stam CJ, van der Flier WM, Scheltens P, de Waal H, van Straaten EC. Declining functional connectivity and changing hub locations in Alzheimer's disease: an EEG study. BMC Neurol. 2015 Aug 20;15:145. doi: 10.1186/s12883-015-0400-7.

  PMID: 26289045 BACKGROUND

• Faroqi-Shah, Y., & Virion, C. R. (2009). Constraint-induced language therapy for agrammatism: Role of grammaticality constraints. Aphasiology, 23(7-8), 977-988.

  BACKGROUND

• Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 10.1016/0022-3956(75)90026-6. No abstract available.

  PMID: 1202204 BACKGROUND

• Fornito A, Zalesky A, Breakspear M. The connectomics of brain disorders. Nat Rev Neurosci. 2015 Mar;16(3):159-72. doi: 10.1038/nrn3901.

  PMID: 25697159 BACKGROUND

• Haffen E, Chopard G, Pretalli JB, Magnin E, Nicolier M, Monnin J, Galmiche J, Rumbach L, Pazart L, Sechter D, Vandel P. A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease. Brain Stimul. 2012 Jul;5(3):264-266. doi: 10.1016/j.brs.2011.03.003. Epub 2011 Mar 30. No abstract available.

  PMID: 22037125 BACKGROUND

• Hameister, I., Nickels, L., Abel, S., & Croot, K. (2017). "Do you have mowing the lawn?"-improvements in word retrieval and grammar following constraint-induced language therapy in primary progressive aphasia. Aphasiology, 31(3), 308-331.

  BACKGROUND

• Hodges JR, Salmon DP, Butters N. Semantic memory impairment in Alzheimer's disease: failure of access or degraded knowledge? Neuropsychologia. 1992 Apr;30(4):301-14. doi: 10.1016/0028-3932(92)90104-t.

  PMID: 1603295 BACKGROUND

• Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.

  PMID: 29277405 BACKGROUND

• Lee J, Choi BH, Oh E, Sohn EH, Lee AY. 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. 2016 Jan;12(1):57-64. doi: 10.3988/jcn.2016.12.1.57. Epub 2015 Sep 11.

  PMID: 26365021 BACKGROUND

• Martin A, Fedio P. Word production and comprehension in Alzheimer's disease: the breakdown of semantic knowledge. Brain Lang. 1983 May;19(1):124-41. doi: 10.1016/0093-934x(83)90059-7.

  PMID: 6860932 BACKGROUND

• Medaglia JD, Lynall ME, Bassett DS. Cognitive network neuroscience. J Cogn Neurosci. 2015 Aug;27(8):1471-91. doi: 10.1162/jocn_a_00810. Epub 2015 Mar 24.

  PMID: 25803596 BACKGROUND

• Mohs RC, Rosen WG, Davis KL. The Alzheimer's disease assessment scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983;19(3):448-50. No abstract available.

  PMID: 6635122 BACKGROUND

• Norise C, Hamilton RH. Non-invasive Brain Stimulation in the Treatment of Post-stroke and Neurodegenerative Aphasia: Parallels, Differences, and Lessons Learned. Front Hum Neurosci. 2017 Jan 23;10:675. doi: 10.3389/fnhum.2016.00675. eCollection 2016.

  PMID: 28167904 BACKGROUND

• Rabey JM, Dobronevsky E. 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 (Vienna). 2016 Dec;123(12):1449-1455. doi: 10.1007/s00702-016-1606-6. Epub 2016 Sep 8.

  PMID: 27631152 BACKGROUND

• Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, Khaigrekht M. 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 (Vienna). 2013 May;120(5):813-9. doi: 10.1007/s00702-012-0902-z. Epub 2012 Oct 18.

  PMID: 23076723 BACKGROUND

• Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.

  PMID: 19833552 BACKGROUND

• Rubinov M, Sporns O. Complex network measures of brain connectivity: uses and interpretations. Neuroimage. 2010 Sep;52(3):1059-69. doi: 10.1016/j.neuroimage.2009.10.003. Epub 2009 Oct 9.

  PMID: 19819337 BACKGROUND

• Saur D, Lange R, Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, Weiller C. Dynamics of language reorganization after stroke. Brain. 2006 Jun;129(Pt 6):1371-84. doi: 10.1093/brain/awl090. Epub 2006 Apr 25.

  PMID: 16638796 BACKGROUND

• Stam CJ. Modern network science of neurological disorders. Nat Rev Neurosci. 2014 Oct;15(10):683-95. doi: 10.1038/nrn3801. Epub 2014 Sep 4.

  PMID: 25186238 BACKGROUND

• Szatloczki G, Hoffmann I, Vincze V, Kalman J, Pakaski M. Speaking in Alzheimer's Disease, is That an Early Sign? Importance of Changes in Language Abilities in Alzheimer's Disease. Front Aging Neurosci. 2015 Oct 20;7:195. doi: 10.3389/fnagi.2015.00195. eCollection 2015.

  PMID: 26539107 BACKGROUND

• Vacas SM, Stella F, Loureiro JC, Simoes do Couto F, Oliveira-Maia AJ, Forlenza OV. Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: A systematic review and meta-analysis. Int J Geriatr Psychiatry. 2019 Sep;34(9):1336-1345. doi: 10.1002/gps.5003. Epub 2018 Oct 17.

  PMID: 30246461 BACKGROUND

• van den Heuvel MP, Hulshoff Pol HE. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur Neuropsychopharmacol. 2010 Aug;20(8):519-34. doi: 10.1016/j.euroneuro.2010.03.008. Epub 2010 May 14.

  PMID: 20471808 BACKGROUND

• van den Heuvel MP, Sporns O. Network hubs in the human brain. Trends Cogn Sci. 2013 Dec;17(12):683-96. doi: 10.1016/j.tics.2013.09.012.

  PMID: 24231140 BACKGROUND

• Wu Y, Xu W, Liu X, Xu Q, Tang L, Wu S. Adjunctive treatment with high frequency repetitive transcranial magnetic stimulation for the behavioral and psychological symptoms of patients with Alzheimer's disease: a randomized, double-blind, sham-controlled study. Shanghai Arch Psychiatry. 2015 Oct;27(5):280-8. doi: 10.11919/j.issn.1002-0829.215107.

  PMID: 26977125 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Daniela Sacchetti, MS
• Organization: Clinical Research Coordinator

danielas@pennmedicine.upenn.edu

215-573-4336

Study Officials

• H. Branch Coslett, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The individual administering TMS will keep the master file of subject assignments, but all other individuals in contact with the subject or their data will be unaware of group assignment. Participants will not be informed of their assignment to active or sham status.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Participants will be randomized to either TMS or sham TMS in a 2:1 allocation ratio.

Study Record Dates

• First Submitted: July 17, 2020
• First Posted: July 22, 2020
• Study Start: February 19, 2020
• Primary Completion: August 31, 2024
• Study Completion: August 31, 2024
• Last Updated: September 15, 2025
• Results First Posted: September 15, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)