Anna Bacon Moore

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.

Left and right basal ganglia and frontal activity during language generation: Contributions to lexical, semantic, and phonological processes

fMRI was used to determine the frontal, basal ganglia, and thalamic structures engaged by three facets of language generation: lexical status of generated items, the use of semantic vs. phonological information during language generation, and rate of generation. During fMRI, 21 neurologically normal subjects performed four tasks: generation of nonsense syllables given beginning and ending consonant blends, generation of words given a rhyming word, generation of words given a semantic category at a fast rate (matched to the rate of nonsense syllable generation), and generation of words given a semantic category at a slow rate (matched to the rate of generating of rhyming words). Components of a left pre-SMA-dorsal caudate nucleus-ventral anterior thalamic loop were active during word generation from rhyming or category cues but not during nonsense syllable generation. Findings indicate that this loop is involved in retrieving words from pre-existing lexical stores. Relatively diffuse activity in the right basal ganglia (caudate nucleus and putamen) also was found during word-generation tasks but not during nonsense syllable generation. Given the relative absence of right frontal activity during the word generation tasks, we suggest that the right basal ganglia activity serves to suppress right frontal activity, preventing right frontal structures from interfering with language production. Current findings establish roles for the left and the right basal ganglia in word generation. Hypotheses are discussed for future research to help refine our understanding of basal ganglia functions in language generation.

Role of the Right and Left Hemispheres in Recovery of Function during Treatment of Intention in Aphasia

Two patients with residual nonfluent aphasia after ischemic stroke received an intention treatment that was designed to shift intention and language production mechanisms from the frontal lobe of the damaged left hemisphere to the right frontal lobe. Consistent with experimental hypotheses, the first patient showed improvement on the intention treatment but not on a similar attention treatment. In addition, in keeping with experimental hypotheses, the patient showed a shift of activity to right presupplementary motor area and the right lateral frontal lobe from pre-to post-intention treatment functional magnetic resonance imaging (fMRI) of language production. In contrast, the second patient showed improvement on both the intention and attention treatments. During pre-treatment fMRI, she already showed lateralization of intention and language production mechanisms to the right hemisphere that continued into post-intention treatment imaging. From pre-to post-treatment fMRI of language production, both patients demonstrated increased activity in the posterior perisylvian cortex, although this activity was lateralized to left-hemisphere language areas in the second but not the first patient. The fact that the first patients lesion encompassed almost all of the dominant basal ganglia and thalamus whereas the second patients lesion spared these structures suggests that the dominant basal ganglia could play a role in spontaneous reorganization of language production functions to the right hemisphere. Implications regarding the theoretical framework for the intention treatment are discussed.

Functional Magnetic Resonance Imaging Before and After Aphasia Therapy Shifts in Hemodynamic Time to Peak During an Overt Language Task

Background and Purpose— Comparing the temporal characteristics of hemodynamic responses in activated cortical regions of aphasic patients before and after therapy would provide insight into the relationship between improved task performance and changes in blood oxygenation level–dependent (BOLD) functional MRI (fMRI) signal. This study investigated differences in the time to peak (TTP) of hemodynamic responses in activated regions of interest (ROIs), before and after therapy, and related them to changes in task performance. Methods— Three aphasic patients and 3 controls overtly generated a single exemplar in response to a category. For the patients, TTP of hemodynamic responses in selected ROIs was compared before and after language therapy. The timing differences between auditory cues and verbal responses were compared with TTP differences between auditory and motor cortices. Results— The selected ROIs were significantly activated in both aphasic patients and controls during overt word generation. In the aphasic patients, both the timing difference from auditory cues to verbal responses and the TTP difference between auditory and motor cortices decreased after rehabilitation, becoming similar to the values found in controls. Conclusions— Findings indicate that (1) rehabilitation increased the speed of word-finding processes; (2) TTP analysis was sensitive to this functional change and can be used to represent improvement in behavior; and (3) it is important to monitor the behavioral performance that might correlate with the temporal pattern of the hemodynamic response.

Activation and Effective Connectivity Changes Following Explicit-Memory Training for Face–Name Pairs in Patients With Mild Cognitive Impairment A Pilot Study

Background. Mild cognitive impairment (MCI) is often a precursor to Alzheimer disease. Little research has examined the efficacy of cognitive rehabilitation in patients with MCI, and the relevant neural mechanisms have not been explored. The authors previously showed the behavioral efficacy of cognitive rehabilitation using mnemonic strategies for face–name associations in patients with MCI. Here, the authors used functional magnetic resonance imaging (fMRI) to test whether there were training-specific changes in activation and connectivity within memory-related areas. Methods. A total of 6 patients with amnestic, multidomain MCI underwent pretraining and posttraining fMRI scans, during which they encoded 90 novel face–name pairs and completed a 4-choice recognition memory test immediately after scanning. Patients were taught mnemonic strategies for half the face–name pairs during 3 intervening training sessions. Results. Training-specific effects comprised significantly increased activation within a widespread cerebral cortical network involving medial frontal, parietal, and occipital regions; the left frontal operculum and angular gyrus; and regions in the left lateral temporal cortex. Increased activation common to trained and untrained stimuli was found in a separate network involving inferior frontal, lateral parietal, and occipital cortical regions. Effective connectivity analysis using multivariate, correlation-purged Granger causality analysis revealed generally increased connectivity after training, particularly involving the middle temporal gyrus and foci in the occipital cortex and the precuneus. Conclusion. The authors’ findings suggest that the effectiveness of explicit-memory training in patients with MCI is associated with training-specific increases in activation and connectivity in a distributed neural system that includes areas involved in explicit memory.

Explicit memory training leads to improved memory for face–name pairs in patients with mild cognitive impairment: Results of a pilot investigation

Relatively few studies have examined the use of cognitive rehabilitation in patients with mild cognitive impairment (MCI), largely due to the assumption that training will not improve functioning in patients with progressive conditions. Face-name association, an ecologically valid task, is both dependent on the explicit memory system and difficult for MCI patients. During three hour-long sessions, eight patients diagnosed with MCI were trained in the use of explicit memory strategies with 45 face-name pairs. For each pair, they were taught to visually identify a facial feature, link a phonological cue to that feature, and recall the associated name. There was significant improvement in recognition accuracy, along with faster reaction times, for trained face-name pairs. Improved accuracy persisted when tested one month after training. Significant, but less, improvement was also found on untrained stimuli, raising the possibility of generalization of training strategies. Preliminary results suggest strategy-based cognitive rehabilitation may be beneficial in patients with MCI, though these results must be replicated with a control group to rule out practice effects.

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.

Treatment of naming in nonfluent aphasia through manipulation of intention and attention: A phase 1 comparison of two novel treatments

Twenty-three chronic nonfluent aphasia patients with moderate or severe word-finding impairments and 11 with profound word-finding impairments received two novel picture-naming treatments. The intention treatment initiated picture-naming trials with a complex left-hand movement and was designed to enhance right frontal participation during word retrieval. The attention treatment required patients to view visual stimuli for picture-naming trials in their left hemispace and was designed to enhance right posterior perisylvian participation during word retrieval. Because the intention treatment addressed action mechanisms and nonfluent aphasia reflects difficulty initiating or maintaining action (i.e., language output), it was hypothesized that intention component of the treatment would enhance re-acquisition of picture naming more than the attention component. Patients with moderate and severe word-finding impairment showed gains with both treatments but greater incremental improvement from one treatment phase to the next with the intention than the attention treatment. Thus, the hypothesis that intention component would be a more active constituent than the attention component was confirmed for these patients. Patients with profound word-finding impairment showed some improvement with both treatments but no differential effects for the intention treatment. Almost all patients who showed treatment gains on either treatment also demonstrated generalization from trained to untrained items.

Asymmetric connectivity reduction and its relationship to “HAROLD” in aging brain

Hemispheric asymmetry reduction in older adults (HAROLD) has been frequently reported in studies of functional brain aging. It is commonly considered to be a plastic brain reorganization that provides compensation for declining unilateral neural efficiency. However, plastic functional alterations may also be associated with neural connectivity changes. Using activation and resting state functional magnetic resonance imaging (fMRI) as well as diffusion tensor imaging (DTI), we examined whether functional and structural connectivity related to prefrontal working memory function is asymmetrically reduced in the two hemispheres of the aging brain; and if yes, whether these asymmetric connectivity declines are correlated with asymmetry reduction in functional activation. With regions of interests defined by verbal working memory activations, it is revealed that although neural connectivity is generally reduced in the aging brain, prefrontal-parietal resting functional connectivity is better preserved in the left hemisphere while prefrontal DTI fiber pathways are better preserved in the right hemisphere. In addition, the laterality change of the functional activation is negatively correlated with that of the resting connectivity and positively correlated with that of the structural connectivity. These results reveal additional aspects of the neuronal alterations of aging and suggest a link between asymmetric connectivity reduction and HAROLD.

Errorless practice as a possible adjuvant to donepezil in Alzheimer's disease.

Six individuals with probable Alzheimers disease (AD) participated in a phase 1 study employing a repeated measures, parallel baseline design testing the hypothesis that error-free experience during word production practice combined with an acetyl cholinesterase inhibitor would improve confrontation naming ability. While acetyl cholinesterase inhibitors are safe and delay cognition decline associated with AD, improvement over baseline cognition is less evident; clinically significant cognitive deficits persist and progress. Both animal and clinical research strongly implicate acetylcholine in learning, a form of neuroplasticity. In clinical practice, however, people with AD are given cholinergic medications without concomitant systematic/targeted retraining. In this study six participants with probable AD and taking donepezil participated in targeted word production practice using an errorless learning strategy. Results showed that combining behavioral enrichment training and an acetyl cholinesterase inhibitor resulted in significant improvements in verbal confrontation naming of trained items for three of six participants. Differences in baseline dementia severity, living conditions, and medications may have influenced the training response. Detection of substantial treatment effects in 50% of subjects suggests further language treatment studies in AD in combination with an acetyl cholinesterase inhibitor are warranted and provide useful information on inclusion/exclusion criteria for use in subsequent studies.