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1.  Modulation of working memory function by motivation through loss-aversion 
Human brain mapping  2011;34(4):762-774.
Cognitive performance is affected by motivation. Few studies, however, have investigated the neural mechanisms of the influence of motivation through potential monetary punishment on working memory. We employed functional MRI during a delayed recognition task that manipulated top-down control demands with added monetary incentives to some trials in the form of potential losses of bonus money. Behavioral performance on the task was influenced by loss-threatening incentives in the form of faster and more accurate performance. As shown previously, we found enhancement of activity for relevant stimuli occurs throughout all task periods (e.g. stimulus encoding, maintenance, and response) in both prefrontal and visual association cortex. Further, these activation patterns were enhanced for trials with possible monetary loss relative to non-incentive trials. During the incentive cue, the amygdala and striatum showed significantly greater activation when money was at a possible loss on the trial. We also evaluated patterns of functional connectivity between regions responsive to monetary consequences and prefrontal areas responsive to the task. This analysis revealed greater delay period connectivity between and the left insula and prefrontal cortex with possible monetary loss relative to non-incentive trials. Overall, these results reveal that incentive motivation can modulate performance on working memory tasks through top-down signals via amplification of activity within prefrontal and visual association regions selective to processing the perceptual inputs of the stimuli to be remembered.
PMCID: PMC3337893  PMID: 22113962
event-related fMRI; working memory; prefrontal cortex; top-down processing; motivation
2.  Altered neural activation in ornithine transcarbamylase deficiency (OTCD) during executive cognition: An fMRI study 
Human brain mapping  2011;34(4):753-761.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition.
To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task.
Design, Setting and Patients
Nineteen subjects with OTCD and 21 healthy controls participated in a case-control, IRB-approved study at Georgetown University Medical Center.
An N-back working memory task was performed in a block design using 3T functional magnetic resonance imaging.
In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls.
Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub-optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects.
PMCID: PMC3338900  PMID: 22110002
ammonia; dorsolateral prefrontal cortex (DLPFC); fMRI; ornithine transcarbamylase deficiency (OTCD); hyperammonemia (HA
Human brain mapping  2011;34(4):945-955.
Inducing and experiencing emotions about others’ mental and physical circumstances is thought to involve self-relevant processing and personal memories of similar experiences. The hippocampus is important for self-referential processing during recall and prospection; however, its contributions during social emotions have not been systematically investigated. We use event-related averaging and Granger causal connectivity mapping to investigate hippocampal contributions during the processing of varieties of admiration and compassion pertaining to protagonists’ mental versus physical circumstances (admiration for virtue, AV, versus for skill; compassion for social/psychological pain, CSP, versus for physical pain). Data were collected using a multistep emotion induction paradigm that included psychosocial interviews, BOLD fMRI and simultaneous psychophysiological recording. Given that mnemonic demands were equivalent among conditions, we tested whether: (1) the hippocampi would be recruited more strongly and for a longer duration during the processing of AV and CSP; (2) connectivity between the hippocampi and cortical systems involved in visceral somatosensation/emotional feeling, social cognitive, and self-related processing would be more extensive during AV and CSP. Results elucidate the hippocampus’ facilitative role in inducing and sustaining appropriate emotional reactions, the importance of self-related processing during social emotions, and corroborate the conception that varieties of emotional processing pertaining to others’ mental and physical situations engage at least partially distinct neural mechanisms.
PMCID: PMC3340463  PMID: 22012639
admiration; compassion; social cognition; self processing; insula
4.  Dysmaturation of the Default Mode Network in Autism 
Human brain mapping  2013;35(4):1284-1296.
Two hypotheses of autism spectrum disorder (ASD) propose that this condition is characterized by deficits in Theory of Mind and by hypoconnectivity between remote cortical regions with hyperconnectivity locally. The default mode network (DMN) is a set of remote, functionally connected cortical nodes less active during executive tasks than at rest and is implicated in Theory of Mind, episodic memory, and other self-reflective processes. We show that children with ASD have reduced connectivity between DMN nodes and increased local connectivity within DMN nodes and the visual and motor resting-state networks. We show that, like the trajectory of synaptogenesis, internodal DMN functional connectivity increased as a quadratic function of age in typically developing children, peaking between, 11 and 13 years. In children with ASD, these long-distance connections fail to develop during adolescence. These findings support the “developmental disconnection model” of ASD, provide a possible mechanistic explanation for the Theory-of-Mind hypothesis of ASD, and show that the window for effectively treating ASD could be wider than previously thought.
PMCID: PMC3651798  PMID: 23334984
autism; default mode network; functional connectivity; development; Theory of Mind; synaptogenesis
5.  DTI correlates of distinct cognitive impairments in Parkinson’s disease 
Human brain mapping  2013;35(4):1325-1333.
The spectrum of cognitive symptoms in Parkinson’s disease (PD) can span various domains, including executive function, language, attention, memory and visuospatial skills. These symptoms may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. The primary purpose of this study is to find microstructural correlates of impairments across these cognitive domains in PD using diffusion tensor imaging (DTI). Sixteen PD patients with comprehensive neuropsychological evaluation and DTI data were retrospectively studied. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated for 40 regions of interest (ROIs) and were regressed against neurocognitive scores in each domain. Executive function directly correlated with FA and inversely correlated with MD in mostly frontal white matter tracts, especially the anterior limb of the internal capsule and genu of the corpus callosum. Likewise, language and attentional performance demonstrated correlations with DTI parameters in the frontal regions, but the attention domain additionally recruited regions widespread throughout the brain, with the most significant correlation identified in cingulate gyrus (cingulum). Lastly, memory impairment mainly involved MD alterations within the fornix. No significant correlations were found between visuospatial skills and DTI measures. Despite some overlap, unique patterns of white matter diffusivity underlie impairments in distinct cognitive domains in patients with PD. DTI combined with neurocognitive tests may be a valuable biomarker for identifying cognitive impairments in PD.
PMCID: PMC3664116  PMID: 23417856
Cognition; Parkinson’s; connectivity; tractography; neurodegenerative; white matter; neuroimaging; brain
6.  Spatial Orienting in Complex Audiovisual Environments 
Human brain mapping  2013;35(4):1597-1614.
Previous studies on crossmodal spatial orienting typically used simple and stereotyped stimuli in the absence of any meaningful context. This study combined computational models, behavioural measures and functional magnetic resonance imaging to investigate audiovisual spatial interactions in naturalistic settings. We created short videos portraying everyday life situations that included a lateralised visual event and a co-occurring sound, either on the same or on the opposite side of space. Subjects viewed the videos with or without eye-movements allowed (overt or covert orienting). For each video, visual and auditory saliency maps were used to index the strength of stimulus-driven signals, and eye-movements were used as a measure of the efficacy of the audiovisual events for spatial orienting. Results showed that visual salience modulated activity in higher-order visual areas, whereas auditory salience modulated activity in the superior temporal cortex. Auditory salience modulated activity also in the posterior parietal cortex, but only when audiovisual stimuli occurred on the same side of space (multisensory spatial congruence). Orienting efficacy affected activity in the visual cortex, within the same regions modulated by visual salience. These patterns of activation were comparable in overt and covert orienting conditions. Our results demonstrate that, during viewing of complex multisensory stimuli, activity in sensory areas reflects both stimulus-driven signals and their efficacy for spatial orienting; and that the posterior parietal cortex combines spatial information about the visual and the auditory modality.
PMCID: PMC3786006  PMID: 23616340
attention; space; visual; auditory; multisensory; eye movements; saliency; orienting; ecological; posterior parietal cortex
7.  Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults 
Human brain mapping  2013;35(4):1390-1403.
This study characterized human cerebellar activity during eyeblink classical conditioning (EBC) in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps, and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired. Although all participants demonstrated significant conditioning, the adults produced more conditioned responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex (Crus I– II, lateral lobules IV–IX, and vermis IV–VI) in all participants, suggesting multiple sites of associative learning-related plasticity. Despite their less optimal behavioral performance, the children showed greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning. Correlation analyses relating brain activations to behavioral CRs showed a positive association of activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children versus adults during eyeblink classical conditioning.
PMCID: PMC3823743  PMID: 23674498
cerebellum; development; learning; memory; neuroimaging
8.  Functional Connectivity-Based Parcellation of Amygdala Using Self-Organized Mapping: A Data Driven Approach 
Human brain mapping  2013;35(4):1247-1260.
The overall goal of this work is to demonstrate how resting state functional magnetic resonance imaging (fMRI) signals may be used to objectively parcellate functionally heterogeneous subregions of the human amygdala into structures characterized by similar patterns of functional connectivity. We hypothesize that similarity of functional connectivity of subregions with other parts of the brain can be a potential basis to segment and cluster voxels using data driven approaches. In this work, self-organizing map (SOM) was implemented to cluster the connectivity maps associated with each voxel of the human amygdala, thereby defining distinct subregions. The functional separation was optimized by evaluating the overall differences in functional connectivity between the subregions at group level. Analysis of 25 resting state fMRI data sets suggests that SOM can successfully identify functionally independent nuclei based on differences in their inter subregional functional connectivity, evaluated statistically at various confidence levels. Although amygdala contains several nuclei whose distinct roles are implicated in various functions, our objective approach discerns at least two functionally distinct volumes comparable to previous parcellation results obtained using probabilistic tractography and cytoarchitectonic analysis. Association of these nuclei with various known functions and a quantitative evaluation of their differences in overall functional connectivity with lateral orbital frontal cortex and temporal pole confirms the functional diversity of amygdala. The data driven approach adopted here may be used as a powerful indicator of structure–function relationships in the amygdala and other functionally heterogeneous structures as well.
PMCID: PMC3919874  PMID: 23418140
functional connectivity; self-organized mapping; connectivity-based parcellation
9.  Segregated and overlapping neural circuits exist for the production of static and dynamic precision grip force 
Human brain mapping  2011;34(3):698-712.
A central topic in sensorimotor neuroscience is the static-dynamic dichotomy that exists throughout the nervous system. Previous work examining motor unit synchronization reports that the activation strategy and timing of motor units differ for static and dynamic tasks. However, it remains unclear whether segregated or overlapping blood-oxygen-level-dependent (BOLD) activity exists in the brain for static and dynamic motor control. This study compared the neural circuits associated with the production of static force to those associated with the production of dynamic force pulses. To that end, healthy young adults (n = 17) completed static and dynamic precision grip force tasks during functional magnetic resonance imaging (fMRI). Both tasks activated core regions within the visuomotor network, including primary and sensory motor cortices, premotor cortices, multiple visual areas, putamen, and cerebellum. Static force was associated with unique activity in a right-lateralized cortical network including inferior parietal lobe, ventral premotor cortex, and dorsolateral prefrontal cortex. In contrast, dynamic force was associated with unique activity in left-lateralized and midline cortical regions, including supplementary motor area, superior parietal lobe, fusiform gyrus, and visual area V3. These findings provide the first neuroimaging evidence supporting a lateralized pattern of brain activity for the production of static and dynamic precision grip force.
PMCID: PMC3292669  PMID: 22109998
grasping; precision grip force; functional magnetic resonance imaging (fMRI); motor control
10.  Neural events leading to and associated with detection of sounds under high processing load 
Human brain mapping  2011;34(3):587-597.
The neural events that lead to successful or failed detection of supra-threshold sounds are not well established. In this experiment, event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) were recorded while participants performed two tasks: a primary difficult duration judgment task on a sequence of tones presented to one ear, and a secondary target detection task on an auditory oddball stream presented to the other ear. The paradigm was designed to elicit competition and variability in detection of auditory targets despite identical input. Successful detection of auditory targets was associated mainly with greater fMRI activity in superior parietal cortex and thalamus. In the ERPs, successful detection was linked with a larger fronto-central negativity at 200–400 ms, and a later centro-posterior positivity. Failure to detect targets was associated with greater fMRI signal in the default mode network, a significantly smaller electrical fronto-central negativity and no late positivity. These findings demonstrate that variability in auditory detection is related to modulation of activity in multimodal parietal and frontal networks active approximately 200 ms after target onset. Results are consistent with a limited capacity and late selection view of attention.
PMCID: PMC3297708  PMID: 22102362
Auditory; Attention; Capacity; ERP; fMRI
11.  Improved method for retinotopy constrained source estimation of visual evoked responses 
Human brain mapping  2011;34(3):665-683.
Retinotopy constrained source estimation (RCSE) is a method for non-invasively measuring the time courses of activation in early visual areas using magnetoencephalography (MEG) or electroencephalography (EEG). Unlike conventional equivalent current dipole or distributed source models, the use of multiple, retinotopically-mapped stimulus locations to simultaneously constrain the solutions allows for the estimation of independent waveforms for visual areas V1, V2, and V3, despite their close proximity to each other. We describe modifications that improve the reliability and efficiency of this method. First, we find that increasing the number and size of visual stimuli results in source estimates that are less susceptible to noise. Second, to create a more accurate forward solution, we have explicitly modeled the cortical point spread of individual visual stimuli. Dipoles are represented as extended patches on the cortical surface, which take into account the estimated receptive field size at each location in V1, V2, and V3 as well as the contributions from contralateral, ipsilateral, dorsal, and ventral portions of the visual areas. Third, we implemented a map fitting procedure to deform a template to match individual subject retinotopic maps derived from functional magnetic resonance imaging (fMRI). This improves the efficiency of the overall method by allowing automated dipole selection, and it makes the results less sensitive to physiological noise in fMRI retinotopy data. Finally, the iteratively reweighted least squares (IRLS) method was used to reduce the contribution from stimulus locations with high residual error for robust estimation of visual evoked responses.
PMCID: PMC3299883  PMID: 22102418
12.  Measuring extrastriatal dopamine release during a reward learning task 
Human brain mapping  2011;34(3):575-586.
Reward learning is critical for survival. Animal research emphasizes the role of dopaminergic (DA) mesocorticolimbic pathways in reward learning, but few studies have evaluated extrastriatal DA functioning in humans. The purpose of this study was to examine presynaptic DA release in extrastriatal regions of the reward circuit by measuring displacement of the high affinity D2/D3 radioligand [18F]Fallypride during a reward task.
Ten healthy volunteers underwent a [18F]Fallypride Positron Emission Tomography protocol while performing a reward task, allowing us to assess participants’ ability to modulate behavior as a function of reward. DA receptor ligand displacement was correlated with task performance and self-reported anhedonia.
Parametric t-maps revealed significant decrease in [18F]Fallypride binding in the medial orbitofrontal cortex (mOFC), ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC), indicating endogenous DA release in these regions. Increasing anhedonic symptoms correlated with DA release in the left vmPFC, left dACC, and right dACC emerged (all rs > 0.65, ps < 0.05). Similarly, reduced reward learning correlated with higher DA release in left vmPFC, right vmPFC, and left dACC (all rs < −0.64, ps < 0.05). Left dACC (r = 0.66, p = 0.04) and left vmPFC (r = 0.74, p = 0.01) DA release showed a significant positive correlation with impaired tendency to modulate behaviour as a function of prior positive reinforcements.
These findings support the hypothesis that DA release in mOFC, vmPFC and dACC regions plays an important role in reinforcement learning in the human brain.
PMCID: PMC3366062  PMID: 22109979
Positron emission tomography; PET; Reward learning; Extrastriatal Reward Circuit; Dopamine; [18F]Fallypride; Anhedonia
13.  Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer’s disease 
Human brain mapping  2011;34(3):530-542.
The medial temporal lobes (MTL) and frontal cortex have been shown to subserve memory processes. Neurodegenerative diseases, such as Alzheimer’s disease (AD), disrupt the neuronal networks that underlie memory processing. The ε4 allele of the apolipoprotein E gene is a genetic risk factor for AD and is associated with decrements in memory and in olfactory function. The present study utilized EQS, a structural equation modeling software program, to examine differences in the neuronal networks between non-demented ε4 carriers and ε4 non-carriers during a cross-modal olfactory recognition memory paradigm. Prior to fMRI scanning, participants were presented with 16 odors. During two scans, participants discriminated between names of odors presented before scanning (targets) or not presented (foils). The results indicate significant connections between bilateral frontal lobes and MTL for ε4 carriers when they misidentified a foil as a target. When ε4 non-carriers correctly identified a target, there were greater associations between the amygdala, MTL, and right frontal lobe; these associations also modeled the brain’s response when ε4 non-carriers misidentified a foil as a target. During memory retrieval, affective cues may facilitate retrieval in ε4 non-carriers relative to ε4 carriers. Last, no model was found that best represented the functional network used by ε4 carriers when they correctly identified a target, which may reflect variability of neuronal recruitment within this population.
PMCID: PMC3566346  PMID: 22102296
fMRI; olfaction; apolipoprotein E4; aging; neuroimaging; medial temporal lobe
14.  Working memory-related changes in functional connectivity persist beyond task disengagement 
Human brain mapping  2012;35(3):1004-1017.
We examined whether altered connectivity in functional networks during working memory performance persists following conclusion of that performance, into a subsequent resting state. We conducted functional magnetic resonance imaging (fMRI) in 50 young adults during an initial resting state, followed by an N-back working memory task and a subsequent resting state, in order to examine changes in functional connectivity within and between the default-mode network (DMN) and the task-positive network (TPN) across the three states. We found that alterations in connectivity observed during the N-back task persisted into the subsequent resting state within the TPN and between the DMN and TPN, but not within the DMN. Further, speed of working memory performance and TPN connectivity strength during the N-back task predicted connectivity strength in the subsequent resting state. Finally, DMN connectivity measured before and during the N-back task predicted individual differences in self-reported inattentiveness, but this association was not found during the post-task resting state. Together, these findings have important implications for models of how the brain recovers following effortful cognition, as well as for experimental designs using resting and task scans.
PMCID: PMC3637867  PMID: 23281202
fMRI; functional connectivity; resting state; working memory
15.  Defining Language Networks From Resting-State fMRI for Surgical Planning—A Feasibility Study 
Human brain mapping  2013;35(3):1018-1030.
Presurgical language mapping for patients with lesions close to language areas is critical to neurosurgical decision-making for preservation of language function. As a clinical noninvasive imaging technique, functional MRI (fMRI) is used to identify language areas by measuring blood-oxygen-level dependent (BOLD) signal change while patients perform carefully timed language vs. control tasks. This task-based fMRI critically depends on task performance, excluding many patients who have difficulty performing language tasks due to neurologic deficits. On the basis of recent discovery of resting-state fMRI (rs-fMRI), we propose a “task-free” paradigm acquiring fMRI data when patients simply are at rest. This paradigm is less demanding for patients to perform and easier for technologists to administer. We investigated the feasibility of this approach in right-handed healthy control subjects. First, group independent component analysis (ICA) was applied on the training group (14 subjects) to identify group level language components based on expert rating results. Then, four empirically and structurally defined language network templates were assessed for their ability to identify language components from individuals’ ICA output of the testing group (18 subjects) based on spatial similarity analysis. Results suggest that it is feasible to extract language activations from rs-fMRI at the individual subject level, and two empirically defined templates (that focuses on frontal language areas and that incorporates both frontal and temporal language areas) demonstrated the best performance. We propose a semi-automated language component identification procedure and discuss the practical concerns and suggestions for this approach to be used in clinical fMRI language mapping.
PMCID: PMC3683367  PMID: 23288627
language mapping; independent component analysis (ICA); functional connectivity; “task-free” paradigm; task-based fMRI; resting-state networks (RSNs)
16.  Regionally Specific Increased Volume of the Amygdala in Williams Syndrome. Evidence From Surface-based Modeling 
Human brain mapping  2012;35(3):866-874.
Williams syndrome (WS) is a condition caused by a contiguous deletion of approximately 26–28 genes from chromosome 7, and is characterized by abnormal social and emotional processing and abnormal structure and function of the amygdala. Prior studies show that the amygdala is relatively enlarged in WS, but very little is known regarding the regional specificity of increased amygdalar volume in this condition. Here we investigated the regional specificity of structural alterations of the amygdala in WS, compared to a typically developing (TD) control group. We acquired high resolution brain MRI data from 79 participants (39 WS, 40 TD) and used a surface-based analytical modeling approach. The WS group exhibited several areas of increased radial expansion of the amygdalar surface and no areas of decreased radial expansion of the amygdalar surface compared to TD controls. The areas found to exhibit particularly increased radial expansion in WS included the bilateral posterior cortical nucleus, lateral nucleus, and the central nucleus. This greater regional and anatomical specificity of altered amygdala structure in WS contributes to a model relating genetic risk in WS to the development of key brain regions for social and emotional functioning.
PMCID: PMC3751984  PMID: 23152007
Williams syndrome; genetics; amygdala; shape
17.  The parahippocampal gyrus links the default-mode cortical network with the medial temporal lobe memory system 
Human brain mapping  2013;35(3):1061-1073.
The default-mode network (DMN) is a distributed functional-anatomic network implicated in supporting memory. Current resting-state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting-state. Our findings using functional connectivity MRI analyses of resting-state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting-state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting-state. Additionally, a mediation analysis showed that resting-state connectivity between the hippocampus and posterior cingulate cortex — a major hub of the DMN — is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional sub-network that relates to the cortical nodes of the DMN through parahippocampal functional connections.
PMCID: PMC3773261  PMID: 23404748
Brain mapping; physiology; human; resting state; functional connectivity; brain networks; Magnetic Resonance Imaging; MTL; mediation; young adult
18.  Frontal and temporal contributions to understanding the iconic co-speech gestures that accompany speech 
Human brain mapping  2012;35(3):900-917.
In everyday conversation, listeners often rely on a speaker’s gestures to clarify any ambiguities in the verbal message. Using fMRI during naturalistic story comprehension, we examined which brain regions in the listener are sensitive to speakers’ iconic gestures. We focused on iconic gestures that contribute information not found in the speaker’s talk, compared to those that convey information redundant with the speaker’s talk. We found that three regions—left inferior frontal gyrus triangular (IFGTr) and opercular (IFGOp) portions, and left posterior middle temporal gyrus (MTGp)—responded more strongly when gestures added information to non-specific language, compared to when they conveyed the same information in more specific language; in other words, when gesture disambiguated speech as opposed to reinforced it. An increased BOLD response was not found in these regions when the non-specific language was produced without gesture, suggesting that IFGTr, IFGOp, and MTGp are involved in integrating semantic information across gesture and speech. In addition, we found that activity in the posterior superior temporal sulcus (STSp), previously thought to be involved in gesture-speech integration, was not sensitive to the gesture-speech relation. Together, these findings clarify the neurobiology of gesture-speech integration and contribute to an emerging picture of how listeners glean meaning from gestures that accompany speech.
PMCID: PMC3797208  PMID: 23238964
gestures; semantic; language; inferior frontal gyrus; posterior superior temporal sulcus; posterior middle temporal gyrus
19.  S-HAMMER: Hierarchical Attribute-Guided, Symmetric Diffeomorphic Registration for MR Brain Images 
Human brain mapping  2013;35(3):1044-1060.
Deformable registration has been widely used in neuroscience studies for spatial normalization of brain images onto the standard space. Because of possible large anatomical differences across different individual brains, registration performance could be limited when trying to estimate a single directed deformation pathway, i.e., either from template to subject or from subject to template. Symmetric image registration, however, offers an effective way to simultaneously deform template and subject images toward each other until they meet at the middle point. Although some intensity-based registration algorithms have nicely incorporated this concept of symmetric deformation, the pointwise intensity matching between two images may not necessarily imply the matching of correct anatomical correspondences. Based on HAMMER registration algorithm (Shen and Davatzikos, [2002]: IEEE Trans Med Imaging 21:1421–1439), we integrate the strategies of hierarchical attribute matching and symmetric diffeomorphic deformation to build a new symmetric-diffeomorphic HAMMER registration algorithm, called as S-HAMMER. The performance of S-HAMMER has been extensively compared with 14 state-of-the-art nonrigid registration algorithms evaluated in (Klein et al., [2009]: NeuroImage 46:786–802) by using real brain images in LPBA40, IBSR18, CUMC12, and MGH10 datasets. In addition, the registration performance of S-HAMMER, by comparison with other methods, is also demonstrated on both elderly MR brain images (>70 years old) and the simulated brain images with ground-truth deformation fields. In all experiments, our proposed method achieves the best registration performance over all other registration methods, indicating the high applicability of our method in future neuroscience and clinical applications.
PMCID: PMC3835769  PMID: 23283836
symmetric registration; anatomical correspondence; hierarchical attribute matching; diffeomorphism; HAMMER
20.  Resting state functional connectivity of the hippocampus associated with neurocognitive function in left temporal lobe epilepsy 
Human brain mapping  2012;35(3):735-744.
The majority of patients with temporal lobe epilepsy (TLE) experience disturbances of episodic memory from structural damage or dysfunction of the hippocampus. The objective of this study was to use functional Magnetic Resonance Imaging (fMRI) to identify regions where resting state connectivity to the left hippocampus (LH) is correlated with neuropsychological measures of verbal memory retention in TLE patients.
Eleven left TLE (LTLE) patients and 15 control subjects participated in resting state fMRI scans. All LTLE patients underwent neuropsychological testing. Resting state functional connectivity maps to the LH were calculated for each patient, and subsequently used in a multiple regression analysis with verbal memory retention scores as a covariate. The analysis identified brain regions whose connectivity to the LH was linearly related to memory retention scores across the group of patients.
In LTLE patients, right sided (contralateral) clusters in the precuneus and inferior parietal lobule (IPL) exhibited increased connectivity to the LH with increased memory retention score; left sided (ipsilateral) regions in the precuneus and IPL showed increased connectivity to the LH with decreased retention score. Patients with high memory retention scores had greater connectivity between the LH – right parietal clusters than between the LH – left parietal clusters; in contrast, control subjects had significantly and consistently greater LH – left hemisphere than LH – right hemisphere connectivity
Our results suggest that increased connectivity in contralateral hippocampal functional pathways within the episodic verbal memory network represents a strengthening of alternative pathways in LTLE patients with strong verbal memory retention abilities.
PMCID: PMC3915042  PMID: 23124719
temporal lobe epilepsy; brain; functional MRI; connectivity; episodic memory
21.  The Human Amygdala and Pain: Evidence from Neuroimaging 
Human brain mapping  2012;35(2):527-538.
The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala’s role in pain processing.
PMCID: PMC3920543  PMID: 23097300
chronic pain; fMRI; PET; meta-analysis; experimental pain
22.  Transcallosal sensorimotor fiber tract structure-function relationships 
Human brain mapping  2011;34(2):384-395.
Recent studies have demonstrated neuroanatomically selective relationships between white matter tract microstructure, physiological function and task performance. Such findings suggest that the microstructure of transcallosal motor fibers may reflect the capacity for interhemispheric inhibition between the primary motor cortices, although full characterization of the transcallosal inhibitory sensorimotor network is lacking. Thus, the goal of the current study was to provide a comprehensive description of transcallosal fibers connecting homologous sensorimotor cortical regions and to identify the relationship(s) between fiber tract microstructure and interhemispheric inhibition during voluntary cortical activity. To this end, we assessed microstructure of fiber tracts connecting homologous sensorimotor regions of the cortex with diffusion tensor imaging. We also assessed interhemispheric inhibition by eliciting the ipsilateral silent period (iSP) within the same participants. We mapped mutually exclusive transcallosal connections between homologous sensorimotor regions and computed quantitative metrics of each fiber tract. Paralleling work in non-human primates we found the densest interhemispheric sensorimotor connections to be between the medial motor areas. Additionally, we provide a mid-sagittal callosal atlas in normalized MNI space for future studies to use when investigating callosal fiber tracts connecting primary and secondary sensorimotor cortices. Finally, we report a strong, positive relationship (r = 0.76) between strength of interhemispheric inhibition (iSP) and microstructure of interhemispheric fibers that is specific to tracts connecting the primary motor cortices. Thus, increased fiber microstructure in young adults predicts interhemispheric inhibitory capacity.
PMCID: PMC3271163  PMID: 22042512
Corpus Callosum; Diffusion Tensor Imaging; Ipsilateral Silent Period; Interhemispheric Inhibition; Tractography
23.  Probing Tissue Microstructure with Restriction Spectrum Imaging: Histological and Theoretical Validation 
Human brain mapping  2012;34(2):327-346.
Diffusion magnetic resonance imaging (dMRI) is a powerful tool for studying biological tissue microarchitectures in vivo. Recently, there has been increased effort to develop quantitative dMRI methods to probe both length scale and orientation information in diffusion media. Diffusion spectrum imaging (DSI) is one such approach that aims to resolve such information on the basis of the three-dimensional diffusion propagator at each voxel. However, in practice only the orientation component of the propagator function is preserved when deriving the orientation distribution function. Here, we demonstrate how a straightforward extension of the linear spherical deconvolution (SD) model can be used to probe tissue orientation structures over a range (or “spectrum”) of length scales with minimal assumptions on the underlying microarchitecture. Using high b-value Cartesian q-space data on a fixed rat brain sample, we demonstrate how this “restriction spectrum imaging” (RSI) model allows for separating the volume fraction and orientation distribution of hindered and restricted diffusion, which we argue stems primarily from diffusion in the extra- and intra-neurite water compartment, respectively. Moreover, we demonstrate how empirical RSI estimates of the neurite orientation distribution and volume fraction capture important additional structure not afforded by traditional DSI or fixed-scale SD-like reconstructions, particularly in grey matter. We conclude that incorporating length scale information in geometric models of diffusion offers promise for advancing state-of-the-art dMRI methods beyond white matter into grey matter structures while allowing more detailed quantitative characterization of water compartmentalization and histoarchitecture of healthy and diseased tissue.
PMCID: PMC3538903  PMID: 23169482
Diffusion MRI; DTI; HARDI; DSI; FOD; Fiber Orientation; Tractography; Histology; Cerebellum; Cerebral Cortex; Striatum; Basal Ganglia; Rat
24.  Fiber Tract-Specific White Matter Lesion Severity: Findings in Late-Life Depression and by AGTR1 A1166C Genotype 
Human brain mapping  2011;34(2):295-303.
Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F1,86 = 4.62, p = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.
PMCID: PMC3772522  PMID: 22021115
25.  Disruption of Functional Organization Within the Primary Motor Cortex in Children With Autism 
Human brain mapping  2012;35(2):567-580.
Accumulating evidence suggests that motor impairments are prevalent in autism spectrum disorder (ASD), relate to the social and communicative deficits at the core of the diagnosis and may reflect abnormal connectivity within brain networks underlying motor control and learning. Parcellation of resting-state functional connectivity data using spectral clustering approaches has been shown to be an effective means of visualizing functional organization within the brain but has most commonly been applied to explorations of normal brain function. This article presents a parcellation of a key area of the motor network, the primary motor cortex (M1), a key area of the motor control network, in adults, typically developing (TD) children and children with ASD and introduces methods for selecting the number of parcels, matching parcels across groups and testing group differences. The parcellation is based solely on patterns of connectivity between individual M1 voxels and all voxels outside of M1, and within all groups, a gross dorsomedial to ventrolateral organization emerged within M1 which was left–right symmetric. Although this gross organizational scheme was present in both groups of children, statistically significant group differences in the size and segregation of M1 parcels within regions of the motor homunculus corresponding to the upper and lower limbs were observed. Qualitative comparison of the M1 parcellation for children with ASD with that of younger and older TD children suggests that these organizational differences, with a lack of differentiation between lower limb/trunk regions and upper limb/hand regions, may be due, at least in part, to a delay in functional specialization within the motor cortex.
PMCID: PMC3864146  PMID: 23118015
resting state; functional connectivity; clustering; motor cortex; autistic disorder

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