Longitudinal fMRI study of language recovery after a left hemispheric ischemic stroke.

BACKGROUND: Recovery from stroke-induced aphasia is typically protracted and involves complex functional reorganization. The relative contributions of the lesioned and non-lesioned hemispheres to this process have been examined in several cross-sectional studies but longitudinal studies involving several time-points and large numbers of subjects are scarce. OBJECTIVE: The aim of this study was to address the gaps in the literature by longitudinally studying the evolution of post-stroke lateralization and localization of language-related fMRI activation in the first year after single left hemispheric ischemic stroke. METHOD: Seventeen patients with stroke-induced aphasia were enrolled to undergo detailed behavioral testing and fMRI at 2, 6, 12, 26, and 52 weeks post-stroke. Matched for age, handedness and sex participants were also enrolled to visualize canonical language regions. RESULTS: Behavioral results showed improvements over time for all but one of the behavioral scores (Semantic Fluency Test). FMRI results showed that the left temporal area participates in compensation for language deficits in the first year after stroke, that there is a correlation between behavioral improvement and the left cerebellar activation over time, and that there is a shift towards stronger frontal left-lateralization of the fMRI activation over the first year post-stroke. Temporary compensation observed in the initial phases of post-stroke recovery that involves the non-lesioned hemisphere may not be as important as previously postulated, since in this study the recovery was driven by activations in the left fronto-temporal regions. CONCLUSION: Language recovery after left hemispheric ischemic stroke is likely driven by the previously involved in language and attention left hemispheric networks.

Age-related language lateralization assessed by fMRI: The effects of sex and handedness.

Previous studies focusing on the relationship between lateralization of language function and age suffer from lack of a balanced distribution of age and handedness among participants, especially in the extremes of age. This limits our understanding of the influence of these factors on lateralization of language circuitry. The hemispheric asymmetry reduction in older adults (HAROLD) model suggests that under similar circumstances, involvement in cognitive processes of prefrontal (and potentially other) cortical areas tends to be less lateralized with age. In this study, we aimed to investigate the link between age, gender, and language lateralization in a large group of healthy participants with a relatively even distribution of age and handedness in order to further test the HAROLD model. 99 healthy men (33 left-handed; age range 18-74years) and 125 women (44 left-handed; age range 19-76) were recruited. All participants underwent fMRI at 3T with a semantic decision and a verb generation tasks and received a battery of linguistic tests. Lateralization indexes (LI) were calculated for each participant based on fMRI results for each task separately. LIs were found to be significantly decreasing with age only in right-handed men and only in temporo-parietal cortical area. LIs did not change with age in other brain regions or in left-handed subjects. Our results do not support the HAROLD model and suggest a potentially different relationship between aging and lateralization of language functions.

Neuroimaging Correlates of Post-Stroke Aphasia Rehabilitation in a Pilot Randomized Trial of Constraint-Induced Aphasia Therapy.

BACKGROUND Recovery from post-stroke aphasia is a long and complex process with an uncertain outcome. Various interventions have been proposed to augment the recovery, including constraint-induced aphasia therapy (CIAT). CIAT has been applied to patients suffering from post-stroke aphasia in several unblinded studies to show mild-to-moderate linguistic gains. The aim of the present study was to evaluate the neuroimaging correlates of CIAT in patients with chronic aphasia related to left middle cerebral artery stroke. MATERIAL AND METHODS Out of 24 patients recruited in a pilot randomized blinded trial of CIAT, 19 patients received fMRI of language. Eleven of them received CIAT (trained) and eight served as a control group (untrained). Each patient participated in three fMRI sessions (before training, after training, and 3 months later) that included semantic decision and verb generation fMRI tasks, and a battery of language tests. Matching healthy control participants were also included (N=38; matching based on age, handedness, and sex). RESULTS Language testing showed significantly improved performance on Boston Naming Test (BNT; p<0.001) in both stroke groups over time and fMRI showed differences in the distribution of the areas involved in language production between groups that were not present at baseline. Further, regression analysis with BNT indicated changes in brain regions correlated with behavioral performance (temporal gyrus, postcentral gyrus, precentral gyrus, thalamus, left middle and superior frontal gyri). CONCLUSIONS Overall, our results suggest the possibility of language-related cortical plasticity following stroke-induced aphasia with no specific effect from CIAT training.

Age related-changes in the neural basis of self-generation in verbal paired associate learning.

Verbal information is better retained when it is self-generated rather than when it is received passively. The application of self-generation procedures has been found to improve memory in healthy elderly and in individuals with impaired cognition. Overall, the available studies support the notion that active participation in verbal encoding engages memory mechanisms that supplement those used during passive observation. Thus, the objective of this study was to investigate the age-related changes in the neural mechanisms involved in the encoding of paired-associates using a self-generation method that has been shown to improve memory performance across the lifespan. Subjects were 113 healthy right-handed adults (Edinburgh Handedness Inventory >50; 67 females) ages 18-76, native speakers of English with no history of neurological or psychiatric disorders. Subjects underwent fMRI at 3 T while performing didactic learning ("read") or self-generation learning ("generate") of 30 word pairs per condition. After fMRI, recognition memory for the second word in each pair was evaluated outside of the scanner. On the post-fMRI testing more "generate" words were correctly recognized than "read" words (p < 0.001) with older adults recognizing the "generated" words less accurately (p < 0.05). Independent component analysis of fMRI data identified task-related brain networks. Several components were positively correlated with the task reflecting multiple cognitive processes involved in self-generated encoding; other components correlated negatively with the task, including components of the default-mode network. Overall, memory performance on generated words decreased with age, but the benefit from self-generation remained consistently significant across ages. Independent component analysis of the neuroimaging data revealed an extensive set of components engaged in self-generation learning compared with didactic learning, and identified areas that were associated with age-related changes independent of performance.

Placebo effect of medication cost in Parkinson disease: a randomized double-blind study.

OBJECTIVE: To examine the effect of cost, a traditionally "inactive" trait of intervention, as contributor to the response to therapeutic interventions. METHODS: We conducted a prospective double-blind study in 12 patients with moderate to severe Parkinson disease and motor fluctuations (mean age 62.4 ± 7.9 years; mean disease duration 11 ± 6 years) who were randomized to a "cheap" or "expensive" subcutaneous "novel injectable dopamine agonist" placebo (normal saline). Patients were crossed over to the alternate arm approximately 4 hours later. Blinded motor assessments in the "practically defined off" state, before and after each intervention, included the Unified Parkinson's Disease Rating Scale motor subscale, the Purdue Pegboard Test, and a tapping task. Measurements of brain activity were performed using a feedback-based visual-motor associative learning functional MRI task. Order effect was examined using stratified analysis. RESULTS: Although both placebos improved motor function, benefit was greater when patients were randomized first to expensive placebo, with a magnitude halfway between that of cheap placebo and levodopa. Brain activation was greater upon first-given cheap but not upon first-given expensive placebo or by levodopa. Regardless of order of administration, only cheap placebo increased activation in the left lateral sensorimotor cortex and other regions. CONCLUSION: Expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa. Perceptions of cost are capable of altering the placebo response in clinical studies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that perception of cost is capable of influencing motor function and brain activation in Parkinson disease.

Recovered vs. not-recovered from post-stroke aphasia: the contributions from the dominant and non-dominant hemispheres.

PURPOSE: Several adult studies have documented the importance of the peri-stroke areas to aphasia recovery. But, studies examining the differences in patterns of cortical participation in language comprehension in patients who have (LMCA-R) or have not recovered (LMCA-NR) from left middle cerebral artery infarction have not been performed up to date. METHODS: In this study, we compare cortical correlates of language comprehension using fMRI and semantic decision/tone decision task in 9 LMCA-R and 18 LMCA-NR patients matched at the time of stroke for age and handedness. We examine the cortical correlates of language performance by correlating intra- and extra-scanner measures of linguistic performance with fMRI activation and stroke volumes. RESULTS: Our analyses show that LMCA-R at least 1 year after stroke show a return to typical fMRI language activation patterns and that there is a compensatory reorganization of language function in LMCA-NR patients with shifts to the right hemispheric brain regions. Further, with increasing strength of the left-hemispheric fMRI signal shift there are associated improvements in performance as tested with standardized linguistic measures. A negative correlation between the size of the stroke and performance on some of the linguistic tests is also observed. CONCLUSIONS: This right-hemispheric shift as a mechanism of post-stroke recovery in adults appears to be an ineffective mode of language function recovery with increasing right-hemispheric shift associated with lower language performance. Thus, normalization of the post-stroke language activation patterns is needed for better language performance while shifts of the activation patterns to the non-dominant (right) hemisphere and/or large stroke size are associated with decreased linguistic abilities after stroke.

Cortical correlates of self-generation in verbal paired associate learning.

Behavioral studies have shown that verbal information is better retained when it is self-generated rather than read (learned passively). We used fMRI and a paired associates task to examine brain networks underlying self-generated memory encoding. Subjects were 49 healthy English speakers ages 19-62 (30 female). In the fMRI task, related word pairs were presented in a "read" condition, where subjects viewed both words and read the second word aloud, or a "generate" condition, where the second word was presented with only the first letter and the subject was required to generate the word. Thirty word pairs were presented in each condition. After the fMRI scan, words that were read or generated were presented, each with two foils, in a forced-choice recognition task. On the recognition post-test, words from the "generate" condition were more correctly recognized than from the "read" condition (80.0% for generated words versus 72.0% for read words; t(48)=5.17, p<0.001). FMRI revealed increased activation for generate>read in inferior/middle frontal gyri bilaterally (L>R), anterior cingulate, and caudate nucleus and the temporo-parietal-occipital junction bilaterally. For the "read" condition, better subsequent memory performance across individual subjects was positively correlated with activation in the cuneus bilaterally. In the "generate" condition, better subsequent memory performance was positively correlated with activation in the left superior temporal gyrus. These results suggest that self-generation improves memory performance, that enhanced cortical activation accompanies self-generated encoding, and that recruitment of a specific brain network underlies self-generated encoding. The findings may have implications for the development of procedures to enhance memory performance.

Females and males are highly similar in language performance and cortical activation patterns during verb generation.

OBJECTIVE: To test the existence of sex differences in cortical activation during verb generation when performance is controlled for. METHODS: Twenty male and 20 female healthy adults underwent functional magnetic resonance imaging (fMRI) using a covert block-design verb generation task (BD-VGT) and its event-related version (ER-VGT) that allowed for intra-scanner recordings of overt responses. Task-specific activations were determined using the following contrasts: BD-VGT covert generation>finger-tapping; ER-VGT overt generation>repetition; ER-VGT overt>covert generation. Lateral cortical regions activated during each contrast were used for calculating language lateralization index scores. Voxelwise regressions were used to determine sex differences in activation, with and without controlling for performance. Each brain region showing male/female activation differences for ER-VGT overt generation>repetition (isolating noun-verb association) was defined as a region of interest (ROI). For each subject, the signal change in each ROI was extracted, and the association between ER-VGT activation related to noun-verb association and performance was assessed separately for each sex. RESULTS: Males and females performed similarly on language assessments, had similar patterns of language lateralization, and exhibited similar activation patterns for each fMRI task contrast. Regression analysis controlling for overt intra-scanner performance either abolished (BD-VGT) or reduced (ER-VGT) the observed differences in activation between sexes. The main difference between sexes occurred during ER-VGT processing of noun-verb associations, where males showed greater activation than females in the right middle/superior frontal gyrus (MFG/SFG) and the right caudate/anterior cingulate gyrus (aCG) after controlling for performance. Better verb generation performance was associated with increased right caudate/aCG activation in males and with increased right MFG/SFG activation in females. CONCLUSIONS: Males and females exhibit similar activation patterns during verb generation fMRI, and controlling for intra-scanner performance reduces or even abolishes sex differences in language-related activation. These results suggest that previous findings of sex differences in neuroimaging studies that did not control for task performance may reflect false positives.

Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia.

BACKGROUND: Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca's area for chronic aphasia treatment. MATERIAL/METHODS: We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca's area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca's. RESULTS: 6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS. CONCLUSIONS: FMRI-guided, excitatory rTMS applied to the affected Broca's area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.

Poststroke aphasia recovery assessed with functional magnetic resonance imaging and a picture identification task.

Stroke patients often display deficits in language function, such as correctly naming objects. Our aim was to evaluate the reliability and the patterns of poststroke language recovery using a picture identification task during functional magnetic resonance imaging (fMRI) at 4 T. Four healthy subjects and 4 subjects with left middle cerebral artery stroke with chronic (>1 year) aphasia were enrolled in the study. In each subject, 10 fMRI scans were performed over a 10-week period using a picture-identification task. The active condition involved presenting subject with a panel of 4 figures (eg, drawings of 4 animals) every 6 seconds and asking the subject to indicate which figure matched the written name in the center. The control condition was a same/different judgment task with pairs of geometric figures (squares, octagons, or combination) presented every 6 seconds. Thirty-second active/control blocks were repeated 5 times each, and responses were recorded. The stoke subjects and controls had similar demographic characteristics, including age (46 vs 53 years), personal handedness (Edinburg Handedness Inventory, 89 vs 95), familial handedness (93 vs 95), and years of education (14.3 vs 14.8). For the active condition, the controls performed better than the stroke subjects (97.7% vs 89.1%; P < .001); the 2 groups performed similarly for the control condition (99.5% vs 98.8%; P = .23). On fMRI, the controls exhibited bilateral, L > R positive blood oxygenation level-dependent (BOLD) activations in frontal and temporal language areas and symmetric retrosplenial and posterior cingulate areas and symmetric negative BOLD activations in bilateral frontotemporal language networks. In contrast, the stroke subjects exhibited positive BOLD activations predominantly in peristroke areas and negative BOLD activations in the unaffected (right) hemisphere. Both groups displayed high activation reliability (as measured by the intraclass correlation coefficient [ICC]) in the left frontal and temporal language areas, although in the stroke subjects the ICC in the frontal regions was spread over a much larger peristroke area. This study documents the utility of the picture-identification task for poststroke language recovery evaluation. Our data suggest that adult stroke patients use functional peristroke areas to perform language functions.

Cortical and subcortical contributions to absence seizure onset examined with EEG/fMRI.

In patients with idiopathic generalized epilepsies (IGEs), bursts of generalized spike and wave discharges (GSWDs) lasting > or =2 seconds are considered absence seizures. The location of the absence seizures generators in IGEs is thought to involve interplay between various components of thalamocortical circuits; we have recently postulated that medication resistance may, in part, be related to the location of the GSWD generators [Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Epilepsy Behav. 2010;17:525-30]. In the present study we hypothesized that patients with medication-refractory IGE (R-IGE) and continued absence seizures may have GSWD generators in locations other than the thalamus, as typically seen in patients with IGE. Hence, the objective of this study was to determine the location of the GSWD generators in patients with R-IGE using EEG/fMRI. Eighty-three patients with IGE received concurrent EEG/fMRI at 4 T. Nine of them (aged 15-55) experienced absence seizures during EEG/fMRI and were included; all were diagnosed with R-IGE. Subjects participated in up to three 20-minute EEG/fMRI sessions (400 volumes, TR=3 seconds) performed at 4 T. After removal of fMRI and ballistocardiographic artifacts, 36 absence seizures were identified. Statistical parametric maps were generated for each of these sessions correlating seizures to BOLD response. Timing differences between brain regions were tested using statistical parametric maps generated by modeling seizures with onset times shifted relative to the GSWD onsets. Although thalamic BOLD responses peaked approximately 6 seconds after the onset of absence seizures, other areas including the prefrontal and dorsolateral cortices showed brief and nonsustained peaks occurring approximately 2 seconds prior to the maximum of the thalamic peak. Temporal lobe peaks occurred at the same time as the thalamic peak, with a cerebellar peak occurring approximately 1 second later. Confirmatory analysis averaging cross-correlation between cortical and thalamic regions of interest across seizures corroborated these findings. Finally, Granger causality analysis showed effective connectivity directed from frontal lobe to thalamus, supporting the notion of earlier frontal than thalamic involvement. The results of this study support our original hypothesis and indicate that in the patients with R-IGE studied, absence seizures may be initiated by widespread cortical (frontal and parietal) areas and sustained in subcortical (thalamic) regions, suggesting that the examined patients have cortical onset epilepsy with propagation to thalamus.

Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response.

In a minority of patients with idiopathic generalized epilepsies (IGEs), seizures continue despite appropriate treatment. We sought to determine the clinical and EEG factors associated with medication response in these patients. All patients with IGEs evaluated by epilepsy specialists between 17 November 2008 and 16 November 2009 were included. We collected information on seizure freedom (dependent variable), EEG asymmetries, response to valproic acid (VPA), MRI characteristics, medication use, demographics, and seizure history (predictors). We identified 322 patients with IGEs; 45 (14%) were excluded from analyses because they had always had a normal EEG (N=26), there were no EEG data (N=3), or they were non-compliant with medication (N=26). Patients with juvenile myoclonic epilepsy were more likely to respond to VPA than were patients with other IGEs, and VPA response was associated with seizure freedom. When EEG characteristics were considered, presence of any focal EEG abnormalities (focal slowing, focal epileptiform discharges, or both) was associated with decreased odds of seizure freedom. These findings suggest that patients with IGEs with poor seizure control may have atypical IGEs with possibly focal, for example, frontal, rather than thalamic onset.

Reliability of fMRI for studies of language in post-stroke aphasia subjects.

Quantifying change in brain activation patterns associated with post-stroke recovery and reorganization of language function over time requires accurate understanding of inter-scan and inter-subject variability. Here we report inter-scan variability measures for fMRI activation patterns associated with verb generation (VG) and semantic decision/tone decision (SDTD) tasks in 4 healthy controls and 4 aphasic left middle cerebral artery (LMCA) stroke subjects. A series of 10 fMRI scans was completed on a 4T Varian scanner for each task for each subject, except for one stroke subject who completed 5 and 6 scans for SDTD and VG, thus yielding 35 and 36 total stroke subject scans for SDTD and VG, respectively. Group composite and intraclass correlation coefficient (ICC) maps were computed across all subjects and trials for each task. The patterns of reliable activation for the VG and SDTD tasks correspond well to those regions typically activated by these tasks in healthy and aphasic subjects. ICCs for activation were consistently high (R(0.05) approximately 0.8) for individual tasks among both control and aphasic subjects. These voxel-wise measures of reliability highlight regions of low inter-scan variability within language circuitry for control and post-recovery stroke subjects. ICCs computed from the combination of the SDTD/VG data were markedly reduced for both control and aphasic subjects as compared with the ICCs for the individual tasks. These quantitative measures of inter-scan variability support the proposed use of these fMRI paradigms for longitudinal mapping of neural reorganization of language processing following left hemispheric insult.