An MRI method for parcellating the human striatum into matrix and striosome compartments in vivo.

The mammalian striatum is comprised of intermingled tissue compartments, matrix and striosome. Though indistinguishable by routine histological techniques, matrix and striosome have distinct embryologic origins, afferent/efferent connections, surface protein expression, intra-striatal location, susceptibilities to injury, and functional roles in a range of animal behaviors. Distinguishing the compartments previously required post-mortem tissue and/or genetic manipulation; we aimed to identify matrix/striosome non-invasively in living humans. We used diffusion MRI (probabilistic tractography) to identify human striatal voxels with connectivity biased towards matrix-favoring or striosome-favoring regions (determined by prior animal tract-tracing studies). Segmented striatal compartments replicated the topological segregation and somatotopic organization identified in animal matrix/striosome studies. Of brain regions mapped in prior studies, our human brain data confirmed 93% of the compartment-selective structural connectivity demonstrated in animals. Test-retest assessment on repeat scans found a voxel classification error rate of 0.14%. Fractional anisotropy was significantly higher in matrix-like voxels, while mean diffusivity did not differ between the compartments. As mapped by the Talairach human brain atlas, 460 regions were significantly biased towards either matrix or striosome. Our method allows the study of striatal compartments in human health and disease, in vivo, for the first time.

Evaluation of a Standardized Cardiac Athletic Screening for National Collegiate Athletic Association (NCAA) Athletes.

INTRODUCTION: Sudden cardiac death is a rare cause of death in young athletes. Current screening techniques include history and physical exam (H and P), with or without an electrocardiogram (ECG). Adding point of care cardiac ultrasound has demonstrated benefits, but there is limited data about implementing this technology. We evaluated the feasibility of adding ultrasound to preparticipation screening for collegiate athletes. METHODS: We prospectively enrolled 42 collegiate athletes randomly selected from several sports. All athletes were screened using a 14-point H and P based on 2014 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, ECG, and cardiac ultrasound. RESULTS: We screened 11 female and 31 male athletes. On ultrasound, male athletes demonstrated significantly larger interventricular septal wall thickness (p = 0.002), posterior wall thickness (p <0.001) and aortic root breadth (p = 0.002) compared to females. Based on H and P and ECGs alone and a combination of H and P with ECG, no athletes demonstrated a positive screening for cardiac abnormalities. However, with combined H and P, ECG, and cardiac ultrasound, one athlete demonstrated positive findings. CONCLUSIONS: We believe that adding point of care ultrasound to the preparticipation exam of college athletes is feasible. This workflow may provide a model for athletic departments' screening.

A registration method for improving quantitative assessment in probabilistic diffusion tractography.

Diffusion MRI-based probabilistic tractography is a powerful tool for non-invasively investigating normal brain architecture and alterations in structural connectivity associated with disease states. Both voxelwise and region-of-interest methods of analysis are capable of integrating population differences in tract amplitude (streamline count or density), given proper alignment of the tracts of interest. However, quantification of tract differences (between groups, or longitudinally within individuals) has been hampered by two related features of white matter. First, it is unknown to what extent healthy individuals differ in the precise location of white matter tracts, and to what extent experimental factors influence perceived tract location. Second, white matter lacks the gross neuroanatomical features (e.g., gyri, histological subtyping) that make parcellation of grey matter plausible - determining where tracts "should" lie within larger white matter structures is difficult. Accurately quantifying tractographic connectivity between individuals is thus inherently linked to the difficulty of identifying and aligning precise tract location. Tractography is often utilized to study neurological diseases in which the precise structural and connectivity abnormalities are unknown, underscoring the importance of accounting for individual differences in tract location when evaluating the strength of structural connectivity. We set out to quantify spatial variance in tracts aligned through a standard, whole-brain registration method, and to assess the impact of location mismatch on groupwise assessments of tract amplitude. We then developed a method for tract alignment that enhances the existing standard whole brain registration, and then tested whether this method improved the reliability of groupwise contrasts. Specifically, we conducted seed-based probabilistic diffusion tractography from primary motor, supplementary motor, and visual cortices, projecting through the corpus callosum. Streamline counts decreased rapidly with movement from the tract center (-35% per millimeter); tract misalignment of a few millimeters caused substantial compromise of amplitude comparisons. Alignment of tracts "peak-to-peak" is essential for accurate amplitude comparisons. However, for all transcallosal tracts registered through the whole-brain method, the mean separation distance between an individual subject's tract and the average tract (3.2 mm) precluded accurate comparison: at this separation, tract amplitudes were reduced by 74% from peak value. In contrast, alignment of subcortical tracts (thalamo-putaminal, pallido-rubral) was substantially better than alignment for cortical tracts; whole-brain registration was sufficient for these subcortical tracts. We demonstrated that location mismatches in cortical tractography were sufficient to produce false positive and false negative amplitude estimates in both groupwise and longitudinal comparisons. We then showed that our new tract alignment method substantially reduced location mismatch and improved both reliability and statistical power of subsequent quantitative comparisons.

Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

BACKGROUND AND PURPOSE: X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. METHODS: Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. RESULTS: All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. CONCLUSIONS: This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction.

Partial closure of skin wounds after kidney transplantation decreases the incidence of postoperative wound infections.

Wound infections are a major cause of morbidity after kidney transplantation. The purpose of our study was to evaluate an improved technique of wound closure. Data corresponding to 104 consecutive live donor kidney recipients were prospectively collected and analyzed. Our routine standard technique involved closure of the abdominal wall muscle and fascia in one layer with interrupted nonabsorbable full thickness sutures. No drains were used. The skin was closed with interrupted 2-0 nylon sutures 4 to 5 cm apart, leaving the skin and subcutaneous tissue in between partially open. Patients were allowed to shower starting on the first postoperative day. Examination of the wounds was continued for at least 1 month postoperatively, and then routinely as needed. All patients were thoroughly informed preoperatively of our technique. There were no immediate postoperative wound infections. There were no instances of dehiscence, evisceration, or need for revision. All patients were able to continue with their routine daily activities. Cosmetic results were satisfactory in all cases. We did not experience any patient complaints with respect to our technique. Patient satisfaction scores conducted by Press Ganey and Associates ranked in the 99 percentile with respect to peers undergoing kidney transplantation. Three patients returned six months postoperatively with suture granulomas which were treated nonoperatively. Partial closure of the skin wound with no associated drains is an effective and cosmetically desirable way to decrease the incidence of postoperative infections in kidney transplantation.

BDNF, relative preference, and reward circuitry responses to emotional communication.

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for approximately 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions.

Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion.

We used positron emission tomography to study neural mechanisms underlying intensely pleasant emotional responses to music. Cerebral blood flow changes were measured in response to subject-selected music that elicited the highly pleasurable experience of "shivers-down-the-spine" or "chills." Subjective reports of chills were accompanied by changes in heart rate, electromyogram, and respiration. As intensity of these chills increased, cerebral blood flow increases and decreases were observed in brain regions thought to be involved in reward/motivation, emotion, and arousal, including ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex. These brain structures are known to be active in response to other euphoria-inducing stimuli, such as food, sex, and drugs of abuse. This finding links music with biologically relevant, survival-related stimuli via their common recruitment of brain circuitry involved in pleasure and reward.

Cortical deafness to dissonance.

Ordinary listeners, including infants, easily distinguish consonant from dissonant pitch combinations and consider the former more pleasant than the latter. The preference for consonance over dissonance was tested in a patient, I.R., who suffers from music perception and memory disorders as a result of bilateral lesions to the auditory cortex. In Experiment 1, I.R. was found to be unable to distinguish consonant from dissonant versions of musical excerpts taken from the classical repertoire by rating their pleasantness. I.R.'s indifference to dissonance was not due to a loss of all affective responses to music, however, since she rated the same excerpts as happy or sad, as normal controls do. In Experiment 2, I.R.'s lack of responsiveness to varying degrees of dissonance was replicated with chord sequences which had been used in a previous study using PET, in examining emotional responses to dissonance. A CT scan of I.R.'s brain was co-registered with the PET activation data from normal volunteers. Comparison of I.R.'s scan with the PET data revealed that the damaged areas overlapped with the regions identified to be involved in the perceptual analysis of the musical input, but not with the paralimbic regions involved in affective responses. Taken together, the findings suggest that dissonance may be computed bilaterally in the superior temporal gyri by specialized mechanisms prior to its emotional interpretation.

Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions.

Neural correlates of the often-powerful emotional responses to music are poorly understood. Here we used positron emission tomography to examine cerebral blood flow (CBF) changes related to affective responses to music. Ten volunteers were scanned while listening to six versions of a novel musical passage varying systematically in degree of dissonance. Reciprocal CBF covariations were observed in several distinct paralimbic and neocortical regions as a function of dissonance and of perceived pleasantness/unpleasantness. The findings suggest that music may recruit neural mechanisms similar to those previously associated with pleasant/unpleasant emotional states, but different from those underlying other components of music perception, and other emotions such as fear.

Optical intrinsic signal imaging responses are modulated in rodent somatosensory cortex during simultaneous whisker and forelimb stimulation.

Optical intrinsic signal imaging (OIS) was used to investigate physiologic interactions between spatially and functionally distinct cortical somatosensory systems. The OIS response magnitude was evaluated after simultaneous stimulation of single whiskers and forelimb digits. Whisker C1 was deflected at a frequency of 10 Hz for 2 seconds while low- or high-intensity vibratory stimuli were applied to forelimb digits. The OIS responses to simultaneous whisker and forelimb stimulation were compared with lone whisker stimulated controls. Overall, addition of a second stimulus caused decreases in barrel cortex response magnitude. Three different response patterns were detected within individual trial sets. Modulation of barrel cortex evoked potentials provided evidence that changes in OIS responses observed here may be partially influenced by vascular responses to changes in neuronal activity. However, OIS responses in the barrel region during lone forelimb stimulation that were unaccompanied by evoked potentials suggested the possibility of independent vascular dynamic influences on response modulation. This study demonstrates that cortical responses at the level of primary sensory processing may be significantly influenced by activity in adjacent regions. Furthermore, it reveals that vascular and neuronal characteristics of interregional modulation do not co-localize and may produce responses in which one component increases while the other decreases.

The evolution of optical signals in human and rodent cortex.

The time course of optical intrinsic signals was examined in order to characterize the evolution of response in human and rodent cortex. Both subtraction/ratio and principal component analyses were used to construct time-course curves. The time course began at a prestimulus baseline, responded with a finite delay, overcompensated, reduced to a maintenance level, and then disappeared. The magnitude, spatial involvement, and principal components demonstrated similar time-course curves both in human and in rodent. For acute stimuli, peak response was reached between 2 and 3 s and returned to baseline by 6 s poststimulation. The shape of the time-course curve is consistent with the need to satisfy neuronal demand and the contributions of vascular smooth muscle properties to the response behavior. The temporal delays and nonlinear phenomena observed in the time-course curves are consistent with a hydraulic model of neurovascular supply/demand behavior.

Stimulus parameters influence characteristics of optical intrinsic signal responses in somatosensory cortex.

Optical imaging of intrinsic signals was performed in the barrel cortex of the rat during whisker deflections of varying frequencies (1 to 20 Hz) and durations (0.1 to 5 s). A dose-response relationship was shown between these stimuli and the characteristics of the optically recorded intrinsic signal response. At constant frequencies, longer stimulus durations increased response magnitude, as defined by mean pixel value in statistically determined regions of interest. At constant durations, higher stimulus frequencies increased response magnitude. Response magnitude was also increased by greater numbers of deflections. When stimulus number was constant, there were no differences in response magnitude, regardless of stimulus frequency and duration. Spatial extent of responses, as defined by number of pixels in regions of interest, did not differ between stimulus frequencies, durations, or numbers. Comparison of the time to reach peak intrinsic signal response after stimulus onset ("time-to-peak") suggested that higher frequencies were associated with faster time-to-peak. Registration of intrinsic signal responses with cytochrome oxidase-stained whisker barrels demonstrated that responses were located over the barrel corresponding to the stimulated whisker. In summary, we have shown that the absolute number of stimuli delivered to the system is, at least for short stimulus periods (< or = 5 s), a determining factor for the magnitude of these responses, whereas stimulus frequency appears to influence time-to-peak response.

Functional increases in cerebral blood volume over somatosensory cortex.

We have examined the relationship between cerebral blood volume (CBV) and electrophysiology over primary somatosensory cortex (S-I) in the rat. We did this by comparing the spatial characteristics and time course of activity-related changes in plasma fluorescence, intrinsic optical reflectance signals, and single unit electrophysiology in S-I to identical stimuli. S-Is of urethane-anesthetized male Sprague-Dawley rats were exposed, and fluorescent Texas Red dextran dye (MW 70,000) was administered intravenously. Subsequently, foredigit electroshock or vibrissal deflection was associated with fluorescence increases over contralateral forelimb or posteromedial barrel subfield cortex. Fluorescence was delayed and prolonged, indicating that CBV increases at 1-1.5 s and peaks 2-2.5 s after the onset of stimulation in both regions. When stimulus intensity was adjusted to produce barely detectable fluorescence foci (10% above back-ground), significant electrophysiologic spiking was seen. At these parameters, fluorescence change overlay areas of increased cortical layer III cell firing on single unit recordings. However, surface boundaries of the smallest observable fluorescence foci at their peak spatial extents consistently overspilled electrophysiologic center receptive fields. Corresponding intrinsic optical reflectance decreases were seen at 610 and 850 nm, exhibiting similar timing and colocalizing closely with fluorescence increase at both wavelengths after identical stimuli. These signals similarly overspilled electrophysiologic activity. Thus, we observed delayed increases in vascular fluorescence (related to CBV) over activated cortex. The smallest detectable fluorescence changes overspilled the center receptive field boundaries and were associated with appreciable electrophysiologic firing. In addition, the striking spatial and temporal similarity between intrinsic optical reflectance and fluorescence activity suggests that changes in intrinsic cortical reflectance are strongly related to changes in CBV.

Imaging optical reflectance in rodent barrel and forelimb sensory cortex.

Novel neuroimaging techniques are extending the scope for studying dynamic brain function. We have developed a system which enables the repeatable imaging of rapid function in rodent primary somatosensory cortex (S-I), based on activity-related changes in its optical reflectance (intrinsic signals). The S-I cortices of anesthetized male Sprague-Dawley rats were exposed. Images were acquired with a slow-scan, cooled, charge-coupled device camera (CCD) through filters at 550, 610, and 850 nm before, during, and after contralateral stimulation (vibrissal deflection or forepaw stimulation). Images were divided by prestimulus controls and then averaged across 9-27 trials to produce maps of stimulus-related reflectance change. Optical activity had magnitude 10(-3) of baseline reflectance and consistently comprised two distinct spatiotemporal components over cortex, depending on paradigm. The diffuse signal at 610 nm begins 0.5-1 s after stimulus onset and has a duration of 4-5 s. The second signal is macrovenous and is delayed by 1 s. Similar response patterns were observed at 550 and 850 nm. Evoked potentials, recorded at sites inside and outside the zone of optical activity, confirmed the functional nature of these signals. Using a CCD we have imaged functional reflectance changes over rodent S-I which commence, peak, and extinguish over a time scale of seconds. This optical activity is consistent with the etiologies of microvascular recruitment and chromophore redox change.