Keith M. McGregor

Functional MRI of Language in Aphasia: A Review of the Literature and the Methodological Challenges

Animal analogue studies show that damaged adult brains reorganize to accommodate compromised functions. In the human arena, functional magnetic resonance imaging (fMRI) and other functional neuroimaging techniques have been used to study reorganization of language substrates in aphasia. The resulting controversy regarding whether the right or the left hemisphere supports language recovery and treatment progress must be reframed. A more appropriate question is when left-hemisphere mechanisms and when right-hemisphere mechanisms support recovery of language functions. Small lesions generally lead to good recoveries supported by left-hemisphere mechanisms. However, when too much language eloquent cortex is damaged, right-hemisphere structures may provide the better substrate for recovery of language. Some studies suggest that recovery is particularly supported by homologues of damaged left-hemisphere structures. Evidence also suggests that under some circumstances, activity in both the left and right hemispheres can interfere with recovery of function. Further research will be needed to address these issues. However, daunting methodological problems must be managed to maximize the yield of future fMRI research in aphasia, especially in the area of language production. In this review, we cover six challenges for imaging language functions in aphasia with fMRI, with an emphasis on language production: (1) selection of a baseline task, (2) structure of language production trials, (3) mitigation of motion-related artifacts, (4) the use of stimulus onset versus response onset in fMRI analyses, (5) use of trials with correct responses and errors in analyses, and (6) reliability and stability of fMRI images across sessions. However, this list of methodological challenges is not exhaustive. Once methodology is advanced, knowledge from conceptually driven fMRI studies can be used to develop theoretically driven, mechanism-based treatments that will result in more effective therapy and to identify the best patient candidates for specific treatments. While the promise of fMRI in the study of aphasia is great, there is much work to be done before this technique will be a useful clinical tool.

STRUCTURAL CONNECTIVITY OF BROCA’S AREA AND MEDIAL FRONTAL CORTEX

Despite over 140 years of research on Brocas area, the connections of this region to medial frontal cortex remain unclear. The current study investigates this structural connectivity using diffusion-weighted MRI tractography in living humans. Our results show connections between Brocas area and Brodmanns areas (BA) 9, 8, and 6 (both supplementary motor area (SMA) in caudal BA 6, and Pre-SMA in rostral BA 6). Trajectories follow an anterior-to-posterior gradient, wherein the most anterior portions of Brocas area connect to BA 9 and 8 while posterior Brocas area connects to Pre-SMA and SMA. This anterior-posterior connectivity gradient is also present when connectivity-based parcellation of Brocas area is performed. Previous studies of language organization suggest involvement of anterior Brocas area in semantics and posterior Brocas area in syntax/phonology. Given corresponding patterns of functional and structural organization of Brocas area, it seems well warranted to investigate carefully how anterior vs. posterior medial frontal cortex differentially affect semantics, syntax and phonology.

Regional Changes in Word-Production Laterality After a Naming Treatment Designed to Produce a Rightward Shift in Frontal Activity

Five nonfluent aphasia patients participated in a picture-naming treatment that used an intention manipulation (opening a box and pressing a button on a device in the box with the left hand) to initiate naming trials and was designed to re-lateralize word production mechanisms from the left to the right frontal lobe. To test the underlying assumption regarding re-lateralization, patients participated in fMRI of category-member generation before and after treatment. Generally, the four patients who improved during treatment showed reduced frontal activity from pre- to post-treatment fMRI with increasing concentration of activity in the right posterior frontal lobe (motor/premotor cortex, pars opercularis), demonstrating a significant shift in lateraliity toward the right lateral frontal lobe, as predicted. Three of these four patients showed no left frontal activity by completion of treatment, indicating that right posterior lateral frontal activity supported category-member generation. Patients who improved in treatment showed no difference in lateralization of lateral frontal activity from normal controls pre-treatment, but post-treatment, their lateral frontal activity during category-member generation was significantly more right lateralized than that of controls. Patterns of activity pre- and post-treatment suggested increasing efficiency of cortical processing as a result of treatment in the four patients who improved. The one patient who did not improve during treatment showed a leftward shift in lateral frontal lateralization that was significantly different from the four patients who did improve. Neither medial frontal nor posterior perisylvian re-lateralization from immediately pre- to immediately post-treatment images was a necessary condition for significant treatment gains or shift in lateral frontal lateralization. Of the three patients who improved and in whom posterior perisylvian activity could be measured at post-treatment fMRI, all maintained equal or greater amounts of left-hemisphere perisylvian activity as compared to right. This finding is consistent with reviews suggesting both hemispheres are involved in recovery of language in aphasia patients.

Impact of changed positive and negative task-related brain activity on word-retrieval in aging

Previous functional imaging studies that compared activity patterns in older and younger adults during nonlinguistic tasks found evidence for 2 phenomena: older participants usually show more pronounced task-related positive activity in the brain hemisphere that is not dominant for the task and less pronounced negative task-related activity in temporo-parietal and midline brain regions. The combined effects of these phenomena and the impact on word retrieval, however, have not yet been assessed. We used functional magnetic resonance imaging to explore task-related positive (active task > baseline) and negative activity (baseline > active task) during semantic and phonemic verbal fluency tasks. Increased right frontal positive activity during the semantic task and reduced negative activity in the right hemisphere during both tasks was associated with reduced performance in older subjects. No substantial relationship between changes in positive and negative activity was observed in the older participants, pointing toward 2 partially independent but potentially co-occurring processes. Underlying causes of the observed functional network inefficiency during word retrieval in older adults need to be determined in the future.

Broca's area and its striatal and thalamic connections: a diffusion-MRI tractography study.

In the recent decades structural connectivity between Brocas area and the basal ganglia has been postulated in the literature, though no direct evidence of this connectivity has yet been presented. The current study investigates this connectivity using a novel diffusion-weighted imaging (DWI) fiber tracking method in humans in vivo. Our findings suggest direct connections between sub-regions of Brocas area and the anterior one-third of the putamen, as well as the ventral anterior nucleus of the thalamus. Thus, we are the first to provide a detailed account of inferred circuitry involving basal ganglia, thalamus, and Brocas area, which would be a prerequisite to substantiate their support of language processing.

Physical activity and neural correlates of aging: A combined TMS/fMRI study

Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition.

Functional Imaging and Related Techniques: An Introduction for Rehabilitation Researchers

Over the past 25 years, techniques to image brain structure and function have offered investigators in the cognitive neurosciences and related fields unprecedented opportunities to study how human brain systems work and are connected. Indeed, the number of peer-reviewed research articles using these techniques has grown at an exponential rate during this period. Inevitably, investigators have become interested in mapping neuroplastic changes that support learning and memory using functional neuroimaging, and concomitantly, rehabilitation researchers have become interested in mapping changes in brain systems responsible for treatment effects during the rehabilitation of patients with stroke, traumatic brain injury, and other brain injury or disease. This new rehabilitation research and development arena is important because a greater understanding of how and why brain systems remap in the service of rehabilitation will lead to the development of better treatments. At the same time that functional neuroimaging methods have been developed, new structural neuroimaging techniques also have been added to the tool box of rehabilitation researchers. For example, diffusion tensor imaging (DTI) and related magnetic resonance (MR) techniques offer the ability to assess human white matter pathways in vivo. Not only can these techniques be used to estimate the integrity of a given volume of white matter, but they also can be used to trace fiber tracts within the brain. This latter development is exciting because most of what we know (or at least thought we knew) about the connections of the human cortex has actually come from research on nonhuman primates, leaving questions especially about the phylogenetically newer portions of the cortex. In the rehabilitation arena, a better understanding of how the brain’s connections are damaged could help us to predict what treatments are best for different research subjects and, eventually, might be useful in selecting the best treatment strategies for individual patients. Because the newer functional and structural neuroimaging techniques have enormous implications for rehabilitation research and development, it is highly desirable that rehabilitation researchers be able to evaluate the usefulness of the techniques for rehabilitation research and that the consumers of rehabilitation research (i.e., clinicians and researchers) be able to evaluate research findings that have applied the techniques. The purpose of this article is to discuss functional and structural imaging techniques used in rehabilitation research. We will not cover routine clinical MR or x-ray computerized tomography (CT) images. Rather, we will concentrate on a variety of techniques used most frequently, though not necessarily exclusively, in research settings. The article will consist of two main sections: (1) Because of the extraordinary versatility or MR techniques, the large number of MR techniques will be discussed first. (2) Subsequently, other functional neuroimaging techniques will be discussed, including: Positron Emission Tomography (PET), Magnetoencephalography/Magnetic Source Imaging (MEG/MSI), Near Infrared Spectroscopy (NIRS), Transcranial Magnetic Stimulation (TMS), and Electroencephalography/Evoked Potentials (EEG/EPs). For each imaging modality, we will give a brief explanation of the modality, its uses/potential uses in rehabilitation research, its strengths and limitations, and an example of research in the area.

Effects of aerobic fitness on aging-related changes of interhemispheric inhibition and motor performance

Physical fitness has been long associated with maintenance and improvement of motor performance as we age. In particular, measures of psychomotor speed and motor dexterity tend to be higher in physically fit aging adults as compared to their sedentary counterparts. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS), we explored the patterns of neural activity that may, in part, account for differences between individuals of varying physical fitness levels. In this study, we enrolled both sedentary and physically fit middle age (40–60) and younger (18–30) adults and measured upper extremity motor performance during behavioral testing. In a follow-up session, we employed TMS and fMRI to assess levels of interhemispheric communication during unimanual tasks. Results show that increased physical fitness is associated with better upper extremity motor performance on distal dexterity assessments and increased levels of interhemispheric inhibition in middle age adults. Further, the functional correlates of changes of ipsilateral activity appears to be restricted to the aging process as younger adults of varying fitness levels do not differ in hemispheric patterns of activity or motor performance. We conclude that sedentary aging confers a loss of interhemispheric inhibition that is deleterious to some aspects of motor function, as early as midlife, but these changes can be mediated by chronic engagement in aerobic exercise.

Neural substrates of syntactic mapping treatment: An fMRI study of two cases

Two patients (G01, J02) with chronic nonfluent aphasia and sentence production deficits received syntactic mapping treatment to improve sentence production. The patients had dramatically different outcomes in that improved syntax production generalized to nontreatment tasks for G01, but not for JO2. To learn how treatment influenced the neural substrates for syntax production, both patients underwent pre- and posttreatment functional magnetic resonance imaging (fMRI) of sentence generation. G01 showed more robust activity posttreatment than pretreatment in Brocas area; ventral temporal activity decreased slightly from pre- to posttreatment. Comparison of J02s pretreatment and posttreatment images revealed little change, although activity was more diffuse pre- than posttreatment. Findings suggest that for G01, rehabilitation led to engagement of an area (Brocas area) used minimally during the pretreatment scan, whereas for J02, rehabilitation may have led to more efficient use of areas already involved in sentence generation during the pretreatment scan. fMRI findings are discussed in the context of sentence-production outcome and generalization.

An fMRI Study of the Differences in Brain Activity During Active Ankle Dorsiflexion and Plantarflexion

Little is known regarding the differences in active cortical and subcortical systems during opposing movements of an agonist-antagonist muscle group. The objective of this study was to characterize the differences in cortical activation during active ankle dorsiflexion and plantarflexion using functional MRI (fMRI). Eight right-handed healthy adults performed auditorily cued right ankle dorsiflexions and plantarflexions during fMRI. Differences in activity patterns between dorsiflexion and plantarflexion during fMRI were assessed using between- and within-subject voxel-wise t-tests. Results indicated that ankle dorsiflexion recruited significantly more regions in left M1, the supplementary motor area (SMA) bilaterally, and right cerebellum. Both movements activated similar left hemisphere regions in the putamen and thalamus. Dorsiflexion activated additional areas in the right putamen. Results suggest that ankle dorsiflexion and plantarflexion may be controlled by both shared and independent neural circuitry. This has important implications for functional investigations of gait pathology and how rehabilitation may differentially affect each movement.