Functional partitioning of sentence processing and emotional prosody in the right perisylvian cortex after perinatal stroke.

In healthy adults different language abilities-sentence processing versus emotional prosody-are supported by the left (LH) versus the right hemisphere (RH), respectively. However, after LH stroke in infancy, RH regions support both abilities with normal outcomes. We investigated how these abilities co-exist in RH regions after LH perinatal stroke by evaluating the overlap in the activation between two fMRI tasks that probed auditory sentence processing and emotional prosody processing. We compared the overlap for these two functions in the RH of individuals with perinatal stroke with the symmetry of these functions in the LH and RH of their healthy siblings. We found less activation overlap in the RH of individuals with LH perinatal stroke than would be expected if both functions retained their typical spatial layout, suggesting that their spatial segregation may be an important feature of a functioning language system.

One right can make a left: sentence processing in the right hemisphere after perinatal stroke.

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH.

Spoken language processing activates the primary visual cortex.

Primary visual cortex (V1) is generally thought of as a low-level sensory area that primarily processes basic visual features. Although there is evidence for multisensory effects on its activity, these are typically found for the processing of simple sounds and their properties, for example spatially or temporally-congruent simple sounds. However, in congenitally blind individuals, V1 is involved in language processing, with no evidence of major changes in anatomical connectivity that could explain this seemingly drastic functional change. This is at odds with current accounts of neural plasticity, which emphasize the role of connectivity and conserved function in determining a neural tissue's role even after atypical early experiences. To reconcile what appears to be unprecedented functional reorganization with known accounts of plasticity limitations, we tested whether V1's multisensory roles include responses to spoken language in sighted individuals. Using fMRI, we found that V1 in normally sighted individuals was indeed activated by comprehensible spoken sentences as compared to an incomprehensible reversed speech control condition, and more strongly so in the left compared to the right hemisphere. Activation in V1 for language was also significant and comparable for abstract and concrete words, suggesting it was not driven by visual imagery. Last, this activation did not stem from increased attention to the auditory onset of words, nor was it correlated with attentional arousal ratings, making general attention accounts an unlikely explanation. Together these findings suggest that V1 responds to spoken language even in sighted individuals, reflecting the binding of multisensory high-level signals, potentially to predict visual input. This capability might be the basis for the strong V1 language activation observed in people born blind, re-affirming the notion that plasticity is guided by pre-existing connectivity and abilities in the typically developed brain.

Interpreting the CPASS Trial: Do Not Shift Motor Therapy to the Subacute Phase.

The Critical Periods After Stroke Study (CPASS, n = 72) showed that, compared to controls, an additional 20 hours of intensive upper limb therapy led to variable gains on the Action Research Arm Test depending on when therapy was started post-stroke: the subacute group (2-3 months) improved beyond the minimal clinically important difference and the acute group (0-1 month) showed smaller but statistically significant improvement, but the chronic group (6-9 months) did not demonstrate improvement that reached significance. Some have misinterpreted CPASS results to indicate that all inpatient motor therapy should be shifted to outpatient therapy delivered 2 to 3 months post-stroke. Instead, however, CPASS argues for a large dose of motor therapy delivered continuously and cumulatively during the acute and subacute phases. When interpreting trials like CPASS, one must consider the substantial dose of early usual customary care (UCC) motor therapy that all participants received. CPASS participants averaged 27.9 hours of UCC occupational therapy (OT) during the first 2 months and 9.8 hours of UCC OT during the third and fourth months post-stroke. Any recovery experienced would therefore result not just from CPASS intensive motor therapy but the combined effects of experimental therapy plus UCC. Statistical limitations also did not allow direct comparisons of the acute and subacute group outcomes in CPASS. Instead of shifting inpatient therapy hours to the subacute phase, CPASS argues for preserving inpatient UCC. We also recommend conducting multi-site dosing trials to determine whether additional intensive motor therapy delivered in the first 2 to 3 months following inpatient rehabilitation can further improve outcomes.

Effects of healthy aging and left hemisphere stroke on statistical language learning.

Spoken sentences are continuous streams of sound, without reliable acoustic cues to word boundaries. We have previously proposed that language learners identify words via an implicit statistical learning mechanism that computes transitional probabilities between syllables. Neuroimaging studies in healthy young adults associate this learning with left inferior frontal gyrus, left arcuate fasciculus, and bilateral striatum. Here, we test the effects of healthy aging and left hemisphere (LH) injury on statistical learning. Following 10-minute exposure to an artificial language, participants rated familiarity of Words, Part-words (sequences spanning word boundaries), and Non-words (unfamiliar sequences). Young controls (N=14) showed robust learning, rating Words>Part-words>Non-words. Older controls (N=28) showed this pattern to a weaker degree. Stroke survivors (N=24) as a group showed no learning. A lesion comparison examining individual differences revealed that "non-learners" are more likely to have anterior lesions. Together, these findings demonstrate that word segmentation is sensitive to healthy aging and LH injury.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

A Weak Shadow of Early Life Language Processing Persists in the Right Hemisphere of the Mature Brain.

Studies of language organization show a striking change in cerebral dominance for language over development: We begin life with a left hemisphere (LH) bias for language processing, which is weaker than that in adults and which can be overcome if there is a LH injury. Over development this LH bias becomes stronger and can no longer be reversed. Prior work has shown that this change results from a significant reduction in the magnitude of language activation in right hemisphere (RH) regions in adults compared to children. Here we investigate whether the spatial distribution of language activation, albeit weaker in magnitude, still persists in homotopic RH regions of the mature brain. Children aged 4-13 (n = 39) and young adults (n = 14) completed an auditory sentence comprehension fMRI (functional magnetic resonance imaging) task. To equate neural activity across the hemispheres, we applied fixed cutoffs for the number of active voxels that would be included in each hemisphere for each participant. To evaluate homotopicity, we generated left-right flipped versions of each activation map, calculated spatial overlap between the LH and RH activity in frontal and temporal regions, and tested for mean differences in the spatial overlap values between the age groups. We found that, in children as well as in adults, there was indeed a spatially intact shadow of language activity in the right frontal and temporal regions homotopic to the LH language regions. After a LH stroke in adulthood, recovering early-life activation in these regions might assist in enhancing recovery of language abilities.

Learning a language from inconsistent input: Regularization in child and adult learners.

When linguistic input contains inconsistent use of grammatical forms, children produce these forms more consistently, a process called 'regularization.' Deaf children learning American Sign Language from parents who are non-native users of the language regularize their parents' inconsistent usages (Singleton & Newport, 2004). In studies of artificial languages containing inconsistently used morphemes (Hudson Kam & Newport, 2005, 2009), children, but not adults, regularized these forms. However, little is known about the precise circumstances in which such regularization occurs. In three experiments we investigate how the type of input variation and the age of learners affects regularization. Overall our results suggest that while adults tend to reproduce the inconsistencies found in their input, young children introduce regularity: they learn varying forms whose occurrence is conditioned and systematic, but they alter inconsistent variation to be more regular. Older children perform more like adults, suggesting that regularization changes with maturation and cognitive capacities.

Developmental changes in neural lateralization for visual-spatial function: Evidence from a line-bisection task.

Studies of hemispheric specialization have traditionally cast the left hemisphere as specialized for language and the right hemisphere for spatial function. Much of the supporting evidence for this separation of function comes from studies of healthy adults and those who have sustained lesions to the right or left hemisphere. However, we know little about the developmental origins of lateralization. Recent evidence suggests that the young brain represents language bilaterally, with 4-6-year-olds activating the left-hemisphere regions known to support language in adults as well as homotopic regions in the right hemisphere. This bilateral pattern changes over development, converging on left-hemispheric activation in late childhood. In the present study, we ask whether this same developmental trajectory is observed in a spatial task that is strongly right-lateralized in adults-the line bisection (or "Landmark") task. We examined fMRI activation among children ages 5-11 years as they were asked to judge which end of a bisected vertical line was longer. We found that young children showed bilateral activation, with activation in the same areas of the right hemisphere as has been shown among adults, as well as in the left hemisphere homotopic regions. By age 10, activation was right-lateralized. This strongly resembles the developmental trajectory for language, moving from bilateral to lateralized activation. We discuss potential underlying mechanisms and suggest that understanding the development of lateralization for a range of cognitive functions can play a crucial role in understanding general principles of how and why the brain comes to lateralize certain functions.

Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans.

Restoration of human brain function after injury is a signal challenge for translational neuroscience. Rodent stroke recovery studies identify an optimal or sensitive period for intensive motor training after stroke: near-full recovery is attained if task-specific motor training occurs during this sensitive window. We extended these findings to adult humans with stroke in a randomized controlled trial applying the essential elements of rodent motor training paradigms to humans. Stroke patients were adaptively randomized to begin 20 extra hours of self-selected, task-specific motor therapy at ≤30 d (acute), 2 to 3 mo (subacute), or ≥6 mo (chronic) after stroke, compared with controls receiving standard motor rehabilitation. Upper extremity (UE) impairment assessed by the Action Research Arm Test (ARAT) was measured at up to five time points. The primary outcome measure was ARAT recovery over 1 y after stroke. By 1 y we found significantly increased UE motor function in the subacute group compared with controls (ARAT difference = +6.87 ± 2.63, P = 0.009). The acute group compared with controls showed smaller but significant improvement (ARAT difference = +5.25 ± 2.59 points, P = 0.043). The chronic group showed no significant improvement compared with controls (ARAT = +2.41 ± 2.25, P = 0.29). Thus task-specific motor intervention was most effective within the first 2 to 3 mo after stroke. The similarity to rodent model treatment outcomes suggests that other rodent findings may be translatable to human brain recovery. These results provide empirical evidence of a sensitive period for motor recovery in humans.

Functional connectivity hemispheric contrast (FC-HC): A new metric for language mapping.

Development of a task-free method for presurgical mapping of language function is important for use in young or cognitively impaired patients. Resting state connectivity fMRI (RS-fMRI) is a task-free method that may be used to identify cognitive networks. We developed a voxelwise RS-fMRI metric, Functional Connectivity Hemispheric Contrast (FC-HC), to map the language network and determine language laterality through comparison of within-hemispheric language network connections (Integration) to cross-hemispheric connections (Segregation). For the first time, we demonstrated robustness and efficacy of a RS-fMRI metric to map language networks across five groups (total N = 243) that differed in MRI scanning parameters, fMRI scanning protocols, age, and development (typical vs pediatric epilepsy). The resting state FC-HC maps for the healthy pediatric and adult groups showed higher values in the left hemisphere, and had high agreement with standard task language fMRI; in contrast, the epilepsy patient group map was bilateral. FC-HC has strong but not perfect agreement with task fMRI and thus, may reflect related and complementary information about language plasticity and compensation.

Development of bilateral parietal activation for complex visual-spatial function: Evidence from a visual-spatial construction task.

The neural representation of visual-spatial functions has traditionally been ascribed to the right hemisphere, but little is known about these representations in children, including whether and how lateralization of function changes over the course of development. Some studies suggest bilateral activation early in life that develops toward right-lateralization in adulthood, while others find evidence of right-hemispheric dominance in both children and adults. We used a complex visual-spatial construction task to examine the nature of lateralization and its developmental time course in children ages 5-11 years. Participants were shown two puzzle pieces and were asked whether the pieces could fit together to make a square; responses required either mental translation of the pieces (Translation condition) or both mental translation and rotation of the pieces (Rotation condition). Both conditions were compared to a matched Luminance control condition that was similar in terms of visual content and difficulty but required no spatial analysis. Group and single-subject analyses revealed that the Rotation and Translation conditions elicited strongly bilateral activation in the same parietal and occipital locations as have been previously found for adults. These findings show that visual-spatial construction consistently elicits robust bilateral activation from age 5 through adulthood. This challenges the idea that spatial functions are all right-lateralized, either during early development or in adulthood. More generally, these findings provide insights into the developmental course of lateralization across different spatial skills and how this may be influenced by the computational requirements of the particular functions involved.

The neural basis of language development: Changes in lateralization over age.

We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca's area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.

What you say versus how you say it: Comparing sentence comprehension and emotional prosody processing using fMRI.

While language processing is often described as lateralized to the left hemisphere (LH), the processing of emotion carried by vocal intonation is typically attributed to the right hemisphere (RH) and more specifically, to areas mirroring the LH language areas. However, the evidence base for this hypothesis is inconsistent, with some studies supporting right-lateralization but others favoring bilateral involvement in emotional prosody processing. Here we compared fMRI activations for an emotional prosody task with those for a sentence comprehension task in 20 neurologically healthy adults, quantifying lateralization using a lateralization index. We observed right-lateralized frontotemporal activations for emotional prosody that roughly mirrored the left-lateralized activations for sentence comprehension. In addition, emotional prosody also evoked bilateral activation in pars orbitalis (BA47), amygdala, and anterior insula. These findings are consistent with the idea that analysis of the auditory speech signal is split between the hemispheres, possibly according to their preferred temporal resolution, with the left preferentially encoding phonetic and the right encoding prosodic information. Once processed, emotional prosody information is fed to domain-general emotion processing areas and integrated with semantic information, resulting in additional bilateral activations.

Children and Adults as Language Learners: Rules, Variation, and Maturational Change.

Here we overview our recent research investigating children and adults' learning of rules and variation. In all these studies, our findings are that children and adults differ in how they acquire linguistic patterns that are productive, variable, inconsistently used, or lexically restricted. Some of our studies examine children's learning of natural languages; other studies expose learners to miniature languages and then ask them to produce novel sentences or judge their grammaticality. In every case there are important differences between learners as a function of their ages. Young children learn categorical rules and categorically follow patterns that are widespread in natural languages, even when their linguistic input exemplifies these patterns only probabilistically. In contrast, adult learners reproduce the probabilistic patterns of the input. Older children are in between, producing regular patterns somewhat more often than they appear in the input but also acquiring some probabilistic variation. These results suggest that the outcome of learning is quite different at different ages and that many of the properties of natural languages may be shaped by the behavior of children as they learn their native languages.

Revisiting the Landmark Task as a tool for studying hemispheric specialization: What's really right?

The "Landmark Task" (LT) is a line bisection judgment task that predominantly activates right parietal cortex. The typical version requires observers to judge bisections for horizontal lines that cross their egocentric midline and therefore may depend on spatial attention as well as spatial representation of the line segments. To ask whether the LT is indeed right-lateralized regardless of spatial attention (for which the right hemisphere is known to be important), we examined LT activation in 26 neurologically healthy young adults using vertical (instead of horizontal) stimuli, as compared with a luminance control task that made similar demands on spatial attention. We also varied task difficulty, which is known to affect lateralization in both spatial and language tasks. Despite these changes to the task, we observed right-lateralized parietal activations similar to those reported in other LT studies, both at group level and in individual lateralization indices. We conclude that LT activation is robustly right-lateralized, perhaps uniquely so among commonly-studied spatial tasks. We speculate that the unique properties of the LT reside in its requirement to judge relative magnitudes of the two line segments, rather than in the more general aspects of spatial attention or visual-spatial representation.

Cortical tracking of constituent structure in language acquisition.

Linguistic units are organized at multiple levels: words combine to form phrases, which combine to form sentences. Ding, Melloni, Zhang, Tian, and Poeppel (2016) discovered that the brain tracks units at each level of hierarchical structure simultaneously. Such tracking requires knowledge of how words and phrases are structurally related. Here we asked how neural tracking emerges as knowledge of phrase structure is acquired. We recorded electrophysiological (MEG) data while adults listened to a miniature language with distributional cues to phrase structure or to a control language which lacked the crucial distributional cues. Neural tracking of phrases developed rapidly, only in the condition in which participants formed mental representations of phrase structure as measured behaviorally. These results illuminate the mechanisms through which abstract mental representations are acquired and processed by the brain.