Update in Aphasia Research

Abstract

The sequelae of post-stroke aphasia are considerable, with implications at the societal and personal levels. An understanding of the mechanisms of recovery of cognitive and language processes after stroke and the factors associated with increased risk of post-stroke language and cognitive deficits is vital in providing optimal care of individuals with aphasia and in counseling to their families and caregivers. Advances in neuroimaging facilitate the identification of dysfunctional or damaged brain tissue responsible for these cognitive/language deficits and contribute insights regarding the functional neuroanatomy of language. Evidence-based person-centered behavioral therapy remains the mainstay for rehabilitation of aphasia, although emerging evidence shows that neuromodulation is a promising adjunct to traditional therapy. These topics are discussed in this review, illustrating with recent studies from the Stroke Cognitive Outcomes and REcovery (SCORE) lab.

Introduction

Aphasia, and its recovery and rehabilitation, are compelling topics of discussion and investigation for clinicians, researchers, stroke survivors, and their families and caregivers. Stroke survivors and their families/caregivers are interested in understanding the nature of aphasia and in knowing what to expect in terms of recovery in order to plan for the future. Clinicians need to be knowledgeable about post-stroke aphasia to educate patients and families appropriately and to have meaningful dialog about prognosis. Researchers strive to identify areas of the brain critical for cognitive/language functions and mechanisms for recovery which can inform treatment.

Post-stroke aphasia has considerable impact on both public and personal health, and on societal costs. Aphasia is present in 15 [1] to 33 % [2] of individuals with acute stroke. Between 1997 and 2006, the number of individuals with aphasia was approximately 100,000 per year [3]. Costs for stroke-related healthcare exceeded $25 billion in 2007 [4]. Reintegration into school, work, and family life may be constrained, or even precluded, because of cognitive/language deficits; the resulting social isolation can be a devastating consequence of aphasia [5]. Aphasia, in general [6], and specific language deficits [7••], affect discharge placement. A review of specific language impairments and their association with discharge destination of 152 stroke patients revealed that deficits in auditory comprehension, reading comprehension, and tactile naming increased the odds of discharge from acute care to a setting other than the home environment after adjustment for potential confounding variables, including age and physical therapy/occupational therapy recommendations. These language impairments were judged to necessitate discharge to more restrictive environments so that accommodations can be provided to compensate for these language impairments [7••]. Furthermore, post-stroke language impairments were found to be of particular concern to patients and caregivers. A survey of stroke patients and their caregivers revealed that difficulty with spelling and writing was the single most frequently reported important/moderate consequence of left hemisphere stroke [8]. Spoken and written communications are vital for full participation in society, and deficits in these areas diminish this engagement [9].

This review will focus on the mechanisms of recovery of cognitive and language processes after stroke, factors associated with increased risk of post-stroke language and cognitive deficits, identification of dysfunctional or damaged brain tissue responsible for these cognitive/language deficits, and new treatment modalities to address these deficits, highlighting work done in the Stroke Cognitive Outcomes and REcovery (SCORE) lab.

Mechanisms of Stroke Recovery

Mechanisms of recovery after stroke include restoration of blood flow, recovery from diaschisis (i.e., language impairment that is caused by loss of input due to a remote lesion functionally connected to the cortical areas responsible for that language ability), and reorganization of structure-function relationships in the brain associated with neuroplasticity (i.e., the adaptive ability of the brain to reorganize and modify tissue functions in the setting of pathology). These mechanisms are operative at different times over the course of recovery and vary across individuals. Early recovery from vascular aphasia syndromes is likely attributable to restoration of blood flow, whereas later recovery may be attributable to reorganization in which other areas of the brain assume functions of a damaged area, an adaptation requiring time [10]. Broca’s aphasia, one vascular aphasia syndrome, is typically associated with damage or dysfunction in the posterior inferior frontal gyrus which includes Broca’s area (Brodmann areas 44 and 45) [11•]. Broca’s aphasia was found to be more consistently associated with infarction/hypoperfusion of Broca’s area in acute than chronic stroke, suggesting that recovery of language function occurred because of reorganization of structure-function relationships over time [12]. For example, reorganization of the language functions (including repetition) by the right hemisphere was hypothesized to be the mechanism of recovery in a patient with intact comprehension, articulation, naming, and word repetition and relatively intact sentence repetition 3 years post stroke, despite destruction of the entire left middle cerebral artery territory and complete lack of the left superior longitudinal fasciculus III component of the arcuate fasciculus [13••].

An extensive literature documents increased activation of right hemisphere homologues of language areas, as well as activation of perilesional areas of the left hemisphere, to compensate for damaged areas of the language network in stroke recovery [14-16]. These activation patterns are not static, but rather, the areas recruited to perform particular language tasks change over time. For example, Saur et al. [17] found that there was little activation in either hemisphere during an auditory sentence comprehension task in the acute post-stroke phase, predominately right hemisphere activation in the subacute phase, and a return to primarily left hemisphere activation in the chronic phase. Time post onset, then, is one variable that influences whether right or left hemisphere areas are engaged in auditory comprehension, and whether the right hemisphere may assume specific language functions, such as repetition.

Patterns and mechanisms of recovery also vary across time and individuals. Jarso et al. [18••] described different mechanisms of recovery in a case series of five individuals with acute ischemic left hemisphere stroke. Improvement in naming was demonstrated in one individual after undergoing an investigational therapy to elevate blood pressure temporarily to reperfuse hypoperfused cortical tissue in the first week post stroke. A second individual demonstrated improvement on a word generation task through recovery from diaschisis. At onset, this individual showed near absence of left hemisphere activation during a word generation task, despite no hypoperfusion or structural disconnection. At 8 weeks post stroke, there was activation of the left hemisphere. In a third individual, left hemisphere language network was restored after recovery from structural disconnection between thalamus and posterior frontal cortex. This individual had reduced left frontal activation during a picture-naming task due to disruption of thalamocortical tracts acutely. At 8 weeks post stroke, there was left frontal area activation despite persisting disruption of these tracts. Recovery was attributed to either functional reconnection, or new synaptic connections, developing between the thalamus and frontal cortex. And finally, in two individuals with similar lesion sizes and locations, different areas of the brain were recruited for the same orthographic task, suggesting different patterns of structure-function reorganization, indicating that individual factors (such as education) also influence recovery through neuroplasticity.

Further support for the role of diaschisis in language impairment is documented in a case series of 10 patients with isolated left thalamic lesions. Five had aphasia; only one had cortical hypoperfusion, revealing that left cortical hypoperfusion was not necessary to explain either naming or auditory comprehension impairments acutely after left thalamic infarct. Instead, the language deficits were judged to be caused by dysfunction of the thalamic-cortical system via diaschisis [19••].

In addition to the influence of time and individual patient characteristics, site and size of lesion affect activation patterns. Sebastian and Kiran [20] found that a semantic judgment task elicited bilateral activation of the inferior frontal gyrus (IFG) in chronic (largely recovered) aphasic individuals with left frontal lesions, but only left IFG activation in those without lesions involving the left frontal region. They also reported that larger left frontal lesions were associated with right lateralized activation.

Evidence From Medical Therapy Supporting the Role of Hypoperfusion

In the first few days of stroke, when the severity of language impairment demonstrated clinically cannot be accounted for by the structural lesion seen on diffusion-weighted imaging (DWI), marginally perfused tissue beyond the infarct may explain these deficits. In acute stroke, there often exists tissue beyond the infarct that is receiving sufficient blood flow to survive, but not to function, referred to as the “ischemic penumbra” [21, 22•, 23•]. This salvageable hypoperfused cortical tissue is at risk for further ischemia, and so a “diffusion-clinical match” prompts medical intervention [24]. An illustrative patient with Wernicke’s aphasia had only a tiny lesion on DWI in the insula that could not account for his deficits. His “diffusion-clinical mismatch” prompted further imaging with perfusion-weighted imaging (PWI) the same day and intervention to reperfuse Wernicke’s area. His Wernicke’s aphasia resolved by day 3 with restored blood flow to Wernicke’s area [11•]. In another patient, reading and spelling abilities were recovered after reperfusion of left fusiform cortex (medial Brodmann area 37), and yet in two other patients, picture and tactile naming and spelling were recovered after reperfusion of left inferior temporal cortex (lateral Brodmann area 37) [25••]. Other studies have shown that individuals with left hemisphere hypoperfusion show improvement in aphasia with reperfusion [26-30, 31••].

Factors Associated with Higher Risk of Language/Cognitive Deficits Post Stroke

There are multiple predictors of cognitive/language dysfunction in acute and subacute stroke. These factors may be considered by the stroke neurologist when counseling patients and families regarding prognosis. Predictors of poorer functional and cognitive outcomes post stroke include older age, female gender (men tend to have more lacunar strokes; women tend to have cardioembolic strokes and tend to have strokes at older ages than men), medical co-morbidities such as seizures and prior stroke, baseline cognitive deficits and dementia, and use of sedating medications [32]. In a large study of chronic aphasia recovery, time post onset was found to be the single most important determinant of recovery of speech production, indicating that improvement continues over time, even in the chronic stage [33••]. Chronic aphasia recovery is positively influenced by higher education and current antidepressant use (primarily selective serotonin reuptake inhibitors), as well as smaller lesion size and younger age (independently of one another) [34]. In addition, education influences performance on language testing acutely, and may even “protect” learned language functions. Error rates were lower on tests of auditory and written comprehension, written naming, oral reading, oral spelling, and written spelling of fifth grade vocabulary in stroke patients with 12 or more years of education, adjusting for socioeconomic status [35]. Volume of infarct is typically considered to be an important prognostic variable for motor and language recovery post stroke, although the association is relatively weak [36••].

Identification of Dysfunctional or Damaged Brain Tissue Responsible for Post-Stroke Cognitive/Language Deficits

While traditional aphasia classifications, such as Broca’s, Wernicke’s, global, conduction, anomic, and transcortical aphasias, are clinically useful in predicting areas of ischemia and patterns of recovery, and in selecting rehabilitation approaches [10, 37, 38], functional imaging of healthy participants and lesion studies show that areas beyond Broca’s and Wernicke’s areas are important for language [39-43]. Other areas of the cortex, such as inferior and anterior temporal cortex [5] and the basal ganglia and thalamus [44], are also activated during language tasks. Language impairments can result from damage or dysfunction of several different brain regions [45-48] due to the impact of the lesion not only on the function of the affected region, but also on the many regions connected to it within the language network [48].

Studies of patients at onset of stroke facilitate the identification of areas of ischemia or hypoperfusion which are responsible for language deficits before recovery or neuroanatomical reorganization can occur [30, 49, 50]. This concept of networks of the brain regions is supported in a study of the controversial role of the anterior temporal lobe in cognition and language. Several studies have recently concluded that the temporal pole is the “hub” of semantic processing—that it connects many other regions essential for semantics. However, Tsapkini et al. [51] found no difference between patients with and without acute left temporal pole infarcts on auditory word comprehension and object naming tasks. This finding suggests that damage to the left temporal pole is not sufficient to cause significant semantic deficits; instead, the temporal pole is likely part of a network responsible for comprehension and naming of objects. Similarly, other language skills, such as comprehension of yes/no questions and verbal working memory, are associated with multiple brain regions and their connections [52••, 53••].

Treatment: Behavioral Therapy

Speech-language pathology intervention is the mainstay for treatment of aphasia. Behavioral therapy can be both restitutive and compensatory. Lazar et al. [54] showed that individuals with mild-moderate aphasia who received even minimal speech-language pathology intervention post stroke showed recovery of language to 70 % of the individual’s maximum possible, but the one individual with mild-moderate aphasia who did not have language therapy failed to show this improvement. Although gains in therapy vary widely [55, 56], those who do not receive speech-language pathology intervention do not show steady spontaneous recovery of language after stroke. In fact, some show decline, consistent with recent large outcome studies showing that 25–30 % of patients show cognitive and functional decline, rather than recovery, after a single stroke [57, 58]. Current practice standards dictate that therapy should be evidence-based and person-centered. Evidence-based practice refers to an approach in which current high-quality research evidence is integrated with practitioner expertise and client preferences and values [59-61].

The patient-centered model of therapy is a collaborative process, encompassing the authentic involvement of users (patients), creation of engaging experiences, user control, and accountability [62]. Person-centered practice “involves valuing the individual needs and rights of patients, understanding patients’ illness and health care experiences, and embracing them within effective relationships which enable patients to participate in clinical reasoning” ([63], p. 68). The Life Participation Approach to Aphasia is an example of a patient-centered therapy paradigm [64], although clinicians can tailor specific therapy tasks to meet individuals’ unique needs [65]. The active involvement of patients, family member, and caregivers in the development of treatment plans is consistent with the conceptual framework for contemporary models of health care of the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO) [66].

The ICF is structured around the components of body structures and functions, activities (related to tasks and actions by individuals), and participation (involvement in life situations). This framework encourages patient-centered care, focusing on development of goals which address individual needs and circumstances in meaningful ways. For example, an activity level goal may be “demonstrating the ability to speak in sentences” and the participation level outcomes are “engaging in a parent-teacher conference” and “giving a professional oral presentation” [67]. The value of considering multiple sources of information, as well as daily life functioning and communication contexts, as part of the intervention process, is endorsed by the Academy of Neurologic Communication Disorders and Sciences Practice Guidelines Group [68].

Application of principles governing brain organization and reorganization may contribute to the development of meaningful therapy goals. The rationale for early and intensive aphasia therapy is based on the governing principle of neuroplasticity [69]. Intensive aphasia therapy over a short period of time is associated with improved speech and language outcomes [55]. Practicing a language task, which targets a particular ability, such as confrontation naming, may facilitate functional performance, such as conveying communicative intentions, as a result of the adaptive property of the brain.

Treatment goals may also be reframed based on the contemporary models of language organization. For example, in the dual stream model of the cortical organization of language comprehension and production, two pathways are proposed: a ventral stream for mapping sound onto meaning and a dorsal stream for mapping sound onto motoric productions [70-73]. Wernicke’s aphasia could be conceived as a disruption of the ventral stream; Broca’s aphasia could be conceived as a disruption of the dorsal stream. For individuals with Wernicke’s aphasia, therapy may emphasize processing speech for comprehension in words or sentences. For those with Broca’s aphasia, therapy may stress translating sound to motor speech productions at the word or sentence level [74•].

The implementation of evidence-based patient-centered care, which incorporates discoveries in the functional neuroanatomy of language, is both exciting and challenging. These challenges include learning how to facilitate the active participation of individuals with aphasia in goal setting, resolving discrepancies between clinician- and patient-targeted goals when inevitable differences arise, and supplementing traditional modes of treatment to optimize outcomes through new neuromodulation with transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).

Neuromodulation

Prosthetic stimulation offers a potentially important adjunctive approach to behavioral therapy. Neuromodulation with transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) increases the efficiency of speech-language therapy [75]. TMS is thought to modify cortical excitability, increasing or decreasing activity in targeted areas of the cortex. Protocols employing TMS improve naming in individuals with nonfluent aphasia. The mechanism proposed to explain this treatment effect is suppression of overactive right hemisphere homologues [76••, 77]. tDCS is designed to facilitate synaptic plasticity [78]. It is thought that tDCS changes the membrane potentials of neurons in a relatively focal area of brain tissue under the skull [79]. Anodal stimulation increases the likelihood of neural firing [80].

tDCS induces a subthreshold polarization of neurons too weak to generate action potentials, but sufficient to modulate the neuronal response threshold, altering the spontaneous firing rate of neurons to modulate their response to afferent signals [81, 82]. These changes in response threshold correlate with task performance. Increased or decreased cortical excitability induced by tDCS is believed to promote long-term potentiation (LTP) or long-term depression (LTD). The changes in brain networks may include recruitment of undamaged areas of the brain to assume functions of damaged areas during language tasks [83], which is one mechanism of recovery. Anodal tDCS has been used to enhance cortical excitability and function [84-86] in healthy individuals during tasks of word fluency, interference, picture naming, verbal learning, and proper noun learning. In studies of chronic stroke, anodal tDCS applied to the structurally intact perilesional left cortex facilitated naming performance post treatment [86-88, 89••]. In acute stroke, tDCS was used to stimulate the right hemisphere to improve spontaneous speech, auditory verbal comprehension, and test performance as reflected by aphasia quotients [90, 91].

Evidence supporting neuromodulation as an adjunct to behavioral therapy is promising; however, the precise mechanisms of language recovery after TMS and tDCS remain unclear, and a fuller understanding of the neural networks underlying cognition/language and the variables that influence recovery is essential to optimize the implementation of cortical brain stimulation. In addition, the optimal timing of the implementation of these novel treatments requires further study. The greatest improvement from post-stroke aphasia occurs within the first 3 months [54]; however, data are limited regarding tDCS in the acute phase of recovery. It is reasonable that the effects of tDCS would be potentiated if this adjunctive cortical stimulation is delivered during the first 3 months post stroke. Finally, further investigation of the long-term benefits of cortical stimulation is needed. Synaptic connectivity changes are evidence of robust learning. Durable effects of tDCS should be manifested in connectivity changes between nodes of neural networks. Studies in healthy controls that looked at the effects of tDCS on functional connectivity using resting state fMRI revealed significant changes [92-94], a reassuring finding indicative of potential long-term benefit of cortical stimulation on language function.

Conclusion

Management of individuals with aphasia is increasingly refined as clinicians and researchers become more sophisticated about the mechanisms of recovery of cognitive and language processes after stroke, prognostic factors associated with increased risk of post-stroke language and cognitive deficits, identification of cortical networks responsible for cognition/language, and emerging treatment modalities. Mechanisms of recovery after stroke include restoration of blood flow, recovery from diaschisis, and reorganization of structure-function relationships. These mechanisms function at different times over the course of recovery and vary across individuals. Determinants of recovery include older age, female gender, medical co-morbidities prior stroke, baseline cognitive deficits and dementia, time post onset, medications, and education. Advances in neuroimaging reveal that areas beyond Broca’s and Wernicke’s areas are important for cognitive/language function. Evidence-based patient-centered speech-language pathology intervention remains the foundation of aphasia rehabilitation, and evidence supporting neuromodulation as an adjunct to behavioral therapy encourages optimism about future advances in clinical care.