|Year : 2022 | Volume
| Issue : 1 | Page : 1-15
Poststroke aphasia treatment: A review of pharmacologic therapies and noninvasive brain stimulation techniques
Allison Nuovo Capizzi1, Jean E Woo2, Elaine Magat3
1 VA Palo Alto Healthcare System, Polytrauma System of Care, Physical Medicine and Rehabilitation, Palo Alto, CA, USA
2 Baylor College of Medicine, Department of Physical Medicine and Rehabilitation, Houston, TX, USA
3 The University of Texas Health Science Center at Houston, McGovern Medical School, Department of Physical Medicine and Rehabilitation, Houston, Texas, USA
|Date of Submission||23-Oct-2021|
|Date of Decision||12-Dec-2021|
|Date of Acceptance||13-Dec-2021|
|Date of Web Publication||08-Feb-2022|
Dr. Allison Nuovo Capizzi
3801 Miranda Ave. Building MB2, Palo Alto, CA 94304
Source of Support: None, Conflict of Interest: None
Aphasia is a common complication of stroke, often causing significant morbidity. To the authors' knowledge, no stroke recovery practice guidelines incorporating pharmacologic or noninvasive brain stimulation (NIBS) therapies for poststroke aphasia (PSA) exist. The aim of this article is to provide a comprehensive review of the evidence regarding pharmacologic and NIBS treatment in PSA. An exhaustive single database search assessing treatment for PSA was performed from 2010 to 2020, resulting in 1876 articles. Articles evaluating either pharmacologic management or NIBS were included. Case reports, case series, original research, systematic reviews, and meta-analyses were allowed. Pharmacologic treatment studies included were represented by the following medication classes: cholinergic, dopaminergic, gamma-aminobutyric acid agonists and derivatives, N-methyl-D-aspartate receptor antagonists, serotonergic, and autonomic agents. NIBS treatment studies regarding transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) were evaluated. No strong evidence was found for any medication to improve PSA. However, the benefit of a medication trial may outweigh the risk of side effects as some evidence exists for functional recovery. Regarding NIBS, weak evidence exists for the treatment effect of tDCS and rTMS on PSA. While additional research is needed, the literature shows promise, especially in chronic phase of stroke when traditional treatment options may be exhausted. More evidence with larger studies and standardized study design is needed.
Keywords: Aphasia, stroke rehabilitation, transcranial direct current stimulation, transcranial magnetic stimulation
|How to cite this article:|
Capizzi AN, Woo JE, Magat E. Poststroke aphasia treatment: A review of pharmacologic therapies and noninvasive brain stimulation techniques. J Int Soc Phys Rehabil Med 2022;5:1-15
|How to cite this URL:|
Capizzi AN, Woo JE, Magat E. Poststroke aphasia treatment: A review of pharmacologic therapies and noninvasive brain stimulation techniques. J Int Soc Phys Rehabil Med [serial online] 2022 [cited 2023 May 28];5:1-15. Available from: https://www.jisprm.org/text.asp?2022/5/1/1/337424
| Introduction|| |
At 1 year following a stroke, approximately 40% of patients are still living with aphasia, a significant cause of morbidity. Lesions to the language centers of the brain, predominantly in the left hemisphere, may result in aphasia. The literature suggests that perilesional regions as well as ipsilateral and contralateral areas contribute to necessary reorganization process required for aphasia recovery. Three general models of aphasia recovery exist. Vicariation is the concept that the hemisphere contralateral to the lesion entirely replaces the lost function of the damaged hemisphere. The interhemispheric competition model assumes that, at baseline (preinjury), the two cerebral hemispheres inhibit each other. Once an injury occurs, the hemisphere contralateral to the lesioned hemisphere inhibits the lesioned hemisphere to a greater degree, limiting recovery of the functions within the lesioned hemisphere. The bimodal balance recovery theory suggests that the amount of undamaged neurons, a type of structural reserve, connecting injured to uninjured areas of the brain, determines the recovery potential. The aim of this article is to provide a thorough review of the literature addressing pharmacologic and noninvasive brain stimulation (NIBS) interventions as treatment options for poststroke aphasia (PSA).
| Methods|| |
This article is a narrative review of the existing literature, and therefore, no human subjects were involved. No informed consent was necessary. As a review, this study was exempt from institutional review board approval. Two exhaustive single database (PubMed) searches were performed with assistance from a skilled librarian evaluating treatments for PSA over a 10-year period (2010–2020). The first search produced 781 results primarily yielding articles on NIBS. The second search was expanded to include all therapy modalities and pharmacologic treatment (1088 results). Complete search terms are included in Supplementary Material. These were screened for relevance by the three authors. Articles on NIBS including transcutaneous direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) as well as pharmacologic treatments were included. Articles solely focusing on other modalities (such as isolated speech therapy) were excluded. Case reports, case series, original research, systematic reviews, and meta-analyses were included if appropriate for the purpose of the article.
| Pharmacologic Trials for Poststroke Aphasia|| |
Ischemic changes in the brain can interrupt the cholinergic projections to cortical areas necessary for language processing.,, Language deficits are common in Alzheimer's dementia (AD) wherein single-photon emission computed tomography and positron emission tomography show cortical acetylcholine (ACh) reduction.,, Early neurochemical studies also suggested a loss of cholinergic neurons or decrease in choline acetyltransferase activity., An ACh receptor antagonist, scopolamine, resulted in cognitive impairment and dose-dependent decline in reading, spelling, verbal fluency, and object naming in healthy subjects., On the other hand, an acetylcholinesterase (AChE) inhibitor, physostigmine, improved naming in three patients with anomia. These findings are cited as a rationale for cholinergic medication trials in PSA.
In animal studies, bifemelane prevented N-methyl-D-aspartate (NMDA) and muscarinic cholinergic receptors' reduction in ischemia and increased ACh release.,, Two small clinical trials were found in the literature [Table 1]. Both point to the benefits of this medication in improving language impairments.
Galantamine is a reversible and competitive AChE inhibitor., This review yielded one study [Table 1] which showed significant improvement in the experimental group's global aphasia severity score.
Donepezil increases ACh via reversible inhibition of AChE. Interest in donepezil for PSA stemmed from earlier studies demonstrating improvements in AD patients' language deficits while taking this medication. The literature yields many published articles showing language improvement in PSA [Table 1].,,,,
Observations of speech improvement following Levodopa (L-dopa) therapy in parkinsonian patients encouraged studies evaluating dopaminergic agents for PSA. Some researchers suggest decreased dopamine input to the frontal lobe causes aphasia in the left frontal lesions by inhibiting the mesocortical pathway.,, Two dopaminergic medications, bromocriptine and L-dopa, are studied for aphasia.
Bromocriptine is a postsynaptic dopamine receptor agonist. The seven bromocriptine trials on PSA primarily involve nonfluent aphasia subjects [Table 2]. The results are variable. Most benefits were noted in smaller studies, case reports, and open-label trials with no placebo. Most double-blinded placebo-controlled trials did not show any significant benefits with bromocriptine compared to placebo.,,, The presence of significant side effects, if mentioned in the articles, appears related to higher medication doses.
A 2004 study involving nonaphasic subjects demonstrated accelerated word learning while taking L-dopa. This study, along with the bromocriptine studies, prompted trials evaluating L-dopa for PSA. Three trials [Table 2] were identified in our literature search, with 2 out of 3 showing no significant effects for PSA.,,
Zolpidem is an imidazopyridine, a gamma-aminobutyric acid A (GABA A) receptor agonist. This medication is unique, being a selective agonist of the alpha 1 subunit of the GABA A receptor complex.,, Reports of its use outside of insomnia started in the late 1990s. Most studies evaluating alternate applications of zolpidem focus on indications for movement disorders and disorders of consciousness (DOC). In the DOC population, zolpidem is theorized to bind GABA A receptors on the dormant nerve cells, leading to normalizing metabolic activity, and restore the pathway connectivity to improve alertness.
Two articles evaluated zolpidem in PSA treatment [Table 3]. One study showed speech improvement, while the other showed naming task improvement. One study theorized that select patients with subcortical lesions and hypometabolic cortical structures may benefit from zolpidem.
Piracetam is a GABA derivative and is the first nootropic agent theorized to have neuroprotective properties by increasing gray matter cerebral blood flow., In healthy subjects, piracetam may improve learning and memory. Piracetam's mechanism of action is unknown but may include facilitating ACh and excitatory amino acid release.,, Initial clinical trials suggested aphasia improvement with piracetam versus placebo group. These include studies by Herrschaft in 1988 and Platt et al. in 1992. Most subsequent studies were blinded randomized control trials (RCTs) [Table 4]., Study outcomes showed improvements in different aspects of language and speech except for one, which did not show clear benefit. A systematic review by Zhang et al. was published in 2016, aiming to assess piracetam in PSA rehabilitation. Seven RCTs were reviewed [Table 4]. This meta-analysis demonstrated short-lived positive effects in written language improvement, but overall aphasia severity did not improve.
N-methyl-D-aspartate receptor antagonist
Glutamate is a major mediator of neuronal plasticity and cell injury/death., The glutamatergic system requires a finely balanced control, with both hypoactivity and hyperactivity of the glutamatergic system, leading to dysfunction. A 1998 animal study showed imbalances between excitatory and inhibitory binding sites in areas away from ischemic tissue damage, namely an upregulation in NMDA receptors binding sites and downregulation of GABA A receptors. Memantine is an uncompetitive (channel-blocking) antagonist of the NMDA-receptor subtype of glutamate receptors.,, Memantine may have the potential to interrupt glutamatergic-mediated neurotoxic cascades without interfering with normal glutamatergic signals.,
A summary of seven studies evaluating the effect of memantine on language or communication in AD and other diagnoses was published in 2014. This 2014 publication showed modest language and communication benefits in AD patients taking memantine, prompting additional research evaluating memantine for PSA severity. One study demonstrated improvement. [Table 5].
Many clinical and preclinical trials suggest that antidepressants, including selective serotonin reuptake inhibitors (SSRIs), provide benefits to stroke outcomes independent of antidepression effect., Previously cited possible indications for SSRIs in poststroke recovery include neuroprotection by reduction of inflammation, enhancement of neurogenesis, modulation of cortical excitability, reestablishment of inhibitory neural network tone, cerebral blood flow regulation, modulation of the autonomic nervous system, and genetic and epigenetic correlates., A meta-analysis of animal studies by McCann et al. in 2014 showed that antidepressants may improve infarct volume and neurobehavioral outcome. In clinical trials, several experiments and meta-analyses suggest improved stroke recovery with SSRI use.,, However, more recent meta-analyses concluded that SSRIs do not improve disability or independence, and if filtered for low bias, no studies evaluating SSRIs in stroke recovery show significant improvement.
Three trials investigating SSRI and its effects on PSA were found in the literature, as summarized in [Table 6].,, Two trials showed improvement in the Boston naming test.,
Dextroamphetamine is a noncatecholamine, sympathomimetic amine. Animal experiments in the 1980s into the 2000s furnished evidence pointing to the role of brain catecholamine in the recovery of function., One of the most studied agents was amphetamine. The mechanism of recovery appears to lie in improved neurite growth and formation of synapses.,,, A preclinical trial and several clinical trials showed improvement in motor function with amphetamine after a stroke. One study showed that a catecholamine antagonist hindered recovery from aphasia. These led to trials aiming to determine the effect of dextroamphetamine on PSA. Older trials were case studies and case series, with majority of studies thereafter using double-blinded, placebo-controlled designs. These trials, summarized in [Table 7],,,,,,,, resulted toward positive improvements in aphasia, except for one; however, only one subject was enrolled in this study arm.
Atomoxetine is a selective norepinephrine reuptake inhibitor at the presynaptic level., One study was found in the literature suggesting a positive outcome with use in aphasia patients [Table 7].
Propranolol is a nonselective beta-adrenergic receptor blocking agent. Several early studies showed improvement with propranolol use in cognitive flexibility during stressful situations and improvement in problem-solving tasks involving lexical-semantic networks. A 1986 three-arm retrospective study included aphasic male subjects taking either propranolol, hydrochlorothiazide (HCTZ), or no treatment. Results indicated that participants taking propranolol had a better recovery than those on HCTZ. A 2007 double-blind cross-over design pilot study investigating the effect of propranolol on PSA showed benefit in naming [Table 7].
| Noninvasive Brain Stimulation for Poststroke Aphasia|| |
Transcutaneous direct current stimulation
Aphasia recovery is considered driven, in part, by spontaneous neuroplasticity. NIBSs such as rTMS and tDCS have been tried as complementary instruments to speech and language therapy (SLT) to promote poststroke reorganization of language networks for optimal recovery. tDCS modulates cortical excitability by changing the resting membrane potential via application of small currents (1–2 mA) to the scalp through the electrodes over a time period (5–30 min) where the anode increases excitability of the underlying cortex, and the cathode decreases it. Based on the schematic model of interhemispheric competition as previously mentioned, most tDCS studies have used anodal stimulation on the left hemisphere such as Broca's (left inferior frontal gyrus) area for activation or cathodal stimulation on the right hemisphere such as Broca's homolog for inhibition.,, Once a stimulation target is determined, several techniques such as fMRI, rTMS, and, most commonly, electroencephalography electrode positioning system can be used to precisely locate the lesion and to place electrodes for each patient. Unlike rTMS, tDCS can be used online, meaning patients can participate in language tasks during stimulation, which was found more effective than offline treatment.
Numerous reviews and meta-analyses have been published with conflicting findings regarding the efficacy of tDCS for improving PSA. Otal et al. did not show significant treatment effects in a 2015 meta-analysis. Shah-Basak et al.'s meta-analysis highlighted significant improvement in language outcome in chronic stages. Meta-analyses by Elsner et al. in 2013, 2015, and 2019 found no effectiveness of tDCS versus control for improving functional communication, naming verbs, and cognition. However, the 2019 study did note improved noun-naming accuracy compared to control group. Another meta-analysis by Rosso et al. demonstrated a significant dose-dependent effect of repetitive tDCS on naming accuracy in chronic stroke patients, more for anodal than cathodal tDCS and for left than right hemisphere stimulation. The most recent meta-analysis in 2019 concluded that tDCS may improve aphasia recovery and produce durable results, especially for the naming performance, in the chronic phase.
A 2019 systematic review by Biou et al. highlighted the effects of anodal tDCS over Broca's area combined with various language training tasks. Simultaneous repetition tasks improved accuracy in speech production, naming tasks improved naming accuracy, and conversational therapy improved picture naming, noun, and verb naming. Participants also demonstrated more informative and cohesive speech,, as well as improved reading ability. The authors concluded that selecting the correct combination between the behavioral task and stimulation site was crucial to optimize the combined effects of tDCS and language training. For other specific areas, cathodal stimulation over the right Wernicke's homolog, anodal stimulation over the Wernicke's area, and anodal stimulation over the left posterior perisylvian region improved auditory verbal comprehension., The authors concluded that tDCS was effective for PSA rehabilitation in the chronic stages.
Interestingly, improvement has been found after both anodal and/or cathodal stimulation over the right hemisphere in studies which seems counterintuitive in models of interhemispheric competition. However, as per vicariation model, the right hemisphere may aid aphasia recovery. Inhibiting the right hemisphere might be useful only when its activity is excessive and maladaptive but might be harmful when the right hemisphere activity is compensatory. In a review article, Bucur and Papagno noted that stroke phase determines the brain state, and ongoing plastic changes may influence treatment effect. The authors presented the potential efficacy of downregulating the right hemisphere during the subacute period and activating the perilesional regions during the chronic phase. Similar to this, Biou et al. concluded that right Broca's homolog and supplementary motor area seem involved in the subacute phase of stroke, followed by a normalization and re-shifting of cortex activity toward the left during the chronic stage. Hence, many trials that aimed to facilitate the left hemisphere during the subacute phase did not find significant results. The conclusion suggesting a shift in language area activation in acute versus chronic stroke is further supported by Saur et al.'s fMRI observations on dynamics of language reorganization. Saur et al. showed reduced activation of perilesional language areas in the acute phase of stroke, followed by an upregulation with recruitment of the right Broca's homolog, which strongly correlated with improved language function. This shift was followed by normalization of activation patterns during the chronic phase which was associated with further language improvement.
Several uncommon stimulation sites have been targeted with the principle of improving language via modulation of motor-language connections. Anodal stimulation of the left dorsolateral prefrontal cortex and primary motor cortex has shown to improve verbal fluency and functional communication, respectively, both of which propose a need for motor networks in aphasia recovery. Other studies found improved spelling, verb generation, and verbal fluency, with various cerebellar stimulations. Cerebellar stimulation is thought to improve the nonlinguistic aspects of task performance through its contribution in higher-level cerebral functions., One study stimulated the spinal cord with positive effects on verb retrieval, suggesting its influence on the ascending somatosensory pathways, ultimately modulating the language network in the sensorimotor cortex.
No study reported serious adverse effects of tDCS. Side effects reported include local discomfort at the stimulation site, such as itching and tingling, dull headache, and dizziness.
There were several prominent limitations that could cause inconsistent findings among tDCS trials. Study designs are significantly heterogeneous varying in the number of sessions, treatment frequency, intervention protocol, tDCS montage, types and chronicity of stroke, aphasic symptoms and severity, patient's anatomy, etc. There is also a concern for genetic variation affecting the response to tDCS. Fridriksson et al. found that patients with a typical BDNF genotype seemed to have milder symptoms of aphasia and better improvement induced by anodal tDCS. Another major limitation is the lack of comprehensive aphasia assessment tools. Picture naming task was selected as a central measure of language improvement in many studies although some investigated fluency, reading, and auditory-verbal comprehension. However, functional communication cannot be fully represented by the outcomes measured in single-word production. There is only a few studies that explored the effects of tDCS on suprasegmental and other subtle aspects of language such as intonation, pitching, and prosody. Most of the available objective measures are not able to detect the ease of task and performance that patients experience.
Repetitive transcranial magnetic stimulation
rTMS is a NIBS technique that uses pulses of electromagnetic waves at certain frequencies to enhance recovery of brain functions., The studied applications for rTMS are numerous, including pain, movement disorders, epilepsy, DOC, tinnitus, depression, anxiety disorders, obsessive–compulsive disorder, schizophrenia, craving/addiction, and conversion, among others.
Similar to the proposed mechanisms discussed regarding tDCS, rTMS for aphasia recovery utilizes principles from the interhemispheric competition model for recovery. As in tDCS, meta-analyses of rTMS suggest that the best outcomes of rTMS therapy occur when electromagnetic current is directed to the area contralateral to the initial lesion. For example, if the injury resulted in a nonfluent aphasia, then rTMS treatment would be targeted at the right inferior frontal gyrus near Brodmann's area 44 or 45, contralateral to Broca's area in the left hemisphere. The magnetic current modulates cortical excitability, therefore dampening excess inhibition from the contralateral cortex on the lesioned cortex. By suppressing the inhibiting signals from the contralateral area, the lesioned area then gains more potential for recovery.,
Lefaucheur et al. published comprehensive evidence-based guidelines regarding rTMS therapy in 2014 followed by an update in 2020. These guidelines discuss the evidence of rTMS for multiple conditions, including PSA. Research before 2012 evaluating rTMS for PSA recovery displayed mixed findings. Similar to the limitations noted in the tDCS review section, ambiguity in effectiveness of rTMS may be attributed to the heterogeneity in study designs which previously included all types of aphasia and poststroke patients at all phases of recovery.
Literature after 2012, with more specific inclusion criteria, reveals that the placement of the magnet and the type of rTMS appear to have a significant role in the effectiveness of the intervention. There is evidence low-frequency rTMS (LF-rTMS) is associated with aphasia recovery while high-frequency rTMS does not seem to offer a significant impact. While dual hemisphere stimulation may be beneficial,, stimulation ipsilateral to the lesion has not proven helpful. To date in this current review, only contralateral rTMS is associated with significant benefit in PSA recovery.,
Additional factors including time since injury and type of aphasia appear linked with the amount of benefit derived from rTMS treatment. Thus far, chronic stroke patients (where chronic is defined as greater than 6 months poststroke) are the only population who consistently experienced statistically significant language improvements from rTMS treatments. Within the chronic poststroke population, there is class B level of evidence suggesting that patients with nonfluent aphasia may benefit from rTMS therapy.
While research protocols vary, those which reported positive findings generally used LF-rTMS with a frequency of 1 HZ and an intensity of 90%. The number of pulses varied from 600 to 1200 and the number of total sessions varied from 10 to 20 per study.,,,,
There are several limitations to evaluation of rTMS therapy. Study design heterogeneity is a significant concern facing similar challenges to those described within the tDCS section. It is difficult to interpret the lasting effects of rTMS because most long-term follow-up studies did not track outcomes beyond 3 months, likely restricted by resources and funding. In addition, while rTMS may have statistically significant therapeutic benefit in a research study, the findings may not translate into clinical significance. In addition, to our knowledge, no study with significant findings supporting rTMS used NIBS to treat aphasia in isolation, all compared rTMS with SLT against SLT alone.
Negative side effects related to rTMS are rare. One study by Bae et al., evaluating rTMS in epilepsy patients, noted that 83% of participants experienced no side effects. Of the 17% of participants that experienced side effects, transient headache was the most common followed by a general feeling of discomfort or weakness. Very rarely, seizures have been reported (1.4%), though seizures were associated with patients already diagnosed with epilepsy.
| Discussion|| |
Pharmacologic interventions for PSA aim to augment neurotransmitter activity and the neurochemical networks that are believed to be compromised after a stroke. Although no strong evidence exists for any particular medication to improve PSA, the benefit of a medication trial may outweigh the risk of side effects. In addition, pharmacotherapy can play a role in other neurocognitive pathways and enhance overall function during recovery. Current published reviews and meta-analyses provide weak evidence for treatment effect of tDCS and rTMS on PSA due to a small number of original experimental studies, the heterogeneity of the procedures, a paucity of comprehensive assessment tools for language, and vague understanding of brain reorganization mechanisms. However, the authors of the recent studies are optimistic about the therapeutic effects of NIBS, especially in chronic phase of stroke when no other treatment options are typically available.
Most articles assessing PSA treatment evaluated SLT with either pharmacotherapy or NIBS and did not combine these modalities together. One 2017 study by Keser et al. evaluated the combined effect of pharmacotherapy with NIBS to examine the effect of triple therapy. This was a small cross-over, placebo-controlled, double-blinded trial of chronic poststroke patients with nonfluent aphasia. The participants received a baseline language assessment followed by either 10 mg of dextroamphetamine or a placebo before undergoing tDCS with simultaneous SLT (triple-combination therapy). The Western Aphasia Battery-Revised and Language Quotient were administered before and after the combination treatments. They underwent two cycles of treatment, one experimental and one placebo, with a washout period of approximately 1 week in between. The results show a statistically significant increase in the Aphasia Quotient and Language Quotient in the experimental group compared to placebo. However, the small sample size, short study duration, and low number of treatment sessions limit the broader application of these findings. Despite limitations, Keser et al. highlight the safety and feasibility of their proof-of-concept design for future research.
| Conclusion|| |
The current review finds a lack of strong evidence supporting specific pharmacotherapy and NIBS protocols in management of PSA. However, these treatments may be appropriate to trial on a case-by-case basis under a specialist's guidance, especially in the chronic poststroke phase when standard-of-care therapies have had limited results. Further research is needed, particularly with triple therapy, as noted in Keser et al. Regarding NIBS, finding positive effects of tDCS and rTMS on social communication, overall functional outcome, mood, quality of life, and participation would enhance its clinical values. At last, NIBS safety, relatively low cost, ease of application, and great potential to improve PSA warrant further research.,
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]