Aging-Related Differences in Structural and Functional Interhemispheric Connectivity.

There is substantial evidence of age-related declines in anatomical connectivity during adulthood, with associated alterations in functional connectivity. But the relation of those functional alterations to the structural reductions is unclear. The complexities of both the structural and the functional connectomes make it difficult to determine such relationships. We pursue this question with methods, based on animal research, that specifically target the interhemispheric connections between the visual cortices. We collect t1- and diffusion-weighted imaging data from which we assess the integrity of the white matter interconnecting the bilateral visual cortices. Functional connectivity between the visual cortices is measured with electroencephalography during the presentation of drifting sinusoidal gratings that agree or conflict across hemifields. Our results show age-related reductions in the integrity of the white matter interconnecting the visual cortices, and age-related increases in the difference in functional interhemispheric lagged coherence between agreeing versus disagreeing visual stimuli. We show that integrity of the white matter in the splenium of the corpus callosum predicts the differences in lagged coherence for the agreeing versus disagreeing stimuli; and that this relationship is mediated by age. These results give new insight into the causal relationship between age and functional connectivity.

Prone positioning redistributes gravitational stress in the lung in normal conditions and in simulations of oedema.

NEW FINDINGS: What is the central question of this study? How does the interaction between posture and gravity affect the stresses on the lung, particularly in highly inflated gravitationally non-dependent regions, which are potentially vulnerable to increased mechanical stress and injury? What is the main finding and its importance? Changes in stress attributable to gravity are not well characterized between postures. Using a new metric of gravitational stress, we show that regions of the lung near maximal inflation have the greatest gravitational stresses while supine, but not while prone. In simulations of increased lung weight consistent with severe pulmonary oedema, the prone lung has lower gravitational stress in vulnerable, non-dependent regions, potentially protecting them from overinflation and injury. ABSTRACT: Prone posture changes the gravitational vector, and potentially the stress induced by tissue deformation, because a larger lung volume is gravitationally dependent when supine, but non-dependent when prone. To evaluate this, 10 normal subjects (six male and four female; age, means ± SD = 27 ± 6 years; height, 171 ± 9 cm; weight, 69 ± 13 kg; forced expiratory volume in the first second/forced expiratory volume as a percentage of predicted, 93 ± 6%) were imaged at functional residual capacity, supine and prone, using magnetic resonance imaging, to quantify regional lung density. We defined regional gravitational stress as the cumulative weight, per unit area, of the column of lung tissue below each point. Gravitational stress was compared between regions of differing inflation to evaluate differences between highly stretched, and thus potentially vulnerable, regions and less stretched lung. Using reference density values for normal lungs at total lung capacity (0.10 ± 0.03 g/ml), regions were classified as highly inflated (density < 0.13 g/ml, i.e., close to total lung capacity), intermediate (0.13 ≤ density < 0.16 g/ml) or normally inflated (density ≥ 0.16 g/ml). Gravitational stress differed between inflation categories while supine (-1.6 ± 0.3 cmH2 O highly inflated; -1.4 ± 0.3 cmH2 O intermediate; -1.1 ± 0.1 cmH2 O normally inflated; P = 0.05) but not while prone (-1.4 ± 0.2 cmH2 O highly inflated; -1.3 ± 0.2 cmH2 O intermediate; -1.3 ± 0.1 cmH2 O normally inflated; P = 0.39), and increased more with height from dependent lung while supine (-0.24 ± 0.02 cmH2 O/cm supine; -0.18 ± 0.04 cmH2 O/cm prone; P = 0.05). In simulated severe pulmonary oedema, the gradient in gravitational stress increased in both postures (all P < 0.0001), was greater in the supine posture than when prone (-0.57 ± 0.21 cmH2 O/cm supine; -0.34 ± 0.16 cmH2 O/cm prone; P = 0.0004) and was similar to the gradient calculated from supine computed tomography images in a patient with acute respiratory distress syndrome (-0.51 cmH2 O/cm). The non-dependent lung has greater gravitational stress while supine and might be protected while prone, particularly in the presence of oedema.

Abnormal pulmonary perfusion heterogeneity in patients with Fontan circulation and pulmonary arterial hypertension.

KEY POINTS: The distribution of pulmonary perfusion is affected by gravity, vascular branching structure and active regulatory mechanisms, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. We evaluated pulmonary perfusion in patients who had undergone Fontan procedure, patients with pulmonary arterial hypertension (PAH) and two groups of controls using a proton magnetic resonance imaging technique, arterial spin labelling to measure perfusion. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Gravitational gradients were similar between all groups, but heterogeneity was significantly increased in both patient groups compared to controls and persisted after removing contributions from large blood vessels and gravitational gradients. Patients with Fontan physiology and patients with PAH have increased pulmonary perfusion heterogeneity that is not explainable by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects vascular remodelling in PAH and possibly in Fontan physiology. ABSTRACT: Many factors affect the distribution of pulmonary perfusion, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. An example is following the Fontan procedure, where pulmonary perfusion is passive, and heterogeneity may be increased because of the underlying pathophysiology leading to Fontan palliation, remodelling, or increased gravitational gradients from low flow. Another is pulmonary arterial hypertension (PAH), where gravitational gradients may be reduced secondary to high pressures, but remodelling may increase perfusion heterogeneity. We evaluated regional pulmonary perfusion in Fontan patients (n = 5), healthy young controls (Fontan control, n = 5), patients with PAH (n = 6) and healthy older controls (PAH control) using proton magnetic resonance imaging. Regional perfusion was measured using arterial spin labelling. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Mean perfusion was similar (Fontan = 2.50 ± 1.02 ml min-1  ml-1 ; Fontan control = 3.09 ± 0.58, PAH = 3.63 ± 1.95; PAH control = 3.98 ± 0.91, P = 0.26), and the slopes of gravitational gradients were not different (Fontan = -0.23 ± 0.09 ml min-1  ml-1  cm-1 ; Fontan control = -0.29 ± 0.23, PAH = -0.27 ± 0.09, PAH control = -0.25 ± 0.18, P = 0.91) between groups. Perfusion relative dispersion was greater in both Fontan and PAH than controls (Fontan = 1.46 ± 0.18; Fontan control = 0.99 ± 0.21, P = 0.005; PAH = 1.22 ± 0.27, PAH control = 0.91 ± 0.12, P = 0.02) but similar between patient groups (P = 0.13). These findings persisted after removing contributions from large blood vessels and gravitational gradients (all P < 0.05). We conclude that patients with Fontan physiology and PAH have increased pulmonary perfusion heterogeneity that is not explained by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects the effects of remodelling in PAH and possibly in Fontan physiology.

Pain-related white matter tract abnormalities in mild traumatic brain injury patients with persistent headache.

BACKGROUND: The occurrence of debilitating chronic persistent (24/7) headache after mild traumatic brain injury represents a central neuropathic pain state. Previous studies suggest that this chronic headache state can be attributed to altered supraspinal modulatory functional connectivity in both resting and evoked pain states. Abnormalities in the myelin sheaths along the supraspinal superior longitudinal fasciculus and anterior thalamic radiation are frequently associated with alteration in pain modulation related to functional connectivity deficit with the prefrontal cortex. This study assessed the correlated axonal injury-related white matter tract abnormality underlying these previously observed prefrontal functional connectivity deficits by comparing the fractional anisotropy, axial diffusivity, and radial diffusivity of brain white matter in patients with mild traumatic brain injury-related headache to healthy controls. RESULT: Diffusion tensor imaging data from patients ( N = 12, average age ± SD = 35.0 ± 8.0 years old, 10 male) with mild traumatic brain injury-headache were compared with images acquired from healthy controls. The mild traumatic brain injury cohort demonstrated two areas of significant ( P < 0.01, F value >16, cluster size >50 voxels) white matter tract abnormalities closely related to pain affective and modulatory functions in (1) the left superior longitudinal fasciculus which connects the prefrontal cortices with the parietal cortices and (2) the right anterior thalamic radiation connecting the prefrontal cortices with the anterior cingulate cortex. In addition, a significant ( P < 0.01) decrease in axial diffusivity and increase in radial diffusivity at the superior longitudinal fasciculus cluster were noted in the mild traumatic brain injury cohort. CONCLUSION: The identified white matter tract abnormalities may represent a state of Wallerian degeneration which correlates with the functional connectivity deficit in pain modulation and can contribute to the development of the chronic persistent headache in the patients with mild traumatic brain injury.

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN: Cross-sectional study. SETTING: University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS: 33 euthymic BD and 38 HC participants. MEASUREMENTS: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

The effect of lung deformation on the spatial distribution of pulmonary blood flow.

KEY POINTS: Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes. The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution. Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. ABSTRACT: Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation-perfusion matching. Density-normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non-dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non-dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = -0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = -0.058(0.126), +1 litre = -0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non-dependent [+500 ml = -0.075(0.152), +1 litre = -0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non-dependent lung.

Fusing Functional MRI and Diffusion Tensor Imaging Measures of Brain Function and Structure to Predict Working Memory and Processing Speed Performance among Inter-episode Bipolar Patients.

Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2±10.1 years) and healthy comparison (HC; n=36; age=46.3±11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas-defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD.

MEG source imaging method using fast L1 minimum-norm and its applications to signals with brain noise and human resting-state source amplitude images.

The present study developed a fast MEG source imaging technique based on Fast Vector-based Spatio-Temporal Analysis using a L1-minimum-norm (Fast-VESTAL) and then used the method to obtain the source amplitude images of resting-state magnetoencephalography (MEG) signals for different frequency bands. The Fast-VESTAL technique consists of two steps. First, L1-minimum-norm MEG source images were obtained for the dominant spatial modes of sensor-waveform covariance matrix. Next, accurate source time-courses with millisecond temporal resolution were obtained using an inverse operator constructed from the spatial source images of Step 1. Using simulations, Fast-VESTAL's performance was assessed for its 1) ability to localize multiple correlated sources; 2) ability to faithfully recover source time-courses; 3) robustness to different SNR conditions including SNR with negative dB levels; 4) capability to handle correlated brain noise; and 5) statistical maps of MEG source images. An objective pre-whitening method was also developed and integrated with Fast-VESTAL to remove correlated brain noise. Fast-VESTAL's performance was then examined in the analysis of human median-nerve MEG responses. The results demonstrated that this method easily distinguished sources in the entire somatosensory network. Next, Fast-VESTAL was applied to obtain the first whole-head MEG source-amplitude images from resting-state signals in 41 healthy control subjects, for all standard frequency bands. Comparisons between resting-state MEG sources images and known neurophysiology were provided. Additionally, in simulations and cases with MEG human responses, the results obtained from using conventional beamformer technique were compared with those from Fast-VESTAL, which highlighted the beamformer's problems of signal leaking and distorted source time-courses.

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

Upper airway imaging and function in obstructive sleep apnea in people with and without HIV.

Obstructive sleep apnea (OSA) is common in people living with human immunodeficiency virus (HIV) (PLWH), but the underlying mechanisms are unclear. With improved long-term survival among PLWH, aging and obesity are increasingly prevalent in this population. These are also strong risk factors for the development of obstructive sleep apnea. We used magnetic resonance imaging (MRI) to measure upper airway (UA) anatomy and tongue fat content in PLWH with OSA (PLWH + OSA, n = 9) and in age-, sex-, and body mass index (BMI)-matched OSA controls (OSA, n = 11). We also quantified change in UA dimension during tidal breathing (during wakefulness and natural sleep) at four anatomical levels from the hard palate to the epiglottis along with synchronous MRI-compatible electroencephalogram and nasal flow measurements. All participants underwent on a separate night a baseline polysomnogram to assess OSA severity and an additional overnight physiological sleep study to measure OSA traits. We found no difference between the PLWH + OSA and the OSA control group in UA volume [PLWH + OSA: 12.8 mL (10.1-17.0), OSA: 14.0 mL (13.3-17.9), median (IQR)] or tongue volume [PLWH + OSA: 140.2 mL (125.1-156.9), OSA: 132.4 mL (126.8-154.7)] and a smaller tongue fat content in PLWH + OSA [11.2% (10.2-12.4)] than in the OSA controls [14.8% (13.2-15.5), P = 0.046]. There was no difference in the dynamic behavior of the UA between the two groups. When pooled together, both static and dynamic imaging metrics could be correlated with measures of UA mechanical properties. Our data suggest similar underlying UA physiology in OSA in subjects with and without HIV.NEW & NOTEWORTHY Obstructive sleep apnea is common in people living with human immunodeficiency virus (HIV), but the underlying mechanisms are unclear. We did not find differences in upper airway morphology using magnetic resonance imaging (MRI) during wake and natural sleep between people living with HIV (PLWH) with obstructive sleep apnea (OSA) and age, gender, and body mass index (BMI)-matched people with OSA but without HIV. Nor were there differences in tongue volume or changes in airway size during inspiration and expiration. MRI-derived anatomy was correlated with measures of airway collapse.

Callosal fiber length and interhemispheric connectivity in adults with autism: brain overgrowth and underconnectivity.

Typical adults show an inverse relation between callosal fiber length and degree of interhemispheric connectivity. This has been hypothesized to be a consequence of the influence of conduction delays and cellular costs during development on axonal pruning, both of which increase with fiber length. Autism spectrum disorder (ASD) provides a test of this hypothesis: Children with ASD are known to have enlarged brains; thus, adults with ASD should show reductions in interhemispheric connectivity proportional to their degree of brain overgrowth during development. This prediction was tested by assessing the relation between both the size and structure of the corpus callosum and callosal fiber length, adjusting for intracranial volume, which is thought to reflect maximum brain size achieved during development. Using tractography to estimate the length of callosal fibers emanating from all areas of cortex, and through which region of the corpus callosum they pass, we show that adults with ASD show an inverse relation between callosal fiber length, adjusted for intracranial volume, and callosum size, and a positive relation between adjusted callosal fiber length and radial diffusivity. The results provide support for the hypothesized impact of fiber length during development.

Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection.

MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.

Alterations in white matter microstructure in women recovered from anorexia nervosa.

OBJECTIVE: A recent study of ill individuals with anorexia nervosa (AN) reported microstructural alterations in white matter integrity including lower fractional anisotropy and higher mean diffusivity. This study was designed to determine whether such alterations exist in long-term recovered AN individuals and to examine potential associations with underlying AN traits. METHOD: Twelve adult women recovered from restricting-type AN and 10 control women were studied using diffusion tensor imaging. RESULTS: Overall, there was no significant fractional anisotropy alteration in recovered AN, in contrast to a prior study reporting lower fractional anisotropy in ill AN. Further, recovered AN showed lower mean diffusivity in frontal, parietal and cingulum white matter relative to control women, contrary to elevated mean diffusivity previously reported in ill AN. Lower longitudinal diffusivity in recovered AN was associated with higher harm avoidance. However, more severe illness history was associated with worse white matter integrity after recovery in the same direction as reported in prior work. DISCUSSION: Our findings suggest that fractional anisotropy in recovered AN is not different from controls, however, a novel pattern of lower mean diffusivity was evidenced in recovered AN, and this alteration was associated with harm avoidance. Notably, severity of illness history may have long-term consequences, emphasizing the importance of aggressive treatment.

An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. Injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). We developed a new automated MEG low-frequency source imaging method and applied this method in 45 mild TBI (23 from combat-related blasts, and 22 from non-blast causes) and 10 moderate TBI patients (non-blast causes). Seventeen of the patients with mild TBI from blasts had tertiary injuries resulting from the blast. The results show our method detected abnormalities at the rates of 87% for the mild TBI group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities were 96% and 77% for the blast and non-blast TBI groups, respectively. The spatial characteristics of abnormal slow-wave generation measured by Z scores in the mild blast TBI group significantly correlated with those in non-blast mild TBI group. Among 96 cortical regions, the likelihood of abnormal slow-wave generation was less in the mild TBI patients with blast than in the mild non-blast TBI patients, suggesting possible protective effects due to the military helmet and armor. Finally, the number of cortical regions that generated abnormal slow-waves correlated significantly with the total post-concussive symptom scores in TBI patients. This study provides a foundation for using MEG low-frequency source imaging to support the clinical diagnosis of TBI.

Altered prefronto-striato-parietal network response to mental rotation in HIV.

The present study used functional magnetic resonance imaging to examine the neural substrates of mental rotation in 11 individuals with HIV infection and 13 demographically similar HIV seronegative volunteers. Individuals with HIV showed increased brain response to mental rotation in prefrontal and posterior parietal cortices, striatum, and thalamus, with significant HIV by angle interactions emerging in the prefrontal cortex and caudate. Results indicate that HIV infection is associated with altered brain response to mental rotation in fronto-striato-parietal pathways, which may reflect compensatory strategies, recruitment of additional brain regions, and/or increased neuroenergetic demands during mental rotation needed to offset underlying HIV-associated neural injury.

Nitrogen-based lung clearance index: a valid physiological biomarker for the clinic.

Multiple breath washout (MBW) testing is increasingly used as a physiological measurement in the clinic, due in part to the availability of commercial equipment and reference values for MBW indices. Commercial N2 washout devices are usually based on indirect measurement of N2 concentration (CN2), by directly measuring either molar mass and O2 and CO2, or molar mass and CO2. We aim to elucidate the role of two potential pitfalls associated with N2-MBW testing that could override its physiological content: indirect N2 measurement and blood-solubility of N2. We performed MBW in 12 healthy adult subjects using a commercial device (MBWindirect) with simultaneous direct gas concentration measurements by mass spectrometry (MBWdirect) and compared CN2 between MBWdirect and MBWindirect. We also measured argon concentration during the same washouts to verify the maximal effect gas solubility can have on N2-based functional residual capacity (FRC) and lung clearance index (LCI). Continuous N2 concentration traces were very similar for MBWindirect and MBWdirect, resulting in comparable breath-by-breath washout plots of expired concentration and in no significant differences in FRCN2, LCIN2, Scond, and Sacin between the two methods. Argon washouts were slightly slower than N2 washouts, as expected for a less diffusive and more soluble gas. Finally, comparison between LCIN2 and LCIAr indicates that the maximum impact from blood-tissue represents less than half a LCI unit in normal subjects. In conclusion, we have demonstrated by direct measurement of N2 and twice as soluble argon, that indirect N2 measurement can be safely used as a meaningful physiological measurement.NEW & NOTEWORTHY The physiological content of N2 multibreath washout testing has been questioned due to N2 indirect measurement accuracy and N2 blood solubility. With direct measurement of N2 and twice as soluble argon, we show that these effects are largely outweighed by ease of use.

Detection of Chronic Blast-Related Mild Traumatic Brain Injury with Diffusion Tensor Imaging and Support Vector Machines.

Blast-related mild traumatic brain injury (bmTBI) often leads to long-term sequalae, but diagnostic approaches are lacking due to insufficient knowledge about the predominant pathophysiology. This study aimed to build a diagnostic model for future verification by applying machine-learning based support vector machine (SVM) modeling to diffusion tensor imaging (DTI) datasets to elucidate white-matter features that distinguish bmTBI from healthy controls (HC). Twenty subacute/chronic bmTBI and 19 HC combat-deployed personnel underwent DTI. Clinically relevant features for modeling were selected using tract-based analyses that identified group differences throughout white-matter tracts in five DTI metrics to elucidate the pathogenesis of injury. These features were then analyzed using SVM modeling with cross validation. Tract-based analyses revealed abnormally decreased radial diffusivity (RD), increased fractional anisotropy (FA) and axial/radial diffusivity ratio (AD/RD) in the bmTBI group, mostly in anterior tracts (29 features). SVM models showed that FA of the anterior/superior corona radiata and AD/RD of the corpus callosum and anterior limbs of the internal capsule (5 features) best distinguished bmTBI from HCs with 89% accuracy. This is the first application of SVM to identify prominent features of bmTBI solely based on DTI metrics in well-defined tracts, which if successfully validated could promote targeted treatment interventions.

Dual-Core Beamformer for obtaining highly correlated neuronal networks in MEG.

The "Dual-Core Beamformer" (DCBF) is a new lead-field based MEG inverse-modeling technique designed for localizing highly correlated networks from noisy MEG data. Conventional beamformer techniques are successful in localizing neuronal sources that are uncorrelated under poor signal-to-noise ratio (SNR) conditions. However, they fail to reconstruct multiple highly correlated sources. Though previously published dual-beamformer techniques can successfully localize multiple correlated sources, they are computationally expensive and impractical, requiring a priori information. The DCBF is able to automatically calculate optimal amplitude-weighting and dipole orientation for reconstruction, greatly reducing the computational cost of the dual-beamformer technique. Paired with a modified Powell algorithm, the DCBF can quickly identify multiple sets of correlated sources contributing to the MEG signal. Through computer simulations, we show that the DCBF quickly and accurately reconstructs source locations and their time-courses under widely varying SNR, degrees of correlation, and source strengths. Simulations also show that the DCBF identifies multiple simultaneously active correlated networks. Additionally, DCBF performance was tested using MEG data in humans. In an auditory task, the DCBF localized and reconstructed highly correlated left and right auditory responses. In a median-nerve stimulation task, the DCBF identified multiple meaningful networks of activation without any a priori information. Altogether, our results indicate that the DCBF is an effective and valuable tool for reconstructing correlated networks of neural activity from MEG recordings.

Accurate reconstruction of temporal correlation for neuronal sources using the enhanced dual-core MEG beamformer.

Beamformer spatial filters are commonly used to explore the active neuronal sources underlying magnetoencephalography (MEG) recordings at low signal-to-noise ratio (SNR). Conventional beamformer techniques are successful in localizing uncorrelated neuronal sources under poor SNR conditions. However, the spatial and temporal features from conventional beamformer reconstructions suffer when sources are correlated, which is a common and important property of real neuronal networks. Dual-beamformer techniques, originally developed by Brookes et al. to deal with this limitation, successfully localize highly-correlated sources and determine their orientations and weightings, but their performance degrades at low correlations. They also lack the capability to produce individual time courses and therefore cannot quantify source correlation. In this paper, we present an enhanced formulation of our earlier dual-core beamformer (DCBF) approach that reconstructs individual source time courses and their correlations. Through computer simulations, we show that the enhanced DCBF (eDCBF) consistently and accurately models dual-source activity regardless of the correlation strength. Simulations also show that a multi-core extension of eDCBF effectively handles the presence of additional correlated sources. In a human auditory task, we further demonstrate that eDCBF accurately reconstructs left and right auditory temporal responses and their correlations. Spatial resolution and source localization strategies corresponding to different measures within the eDCBF framework are also discussed. In summary, eDCBF accurately reconstructs source spatio-temporal behavior, providing a means for characterizing complex neuronal networks and their communication.

Clinical factors related to brain structure in HIV: the CHARTER study.

Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.