Brain Correlates of Multimodal Rehabilitation in Chronic Post-stroke Aphasia
Condition: Aphasia; Stroke
MeSH terms: Stroke; Aphasia
Study type: Interventional
Phase: Phase 3

Summary: 
      Post-stroke aphasia (PSA), the partial or total loss of the ability to produce and/or
      understand language associated with stroke, is a highly prevalent and disabling disorder that
      negatively impacts the personal, social and working life of patients and families. Modern
      theory-based language therapies (LT) with proved efficacy in chronic PSA are brief (weeks),
      intensive, and oriented to specific domains (e.g., anomia). However, in order to maximize
      therapeutic benefits, it becomes essential to implement complementary strategies that boost
      gains in language, communication and behaviour and also to identify predictors of treatment
      response (demographics, anatomical) that enable to customize interventions adjusting them to
      each profile (linguistic deficits, brain structure and connectivity). Our group has
      repeatedly shown that LT combined with cognitive enhancing drugs (CED) (e.g., Donepezil and
      Memantine) are safe and promote better outcomes that when these interventions are
      administered separately. Moreover, non-invasive brain stimulation techniques (NIBS), such as
      transcranial direct current stimulation (tDCS), are also emerging as a promising treatment
      option for chronic PSA. However, is still unknown whether or not treatments that combine
      several biological strategies aid to improve outcomes further. Brain changes induced by these
      interventions and the premorbid characteristic of a "good responder" are also unknown. The
      aims of this clinical trial are: (1) Study the efficacy of combined treatments in a sample of
      patients with chronic PSA (n = 40); (2) Document with multimodal neuroimaging the functional
      and connectivity changes (neuroplasticity) promoted by these interventions; and (3) Identify
      linguistic, cognitive and behavioural variables that may predict outcomes for each
      intervention.
    

Detailed description: 
      Aphasia is a devastating disorder involving total or partial loss of language. It can affect
      all communicative, expressive, and receptive modalities, including language production,
      comprehension, reading, writing, and the ability to gesture. Stroke is the most common cause
      of aphasia and its incidence is very high in Europe, varying between 318 and 372 cases in men
      and between 195 and 240 in women per 100,000 inhabitants. In Spain it is the second cause of
      death and the first in women, affecting approximately 130,000 people every year. Between 21
      and 38% of these cases present post-stroke aphasia (PSA) in the acute stage. PSA is
      associated with high morbidity and mortality, and only 20% of those affected recover
      spontaneously. Consequently, PSA is very frequent and evolves to chronicity in most patients.
      There are different subtypes of aphasia depending on the linguistic profile. A distinction is
      made between aphasia with preserved repetition and aphasia with altered repetition. The first
      group includes transcortical aphasias (sensory, motor and mixed) and anomic aphasias, and the
      second, in order of severity, global aphasias, Wernicke aphasias, Broca aphasias, and
      Conduction Aphasias (CA). The latter group is associated with perisylvian lesions and are
      most frequent (>80% of cases). Aphasias in the first 2-3 months tend to evolve into less
      severe profiles, so that Broca and Wernicke aphasias can, in chronic stages, progress to CA.

      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.
    

Intervention name(s): Donepezil; Intensive-Language Action Therapy; Transcranial direct current stimulation
Intervention type(s): Drug; Behavioral; Device
Intervention description(s): 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).; 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.; 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.
Intervention MeSH terms: Donepezil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Aphasia; Stroke; Rehabilitation; Non-invasive brain stimulation; Cognitive enhancing drug; Intensive Language-Action Therapy