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Background Mobility impairment is common in older persons with multiple sclerosis (MS), and further compounded by general age-related mobility decline but its underlying brain substrates are poorly understood. Objective Examine fronto-striatal white matter (WM) integrity and lesion load as imaging correlates of mobility outcomes in older persons with and without MS. Methods Fifty-one older MS patients (age 64.9 ± 3.7 years, 29 women) and 50 healthy, matched controls (66.2 ± 3.2 years, 24 women), participated in the study, which included physical and cognitive test batteries and 3T MRI imaging session. Primary imaging measures were fractional anisotropy (FA) and WM lesion load. The relationship between mobility impairment, defined using a validated short physical performance battery cutoff score, and neuroimaging measures was assessed with stratified logistic regression models. FA was extracted from six fronto-striatal circuits (left/right): dorsal striatum (dStr)-to-anterior dorsolateral prefrontal cortex (aDLPFC), dStr-to-posterior DLPFC, and ventral striatum (vStr)-to-ventromedial prefrontal cortex (VMPFC). Results Mobility impairment was significantly associated with lower FA in two circuits, left dStr-aDLPFC ( P = .003) and left vStr-VMPFC ( P = .004), in healthy controls but not in MS patients ( P > .20), for fully adjusted regression models. Conversely, in MS patients but not in healthy controls, mobility impairment was significantly associated with greater lesion volume ( P Conclusions Comparing older persons with and without MS, we provide compelling evidence of a double dissociation between the presence of mobility impairment and two neuroimaging markers of white matter integrity, fronto-striatal fractional anisotropy, and whole brain lesion load.

Novel biomarkers of upper airway biomechanics may improve diagnosis of obstructive sleep apnea syndrome (OSAS). Upper airway effective compliance (EC), the slope of cross-sectional area versus pressure estimated using computational fluid dynamics (CFD), correlates with apnea-hypopnea index (AHI) and critical closing pressure (P(crit)). The study objectives are to develop a fast, simplified method for estimating EC using dynamic MRI and physiological measurements and to explore the hypothesis that OSAS severity correlates with mechanical compliance during wakefulness and sleep. Five obese children with OSAS and five control subjects with obesity aged 12–17 yr underwent anterior rhinomanometry, polysomnography, and dynamic MRI with synchronized airflow measurement during wakefulness and sleep. Airway cross section in retropalatal and retroglossal section images was segmented using a novel semiautomated method that uses optimized singular value decomposition (SVD) image filtering and k-means clustering combined with morphological operations. Pressure was estimated using rhinomanometry Rohrer’s coefficients and flow rate, and EC was calculated from the area-pressure slope during five normal breaths. Correlations between apnea-hypopnea index (AHI), EC, and cross-sectional area (CSA) change were calculated using Spearman’s rank correlation. The semiautomated method efficiently segmented the airway with average Dice Coefficient above 89% compared with expert manual segmentation. AHI correlated positively with EC at the retroglossal site during sleep (r(s) = 0.74, P = 0.014) and with change of EC from wake to sleep at the retroglossal site (r(s) = 0.77, P = 0.01). CSA change alone did not correlate significantly with AHI. EC, a mechanical biomarker which includes both CSA change and pressure variation, is a potential diagnostic biomarker for studying and managing OSAS. NEW & NOTEWORTHY This study investigated the dynamics of the upper airway at retropalatal and retroglossal sites during wakefulness and sleep by evaluating the effective compliance (EC) of each site and its correlation with apnea-hypopnea index (AHI) using novel semiautomated image processing. AHI correlated significantly with retroglossal EC during sleep and change of retroglossal EC from wake to sleep. The results suggest EC as a promising noninvasive diagnostic marker for estimating the mechanical properties of various upper airway regions in patients with OSAS.

Purpose Upper airway segmentation on MR images is a prerequisite step for quantitatively studying the anatomical structure and function of the upper airway and surrounding tissues. However, the complex variability of intensity and shape of anatomical structures and of different modes of image acquisition commonly used in this application makes automatic upper airway segmentation challenging. In this paper, we develop and test a comprehensive deep-learning-based segmentation system for use on MR images to address this problem. Material & methods In our study, both static and dynamic MRI data sets are utilized including 58 axial static 3D MRI studies, 22 mid-retropalatal dynamic 2D MRI studies, 21 mid-retroglossal dynamic 2D MRI studies, 36 mid-sagittal dynamic 2D MRI studies, and 23 isotropic dynamic 3D MRI studies, involving a total of 160 subjects and over 20,000 MRI slices. Samples of static and 2D dynamic MRI data sets were randomly divided into training, validation, and test sets by an approximate ratio of 5:2:3. Considering that the variability of annotation data among 3D dynamic MRIs was greater than for other MRI data sets, we increased the ratio of training data for these data to improve the robustness of the model. We designed a unified framework consisting of the following procedures. For static MRI, a generalized region of interest (GROI) strategy is applied to localize the partitions of nasal cavity and other portions of upper airway in axial data sets as two separate sub-objects. Subsequently, the two sub-objects are segmented by two separate 2D U-Nets. The two segmentation results are combined as the whole upper airway structure. The generalized ROI strategy is also applied to other MRI modes. To minimize false positive and false negative rates in the segmentation results, we employed a novel loss function based explicitly on these rates to train the segmentation networks. An inter-reader study is conducted to test the performance of our system in comparison to human variability in ground truth (GT) segmentation of these challenging structures. Results The proposed approach yielded mean Dice coefficients of 0.84±0.03, 0.89±0.13, 0.84±0.07, and 0.86±0.05 for static 3D MRI, mid-retropalatal/ mid-retroglossal 2D dynamic MRI, mid-sagittal 2D dynamic MRI, and isotropic dynamic 3D MRI, respectively. The quantitative results show excellent agreement with manual delineation results. The inter-reader study results demonstrate that the segmentation performance of our approach is statistically indistinguishable from manual segmentations considering the inter-reader variability in GT. Conclusions The proposed method can be utilized for routine upper airway segmentation from static and dynamic MR images with high accuracy and efficiency. The proposed approach has the potential to be employed in other dynamic MRI-related applications, such as lung or heart segmentation. This article is protected by copyright. All rights reserved.

Study Objectives Obstructive sleep apnea (OSA) is characterized by recurrent airway collapse during sleep, resulting in intermittent hypoxia and sleep fragmentation that may contribute to alternations in brain structure and function. We hypothesized that OSA in children reorganizes and alters cortical structure, which can cause changes in cortical thickness correlation between brain regions across subjects. Methods We constructed cortical structure networks based on cortical thickness measurements from 41 controls (age 15.54 ± 1.66 years, male 19) and 50 children with OSA (age 15.32 ± 1.65 years, male 29). The global (clustering coefficient [CC], path length, and small-worldness) and regional (nodal betweenness centrality, NBC) network properties and hub region distributions were examined between groups. Results We found increased CCs in OSA compared to controls across a wide range of network densities (p-value Conclusions Our findings suggest that children with OSA exhibit altered global and regional network characteristics compared to healthy controls. Our approach to the investigation of cortical structure in children with OSA could prove useful in understanding the etiology of OSA-related brain functional disorders.

Background Cognitive reserve (CR) protects against cognitive decline, but whether CR influences the efficiency of cortical control of gait has not been reported. The current study addressed this important gap in the literature. Specifically, we determined the role of CR in moderating the efficiency of functional near-infrared spectroscopy (fNIRS)-derived oxygenated hemoglobin (HbO2) in the prefrontal cortex (PFC) assessed during active walking. We hypothesized that higher CR would be associated with more efficient brain activation patterns. Methods Participants were 55 (mean age = 74.84; %female = 49.1) older adults who underwent the combined walking/fNIRS protocol and had magnetic resonance imaging data. We used an established dual-task walking paradigm that consisted of 3 task conditions: single-task walk (STW), single-task alpha (STA, cognitive task), and dual-task walk (DTW). Using the residual approach, CR was derived from a word-reading test score by removing variance accounted for by sociodemographic variables, tests of current cognitive functions, and a measure of structural brain integrity. Results CR moderated the change in fNIRS-derived HbO2 in the PFC across tasks. Higher CR was associated with smaller increases in fNIRS-derived HbO2 from the single tasks to dual-task walking (CR × DTW compared with STW: estimate = 0.183; p < .001; CR × DTW compared with STA: estimate = 0.257; p < .001). The moderation effect of CR remained significant when adjusting for multiple covariates and concurrent moderation effects of measures of gait performance, current cognitive functions, and structural integrity of the brain. Conclusion The current study provided first evidence that higher CR was associated with better neural efficiency of walking in older adults.

Upper airway segmentation in static and dynamic MRI is a prerequisite step for quantitative analysis in patients with disorders such as obstructive sleep apnea. Recently, some semi-automatic methods have been proposed with high segmentation accuracy. However, the low efficiency of such methods makes it difficult to implement for the processing of large numbers of MRI datasets. Therefore, a fully automatic upper airway segmentation approach is needed. In this paper, we present a novel automatic upper airway segmentation approach based on convolutional neural networks. Firstly, we utilize the U-Net network as the basic model for learning the multi-scale feature from adjacent image slices and predicting the pixel-wise label in MRI. In particular, we train three networks with the same structure for segmenting the pharynx/larynx and nasal cavity separately in axial static 3D MRI and axial dynamic 2D MRI. The visualization and quantitative results demonstrate that our approach can be applied to various MRI acquisition protocols with high accuracy and stability.

Dual tasking, a defined facet of executive control processes, is subserved, in part, by the prefrontal cortex (PFC). Previous functional near-infrared spectroscopy (fNIRS) studies revealed elevated PFC oxygenated hemoglobin (HbO(2)) under Dual-Task-Walk (DTW) compared to Single-Task Walk (STW) conditions. Based on the concept of neural inefficiency (i.e., greater activation coupled with similar or worse performance), we hypothesized that decreased cortical thickness across multiple brain regions would be associated with greater HbO(2) increases from STW to DTW. Participants were 55 healthy community-dwelling older adults, whose cortical thickness was measured via MRI. HbO(2) levels in the PFC, measured via fNIRS, were assessed during active walking under STW and DTW conditions. Statistical analyses were adjusted for demographics and behavioral performance. Linear mixed-effects models revealed that the increase in HbO(2) from STW to DTW was moderated by cortical thickness in several regions. Specifically, thinner cortex in specific regions of the frontal, parietal, temporal, and occipital lobes, cingulate cortex, and insula was associated with greater increases in HbO(2) levels from single to dual-task walking. In conclusion, participants with thinner cortex in regions implicated in higher order control of walking employed greater neural resources, as measured by increased HbO(2), in the PFC during DTW, without demonstrating benefits to behavioral performance. To our knowledge, this is the first study to examine cortical thickness as a marker of neural inefficiency during active walking.

Highlights • White matter stiffness is significantly reduced in stable, shunted hydrocephalus patients vs controls. • In patients, age, sex and ventricular volume have significant associations with brain stiffness. • Lower brain stiffness, but not ventricular volume, predicts worse quality of life and depression., Introduction Hydrocephalus that develops early in life is often accompanied by developmental delays, headaches and other neurological deficits, which may be associated with changes in brain shear stiffness. However, noninvasive approaches to measuring stiffness are limited. Magnetic Resonance Elastography (MRE) of the brain is a relatively new noninvasive imaging method that provides quantitative measures of brain tissue stiffness. Herein, we aimed to use MRE to assess brain stiffness in hydrocephalus patients compared to healthy controls, and to assess its associations with ventricular size, as well as demographic, shunt-related and clinical outcome measures. Methods MRE was collected at two imaging sites in 39 hydrocephalus patients and 33 healthy controls, along with demographic, shunt-related, and clinical outcome measures including headache and quality of life indices. Brain stiffness was quantified for whole brain, global white matter (WM), and lobar WM stiffness. Group differences in brain stiffness between patients and controls were compared using two-sample t-tests and multivariable linear regression to adjust for age, sex, and ventricular volume. Among patients, multivariable linear or logistic regression was used to assess which factors (age, sex, ventricular volume, age at first shunt, number of shunt revisions) were associated with brain stiffness and whether brain stiffness predicts clinical outcomes (quality of life, headache and depression). Results Brain stiffness was significantly reduced in patients compared to controls, both unadjusted (p ≤ 0.002) and adjusted (p ≤ 0.03) for covariates. Among hydrocephalic patients, lower stiffness was associated with older age in temporal and parietal WM and whole brain (WB) (beta (SE): −7.6 (2.5), p = 0.004; −9.5 (2.2), p = 0.0002; −3.7 (1.8), p = 0.046), being female in global and frontal WM and WB (beta (SE): −75.6 (25.5), p = 0.01; −66.0 (32.4), p = 0.05; −73.2 (25.3), p = 0.01), larger ventricular volume in global, and occipital WM (beta (SE): −11.5 (3.4), p = 0.002; −18.9 (5.4), p = 0.0014). Lower brain stiffness also predicted worse quality of life and a higher likelihood of depression, controlling for all other factors. Conclusions Brain stiffness is reduced in hydrocephalus patients compared to healthy controls, and is associated with clinically-relevant functional outcome measures. MRE may emerge as a clinically-relevant biomarker to assess the neuropathological effects of hydrocephalus and shunting, and may be useful in evaluating the effects of therapeutic alternatives, or as a supplement, of shunting.

Study ObjectivesThe biomechanical basis of obstructive sleep apnea syndrome (OSAS) may influence upper airway dynamics. In this study, we investigate dynamic changes during respiration in wakefulness and sleep in obese adolescents with and without OSAS.MethodsRespiratory-gated dynamic magnetic resonance imaging (MRI) at the retropalatal and retroglossal regions was performed with simultaneous measurement of SpO2 and nasal-oral mask airflow and pressure. Airway cross-sectional area (CSA) was determined using AMIRA. Percent change in CSA was calculated from five continuous tidal breaths in states of wakefulness and sleep. Mixed effects models were used to evaluate interactions between group (OSAS/control), site (retropalatal/retroglossal), and stage (wake/sleep).ResultsWe studied 24 children with OSAS (mean age 15.49 ± 2.00 years, mean apnea–hypopnea index [AHI] 16.53 ± 8.72 events/h) and 19 controls (mean age 14.86 ± 1.75 years, mean AHI 2.12 ± 1.69 events/h). Groups were similar in age, sex, height, weight, and BMI Z-score. Participants with OSAS had a 48.17% greater increase in percent change of airway CSA during sleep than controls (p < 0.0001), while there was no difference between groups during wakefulness (p = 0.6589). Additionally, participants with OSAS had a 48.80% increase in percent change of airway CSA during sleep as compared with wakefulness (p < 0.0001), whereas no such relationship was observed in controls (p = 0.5513).ConclusionsThis study demonstrates significant effects of sleep on upper airway dynamics in obese children with OSAS. Dynamic MRI with physiological data can potentially provide further insight into the biomechanical basis of OSAS and assist in more effective management.

Highly compliant tissue supporting the pharynx and low muscle tone enhance the possibility of upper airway occlusion in children with obstructive sleep apnea (OSA). The present study describes subject-specific computational modeling of flow-induced velopharyngeal narrowing in a female child with polycystic ovarian syndrome (PCOS) with OSA and a non-OSA control. Anatomically accurate three-dimensional geometries of the upper airway and soft-palate were reconstructed for both subjects using magnetic resonance (MR) images. A fluid-structure interaction (FSI) shape registration analysis was performed using subject-specific values of flow rate to iteratively compute the biomechanical properties of the soft-palate. The optimized shear modulus for the control was 38 percent higher than the corresponding value for the OSA patient. The proposed computational FSI model was then employed for planning surgical treatment for the apneic subject. A virtual surgery comprising of a combined adenoidectomy, palatoplasty and genioglossus advancement was performed to estimate the resulting post-operative patterns of airflow and tissue displacement. Maximum flow velocity and velopharyngeal resistance decreased by 80 percent and 66 percent respectively following surgery. Post-operative flow-induced forces on the anterior and posterior faces of the soft-palate were equilibrated and the resulting magnitude of tissue displacement was 63 percent lower compared to the pre-operative case. Results from this pilot study indicate that FSI computational modeling can be employed to characterize the mechanical properties of pharyngeal tissue and evaluate the effectiveness of various upper airway surgeries prior to their application.

Using multimodal neuroimaging methods, the current study was designed to examine the relationship between white matter microstructural integrity (WMI) and changes in prefrontal cortex (PFC) oxygenated hemoglobin (HbO(2)) during active walking in older adults. Consistent with neural inefficiency, we hypothesized that worse WMI would be associated with a greater increase in PFC HbO(2) from single to dual-task walking in the context of worse or similar gait performance. Fifty-five cognitively healthy older adults (mean age = 74.76 years, 49% women) underwent diffusion tensor imaging (DTI) to derive a whole-brain measure of fractional anisotropy (FA) and functional Near Infrared Spectroscopy (fNIRS), which measured PFC HbO(2) during walking tasks. Gait velocity was assessed using an instrumented walkway. A linear mixed effects model revealed that HbO(2) levels increased from single to dual-task walking (P < 0.01) given the greater cognitive demands inherent in the latter condition. Moreover, WMI moderated the effect of dual tasking on PFC HbO(2) (P < 0.05). Specifically, worse WMI was associated with a larger increase in PFC HbO(2) levels from single to dual-task walking in the context of similar gait velocity. Results suggest that compromised WMI may be a mechanism underlying inefficient brain response to cognitive demands of locomotion.

Objective Greater intraindividual variability (IIV) in behavioral and cognitive performance is a risk factor for adverse outcomes but research concerning IIV in neural signal is scarce. Using functional near-infrared spectroscopy (fNIRS), we showed that IIV in oxygenated hemoglobin (HbO2) levels in the prefrontal cortex increased from single task (Single-Task-Walk–STW; Single-Task-Alpha–STA) to Dual-Task-Walk (DTW) conditions in older adults. Herein, we predicted that, consistent with the neural inefficiency hypothesis, reduced cortical thickness would be associated with greater increases in IIV in fNIRS-derived HbO2 from single tasks to DTW when adjusting for behavioral performance. Method Participants were right-handed older adults without dementia recruited from the community (N = 55; M(SD) age = 74.84(4.97); %female = 49.1). Neuroimaging included fNIRS for HbO2 levels in the prefrontal cortex during tasks and MRI for cortical thickness. IIV was operationalized using the SD of fNIRS-derived HbO2 observations assessed during a 30-s interval in each experimental condition. Results Moderation analyses, assessed through linear mixed effects models, revealed that in several frontal (p Conclusion Reduced cortical thickness was associated with inefficient increases in IIV in fNIRS-derived HbO2 from single tasks to dual-task walking. Worse IIV in gait performance under DTW predicts adverse mobility outcomes. Reduced cortical thickness and worse IIV of fNIRS-derived HbO2 during DTW are possible brain mechanisms that explain the risk of developing mobility impairments in aging and disease populations.

Obstructive sleep apnea syndrome (OSAS) is associated with intermittent hypoxia and sleep loss. In children, impairments of cognitive function are important manifestations, but the underlying pathology is unknown. We hypothesized that OSAS would affect the dentate gyrus, a hippocampal subdivision essential to neurogenesis and cognition, and that this impact would further affect cognitive function in children. In children with OSAS (n= 11) and control subjects (n= 12; age and sex matched), we performed diffusion tensor imaging and structural MRI, polysomnography, and neuropsychological assessments. We found that OSAS was associated with decreased mean diffusivity of the left dentate gyrus (p= 0.002; false discovery rate corrected; adjusting for sex, age, and body mass index), showing a large effect size (partial η2= 0.491), but not with any other structural measures across the brain. Decreased dentate gyrus mean diffusivity correlated with a higher apnea hypopnea index (Spearman'sr= −0.50,p= 0.008) and a greater arousal index (r= −0.44,p= 0.017). OSAS did not significantly affect neuropsychological measures (pvalues >0.5); however, a lower verbal learning score correlated with lower dentate gyrus mean diffusivity (r= 0.54,p= 0.004). Path analysis demonstrated that dentate gyrus mean diffusivity mediates the impact of OSAS on verbal learning capacity. Finally, the diagnostic accuracy of a regression model based on dentate gyrus mean diffusivity reached 85.8% (cross validated). This study demonstrates a likely pathway of effects of OSAS on neurocognitive function in children, as well as potential utility of the dentate gyrus mean diffusivity as an early marker of brain pathology in children with OSAS.SIGNIFICANCE STATEMENTIn this study we investigate the relationships between dentate gyrus structure, hippocampus-dependent cognition, and obstructive sleep apnea syndrome (OSAS). We demonstrate lower mean diffusivity of the dentate gyrus in children with OSAS, which correlates with a lower verbal learning and memory score. This study provides new evidence of disrupted microstructure of the dentate gyrus in children with OSAS that may help explain some of the neurocognitive deficits described in these children.

Background The role of cervical muscle (neck) strength in traumatic brain and spine injury and chronic neck pain disorders is an area of active research. Characterization of the normal ranges of neck strength in healthy young adults is essential to designing future investigations of how strength may act as a modifier for risk and progression in head and neck disorders. Objective To develop a normative reference database of neck strength in a healthy young adult population, and to evaluate the relationship of neck strength to anthropometric measurements. Design Cross-sectional. Setting An academic medical center research institution. Participants A total of 157 healthy young adults (18-35 years of age) had their neck strength measured with fixed frame dynamometry (FFD) during 1 visit to establish a normative neck strength database. Interventions Not applicable. Main Outcome Measurements Peak and average strength of the neck muscles were measured in extension, forward flexion, and right and left lateral flexion using FFD. The ranges of peak and average neck strength were characterized and correlated with anthropometric characteristics. Results In all, 157 subjects (84 male, 73 female; average age 27 years) were included in the normative sample. Neck strength ranged from 38 to 383 Newtons in men and from 15 to 223 Newtons in women. Normative data are provided for each gender in all 4 directions. Weight, body mass index, neck circumference, and estimated neck muscle volume were modestly correlated with neck strength in multiple directions (correlation coefficients Conclusions Neck strength in healthy young adults exhibits a broad range, is significantly different in men from that in women, and correlates only modestly with anthropometric characteristics. Level of Evidence Not applicable.

It has been well established over the last two decades that walking is not merely an automatic, motoric activity; it also utilizes executive function circuits, which play an increasingly important role in walking for older people and those with mobility and cognitive deficits. Dual-task walking, such as walking while performing a cognitive task, is a necessary skill for everyday functioning, and has been shown to activate prefrontal lobe areas in healthy older people. Another well-established point in healthy aging is the loss of grey matter, and in particular loss of frontal lobe grey matter volume. However, the relationship between increased frontal lobe activity during dual-task walking and loss of frontal grey matter in healthy aging remains unknown. In the current study, we combined oxygenated hemoglobin (HbO(2)) data from functional near-infrared spectroscopy (fNIRS), taken during dual-task walking, with structural MRI volumetrics in a cohort of healthy older subjects to identify this relationship. We studied fifty-five relatively healthy, older participants (≥ 65 years) during two separate sessions: fNIRS to measure HbO(2) changes between single-task (i.e., normal walking) and dual-task walking-while-talking, and high-resolution, structural MRI to measure frontal lobe grey matter volumes. Linear mixed effects modeling was utilized to determine the moderation effect of grey matter volume on the change in prefrontal oxygenated hemoglobin between the two walking tasks, while controlling for covariates including task performance. We found a highly significant interaction effect between frontal grey matter volume and task on HbO(2) levels (p < 0.0001). Specifically, increased HbO(2) levels during dual-task compared to single-task walking were associated with reduced frontal grey matter volume. Regional analysis identified bilateral superior and rostral middle gyri as the primary areas driving these results. The findings provide support for the concept of neural inefficiency: in the absence of behavioral gains, grey matter loss in relatively healthy, older individuals leads to over-activation of frontal lobe during a cognitively demanding walking task with established clinical and predictive utility.

Purpose: There are several disease conditions that lead to upper airway restrictive disorders. In the study of these conditions, it is important to take into account the dynamic nature of the upper airway. Currently, dynamic magnetic resonance imaging is the modality of choice for studying these diseases. Unfortunately, the contrast resolution obtainable in the images poses many challenges for an effective segmentation of the upper airway structures. No viable methods have been developed to date to solve this problem. In this paper, the authors demonstrate a practical solution by employing an iterative relative fuzzy connectedness delineation algorithm as a tool. Methods: 3D dynamic images were collected at ten equally spaced instances over the respiratory cycle (i.e., 4D) in 20 female subjects with obstructive sleep apnea syndrome. The proposed segmentation approach consists of the following steps. First, image background nonuniformities are corrected which is then followed by a process to correct for the nonstandardness of MR image intensities. Next, standardized image intensity statistics are gathered for the nasopharynx and oropharynx portions of the upper airway as well as the surrounding soft tissue structures including air outside the body region, hard palate, soft palate, tongue, and other soft structures around the airway including tonsils (left and right) and adenoid. The affinity functions needed for fuzzy connectedness computation are derived based on these tissue intensity statistics. In the next step, seeds for fuzzy connectedness computation are specified for the airway and the background tissue components. Seed specification is needed in only the 3D image corresponding to the first time instance of the 4D volume; from this information, the 3D volume corresponding to the first time point is segmented. Seeds are automatically generated for the next time point from the segmentation of the 3D volume corresponding to the previous time point, and the process continues and runs without human interaction and completes in 10 s for segmenting the airway structure in the whole 4D volume. Results: Qualitative evaluations performed to examine smoothness and continuity of motions of the entire upper airway as well as its transverse sections at critical anatomic locations indicate that the segmentations are consistent. Quantitative evaluations of the separate 200 3D volumes and the 20 4D volumes yielded true positive and false positive volume fractions around 95% and 0.1%, respectively, and mean boundary placement errors under 0.5 mm. The method is robust to variations in the subjective action of seed specification. Compared with a segmentation approach based on a registration technique to propagate segmentations, the proposed method is more efficient, accurate, and less prone to error propagation from one respiratory time point to the next. Conclusions: The proposed method is the first demonstration of a viable and practical approach for segmenting the upper airway structures in dynamic MR images. Compared to registration-based methods, it effectively reduces error propagation and consequently achieves not only more accurate segmentations but also more consistent motion representation in the segmentations. The method is practical, requiring minimal user interaction and computational time.

Traditional neuroimaging methods cannot measure changes in brain function during active walking. This presentation will provide a brief overview of recent research findings using functional-near-infrared spectroscopy (fNIRS) to demonstrate the key functional role of the prefrontal cortex in cortical control of locomotion, notably under attention demanding walking conditions. Over activation of the prefrontal cortex during walking, however, maybe indicative of brain inefficiency that could predispose older adults to poor resilience to mobility decline. In this talk, a multi-modal imaging (DTI and fNIRS) study implemented in a cohort of 55 non-demented older adults, will be used to propose white matter integrity as moderator of (in)efficient prefrontal cortex activation levels, assessed with fNIRS during single and dual-task walking conditions. Understanding complex interactions of structural and functional brain systems vis-à-vis gait performance can inform conceptualizations of resilience to mobility decline

Small vessel disease and/or atherosclerosis produce microvascular and parenchymal inflammation in white matter and results in vascular cognitive impairment (VCI). We have performed bilateral carotid artery stenosis in hypertensive rats (SHR) to better understand disease pathology, targets for intervention and markers. Hypothesis: Complex cognitive deficits and diffuse fiber tract changes relevant to human VCI can be quantified and validated for future use. Methodology: We performed a series of behavioral assays to test declarative memory and executive functioning in stenosis compared to sham surgery SHR. Behavioral assays included T-maze decision making and alternation, novel object recognition (NOR) and active place avoidance (APA). MRI (DTI, DWI, Arterial Spin Labeling; ASL) and FDG-PET imaging was done in Corpus Callosum (CC). Histology-immunohistochemistry included measurements of microglia (Iba-1), astrocytes (GFAP) and Luxol fast blue (for myelin) in CC. Results: Stenosis resulted in consistent executive function decision making (T-maze) deficits (p Conclusion: We have successfully modeled the behavioral, imaging and histologic profile of human VCI in the rat. Currently pre/mature oligodendrocyte changes are being evaluated. This approach provides future opportunities to localize forebrain white matter changes using MR imaging parameters as markers for monitoring VCI demyelination/pathology and intervention.

Purpose A retrospective, respiratory-gated technique for measuring dynamic changes in the upper airway over the respiratory cycle was developed, with the ultimate goal of constructing anatomically and functionally accurate upper airway models in obstructive sleep apnea patients. Methods Three-dimensional cine, retrospective respiratory-gated, gradient echo imaging was performed in six adolescents being evaluated for polycystic ovary syndrome, a disorder with a high obstructive sleep apnea prevalence. A novel retrospective gating scheme, synchronized to flow from a nasal cannula, limited image acquisition to predefined physiological ranges. Images were evaluated with respect to contrast, airway signal leakage, and demonstration of dynamic airway area changes. Results Two patients were diagnosed with obstructive sleep apnea. Motion artifacts were absent in all image sets. Scan efficiency ranged from 48 to 88%. Soft tissue-to-airway contrast-to-noise ratio varied from 6.1 to 9.6. Airway signal leakage varied between 10 and 17% of soft tissue signal. Automated segmentation allowed calculation of airway area changes over the respiratory cycle. In one severe apnea patient, the technique allowed demonstration of asynchronous airway expansion and contraction above and below a severe constriction. Conclusions Retrospective, respiratory gated imaging of the upper airway has been demonstrated, utilizing a gating algorithm to ensure acquisition over specified ranges of respiratory rate and tidal volume. Magn Reson Med 70:1580–1590, 2013. © 2013 Wiley Periodicals, Inc.

OBJECTIVEThe object of this study was to use diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to characterize the long-term effects of hydrocephalus and shunting on white matter integrity and to investigate the relationship of ventricular size and alterations in white matter integrity with headache and quality-of-life outcome measures.METHODSPatients with shunt-treated hydrocephalus and age- and sex-matched healthy controls were recruited into the study and underwent anatomical and DTI imaging on a 3-T MRI scanner. All patients were clinically stable, had undergone CSF shunt placement before 2 years of age, and had a documented history of complaints of headaches. Outcome was scored based on the Headache Disability Inventory and the Hydrocephalus Outcome Questionnaire. Fractional anisotropy (FA) and other DTI-based measures (axial, radial, and mean diffusivity; AD, RD, and MD, respectively) were extracted in the corpus callosum and internal capsule with manual region-of-interest delineation and in other regions with TBSS. Paired t-tests, corrected with a 5% false discovery rate, were used to identify regions with significant differences between patients and controls. Within the patient group, linear regression models were used to investigate the relationship between FA or ventricular volume and outcome, as well as the effect of shunt-related covariates.RESULTSTwenty-one hydrocephalus patients and 21 matched controls completed the study, and their data were used in the final analysis. The authors found significantly lower FA for patients than for controls in 20 of the 48 regions, mostly posterior white matter structures, in periventricular as well as more distal tracts. Of these 20 regions, 17 demonstrated increased RD, while only 5 showed increased MD and 3 showed decreased AD. No areas of increased FA were observed. Higher FA in specific periventricular white matter tracts, tending toward FA in controls, was associated with increased ventricular size, as well as improved clinical outcome.CONCLUSIONSThe study shows that TBSS-based DTI is a sensitive technique for elucidating changes in white matter structures due to hydrocephalus and chronic CSF shunting and provides preliminary evidence that DTI may be a valuable tool for tailoring shunt procedures to monitor ventricular size following shunting and achieve optimal outcome, as well as for guiding the development of alternate therapies for hydrocephalus.

Obstructive sleep apnea syndrome (OSAS) is associated with anatomical abnormalities restricting upper airway size and functional factors decreasing pharyngeal dilator activity in sleep. In this study we hypothesized that OSAS is also associated with altered pharyngeal mechanical compliance during wakefulness. Five OSAS and six control obese girls between 14 and 18 years of age were studied. All underwent polysomnography, critical closing pressure (Pcrit) studies, and dynamic MRI of the upper airway during awake tidal breathing. Effective airway compliance was defined as the slope of cross-sectional area vs. average pressure between maximum inspiration and maximum expiration along the pharyngeal airway. Pharyngeal pressure fields were calculated by using image-based computational fluid dynamics and nasal resistance. Spearman correlations were calculated to test associations between apnea-hypopnea index (AHI), Pcrit, and airway compliance. Effective compliances in the nasopharynx (CNP) and velopharynx (CVP) were lower and negative in OSAS compared with controls: −4.4 vs. 1.9 (mm2/cmH2O, P = 0.012) and −2.1 vs. 3.9 (mm2/cmH2O, P = 0.021), respectively, suggesting a strong phasic pharyngeal dilator activity during inspiration in OSAS compared with controls. For all subjects, CNPand AHI correlated negatively (rS= −0.69, P = 0.02), and passive Pcritcorrelated with CNP(rS= −0.76, P = 0.006) and with AHI (rS= 0.86, P = 0.0006). Pharyngeal mechanics obtained during wakefulness could be used to characterize subjects with OSAS. Moreover, negative effective compliance during wakefulness and its correlation to AHI and Pcritsuggest that phasic dilator activity of the upper pharynx compensates for negative pressure loads in these subjects.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p

While communicating hydrocephalus (CH) is often characterized by increased pulsatile flow of cerebrospinal fluid (CSF) in the cerebral aqueduct, a clear-cut explanation for this phenomenon is lacking. Increased pulsatility of the entire cerebral vasculature including the cortical capillaries has been suggested as a causative mechanism. To test this theory, we used two-photon microscopy to measure flow pulsatility in neocortical capillaries 40 to 500 μm below the pial surface in adult rats with CH at 5 to 7 days (acute, n=8) and 3 to 5 weeks (chronic, n=5) after induction compared with intact controls ( n=9). Averaging over all cortical depths, no increase in capillary pulsatility occurred in acute (pulsatility index (PI): 0.15±0.06) or chronic (0.14±0.05) CH animals compared with controls (0.18±0.07; P=0.07). More specifically, PI increased significantly with cortical depth in controls ( r=0.35, P

Object The intracranial pulse pressure is often increased when neuropathology is present, particularly in cases of increased intracranial pressure (ICP) such as occurs in hydrocephalus. This pulse pressure is assumed to originate from arterial blood pressure oscillations entering the cranium; the fact that there is a coupling between the arterial blood pressure and the ICP is undisputed. In this study, the nature of this coupling and how it changes under conditions of increased ICP are investigated. Methods In 12 normal dogs, intracarotid and parenchymal pulse pressure were measured and their coupling was characterized using amplitude and phase transfer function analysis. Mean intracranial ICP was manipulated via infusions of isotonic saline into the spinal subarachnoid space, and changes in transfer function were monitored. Results Under normal conditions, the ICP wave led the arterial wave, and there was a minimum in the pulse pressure amplitude near the frequency of the heart rate. Under conditions of decreased intracranial compliance, the ICP wave began to lag behind the arterial wave and increased significantly in amplitude. Most interestingly, in many animals the pulse pressure exhibited a minimum in amplitude at a mean pressure that coincided with the transition from a leading to lagging ICP wave. Conclusions This transfer function behavior is characteristic of a resonant notch system. This may represent a component of the intracranial Windkessel mechanism, which protects the microvasculature from arterial pulsatility. The impairment of this resonant notch system may play a role in the altered pulse pressure in conditions such as hydrocephalus and traumatic brain swelling. New models of intracranial dynamics are needed for understanding the frequency-sensitive behavior elucidated in these studies and could open a path for development of new therapies that are geared toward addressing the pulsation dysfunction in pathological conditions, such as hydrocephalus and traumatic brain injury, affecting ICP and flow dynamics.

Objectives: We tested whether dynamic interaction between limbic regions supports a control systems model of excitatory and inhibitory components of a negative feedback loop, and whether dysregulation of those dynamics might correlate with trait differences in anxiety and their cardiac characteristics among healthy adults. Experimental Design: Sixty-five subjects received fMRI scans while passively viewing angry, fearful, happy, and neutral facial stimuli. Subjects also completed a trait anxiety inventory, and were monitored using ambulatory wake ECG. The ECG data were analyzed for heart rate variability, a measure of autonomic regulation. The fMRI data were analyzed with respect to six limbic regions (bilateral amygdala, bilateral hippocampus, Brodmann Areas 9, 45) using limbic time-series cross-correlations, maximum BOLD amplitude, and BOLD amplitude at each point in the time-series. Principal Observations: Diminished coupling between limbic time-series in response to the neutral, fearful, and happy faces was associated with greater trait anxiety, greater sympathetic activation, and lowered heart rate variability. Individuals with greater levels of trait anxiety showed delayed activation of Brodmann Area 45 in response to the fearful and happy faces, and lowered Brodmann Area 45 activation with prolonged left amygdala activation in response to the neutral faces. Conclusions: The dynamics support limbic regulation as a control system, in which dysregulation, as assessed by diminished coupling between limbic time-series, is associated with increased trait anxiety and excitatory autonomic outputs. Trait-anxious individuals showed delayed inhibitory activation in response to overt-affect stimuli and diminished inhibitory activation with delayed extinction of excitatory activation in response to ambiguous-affect stimuli. Hum Brain Mapp 2009. © 2007 Wiley-Liss, Inc.

The tissue-sparing effect of parallel, thin (narrower than 100 μm) synchrotron-generated X-ray planar beams (microbeams) in healthy tissues including the central nervous system (CNS) is known since early 1990s. This, together with a remarkable preferential tumoricidal effect of such beam arrays observed at high doses, has been the basis for labeling the method microbeam radiation therapy (MRT). Recent studies showed that beams as thick as 0.68 mm (“thick microbeams”) retain part of their sparing effect in the rat's CNS, and that two such orthogonal microbeams arrays can be interlaced to produce an unsegmented field at the target, thus producing focal targeting. We measured the half-value layer (HVL) of our 120-keV median-energy beam in water phantoms, and we irradiated stereotactically bis acrylamide nitrogen gelatin (BANG)-gel-filled phantoms, including one containing a human skull, with interlaced microbeams and imaged them with MRI. A 43-mm water HVL resulted, together with an adequately large peak-to-valley ratio of the microbeams’ three-dimensional dose distribution in the vicinity of the 20 mm × 20 mm × 20 mm target deep into the skull. Furthermore, the 80–20% dose falloff was a fraction of a millimeter as predicted by Monte Carlo simulations. We conclude that clinical MRT will benefit from the use of higher beam energies than those used here, although the current energy could serve certain neurosurgical applications. Furthermore, thick microbeams particularly when interlaced present some advantages over thin microbeams in that they allow the use of higher beam energies and they could conceivably be implemented with high power orthovoltage X-ray tubes.

Communicating hydrocephalus (CH) occurs frequently, but clinically-relevant animal models amenable to diagnostic imaging and cerebrospinal fluid shunting are not available. In order to develop and characterize models of subarachnoid space (SAS) obstruction at the basal cisterns (BC) or cerebral convexities (CX), 25% kaolin was injected in adult female Sprague-Dawley rats following halothane anesthesia; intact- or saline-injected animals served as controls. For BC animals (n=28 hydrocephalics, n=20 controls), an anterior approach to the C1-clivus interval was employed and 30 microl of kaolin or saline was injected. For CX injections (n=13 hydrocephalics, n=3 controls), 50-60 microl of kaolin was injected bilaterally after separating the partitions in the SAS. In BC-injected rats, kaolin was observed grossly in the basal cisterns but not in the cisterna magna or at the foramina of Luschka, indicating that communicating (or extra-ventricular)--not obstructive--hydrocephalus had been induced. Following ketamine/xylazine anesthesia, magnetic resonance imaging (MRI) of gadolinium injected into the lateral ventricle also demonstrated CSF flow from the foramina of Luschka. MRI also revealed that ventriculomegaly progressed steadily in BC animals and by 2 weeks post-kaolin the mean Evan's ratio (frontal horn) increased significantly (mean 0.45 compared to 0.31 in intact- and 0.34 in saline-injected controls; p

We present a demonstration of phase contrast balanced steady-state free precession (PC-bSSFP) for measuring cerebrospinal fluid (CSF) flow in the brain and spine, and a comparison of measurements obtained with this technique to conventional phase contrast using incoherent gradient echoes (PC-GRE). With PC-GRE sequences, CSF images suffer from low signal-to-noise ratio (SNR), due to short repetition times required for adequate temporal resolution, and the long relaxation time of CSF. Furthermore, CSF flow is often nonlaminar, causing phase dispersion and signal loss in PC-GRE images. It is hypothesized that PC-bSSFP can improve CSF flow measurements with its high SNR and insensitivity to turbulent flow effects. CSF images acquired from the two techniques were compared in 13 healthy volunteers. Three measures were used to objectively evaluate the PC-bSSFP sequence: the CSF flow percentage, defined as the percentage of the total CSF region exhibiting pulsatile flow, net stroke volume and SNR. Images acquired with PC-bSSFP demonstrated pulsatile CSF flow in 35.8% (P

There are several disease conditions that lead to upper airway restrictive disorders. In the study of these conditions, it is important to take into account the dynamic nature of the upper airway. Currently, dynamic MRI is the modality of choice for studying these diseases. Unfortunately, the contrast resolution obtainable in the images poses many challenges for an effective segmentation of the upper airway structures. No viable methods have been developed to date to solve this problem. In this paper, we demonstrate the adaptation of the iterative relative fuzzy connectedness (IRFC) algorithm for this application as a potential practical tool. After preprocessing to correct for background image non-uniformities and the non-standardness of MRI intensities, seeds are specified for the airway and its crucial background tissue components in only the 3D image corresponding to the first time instance of the 4D volume. Subsequently the process runs without human interaction and completes segmenting the whole 4D volume in 10 sec. Our evaluations indicate that the segmentations are of very good quality achieving true positive and false positive volume fractions and boundary distance with respect to reference manual segmentations of about 93%, 0.1%, and 0.5 mm, respectively.

Using a new method of xenon laser-polarization that permits the generation of liter quantities of hyperpolarized 129Xe gas, the first 129Xe imaging results from the human chest and the first 129Xe spectroscopy results from the human chest and head have been obtained. With polarization levels of approximately 2%, cross-sectional images of the lung gas-spaces with a voxel volume of 0.9 cm3 (signal-to-noise ratio (SNR), 28) were acquired and three dissolved-phase resonances in spectra from the chest were detected. In spectra from the head, one prominent dissolved-phase resonance, presumably from brain parenchyma, was detected. With anticipated improvements in the 129Xe polarization system, pulse sequences, RF coils, and breathing maneuvers, these results suggest the possibility for 129Xe gas-phase imaging of the lungs with a resolution approaching that of current conventional thoracic proton imaging. Moreover, the results suggest the feasibility of dissolved-phase imaging of both the chest and brain with a resolution similar to that obtained with the gas-phase images.

BACKGROUND AND PURPOSE: MR imaging is currently not used to evaluate CSF flow changes due to short-lasting physiological maneuvers. The purpose of this study was to evaluate the ability of MR imaging to assess the CSF flow response to a Valsalva maneuver in healthy participants. MATERIALS AND METHODS: A cardiac-gated fast cine-PC sequence with ≤15-second acquisition time was used to assess CSF flow in 8 healthy participants at the foramen magnum at rest, during, and immediately after a controlled Valsalva maneuver. CSF mean displacement volume V̄(CSF) during the cardiac cycle and CSF flow waveform A(pp) were determined. A work-in-progress real-time pencil-beam imaging method with temporal resolution ≤56 ms was used to scan 2 participants for 90 seconds during which resting, Valsalva, and post-Valsalva CSF flow, respiration, and HR were continuously recorded. Results were qualitatively compared with invasive craniospinal differential pressure measurements from the literature. RESULTS: Both methods showed 1) a decrease from baseline in V̄(CSF) and A(pp) during Valsalva and 2) an increase in V̄(CSF) and A(pp) immediately after Valsalva compared with values measured both at rest and during Valsalva. Whereas fast cine-PC produced a single CSF flow waveform that is an average over many cardiac cycles, pencil-beam imaging depicted waveforms for each heartbeat and was able to capture many dynamic features of CSF flow, including transients synchronized with the Valsalva maneuver. CONCLUSIONS: Both fast cine-PC and pencil-beam imaging demonstrated expected changes in CSF flow with Valsalva maneuver in healthy participants. The real-time capability of pencil-beam imaging may be necessary to detect Valsalva-related transient CSF flow obstruction in patients with pathologic conditions such as Chiari I malformation.

Purpose: To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model. Experimental Design: After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system. Results: Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA. Conclusions: Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment. Clin Cancer Res; 19(16); 4446–54. ©2013 AACR.

The brain lacks a local lymphatic system, primarily due to the closed environment of the skull which sets strict requirements for control of fluid balance and intracranial pressure. Proper fluid and pressure balance are maintained in the brain through the unique systems of cerebrospinal and interstitial fluid as well as a tight coupling between these systems and the surrounding lymphatic drainage pathways, primarily in the cervical lymph nodes. In this chapter, we will review the physiology of cerebrospinal and interstitial fluid, provide an overview of their primary production and drainage mechanisms, and discuss the still-debated issue of the interconnections of these systems and their relevance to human physiology. We present the current evidence pointing to the importance of the extracranial lymphatic system as one of the key drainage pathways for cerebrospinal fluid from the brain, and conclude with the implications of these interconnected pathways to the ongoing revision for the concept of immune privilege of the brain.

Hyperpolarized 129Xe has been used to obtain gas phase images of mouse lung in vivo, showing distinct ventilation variation as a function of the breathing cycle. Spectra of 129Xe in the thorax show complex structure in both the gas phase (-4 to 3 ppm) and tissue-dissolved (190-205 ppm) regions. The alveolar gas peak shows correlated intensity and frequency oscillations, both attributable to changes in lung volume during breathing. The two major dissolved peaks near 195-200 ppm are attributed to lung parenchyma and to blood; they reach maximum intensity in 5-10 s and decay with an apparent T1 of 30 s. Another peak at 190 ppm takes 20-30 s to reach maximum; this must represent other well-vascularized tissue (e.g., heart and other muscles) in the thorax. The maximum integrated area of the tissue components reaches 30-80% of the maximum alveolar gas area, indicating that imaging at tissue frequencies can be achieved.

Proton magnetic resonance spectroscopy ((1)H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo (1)H-MRS from frontal lobe white matter of 27 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials.