Brain Correlates of Multimodal Rehabilitation in Chronic Post-stroke Aphasia
NCT ID: NCT04134416
Last Updated: 2020-11-05
Study Results
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Basic Information
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COMPLETED
PHASE3
20 participants
INTERVENTIONAL
2019-01-08
2020-10-20
Brief Summary
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Detailed Description
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Aphasia has a negative impact on the affected person and their family members, reducing work, personal, affective and social life. It is accompanied by high health and social expenditure, since one third of patients are under 65 years of age and cannot return to work due to the inability to communicate. For this reason, the implementation of strategies aimed at improving aphasia, communication, associated emotional disorders and the quality of life of patients and carers is crucial to achieve autonomy, allowing them to return to work and prevent additional cognitive and affective impairment. Currently, the most popular PSA rehabilitation therapies are: speech rehabilitation therapies, drugs and, more recently, non-invasive neurostimulation techniques.
1. Speech therapies Speech therapy is the treatment of choice in aphasia. The most commonly used is conventional or standard therapy where a specific strategy (description of pictures, repetition of words or phrases, answers to questions) is employed depending on the patient's deficits. They are usually applied 2 or 3 times a week with a duration of 30-45 minutes per session. However, some of the problems with these therapies are their prolonged duration (several years) and, consequently, their high cost, which limits their applicability in Public Health Services. In addition, the logistical limitations (difficulty of transport, shortage of staff) of the treatment centres prevent the administration of the minimum of 2 hours per week of therapy required to obtain clinically relevant benefits. On the other hand, the benefits obtained are insufficient and the progress made decreases once the treatment has been abandoned. For this reason, during the last two decades, speech therapies have been designed in which short (2 weeks) but very intensive (3 hours per day) rehabilitation exercises based on neuroscientific evidence are applied which effectively solve the limitations of traditional therapies. In this sense, Intensive Language-Action Therapy (ILAT) administered for two consecutive weeks (3 hours/day for 2 weeks - 30 hours of treatment -) has gained worldwide acceptance as it is significantly more effective than traditional rehabilitation techniques even when the total therapy time (2 hours/week for 15 weeks - 30 hours of treatment) is the same. In addition, the benefits achieved with ILAT in 2 weeks are maintained for 6 months after completion of treatment. ILAT is a group rehabilitation therapy (2 or 3 participants) that employs a play dynamic among participants, and its ILAT-plus modality also reinforces the training of specific language skills (e.g., repetition).
2. Pharmacological interventions LT is effective in the PSA, even in chronic stages (\> 6 months after stroke). However, in many patients with moderate and severe aphasia the benefits of LT are limited (e.g., partial recovery of verbal fluency and auditory comprehension).These limitations have led to the use of other, more effective interventions to treat PSA. Several clinical trials in patients with acute and chronic PSAs conducted in the last decade have shown that the benefits achieved with rehabilitation can be significantly increased when these therapies are combined with drugs. Several pharmacological agents (Levodopa, Bromocriptine, Piracetam, Amantadine, Dexamfetamine, and others) have been used with variable results. However, several controlled clinical trials have found significant improvements in production deficits, understanding, and in the overall severity of aphasia in patients with PSAs treated with Piracetam, Donepezil, Galantamine, or Memantine. In PSA rehabilitation, biological and behavioral treatments strengthen the activity of perilesional regions and brain areas that previously did not perform language functions, but that after stroke are recruited vicariously increasing the ability of language recovery in the patient. In the last decade, it has been shown that the acetylcholinesterase inhibitor (an enzyme that degrades acetylcholine) Donepezil, and the NMDA receptor antagonist Memantine (antidementia drugs with a good safety/tolerability profile) are more effective than placebo in the treatment of PSA, especially when these are prescribed in association with rehabilitation techniques based on neuroscientific evidence.
3. Neurostimulation Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that induces changes in the excitability of brain tissue by increasing (anodal stimulation, A-tDCS) or decreasing (cathodal stimulation, C-tDCS) the activity of nerve cells by applying weak electrical currents. The theoretical justification for the use of tDCS as an adjuvant technique in PSA rehabilitation is based on the fact that it modulates (increases or decreases) the rate of neuronal discharge, presumably through changes in the resting potential of the membrane, and thus facilitates or hinders the functioning of connections between neuronal groups. tDCS has been shown to be effective in a variety of neurological and psychiatric disorders and has several advantages over other stimulation techniques, e.g. transcranial magnetic stimulation: better safety profile, easy to use, well tolerated by patients and better cost-benefit ratio. Increasingly, studies indicate that tDCS has beneficial effects on language deficits (verbal fluency, naming, grammatical decision) in people with PSA. In addition, when applied in conjunction with ST, it enhances the benefits obtained in PSA. Benefits have been described in patients with PSA using varied stimulation parameters (intensity, type, duration, brain area), each with different theoretical justification. The main modalities are (1) anodal stimulation (A-tDCS; excitatory) of perilesional areas with the aim of promoting the recovery of brain tissue surrounding the lesion; (2) cathodal stimulation (C-tDCS inhibitory stimulation of healthy regions interfering with recovery); (3) A-tDCS on areas of the healthy hemisphere to increase activity and facilitate the reorganization of functions that previously depended on injured areas of the left hemisphere. tDCS is a technique that has been shown to be effective, although more studies are needed leading to the identification of the most suitable stimulation parameters, the location-extent of the lesion, the previous brain structure of each patient, and to determine the added value that this technique provides in combination therapies.
Justification and project contributions Intensive ST, neurostimulation and pharmacological interventions have independently been shown to be effective in the rehabilitation of PSA. Previous work indicates that combination therapies (ILAT and drug therapy) are superior to other treatment options as they enhance synergistic mechanisms that promote improved learning, language and functional communication in affected individuals. However, more research is needed to explore the benefits of combination therapies (e.g. Donepezil, ILAT and tDCS) and to identify the mechanisms and structures that are modulated by each of these rehabilitation therapies and that mediate recovery, with the aim of establishing response predictors.
The aim of the current project is to evaluate the efficacy of ILATplus (ILAT + repetition/imitation training) (3 hours/day for 2 consecutive weeks, total = 30 hours) combined with Donepezil and tDCS in the treatment of cognitive deficits in patients with chronic post-stroke aphasias, with a special emphasis on Conduction Aphasia (CA).
Through the use of different neuroimaging techniques, the investigators seek to identify anatomical and functional changes that are related to the benefits observed after interventions, and analyze the role of the uninjured (right) hemisphere in recovery. The analysis of behavioral and neuroimaging data will allow us to identify possible predictors (demographic, structural, functional) of response.
The investigators hope that the results derived from this clinical trial will have a positive impact reflected in several aspects. This study may show for the first time the potential superiority of combined therapies (ILATplus/Donepezil/tDCS) over other treatment options. The analysis of the results, in combination with the findings of previous studies will allow to optimize the rehabilitation of the PSA with short intensive group therapies (ILAT) and consequently, more ecological and less expensive compared to the current rehabilitation strategies that use prolonged therapies generally with little efficacy. In addition, the results of this study will make it possible to identify patients who will benefit from this type of intervention based on anatomical and demographic predictors of response to treatment, and thereby improve their success.
Finally, this project will be carried out by a multi-disciplinary group with extensive scientific and technical experience in this line of research. The methodology to be used, as well as the potential results, are based on the progress achieved by basic neuroscientific research with translational impact on the neurorehabilitation of language alterations associated with stroke.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Anodal transcranial direct current stimulation
Transcortical direct current stimulation (tDCS) will be applied using a STARSTIM neurostimulation device (Neuroelectrics, Barcelona). Each participant will receive 10 20-minute sessions while receiving REGIAplus (online). Group 1 will receive active stimulation (anodal stimulation, A-tDCS).The active electrode will be placed in the region of the lower right frontal rotation and the reference electrode in the extraencephalic zone (left clavicle). Combined rehabilitation sessions (REGIAplus/tDCS) will be conducted, as indicated above, in weeks 9 and 10 of the trial.
Donepezil
Donepezil shall be administered at the times stipulated in the study design as follows: one 5 mg tablet at night for 4 weeks and then one 10 mg tablet at night until the end of the trial (week 10).
Intensive-Language Action Therapy
All patients participating in the study will receive in weeks 9 and 10 daily three and a half hours of ILATplus therapy. This therapy consists of 30 minutes of specific repetition training (tailored and reinforced by the therapist) before starting with classic ILAT for 3 hours/day during 10 consecutive days.
Transcranial direct current stimulation
Transcortical direct current stimulation (tDCS) will be applied using a STARSTIM neurostimulation device (Neuroelectrics, Barcelona). Each participant will receive either anodal or sham 20-minute sessions while receiving ILATplus. In the sham stimulation, the same helmet and electrode that is used in the active stimulation will be placed but, in this case, we will apply only a slight current at the beginning and end of the session with the objective of simulating the effects that are experienced with the active stimulation without producing significant cortical stimulation. The active electrode will be placed in the region of the lower right frontal rotation and the reference electrode in the extraencephalic zone (left clavicle). Combined rehabilitation sessions (ILATplus/tDCS) will be conducted, as indicated above, in weeks 9 and 10 of the trial.
Sham transcranial direct current stimulation
Group 2 will receive sham stimulation (S-tDCS). In the sham stimulation, the same helmet and electrode that is used in the active stimulation will be placed but, in this case, we will apply only a slight current at the beginning and end of the session with the objective of simulating the effects that are experienced with the active stimulation without producing significant cortical stimulation. The active electrode will be placed in the region of the lower right frontal rotation and the reference electrode in the extraencephalic zone (left clavicle). Combined rehabilitation sessions (REGIAplus/tDCS) will be conducted, as indicated above, in weeks 9 and 10 of the assay.
Donepezil
Donepezil shall be administered at the times stipulated in the study design as follows: one 5 mg tablet at night for 4 weeks and then one 10 mg tablet at night until the end of the trial (week 10).
Intensive-Language Action Therapy
All patients participating in the study will receive in weeks 9 and 10 daily three and a half hours of ILATplus therapy. This therapy consists of 30 minutes of specific repetition training (tailored and reinforced by the therapist) before starting with classic ILAT for 3 hours/day during 10 consecutive days.
Transcranial direct current stimulation
Transcortical direct current stimulation (tDCS) will be applied using a STARSTIM neurostimulation device (Neuroelectrics, Barcelona). Each participant will receive either anodal or sham 20-minute sessions while receiving ILATplus. In the sham stimulation, the same helmet and electrode that is used in the active stimulation will be placed but, in this case, we will apply only a slight current at the beginning and end of the session with the objective of simulating the effects that are experienced with the active stimulation without producing significant cortical stimulation. The active electrode will be placed in the region of the lower right frontal rotation and the reference electrode in the extraencephalic zone (left clavicle). Combined rehabilitation sessions (ILATplus/tDCS) will be conducted, as indicated above, in weeks 9 and 10 of the trial.
Interventions
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Donepezil
Donepezil shall be administered at the times stipulated in the study design as follows: one 5 mg tablet at night for 4 weeks and then one 10 mg tablet at night until the end of the trial (week 10).
Intensive-Language Action Therapy
All patients participating in the study will receive in weeks 9 and 10 daily three and a half hours of ILATplus therapy. This therapy consists of 30 minutes of specific repetition training (tailored and reinforced by the therapist) before starting with classic ILAT for 3 hours/day during 10 consecutive days.
Transcranial direct current stimulation
Transcortical direct current stimulation (tDCS) will be applied using a STARSTIM neurostimulation device (Neuroelectrics, Barcelona). Each participant will receive either anodal or sham 20-minute sessions while receiving ILATplus. In the sham stimulation, the same helmet and electrode that is used in the active stimulation will be placed but, in this case, we will apply only a slight current at the beginning and end of the session with the objective of simulating the effects that are experienced with the active stimulation without producing significant cortical stimulation. The active electrode will be placed in the region of the lower right frontal rotation and the reference electrode in the extraencephalic zone (left clavicle). Combined rehabilitation sessions (ILATplus/tDCS) will be conducted, as indicated above, in weeks 9 and 10 of the trial.
Eligibility Criteria
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Inclusion Criteria
* Right handedness (80 point in the Edinburgh Handedness Inventory)
* Spanish as native language
* Single left-hemisphere stroke
* Diagnosis of aphasia established by a score in the Aphasia Quotient of the Spanish version of the Western Aphasia Battery (WAB) \< 93.8 points.
Exclusion Criteria
* Multiple or bilateral injuries
* Increased risk of a new stroke or unstable neurological condition (e.g. transient ischemic attacks)
* History of severe psychiatric illness (schizophrenia, major depression, bipolar disorder, anxiety disorders)
* Alcohol and substance use or abuse
* Coexistence of aphasia with dementia.
18 Years
70 Years
ALL
No
Sponsors
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University of Malaga
OTHER
Responsible Party
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Marcelo Luis Berthier
Full Professor
Principal Investigators
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Marcelo L Berthier, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Malaga, Spain
Locations
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Centro de Investigaciones Medico-Sanitarias. University of Malaga
Málaga, , Spain
Countries
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References
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Berthier ML. Poststroke aphasia : epidemiology, pathophysiology and treatment. Drugs Aging. 2005;22(2):163-82. doi: 10.2165/00002512-200522020-00006.
Berthier ML, Garcia-Casares N, Walsh SF, Nabrozidis A, Ruiz de Mier RJ, Green C, Davila G, Gutierrez A, Pulvermuller F. Recovery from post-stroke aphasia: lessons from brain imaging and implications for rehabilitation and biological treatments. Discov Med. 2011 Oct;12(65):275-89.
Pulvermuller F, Berthier ML. Aphasia therapy on a neuroscience basis. Aphasiology. 2008 Jun;22(6):563-599. doi: 10.1080/02687030701612213. Epub 2008 May 21.
Berthier ML, Pulvermuller F. Neuroscience insights improve neurorehabilitation of poststroke aphasia. Nat Rev Neurol. 2011 Feb;7(2):86-97. doi: 10.1038/nrneurol.2010.201.
Berthier ML, Pulvermuller F, Davila G, Casares NG, Gutierrez A. Drug therapy of post-stroke aphasia: a review of current evidence. Neuropsychol Rev. 2011 Sep;21(3):302-17. doi: 10.1007/s11065-011-9177-7. Epub 2011 Aug 16.
Berthier ML, Green C, Higueras C, Fernandez I, Hinojosa J, Martin MC. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Neurology. 2006 Nov 14;67(9):1687-9. doi: 10.1212/01.wnl.0000242626.69666.e2.
Berthier ML, Green C, Lara JP, Higueras C, Barbancho MA, Davila G, Pulvermuller F. Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia. Ann Neurol. 2009 May;65(5):577-85. doi: 10.1002/ana.21597.
De-Torres I, Davila G, Berthier ML, Walsh SF, Moreno-Torres I, Ruiz-Cruces R. Repeating with the right hemisphere: reduced interactions between phonological and lexical-semantic systems in crossed aphasia? Front Hum Neurosci. 2013 Oct 18;7:675. doi: 10.3389/fnhum.2013.00675. eCollection 2013.
Torres-Prioris MJ, Lopez-Barroso D, Paredes-Pacheco J, Roe-Vellve N, Dawid-Milner MS, Berthier ML. Language as a Threat: Multimodal Evaluation and Interventions for Overwhelming Linguistic Anxiety in Severe Aphasia. Front Psychol. 2019 May 8;10:678. doi: 10.3389/fpsyg.2019.00678. eCollection 2019.
Mohr B, Stahl B, Berthier ML, Pulvermuller F. Intensive Communicative Therapy Reduces Symptoms of Depression in Chronic Nonfluent Aphasia. Neurorehabil Neural Repair. 2017 Dec;31(12):1053-1062. doi: 10.1177/1545968317744275. Epub 2017 Dec 1.
Berthier ML, De-Torres I, Paredes-Pacheco J, Roe-Vellve N, Thurnhofer-Hemsi K, Torres-Prioris MJ, Alfaro F, Moreno-Torres I, Lopez-Barroso D, Davila G. Cholinergic Potentiation and Audiovisual Repetition-Imitation Therapy Improve Speech Production and Communication Deficits in a Person with Crossed Aphasia by Inducing Structural Plasticity in White Matter Tracts. Front Hum Neurosci. 2017 Jun 14;11:304. doi: 10.3389/fnhum.2017.00304. eCollection 2017.
Barbancho MA, Berthier ML, Navas-Sanchez P, Davila G, Green-Heredia C, Garcia-Alberca JM, Ruiz-Cruces R, Lopez-Gonzalez MV, Dawid-Milner MS, Pulvermuller F, Lara JP. Bilateral brain reorganization with memantine and constraint-induced aphasia therapy in chronic post-stroke aphasia: An ERP study. Brain Lang. 2015 Jun-Jul;145-146:1-10. doi: 10.1016/j.bandl.2015.04.003. Epub 2015 Apr 29.
Edelkraut L, Lopez-Barroso D, Torres-Prioris MJ, Starkstein SE, Jorge RE, Aloisi J, Berthier ML, Davila G. Spectrum of neuropsychiatric symptoms in chronic post-stroke aphasia. World J Psychiatry. 2022 Mar 19;12(3):450-469. doi: 10.5498/wjp.v12.i3.450. eCollection 2022 Mar 19.
Related Links
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webiste of the university of Malaga, Spain
Other Identifiers
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FIM-DON-2017-01
Identifier Type: -
Identifier Source: org_study_id