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1.  The Role of Medical Imaging in the Recharacterization of Mild Traumatic Brain Injury Using Youth Sports as a Laboratory 
The short- and long-term impact of mild traumatic brain injury (TBI) is an increasingly vital concern for both military and civilian personnel. Such injuries produce significant social and financial burdens and necessitate improved diagnostic and treatment methods. Recent integration of neuroimaging and biomechanical studies in youth collision-sport athletes has revealed that significant alterations in brain structure and function occur even in the absence of traditional clinical markers of “concussion.” While task performance is maintained, athletes exposed to repetitive head accelerations exhibit structural changes to the underlying white matter, altered glial cell metabolism, aberrant vascular response, and marked changes in functional network behavior. Moreover, these changes accumulate with accrued years of exposure, suggesting a cumulative trauma mechanism that may culminate in categorization as “concussion” and long-term neurological deficits. The goal of this review is to elucidate the role of medical imaging in recharacterizing TBI, as a whole, to better identify at-risk individuals and improve the development of preventative and interventional approaches.
PMCID: PMC4717183  PMID: 26834695
concussion; traumatic brain injury; functional MRI; magnetic resonance imaging; magnetic resonance spectroscopy; subconcussive
2.  Effects of Dietary Protein and Fiber at Breakfast on Appetite, ad Libitum Energy Intake at Lunch, and Neural Responses to Visual Food Stimuli in Overweight Adults 
Nutrients  2016;8(1):21.
Increasing either protein or fiber at mealtimes has relatively modest effects on ingestive behavior. Whether protein and fiber have additive or interactive effects on ingestive behavior is not known. Fifteen overweight adults (5 female, 10 male; BMI: 27.1 ± 0.2 kg/m2; aged 26 ± 1 year) consumed four breakfast meals in a randomized crossover manner (normal protein (12 g) + normal fiber (2 g), normal protein (12 g) + high fiber (8 g), high protein (25 g) + normal fiber (2 g), high protein (25 g) + high fiber (8 g)). The amount of protein and fiber consumed at breakfast did not influence postprandial appetite or ad libitum energy intake at lunch. In the fasting-state, visual food stimuli elicited significant responses in the bilateral insula and amygdala and left orbitofrontal cortex. Contrary to our hypotheses, postprandial right insula responses were lower after consuming normal protein vs. high protein breakfasts. Postprandial responses in other a priori brain regions were not significantly influenced by protein or fiber intake at breakfast. In conclusion, these data do not support increasing dietary protein and fiber at breakfast as effective strategies for modulating neural reward processing and acute ingestive behavior in overweight adults.
PMCID: PMC4728635  PMID: 26742068
fMRI; food reward; overweight; appetite regulation; dietary protein; dietary fiber
3.  Functionally-Detected Cognitive Impairment in High School Football Players without Clinically-Diagnosed Concussion 
Journal of Neurotrauma  2014;31(4):327-338.
Head trauma and concussion in football players have recently received considerable media attention. Postmortem evidence suggests that accrual of damage to the brain may occur with repeated blows to the head, even when the individual blows fail to produce clinical symptoms. There is an urgent need for improved detection and characterization of head trauma to reduce future injury risk and promote development of new therapies. In this study we examined neurological performance and health in the presence of head collision events in high school football players, using longitudinal measures of collision events (the HIT™ System), neurocognitive testing (ImPACT™), and functional magnetic resonance imaging MRI (fMRI). Longitudinal assessment (including baseline) was conducted in 11 young men (ages 15–19 years) participating on the varsity and junior varsity football teams at a single high school. We expected and observed subjects in two previously described categories: (1) no clinically-diagnosed concussion and no changes in neurological behavior, and (2) clinically-diagnosed concussion with changes in neurological behavior. Additionally, we observed players in a previously undiscovered third category, who exhibited no clinically-observed symptoms associated with concussion, but who demonstrated measurable neurocognitive (primarily visual working memory) and neurophysiological (altered activation in the dorsolateral prefrontal cortex [DLPFC]) impairments. This new category was associated with significantly higher numbers of head collision events to the top-front of the head, directly above the DLPFC. The discovery of this new category suggests that more players are suffering neurological injury than are currently being detected using traditional concussion-assessment tools. These individuals are unlikely to undergo clinical evaluation, and thus may continue to participate in football-related activities, even when changes in brain physiology (and potential brain damage) are present, which will increase the risk of future neurological injury.
PMCID: PMC3922228  PMID: 20883154
behavioral assessment; cognitive function; human studies; magnetic resonance imaging; traumatic brain injury
4.  Auditory Neuroimaging with fMRI and PET 
Hearing research  2013;307:4-15.
For much of the past 30 years, investigations of auditory perception and language have been enhanced or even driven by the use of functional neuroimaging techniques that specialize in localization of central responses. Beginning with investigations using positron emission tomography (PET) and gradually shifting primarily to usage of functional magnetic resonance imaging (fMRI), auditory neuroimaging has greatly advanced our understanding of the organization and response properties of brain regions critical to the perception of and communication with the acoustic world in which we live. As the complexity of the questions being addressed has increased, the techniques, experiments and analyses applied have also become more nuanced and specialized. A brief review of the history of these investigations sets the stage for an overview and analysis of how these neuroimaging modalities are becoming ever more effective tools for understanding the auditory brain. We conclude with a brief discussion of open methodological issues as well as potential clinical applications for auditory neuroimaging.
PMCID: PMC3893048  PMID: 24076424
fMRI; PET; humans; auditory cortex; auditory pathway
5.  How Challenges in Auditory fMRI Led to General Advancements for the Field 
Neuroimage  2012;62(2):641-647.
In the early years of fMRI research, the auditory neuroscience community sought to expand its knowledge of the underlying physiology of hearing, while also seeking to come to grips with the inherent acoustic disadvantages of working in the fMRI environment. Early collaborative efforts between prominent auditory research laboratories and prominent fMRI centers led to development of a number of key technical advances that have subsequently been widely used to elucidate principles of auditory neurophysiology. Perhaps the key imaging advance was the simultaneous and parallel development of strategies to use pulse sequences in which the volume acquisitions were “clustered,” providing gaps in which stimuli could be presented without direct masking. Such sequences have become widespread in fMRI studies using auditory stimuli and also in a range of translational research domains. This review presents the parallel stories of the people and the auditory neurophysiology research that led to these sequences.
PMCID: PMC3348382  PMID: 22245349
clustered volume acquisitions; sparse sampling; tonotopy; auditory cortex
NeuroImage  2013;82:500-509.
Neurobiological correlates of adaptation to spectrally degraded speech were investigated with fMRI before and after exposure to a portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI). The speech processor, in conjunction with isolating insert earphones and a microphone to capture environment sounds, was worn by participants over a two week chronic exposure period. fMRI and behavioral speech comprehension testing was conducted before and after this two week period. After using the simulator each day for 2 hours, participants significantly improved in word and sentence recognition scores. fMRI shows that these improvements came accompanied by changes in patterns of neuronal activation. In particular, we found additional recruitment of visual, motor, and working memory areas after the perceptual training period. These findings suggest that the human brain is able to adapt in a short period of time to a degraded auditory signal under a natural learning environment, and gives insight on how a CI might interact with the central nervous system. This paradigm can be furthered to investigate neural correlates of new rehabilitation, training, and signal processing strategies non-invasively in normal hearing listeners to improve CI patient outcomes.
PMCID: PMC3764992  PMID: 23751864
7.  Psychometrically matched tasks evaluating differential fMRI activation during form and motion processing 
Neuropsychology  2011;25(5):622-633.
Deficits in visual perception and working memory are commonly observed in neuropsychiatric disorders and have been investigated using functional MRI. However, interpretation of differences in brain activation may be confounded with differences in task performance between groups. Differences in task difficulty across conditions may also pose interpretative issues in studies of visual processing in healthy subjects.
In order to address these concerns, the present study characterized brain activation in tasks which were psychometrically matched for difficulty. Functional magnetic resonance imaging (fMRI) was used to assess brain activation in ten healthy subjects during discrimination and working memory judgments for static and moving stimuli. For all task conditions, performance accuracy was matched at 70.7%.
Areas associated with V2 and V5 in the dorsal stream were activated during motion processing tasks and V4 in the ventral stream were activated during form processing tasks. Frontoparietal areas associated with working memory were also statistically significant during the working memory tasks.
Application of psychophysical methods to equate task demands provides a practical method to equate performance levels across conditions in fMRI studies, and to compare healthy and cognitively impaired groups at comparable levels of effort. These psychometrically matched tasks can be applied to patients with a variety of cognitive disorders to investigate dysfunction of multiple a priori defined brain regions. Measuring the changes in typical activation patterns in patients with these diseases can be useful for monitoring disease progression, evaluating new drug treatments, and possibly for developing methods for early diagnosis.
PMCID: PMC3150625  PMID: 21534685
visual processing; fMRI; working memory; form; motion
8.  Functional connectivity in task-negative network of the Deaf: effects of sign language experience 
PeerJ  2014;2:e446.
Prior studies investigating cortical processing in Deaf signers suggest that life-long experience with sign language and/or auditory deprivation may alter the brain’s anatomical structure and the function of brain regions typically recruited for auditory processing (Emmorey et al., 2010; Pénicaud et al., 2013 inter alia). We report the first investigation of the task-negative network in Deaf signers and its functional connectivity—the temporal correlations among spatially remote neurophysiological events. We show that Deaf signers manifest increased functional connectivity between posterior cingulate/precuneus and left medial temporal gyrus (MTG), but also inferior parietal lobe and medial temporal gyrus in the right hemisphere- areas that have been found to show functional recruitment specifically during sign language processing. These findings suggest that the organization of the brain at the level of inter-network connectivity is likely affected by experience with processing visual language, although sensory deprivation could be another source of the difference. We hypothesize that connectivity alterations in the task negative network reflect predictive/automatized processing of the visual signal.
PMCID: PMC4081178  PMID: 25024915
Functional connectivity; Task-negative network; Deaf; Sign language; American sign language; PCC; Inferior parietal cortex; Default network; Medial temporal gyrus
9.  Neural Adaptation and Perceptual Learning using a Portable Real-Time Cochlear Implant Simulator in Natural Environments 
A portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI) has been developed on the Apple iPhone/iPod Touch to permit testing and experimentation under extended exposure in real-world environments. This simulator allows for both a variable number of noise band channels and electrode insertion depth. Utilizing this portable CI simulator, we tested perceptual learning in normal hearing listeners by measuring word and sentence comprehension behaviorally before and after 2 weeks of exposure. To evaluate changes in neural activation related to adaptation to transformed speech, fMRI was also conducted. Differences in brain activation after training occurred in the inferior frontal gyrus and areas related to language processing. A 15–20% improvement in word and sentence comprehension of cochlear implant simulated speech was also observed. These results demonstrate the effectiveness of a portable CI simulator as a research tool and provide new information about the physiological changes that accompany perceptual learning of degraded auditory input.
PMCID: PMC3674485  PMID: 22254517
cochlear implants; fMRI; portable media players
10.  Event segmentation in a visual language: Neural bases of processing American Sign Language predicates 
Neuroimage  2011;59(4):4094-4101.
Motion capture studies show that American Sign Language (ASL) signers distinguish end-points in telic verb signs by means of marked hand articulator motion, which rapidly decelerates to a stop at the end of these signs, as compared to atelic signs (Malaia & Wilbur, in press). Non-signers also show sensitivity to velocity in deceleration cues for event segmentation in visual scenes (Zacks et al., 2010; Zacks et a., 2006), introducing the question of whether the neural regions used by ASL signers for sign language verb processing might be similar to those used by non-signers for event segmentation.
The present study investigated the neural substrate of predicate perception and linguistic processing in ASL. Observed patterns of activation demonstrate that Deaf signers process telic verb signs as having higher phonological complexity as compared to atelic verb signs. These results, together with previous neuroimaging data on spoken and sign languages (Shetreet, Friedmann, & Hadar, 2010; Emmorey et al., 2009), illustrate a route for how a prominent perceptual-kinematic feature used for non-linguistic event segmentation might come to be processed as an abstract linguistic feature due to sign language exposure.
PMCID: PMC3279599  PMID: 22032944
sign language; ASL; fMRI; event structure; verb; neuroplasticity; motion
11.  An fMRI study of nonverbally gifted reading disabled adults: has deficit compensation effected gifted potential? 
Neuroscience has advanced our understanding of the neurological basis of reading disability (RD). Yet, no functional imaging work has been reported on the twice-exceptional dyslexic: individuals exhibiting both non-verbal-giftedness and RD. We compared groups of reading-disabled (RD), non-verbally-gifted (G), non-verbally-gifted-RD (GRD), and control (C) adults on validated word-rhyming and spatial visualization fMRI tasks, and standardized psychometric tests, to ascertain if the neurological functioning of GRD subjects was similar to that of typical RD or G subjects, or perhaps some unique RD subtype. Results demonstrate that GRD adults resemble non-gifted RD adults in performance on paper-and-pencil reading, math and spatial tests, and in patterns of functional activation during rhyming and spatial processing. Data are consistent with what may be a shared etiology of RD and giftedness in GRD individuals that yields a lifespan interaction with reading compensation effects, modifying how their adult brain processes text and spatial stimuli.
PMCID: PMC3756280  PMID: 24009572
giftedness; reading disability; twice-exceptional; neuroimaging; spatial visualization
12.  Effects of combining field strengths on auditory fMRI group analysis: 1.5T and 3T 
To evaluate effects of combining functional MRI data acquired from different field strengths on group analysis as a function of the number of subjects at each field strength.
Materials and Methods
28 subjects (18 at 3T) participated in an auditory task of passively listening to a 0.75s segment of jazz music in an event-related design. Results of single-subject analysis were combined to create all possible subject combinations for a group size of 8 subjects from each of the 3T and 1.5T pools, comprising subject mixtures of (3T/1.5T) 0/8, 2/6, 4/4, 6/2 and 8/0. Group analysis performance of each subject permutation was measured by receiver operating characteristic (ROC) curves and activation overlap maps.
While area under ROC curves, extent of activation in the gold standard region and reliability of activation increased with the number of 3T subjects, marginal gain decreased. ROC performance overlap across mixtures was observed, indicating that some combinations of subjects markedly outperformed others. For detection of activation, 4/4 was arguably the minimum mixture level that was comparable to 3T-only group results.
Inclusion of 1.5T data does not necessarily reduce the validity of group analysis. Lower field strength data was found only to limit detection power, but did not affect specificity. Within the limits of realignment error, these results should also extend to group longitudinal analyses of subject mixtures from different field strengths.
PMCID: PMC3221808  PMID: 21959971
fMRI; 1.5T; 3T; data analysis; ROC analysis
13.  Development of Subject-Specific Geometric Spine Model through Use of Automated Active Contour Segmentation and Kinematic Constraint-Limited Registration 
Journal of Digital Imaging  2010;24(5):926-942.
This paper describes the development of a patient-specific spine model through use of active contour segmentation and registration of intraoperative imaging of porcine vertebra augmented with kinematic constraints. The geometric active contours are fully automated and lead to a discrete representation of the image segmentation results. After determining errors within the segmentations, application of reliability theory allows the selection of active contour parameters to obtain best-fit segmentations from a stack of 2D images. The segmented images are then used in conjunction with C-arm fluoroscope images to simulate the result of intraoperative patient-specific model registration including patient and/or structure motion between preoperative and intraoperative scans. The results are validated through comparison of the error within the patient-specific model generated through use of the C-arm images with a model acquired directly from MRI images of the spine after motion. The results are applicable to the development of a wide variety of patient-specific geometric and biomechanical models.
PMCID: PMC3180553  PMID: 20882395
Segmentation; template geometry; patient-specific model; spine; active contour; fluoroscopy; kinematic constraints; imaging; image error; registration
NeuroImage  2010;54(3):2138-2155.
Reproducibility of three different aspects of fMRI activations—namely binary activation maps, effect size and spatial distribution of local maxima—was evaluated for an auditory sentence comprehension task with high attention demand on a group of 17 subjects that were scanned on five different occasions. While in the scanner subjects were asked to listen to series of six short everyday sentences from the CUNY sentence test. Comprehension and attention to the stimuli was monitored after each listen condition epoch by having subjects answer a series of multiple choice questions. Statistical maps of activation for the listen condition were computed at three different levels: overall results for all imaging sessions, group-level/single-session results for each of the five imaging occasions, and single-subject/single-session results computed for each subject and each scanning occasion independently. The experimental task recruited a distributed bilateral network with processing nodes located in lateral temporal cortex, inferior frontal cortex, medial BA6, medial occipital cortex and subcortical structures such as the putamen and the thalamus. Reproducibility of these activations at the group level was high (83.95% of the imaged volume was consistently classified as active/inactive across all five imaging sessions), indicating that sites of neuronal activity associated with auditory comprehension can reliably be detected with fMRI in healthy subjects, across repeated measures after group averaging. At the single-subject level reproducibility ranged from moderate to high, although no significant differences were found on behavioral measures across subjects or sessions. This result suggests that contextual differences—i.e., those specific to each imaging session, can modulate our ability to detect fMRI activations associated with speech comprehension in individual subjects.
PMCID: PMC3008333  PMID: 20933093
fMRI; functional MRI; reliability; reproducibility; intraclass correlation coefficient; ratio of volume overlap; language; speech; auditory sentence comprehension
15.  Modeling Hemodynamic Responses in Auditory Cortex at 1.5T Using Variable Duration Imaging Acoustic Noise 
NeuroImage  2009;49(4):3027.
A confound for functional magnetic resonance imaging (fMRI), especially for auditory studies, is the presence of imaging acoustic noise generated mainly as a byproduct of rapid gradient switching during volume acquisition and to a lesser extent, the radio-frequency transmit. This work utilized a novel pulse sequence to present actual imaging acoustic noise for characterization of the induced hemodynamic responses and assessment of linearity in the primary auditory cortex with respect to noise duration. Results show that responses to brief duration (46ms) imaging acoustic noise is highly nonlinear while responses to longer duration (>1s) imaging acoustic noise becomes approximately linear, with the right primary auditory cortex exhibiting a higher degree of nonlinearity than the left for the investigated noise durations. This study also assessed the spatial extent of activation induced by imaging acoustic noise, showing that the use of modeled responses (specific to imaging acoustic noise) as the reference waveform revealed additional activations in the auditory cortex not observed with a canonical gamma variate reference waveform, suggesting an improvement in detection sensitivity for imaging acoustic noise-induced activity. Longer duration (1.5s) imaging acoustic noise was observed to induce activity that expanded outwards from Heschl’s gyrus to cover the superior temporal gyrus as well as parts of the middle temporal gyrus and insula, potentially affecting higher level acoustic processing.
PMCID: PMC2818577  PMID: 19948232
imaging acoustic noise; functional MRI; hemodynamic response; linear systems
16.  Partially Adaptive STAP Algorithm Approaches to functional MRI 
In this work, the architectures of three partially adaptive STAP algorithms are introduced, one of which is explored in detail, that reduce dimensionality and improve tractability over fully adaptive STAP when used in construction of brain activation maps in fMRI. Computer simulations incorporating actual MRI noise and human data analysis indicate that element space partially adaptive STAP can attain close to the performance of fully adaptive STAP while significantly decreasing processing time and maximum memory requirements, and thus demonstrates potential in fMRI analysis.
PMCID: PMC2904987  PMID: 19272913
Element-space partially adaptively STAP; fMRI; image processing; space-time adaptive processing
17.  Characterizing Response to Elemental Unit of Acoustic Imaging Noise: An fMRI Study 
Acoustic imaging noise produced during functional magnetic resonance imaging (fMRI) studies can hinder auditory fMRI research analysis by altering the properties of the acquired time-series data. Acoustic imaging noise can be especially confounding when estimating the time course of the hemodynamic response (HDR) in auditory event-related fMRI (fMRI) experiments. This study is motivated by the desire to establish a baseline function that can serve not only as a comparison to other quantities of acoustic imaging noise for determining how detrimental is one's experimental noise, but also as a foundation for a model that compensates for the response to acoustic imaging noise. Therefore, the amplitude and spatial extent of the HDR to the elemental unit of acoustic imaging noise (i.e., a single ping) associated with echoplanar acquisition were characterized and modeled. Results from this fMRI study at 1.5 T indicate that the group-averaged HDR in left and right auditory cortex to acoustic imaging noise (duration of 46 ms) has an estimated peak magnitude of 0.29% (right) to 0.48% (left) signal change from baseline, peaks between 3 and 5 s after stimulus presentation, and returns to baseline and remains within the noise range approximately 8 s after stimulus presentation.
PMCID: PMC2845537  PMID: 19304477
Acoustic noise; auditory system; biomedical image processing; magnetic resonance imaging; modeling
18.  Signal Fluctuations Induced by non-T1-related Confounds in Variable TR fMRI Experiments 
To assess and model signal fluctuations induced by non-T1-related confounds in variable repetition time fMRI and to develop a compensation procedure to correct for the non-T1- related artifacts.
Materials and Methods
Radio-frequency disabled volume gradient sequences were effected at variable offsets between actual image acquisitions, enabling perturbation of the measurement system without perturbing longitudinal magnetization, allowing the study of non-T1-related confounds that may arise in variable TR experiments. Three imaging sessions utilizing a daily quality assurance (DQA) phantom were conducted to assess the signal fluctuations, which were then modeled as a second order system. A modified projection procedure was implemented to correct for signal fluctuations arising from non-T1-related confounds, and statistical analysis was performed to assess the significance of the artifacts with and without compensation.
Assessment using phantom data reveals that the signal fluctuations induced by non-T1- related confounds was consistent in shape across the phantom and well-modeled by a second order system. The phantom exhibited significant spurious detections (at p < 0.01) almost uniformly across the central slices of the phantom. Second-order system modeling and compensation of non-T1-related confounds achieves significant reduction of spurious detection of fMRI activity in a phantom.
PMCID: PMC2728024  PMID: 19388103
variable TR; non-T1-related artifacts; eddy currents; gradient coil heating
19.  New imaging techniques in the diagnosis of multiple sclerosis 
Multiple sclerosis (MS) is a chronic disabling disorder histopathologically characterized by inflammation, demyelination and axonal loss. Conventional MRI has made most contributions to the diagnosis of MS. However, it is not sufficiently sensitive and specific to reveal the extent and severity of the damage in the disease. Other nuclear magnetic resonance (NMR) techniques including magnetic resonance spectroscopy, magnetization transfer imaging, diffusion weighted and diffusion tensor imaging, and functional MRI have provided additional information that improves the diagnosis and understanding of MS. Optical techniques including optical coherence tomography (OCT) and coherent anti-Stokes Raman scattering (CARS) microscopy have shown promise in diagnosis and mechanistic study of myelin diseases.
To review new imaging techniques and their potential in diagnosis of MS.
The principles of three imaging techniques (MRI, OCT and CARS) and their applications to MS studies are described. Their advantages and disadvantages are compared.
Conventional MRI remains a critical tool in the diagnosis of MS. Alternative NMR/MRI techniques have improved specificity for the detection of lesions and provided more quantitative information about MS. Optical techniques including OCT and CARS microscopy are opening up new ways for diagnosis and mechanistic study of myelin diseases.
PMCID: PMC2662586  PMID: 19337386
coherent anti-Stokes Raman scattering microscopy; magnetic resonance imaging; multiple sclerosis; optical coherence tomography

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