Sonya Mehta

The left posterior superior temporal gyrus participates specifically in accessing lexical phonology

Impairments in phonological processing have been associated with damage to the region of the left posterior superior temporal gyrus (pSTG), but the extent to which this area supports phonological processing, independent of semantic processing, is less clear. We used repetition priming and neural repetition suppression during functional magnetic resonance imaging (fMRI) in an auditory pseudoword repetition task as a semantics-free model of lexical (whole-word) phonological access. Across six repetitions, we observed repetition priming in terms of decreased reaction time and repetition suppression in terms of reduced neural activity. An additional analysis aimed at sublexical phonology did not show significant effects in the areas where repetition suppression was observed. To test if these areas were relevant to real word production, we performed a conjunction analysis with data from a separate fMRI experiment which manipulated word frequency (a putative index of lexical phonological access) in picture naming. The left pSTG demonstrated significant effects independently in both experiments, suggesting that this area participates specifically in accessing lexical phonology.

A Neural Signature of Phonological Access: Distinguishing the Effects of Word Frequency from Familiarity and Length in Overt Picture Naming

Cognitive models of word production correlate the word frequency effect (i.e., the fact that words which appear with less frequency take longer to produce) with an increased processing cost to activate the whole-word (lexical) phonological representation. We performed functional magnetic resonance imaging (fMRI) while subjects produced overt naming responses to photographs of animals and manipulable objects that had high name agreement but were of varying frequency, with the purpose of identifying neural structures participating specifically in activating whole-word phonological representations, as opposed to activating lexical semantic representations or articulatory-motor routines. Blood oxygen level-dependent responses were analyzed using a parametric approach based on the frequency with which each word produced appears in the language. Parallel analyses were performed for concept familiarity and word length, which provided indices of semantic and articulatory loads. These analyses permitted us to identify regions related to word frequency alone, and therefore, likely to be related specifically to activation of phonological word forms. We hypothesized that the increased processing cost of producing lower-frequency words would correlate with activation of the left posterior inferotemporal (IT) cortex, the left posterior superior temporal gyrus (pSTG), and the left inferior frontal gyrus (IFG). Scan-time response latencies demonstrated the expected word frequency effect. Analysis of the fMRI data revealed that activity in the pSTG was modulated by frequency but not word length or concept familiarity. In contrast, parts of IT and IFG demonstrated conjoint frequency and familiarity effects, and parts of both primary motor regions demonstrated conjoint effects of frequency and word length. The results are consistent with a model of word production in which lexical-semantic and lexical-phonological information are accessed by overlapping neural systems within posterior and anterior language-related cortices, with pSTG specifically involved in accessing lexical phonology.

The neural substrates of cognitive empathy

Abstract Neuroscientific research has consistently found that the perception of an affective state in another activates the observers own neural substrates for the corresponding state, which is likely the neural mechanism for “true empathy.” However, to date there has not been a brain-imaging investigation of so-called “cognitive empathy”, whereby one “actively projects oneself into the shoes of another person,” imagining someones personal, emotional experience as if it were ones own. In order to investigate this process, we conducted a combined psychophysiology and PET and study in which participants imagined: (1) a personal experience of fear or anger from their own past; (2) an equivalent experience from another person as if it were happening to them; and (3) a nonemotional experience from their own past. When participants could relate to the scenario of the other, they produced patterns of psychophysiological and neuroimaging activation equivalent to those of personal emotional imagery, but when they could not relate to the others story, differences emerged on all measures, e.g., decreased psychophysiological responses and recruitment of a region between the inferior temporal and fusiform gyri. The substrates of cognitive empathy overlap with those of personal feeling states to the extent that one can relate to the state and situation of the other.

Evaluation of voxel-based morphometry for focal lesion detection in individuals

Voxel-based morphometry (VBM) is an automated statistical technique used to detect regional differences in tissue density and tissue amount based on spatially standardized structural magnetic resonance (MR) images. Developed initially to discern differences between groups of subjects, VBM is now being used to characterize structural abnormalities in individual brains. While VBM performance has been qualitatively assessed for this purpose, to date no quantitative validation study has been performed. This study evaluated several commonly used variants of VBM for detecting structural differences at the individual level by assessing their performance in MR images of 10 subjects with stable focal brain lesions. Results were quantitatively compared to expert tracings of the lesions, the current gold standard for lesion detection and delineation. Additionally, analyses using two sets of simulated lesion data were performed to examine the relative impact of the underlying processing steps on VBM results. Performance metrics revealed that (1) for this application, VBM had low sensitivity; (2) detection sensitivity was altered by model parameterization; (3) underperformance was due to the adverse influence of lesions on the preprocessing steps and to insufficient statistical power; and (4) VBM could not satisfactorily delineate the spatial extent of lesions, even in simulations that avoided preprocessing artifacts. In its current form, VBM is not a suitable stand-alone technique for detecting or spatially characterizing focal lesions.

Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting

Objectives: To (1) investigate effects of aerobic walking on motor function, cognition, and quality of life in Parkinson disease (PD), and (2) compare safety, tolerability, and fitness benefits of different forms of exercise intervention: continuous/moderate intensity vs interval/alternating between low and vigorous intensity, and individual/neighborhood vs group/facility setting. Methods: Initial design was a 6-month, 2 × 2 randomized trial of different exercise regimens in independently ambulatory patients with PD. All arms were required to exercise 3 times per week, 45 minutes per session. Results: Randomization to group/facility setting was not feasible because of logistical factors. Over the first 2 years, we randomized 43 participants to continuous or interval training. Because preliminary analyses suggested higher musculoskeletal adverse events in the interval group and lack of difference between training methods in improving fitness, the next 17 participants were allocated only to continuous training. Eighty-one percent of 60 participants completed the study with a mean attendance of 83.3% (95% confidence interval: 77.5%–89.0%), exercising at 46.8% (44.0%–49.7%) of their heart rate reserve. There were no serious adverse events. Across all completers, we observed improvements in maximum oxygen consumption, gait speed, Unified Parkinsons Disease Rating Scale sections I and III scores (particularly axial functions and rigidity), fatigue, depression, quality of life (e.g., psychological outlook), and flanker task scores (p < 0.05 to p < 0.001). Increase in maximum oxygen consumption correlated with improvements on the flanker task and quality of life (p < 0.05). Conclusions: Our preliminary study suggests that aerobic walking in a community setting is safe, well tolerated, and improves aerobic fitness, motor function, fatigue, mood, executive control, and quality of life in mild to moderate PD. Classification of evidence: This study provides Class IV evidence that in patients with PD, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood, and cognition.

Disconnection's renaissance takes shape: Formal incorporation in group-level lesion studies.

Group-level voxelwise statistical analyses of lesion-deficit relationships have been used to implicate brain structures critical for specific aspects of human cognition and behavior. Current approaches fail to account for the role of fiber tract disruptions in causing deficit, and confound cortical damage with damage to fibers of passage. Here, we develop a framework, Generalized Lesion-Symptom Mapping (GLSM), to integrate fiber tract information from DTI-based tractographic atlases in tractwise and voxelwise lesion-deficit analyses. First, we used the geniculo-calcarine system as a validation testbed. Using logistic regressions we predicted right homonymous visual field deficits in 149 subjects with focal brain damage based on lesion location, with and without incorporating fiber tract information. A probabilistic fiber tract atlas [Wakana S, Jiang H, Nagae-Poetscher LM, Van Zijl PC, Mori S. Fiber tract-based atlas of human white matter anatomy. Radiology 2004;230:77-87] coregistered to our reference brain was used to estimate disconnection to the optic radiations and adjacent fiber tracts. When tract information was not incorporated, lesions in multiple sectors of the temporal lobe were associated with visual field defects. When the optic radiations were incorporated, this artifactual association was eliminated and the calcarine cortex was correctly isolated. Among the incorporated tracts, only the optic radiations significantly predicted visual field defects. Second, we applied the approach to impairments of higher visuoperceptual functions in 111 subjects who were administered the Hooper Visual Organization Test. We included all six association fiber tracts available in the atlas, plus the optic radiations. Tract inclusion narrowed the cortical sectors associated with impaired performance in a manner consistent with recent fMRI findings. The left cingulum and inferior longitudinal fasciculus, significantly predicted impairments. The results demonstrate the viability, validity and value of incorporating fiber tract information in lesion-deficit analyses. The enhanced analysis framework opens a new avenue for studying neural systems, with the potential to facilitate identification of both cortical sectors and fiber tracts critical for cognitive functioning.

Effects of spatial transformation on regional brain volume estimates

Spatial transformation of MR brain images is a standard tool used in automated anatomical parcellation and other quantitative and qualitative methods to assess brain tissue volume, composition, and distribution. Despite widespread use, the quantitative effects of spatial transformation on regional brain volume estimates have been little studied. We report on the effects of transformation on regional brain volumes of 38 (17M, 21F) manually parcellated brains. After tracing in native space, regions of interest were transformed using a classic piecewise-linear Talairach transformation (Tal) or a nonlinear registration (AIR 5th order nonlinear algorithm, 158 parameters) to one of three Talairach-based templates: 1) Tal50, constructed from 50 Talairach-transformed normal brains, 2) the MNI 305 atlas, 3) IA38, constructed from MNI305-transformed scans of the 38 subjects used in this study. Native volumes were compared to the transformed volumes. We found that: 1) significant group-level differences can be obtained in transformed data sets that are in the opposite direction of effects obtained in native space; 2) the effects of transformation are heterogeneous across brain regions, even after covarying for total brain volume and age; 3) volumetric intra-class correlations between native and transformed brains differ by registration method and template choice, region, and tissue type; and 4) transformed brains produced hippocampus and corpus callosum volume proportions that were significantly different from those obtained in native space. Our results suggest that region-based volumetric differences uncovered by spatial-transformation-based methods should be replicated in native-space brains, and that meta-analyses should take into account whether volumes are determined using spatially-transformed images and/or specific automated methods.

Analysis of speech-related variance in rapid event-related fMRI using a time-aware acquisition system

Speech production introduces signal changes in fMRI data that can mimic or mask the task-induced BOLD response. Rapid event-related designs with variable ISIs address these concerns by minimizing the correlation of task and speech-related signal changes without sacrificing efficiency; however, the increase in residual variance due to speech still decreases statistical power and must be explicitly addressed primarily through post-processing techniques. We investigated the timing, magnitude, and location of speech-related variance in an overt picture naming fMRI study with a rapid event-related design, using a data acquisition system that time-stamped image acquisitions, speech, and a pneumatic belt signal on the same clock. Using a spectral subtraction algorithm to remove scanner gradient noise from recorded speech, we related the timing of speech, stimulus presentation, chest wall movement, and image acquisition. We explored the relationship of an extended speech event time course and respiration on signal variance by performing a series of voxelwise regression analyses. Our results demonstrate that these effects are spatially heterogeneous, but their anatomic locations converge across subjects. Affected locations included basal areas (orbitofrontal, mesial temporal, brainstem), areas adjacent to CSF spaces, and lateral frontal areas. If left unmodeled, speech-related variance can result in regional detection bias that affects some areas critically implicated in language function. The results establish the feasibility of detecting and mitigating speech-related variance in rapid event-related fMRI experiments with single word utterances. They further demonstrate the utility of precise timing information about speech and respiration for this purpose.

Model assessment and model building in fMRI

Model quality is rarely assessed in fMRI data analyses and less often reported. This may have contributed to several shortcomings in the current fMRI data analyses, including: (1) Model mis‐specification, leading to incorrect inference about the activation‐maps, SPM{t} and SPM{F}; (2) Improper model selection based on the number of activated voxels, rather than on model quality; (3) Under‐utilization of systematic model building, resulting in the common but suboptimal practice of using only a single, pre‐specified, usually over‐simplified model; (4) Spatially homogenous modeling, neglecting the spatial heterogeneity of fMRI signal fluctuations; and (5) Lack of standards for formal model comparison, contributing to the high variability of fMRI results across studies and centers. To overcome these shortcomings, it is essential to assess and report the quality of the models used in the analysis. In this study, we applied images of the Durbin‐Watson statistic (DW‐map) and the coefficient of multiple determination (R2‐map) as complementary tools to assess the validity as well as goodness of fit, i.e., quality, of models in fMRI data analysis. Higher quality models were built upon reduced models using classic model building. While inclusion of an appropriate variable in the model improved the quality of the model, inclusion of an inappropriate variable, i.e., model mis‐specification, adversely affected it. Higher quality models, however, occasionally decreased the number of activated voxels, whereas lower quality or inappropriate models occasionally increased the number of activated voxels, indicating that the conventional approach to fMRI data analysis may yield sub‐optimal or incorrect results. We propose that model quality maps become part of a broader package of maps for quality assessment in fMRI, facilitating validation, optimization, and standardization of fMRI result across studies and centers. Hum. Brain Mapping 20:227–238, 2003.

How sensory-motor systems impact the neural organization for language: direct contrasts between spoken and signed language

To investigate the impact of sensory-motor systems on the neural organization for language, we conducted an H215O-PET study of sign and spoken word production (picture-naming) and an fMRI study of sign and audio-visual spoken language comprehension (detection of a semantically anomalous sentence) with hearing bilinguals who are native users of American Sign Language (ASL) and English. Directly contrasting speech and sign production revealed greater activation in bilateral parietal cortex for signing, while speaking resulted in greater activation in bilateral superior temporal cortex (STC) and right frontal cortex, likely reflecting auditory feedback control. Surprisingly, the language production contrast revealed a relative increase in activation in bilateral occipital cortex for speaking. We speculate that greater activation in visual cortex for speaking may actually reflect cortical attenuation when signing, which functions to distinguish self-produced from externally generated visual input. Directly contrasting speech and sign comprehension revealed greater activation in bilateral STC for speech and greater activation in bilateral occipital-temporal cortex for sign. Sign comprehension, like sign production, engaged bilateral parietal cortex to a greater extent than spoken language. We hypothesize that posterior parietal activation in part reflects processing related to spatial classifier constructions in ASL and that anterior parietal activation may reflect covert imitation that functions as a predictive model during sign comprehension. The conjunction analysis for comprehension revealed that both speech and sign bilaterally engaged the inferior frontal gyrus (with more extensive activation on the left) and the superior temporal sulcus, suggesting an invariant bilateral perisylvian language system. We conclude that surface level differences between sign and spoken languages should not be dismissed and are critical for understanding the neurobiology of language.