Prediction of motor recovery using initial impairment and fMRI 48 h poststroke.

There is substantial interpatient variation in recovery from upper limb impairment after stroke in patients with severe initial impairment. Defining recovery as a change in the upper limb Fugl-Meyer score (ΔFM), we predicted ΔFM with its conditional expectation (i.e., posterior mean) given upper limb Fugl-Meyer initial impairment (FM(ii)) and a putative functional magnetic resonance imaging (fMRI) recovery measure. Patients with first time, ischemic stroke were imaged at 2.5 ± 2.2 days poststroke with 1.5-T fMRI during a hand closure task alternating with rest (fundamental frequency = 0.025 Hz, scan duration = 172 s). Confirming a previous finding, we observed that the prediction of ΔFM by FM(ii) alone is good in patients with nonsevere initial hemiparesis but is not good in patients with severe initial hemiparesis (96% and 16% of the total sum of squares of ΔFM explained, respectively). In patients with severe initial hemiparesis, prediction of ΔFM by the combination of FM(ii) and the putative fMRI recovery measure nonsignificantly increased predictive explanation from 16% to 47% of the total sum of squares of ΔFM explained. The implications of this preliminary negative result are discussed.

Early imaging correlates of subsequent motor recovery after stroke.

OBJECTIVE: To determine whether functional magnetic resonance imaging activation obtained in the first few days after stroke correlates with subsequent motor recovery. METHODS: Twenty-three patients with hemiparesis after first-time stroke were scanned at 2.0 +/- 0.9 days while performing a simple motor task. We defined recovery as the change in Fugl-Meyer score from time of scan to approximately 3 months later (90 +/- 8 days). We performed three different tests to assess correlations between brain activation and change in Fugl-Meyer score: (1) multivariate (most sensitive to spatially diffuse activation); (2) voxel-wise Statistical Parametric Mapping (most sensitive to focal activation), and (3) primary motor cortex region-of-interest analysis (most sensitive to average activation within this region). All tests controlled for initial stroke severity and lesion volume, as well as other established clinical variables. RESULTS: The multivariate test was significant [F (595, 4,934) = 1.93; p < 0.001]. The Statistical Parametric Mapping test detected two small clusters of focal activity located in the ipsilesional postcentral gyrus and cingulate cortex (p < 0.05, corrected). The region-of-interest test was not significant. INTERPRETATION: There is a pattern of brain activation present in the first few days after stroke, of which the postcentral gyrus and cingulate cortex are a part, that correlates with subsequent motor recovery. This result suggests that there are recovery processes engaged early after stroke that could provide a target for intervention.

Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation.

Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and between-day (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention.

Explaining savings for visuomotor adaptation: linear time-invariant state-space models are not sufficient.

Adaptation of the motor system to sensorimotor perturbations is a type of learning relevant for tool use and coping with an ever-changing body. Memory for motor adaptation can take the form of savings: an increase in the apparent rate constant of readaptation compared with that of initial adaptation. The assessment of savings is simplified if the sensory errors a subject experiences at the beginning of initial adaptation and the beginning of readaptation are the same. This can be accomplished by introducing either 1) a sufficiently small number of counterperturbation trials (counterperturbation paradigm [CP]) or 2) a sufficiently large number of zero-perturbation trials (washout paradigm [WO]) between initial adaptation and readaptation. A two-rate, linear time-invariant state-space model (SSM(LTI,2)) was recently shown to theoretically produce savings for CP. However, we reasoned from superposition that this model would be unable to explain savings for WO. Using the same task (planar reaching) and type of perturbation (visuomotor rotation), we found comparable savings for both CP and WO paradigms. Although SSM(LTI,2) explained some degree of savings for CP it failed completely for WO. We conclude that for visuomotor rotation, savings in general is not simply a consequence of LTI dynamics. Instead savings for visuomotor rotation involves metalearning, which we show can be modeled as changes in system parameters across the phases of an adaptation experiment.

Global familiarity of visual stimuli affects repetition-related neural plasticity but not repetition priming.

In this study, we tested the prediction of the component process model of priming [Henson, R.N. (2003). Neuroimaging studies of priming. Prog Neurobiol, 70 (1), 53-81] that repetition priming of familiar and unfamiliar objects produces qualitatively different neural repetition effects. In an fMRI study, subjects viewed four repetitions of familiar objects and globally unfamiliar objects with familiar components. Reliable behavioral priming occurred for both item types across the four presentations and was of a similar magnitude for both stimulus types. The imaging data were analyzed using multivariate linear modeling, which permits explicit testing of the hypothesis that the repetition effects for familiar and unfamiliar objects are qualitatively different (i.e., non-scaled versions of one another). The results showed the presence of two qualitatively different latent spatial patterns of repetition effects from presentation 1 to presentation 4 for familiar and unfamiliar objects, indicating that familiarity with an object's global structural, semantic, or lexical features is an important factor in priming-related neural plasticity. The first latent spatial pattern strongly weighted regions with a similar repetition effect for both item types. The second pattern strongly weighted regions contributing a repetition suppression effect for the familiar objects and repetition enhancement for the unfamiliar objects, particularly the posterior insula, superior temporal gyrus, precentral gyrus, and cingulate cortex. This differential repetition effect might reflect the formation of novel memory representations for the unfamiliar items, which already exist for the familiar objects, consistent with the component process model of priming.

An investigation of statistical power for continuous arterial spin labeling imaging at 1.5 T.

Variance estimates can be used in conjunction with scientifically meaningful effect sizes to design experiments with type II error control. Here we present estimates of intra- and inter-subject variances for region of interest (ROI) from resting cerebral blood flow (CBF) maps obtained using whole brain, spin echo echoplanar (SE-EPI) continuous arterial spin labeling (CASL) imaging on 52 elderly subjects (age=70.5+/-7.9 years, 29 males). There was substantial intrasubject systematic variability in CBF of gray matter ROIs corresponding to a range of standard deviations=[39-168] (ml/(100 g min)). This variability was mainly due to two factors: (1) an expected inverse relationship between ROI volume and intrasubject variance and (2) an increased effective post-labeling delay for more superior slices acquired later in the sequence. For example, intrasubject variance in Brodmann area 4 (BA 4) was approximately 8 times larger than in hippocampus, despite their similar gray matter volumes. Estimated ROI-wise power was computed for various numbers of acquired CBF images, numbers of subjects, and CBF effect sizes for two experimental designs: independent sample t-test and paired t-test. The theoretical effects of pulse sequence and field strength on general applicability of these results are discussed.

Inter-individual variability in the capacity for motor recovery after ischemic stroke.

BACKGROUND: Motor recovery after stroke is predicted only moderately by clinical variables, implying that there is still a substantial amount of unexplained, biologically meaningful variability in recovery. Regression diagnostics can indicate whether this is associated simply with Gaussian error or instead with multiple subpopulations that vary in their relationships to the clinical variables. OBJECTIVE: To perform regression diagnostics on a linear model for recovery versus clinical predictors. METHODS: Forty-one patients with ischemic stroke were studied. Impairment was assessed using the upper extremity Fugl-Meyer Motor Score. Motor recovery was defined as the change in the upper extremity Fugl-Meyer Motor Score from 24 to 72 hours after stroke to 3 or 6 months later. The clinical predictors in the model were age, gender, infarct location (subcortical vs cortical), diffusion weighted imaging infarct volume, time to reassessment, and acute upper extremity Fugl-Meyer Motor Score. Regression diagnostics included a Kolmogorov-Smirnov test for Gaussian errors and a test for outliers using Studentized deleted residuals. RESULTS: In the random sample, clinical variables explained only 47% of the variance in recovery. Among the patients with the most severe initial impairment, there was a set of regression outliers who recovered very poorly. With the outliers removed, explained variance in recovery increased to 89%, and recovery was well approximated by a proportional relationship with initial impairment (recovery congruent with 0.70 x initial impairment). CONCLUSIONS: Clinical variables only moderately predict motor recovery. Regression diagnostics demonstrated the existence of a subpopulation of outliers with severe initial impairment who show little recovery. When these outliers were removed, clinical variables were good predictors of recovery among the remaining patients, showing a tight proportional relationship to initial impairment.

A common neural network for cognitive reserve in verbal and object working memory in young but not old.

Epidemiologic evidence suggests that cognitive reserve (CR) mitigates the effects of aging on cognitive function. The goal of this study was to see whether a common neural mechanism for CR could be demonstrated in brain imaging data acquired during the performance of 2 tasks with differing cognitive processing demands. Young and elder subjects were scanned with functional magnetic resonance imaging (fMRI) while performing a delayed item response task that used either letters (40 young, 18 old) or shapes (24 young, 21 old). Difficulty or load was manipulated by varying the number of stimuli that were presented for encoding. Load-dependent fMRI signal corresponding to each trial component (stimulus presentation, retention delay, and probe) and task (letter or shape) was regressed onto 2 putative CR variables. Canonical variates analysis was applied to the resulting maps of regression coefficients, separately for each trial component, to summarize the imaging data--CR relationships. There was a latent brain pattern noted in the stimulus presentation phase that manifested similar relationships between load-related encoding activation and CR variables across the letter and shape tasks in the young but not the elder age group. This spatial pattern could represent a general neural instantiation of CR that is affected by the aging process.

Age-related changes in brain activation during a delayed item recognition task.

To test competing models of age-related changes in brain functioning (capacity limitation, neural efficiency, compensatory reorganization, and dedifferentiation), young (n=40; mean age=25.1 years) and elderly (n=18; mean age=74.4 years) subjects performed a delayed item recognition task for visually presented letters with three set sizes (1, 3, or 6 letters) while being scanned with BOLD fMRI. Spatial patterns of brain activity corresponding to either the slope or y-intercept of fMRI signal with respect to set size during memory set encoding, retention delay, or probe stimulus presentation trial phases were compared between elder and young populations. Age effects on fMRI slope during encoding and on fMRI y-intercept during retention delay were consistent with neural inefficiency; age effects on fMRI slope during retention delay were consistent with dedifferentiation. None of the other fMRI signal components showed any detectable age effects. These results suggest that, even within the same task, the nature of brain activation changes with aging can vary based on cognitive process engaged.

Structural MRI covariance patterns associated with normal aging and neuropsychological functioning.

Structural magnetic resonance imaging (MRI) studies have shown dramatic age-associated changes in grey and white matter volume, but typically use univariate analyses that do not explicitly test the interrelationship among brain regions. The current study used a multivariate approach to identify covariance patterns of grey and white matter tissue density to distinguish older from younger adults. A second aim was to examine whether the expression of the age-associated covariance topographies is related to performance on cognitive tests affected by normal aging. Eighty-four young (mean age=24.0) and 29 older (mean age=73.1) participants were scanned with a 1.5T MRI machine and assessed with a cognitive battery. Images were spatially normalized and segmented to produce grey and white matter density maps. A multivariate technique, based on the subprofile scaling model, was used to capture sources of between- and within-group variation to produce a linear combination of principal components that represented a "pattern" or "network" that best discriminated between the two age groups. Univariate analyses were also conducted with statistical parametric maps. Grey and white matter covariance patterns were identified that reliably discriminated between the groups with greater than 0.90 sensitivity and specificity. The identified patterns were similar for the univariate and multivariate techniques, and involved widespread regions of the cortex and subcortex. Age and the expression of both patterns were significantly associated with performance on tests of attention, language, memory, and executive functioning. The results suggest that identifiable networks of grey and white matter regions systematically decline with age and that pattern expression is linked to age-related cognitive decline.

Distinct spatial patterns of brain activity associated with memory storage and search.

The time it takes for a human participant to decide whether a given stimulus is an element of a remembered set increases approximately linearly with the number of elements in the set. Here we tested for and detected a spatial pattern of brain activity whose magnitude of expression during this memory search process correlates with set size. We then tested the idea that memory search simply involves a re-activation of neurons involved in remembering the set by statistically comparing the patterns of brain activity corresponding to memory search and set size dependent working memory maintenance. These patterns were significantly different, suggesting that memory search and working memory maintenance are mediated by distinct neural mechanisms.

An event-related fMRI study of the neural networks underlying repetition suppression and reaction time priming in implicit visual memory.

Unfamiliar line drawings were presented to subjects three times during BOLD fMRI scanning. A set of brain areas was detected in which the effect of stimulus repetition on the evoked fMRI response depended on whether or not the drawing could be conceived as a coherent three-dimensional structure. Differential repetition effects were found in the neural response to drawings of both structurally possible and impossible objects. This differential effect of repetition was related to the amount of reaction time priming on the concurrent task involving decisions about three-dimensional structure in the possible but not in the impossible objects. These results point to different neurophysiological processing mechanisms for structurally possible and impossible images and demonstrate neural plasticity that predicts behavioral priming for structurally possible images.

Hemodynamic impairment as a stimulus for functional brain reorganization.

We used functional magnetic resonance imaging to investigate whether hemispheral hemodynamic impairment can play an independent role in the functional reorganization of motor-related activity in the brain. Fourteen patients with large vessel occlusion but no infarct performed a simple motor task with the hand contralateral to the occluded vessel. Statistical parametric maps of regional activity were generated to compare the distribution of motor-related activity among patients with that of control subjects. Patients were classified into normal or abnormal cerebral hemodynamics on the basis of intracerebral vasomotor reactivity using transcranial Doppler and carbon dioxide inhalation. Controls and patients with normal vasomotor reactivity showed typical motor activity in contralateral motor areas. When the 9 patients with abnormal vasomotor reactivity were compared with the 14 control subjects in a single analysis, unique motor activation was identified in ipsilateral motor regions in the nonhypoperfused hemisphere. In a confirmatory analysis, blood oxygen level-dependent (BOLD) signal intensity was averaged in prespecified motor regions of interest. A significant group by hemisphere interaction was identified, driven by higher ipsilateral and lower contralateral hemisphere BOLD signal in patients with abnormal vasomotor reactivity compared with controls (F=12.40, P=0.002). The average ipsilateral motor region signal intensity was also significantly higher in the subgroup of patients with abnormal vasoreactivity and no TIA compared with controls (P=0.04). Our results suggest that hemodynamic impairment in one hemisphere, even in the absence of any focal lesion or any symptoms can be associated with a functional reorganization to the opposite hemisphere.

H215O PET study of impairment of nonverbal recognition with normal aging.

Little research has been conducted regarding age-related changes in nonverbal memory. Using positron emission tomography (PET), the authors studied 17 elderly volunteers and 20 young volunteers, during nonverbal recognition task performance, to examine differences in brain blood flow. The subjects were asked to recognize a study list size (SLS) of shapes that was adjusted so that each subject performed at approximately 75% accuracy. Positron emission tomography results showed that, relative to younger individuals, elderly subjects engaged different regions, including the insula, during recognition. Elderly subjects did not show the relationship between parahippocampal flow and SLS, which was observed in younger subjects. These differences suggest that age-related functional brain changes partly explain performance deficits.

An event-related fMRI study of the neural networks underlying the encoding, maintenance, and retrieval phase in a delayed-match-to-sample task.

Memory loads exceeding the limited capacity of working memory (WM) have been shown to expand the prefrontal areas that participate in WM and have revealed substantial individual differences in performance. We used a delayed-match-to-sample (DMS) task in an event-related fMRI study to map the full extent of the expanded regional activations associated with supracapacity loads. A 6-letter study array was compared to arrays of 1 and 3 letters. The task comprised separate encoding, retention, and retrieval fMRI epochs. A brain-wide spatial covariance analysis was applied to the data of all task epochs to identify patterns of correlated regional activations whose expression increased monotonically across 3 memory-load levels on a subject-by-subject basis. Such load-related activation patterns were in all task phases. Of greatest interest is the activation pattern that was obtained during the maintenance phase: increasing activation with memory load was found not only in the lateral PFC (BA 9,44) but also in the parietal lobe (BA 7,40), anterior cingulate (BA 32), and cerebellum. Decreasing activation was found in the occipito-temporal lobe (BA 19,39) as well as the medial prefrontal cortex (BA 9,10). Subject increases in pattern expression from 1 to 6 items were positively correlated with the corresponding reaction time increases (p<0.05) and negatively correlated with NARTIQ (p<0.05), indicating that people who were faster in their responses and had higher NARTIQ had to increase their subject expression of the memory-load-related activation pattern less and were more efficient at the cognitive task. Our method thus not only reproduced findings of other WM studies but also addressed the issue of interactions between lateral PFC and other parts of the brain during the task, for the retention of the to-be-remembered information. The load-related activation patterns from encoding and retrieval phase and their relationship to behavior are also discussed.

Positive evidence against human hippocampal involvement in working memory maintenance of familiar stimuli.

Subjects (n = 40) performed a delayed item recognition task for visually presented letters with three set sizes (1, 3 or 6 letters). Accuracy was close to ceiling at all set sizes, so we took set size as a proxy for WM load (i.e. the amount of information being maintained in WM). Functional magnetic resonance imaging (fMRI) signal associated with the delay period increased in a nearly linear fashion with WM load in the left inferior frontal gyrus/anterior insula (possibly Broca's area, BA 44/45), right anterior insula, bilateral caudate, bilateral precentral gyrus (BA 6), bilateral middle frontal gyrus (BA 9/46), bilateral inferior parietal lobule (with foci in both BA 39 and 40), left superior parietal lobule (BA 7), medial frontal gyrus (BA 6), anterior cingulate gyrus (BA 32) and bilateral superior frontal gyrus (BA 8). These results lend support to the idea that at least some of the cortical mechanisms of WM maintenance, potentially rehearsal, exhibit a scaling with WM load. In contrast, the delay-related fMRI signal in hippocampus followed an inverted U-shape, being greatest during the intermediate level of WM load, with relatively lower values at the lowest and highest levels of WM load. This pattern of delay-related fMRI activity, orthogonal to WM load, is seemingly not consonant with a role for hippocampus in WM maintenance of phonologically codable stimuli. This finding could possibly be related more to the general familiarity of the letter stimuli than their phonological codability per se.

Hypoperfusion without stroke alters motor activation in the opposite hemisphere.

To specifically investigate the effect that large-vessel disease may have on cortical reorganization, we used functional magnetic resonance imaging to study patients with unilateral hemispheric hypoperfusion and impaired vasomotor reactivity from critical internal carotid or middle cerebral artery disease but without stroke. We hypothesized that when these patients used the hand contralateral to the hypoperfused hemisphere they would show unique activation in motor-related areas of the normally perfused hemisphere, that is, ipsilateral activation. We found that normal performance of two motor tasks was associated with increased ipsilateral hemispheric activation in the patients compared with age-matched controls. In addition, although task difficulty had an effect on ipsilateral activation, the increased ipsilateral activation seen in patients was not dependent on task difficulty. Our findings demonstrate that hemodynamic compromise alone is sufficient to cause atypical ipsilateral activation. This activation may serve to maintain normal motor performance.

Experience-dependent plasticity for attention to threat: Behavioral and neurophysiological evidence in humans.

Biased attention to threat represents a key feature of anxiety disorders. This bias is altered by therapeutic or stressful experiences, suggesting that the bias is plastic. Charting on-line behavioral and neurophysiological changes in attention bias may generate insights on the nature of such plasticity. We used an attention-orientation task with threat cues to examine how healthy individuals alter their response over time to such cues. In Experiments 1 through 3, we established that healthy individuals demonstrate an increased attention bias away from threat over time. For Experiment 3, we used functional magnetic resonance imaging to determine the neural bases for this phenomenon. Gradually increasing attention bias away from threat is associated with increased activation in the occipitotemporal cortex. Examination of plasticity of attention bias with individuals at risk for anxiety disorders may reveal how threatening stimuli come to be categorized differently in this population over time.

Choice selection and reward anticipation: an fMRI study.

We examined neural activations during decision-making using fMRI paired with the wheel of fortune task, a newly developed two-choice decision-making task with probabilistic monetary gains. In particular, we assessed the impact of high-reward/risk events relative to low-reward/risk events on neural activations during choice selection and during reward anticipation. Seventeen healthy adults completed the study. We found, in line with predictions, that (i) the selection phase predominantly recruited regions involved in visuo-spatial attention (occipito-parietal pathway), conflict (anterior cingulate), manipulation of quantities (parietal cortex), and preparation for action (premotor area), whereas the anticipation phase prominently recruited regions engaged in reward processes (ventral striatum); and (ii) high-reward/risk conditions relative to low-reward/risk conditions were associated with a greater neural response in ventral striatum during selection, though not during anticipation. Following an a priori ROI analysis focused on orbitofrontal cortex, we observed orbitofrontal cortex activation (BA 11 and 47) during selection (particularly to high-risk/reward options), and to a more limited degree, during anticipation. These findings support the notion that (1) distinct, although overlapping, pathways subserve the processes of selection and anticipation in a two-choice task of probabilistic monetary reward; (2) taking a risk and awaiting the consequence of a risky decision seem to affect neural activity differently in selection and anticipation; and thus (3) common structures, including the ventral striatum, are modulated differently by risk/reward during selection and anticipation.

Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.