Creatine mapping of the brain at 3T by CEST MRI.

PURPOSE: To assess the feasibility of CEST-based creatine (Cr) mapping in brain at 3T using the guanidino (Guan) proton resonance. METHODS: Wild type and knockout mice with guanidinoacetate N-methyltransferase deficiency and low Cr and phosphocreatine (PCr) concentrations in the brain were used to assign the Cr and protein-based arginine contributions to the GuanCEST signal at 2.0 ppm. To quantify the Cr proton exchange rate, two-step Bloch-McConnell fitting was used to fit the extracted CrCEST line-shape and multi-B1 Z-spectral data. The pH response of GuanCEST was simulated to demonstrate its potential for pH mapping. RESULTS: Brain Z-spectra of wild type and guanidinoacetate N-methyltransferase deficiency mice show a clear Guan proton peak at 2.0 ppm at 3T. The CrCEST signal contributes ∼23% to the GuanCEST signal at B1 = 0.8 µT, where a maximum CrCEST effect of 0.007 was detected. An exchange rate range of 200-300 s-1 was estimated for the Cr Guan protons. As revealed by the simulation, an elevated GuanCEST in the brain is observed when B1 is less than 0.4 µT at 3T, when intracellular pH reduces by 0.2. Conversely, the GuanCEST decreases when B1 is greater than 0.4 µT with the same pH drop. CONCLUSIONS: CrCEST mapping is possible at 3T, which has potential for detecting intracellular pH and Cr concentration in brain.

Simultaneous Measurement of GABA, Glutathione, and Glutamate-Glutamine in the Thalamus using Edited MR Spectroscopy: Feasibility and Applications in Traumatic Brain Injury.

BACKGROUND: MR spectroscopy (MRS) is a noninvasive tool for evaluating biochemical alterations, such as glutamate (Glu)/gamma-aminobutyric acid (GABA) imbalance and depletion of antioxidative glutathione (GSH) after traumatic brain injury (TBI). Thalamus, a critical and vulnerable region post-TBI, is challenging for MRS acquisitions, necessitating optimization to simultaneously measure GABA/Glu and GSH. PURPOSE: To assess the feasibility and optimize acquisition and processing approaches for simultaneously measuring GABA, Glx (Glu + glutamine (Gln)), and GSH in the thalamus, employing Hadamard encoding and reconstruction of MEscher-GArwood (MEGA)-edited spectroscopy (HERMES). STUDY TYPE: Prospective. SUBJECTS: 28 control subjects (age: 35.9 ± 15.1 years), and 17 mild TBI (mTBI) patients (age: 32.4 ± 11.3 years). FIELD STRENGTH/SEQUENCE: 3T/T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE), HERMES. ASSESSMENT: We evaluated the impact of acquisition with spatial saturation bands and post-processing with spectral alignment on HERMES performance in the thalamus among controls. Within-subject variability was examined in five controls through repeated scans within a week. The HERMES spectra in the posterior cingulate cortex (PCC) of controls were used as a reference for assessing HERMES performance in a reliable target. Furthermore, we compared metabolite levels and fitting quality in the thalamus between mTBI patients and controls. STATISTICAL TESTS: Unpaired t-tests and within-subject coefficient-of-variation (CV). A P-value <0.05 was deemed significant. RESULTS: HERMES spectra, acquired with saturation bands and processed with spectral alignment, yielded reliable metabolite measurements in the thalamus. The mean within-subject CV for GABA, Glx, and GSH levels were 18%, 10%, and 16% in the thalamus (7%, 9%, and 16% in the PCC). GABA (3.20 ± 0.60 vs 2.51 ± 0.55, P < 0.01) and Glx (8.69 ± 1.23 vs 7.72 ± 1.19, P = 0.03) levels in the thalamus were significantly higher in mTBI patients than in controls, with GSH (1.27 ± 0.35 vs 1.22 ± 0.28, P = 0.65) levels showing no significant difference. DATA CONCLUSION: Simultaneous measuring GABA/Glx and GSH using HERMES is feasible in the thalamus, providing valuable insight into TBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Toward vendor-independent measurement of cerebral venous oxygenation: Comparison of TRUST MRI across three major MRI manufacturers and association with end-tidal CO2.

Cerebral venous oxygenation (Yv ) is a valuable biomarker for a variety of brain diseases. T2 relaxation under spin tagging (TRUST) MRI is a widely used method for Yv quantification. In this work, there were two main objectives. The first was to evaluate the reproducibility of TRUST Yv measurements across MRI scanners from different vendors. The second was to examine the correlation between Yv and end-tidal CO2 (EtCO2 ) in a multisite, multivendor setting and determine the usefulness of this correlation to account for variations in Yv caused by normal variations and physiological fluctuations. Standardized TRUST pulse sequences were implemented on three scanners from major MRI vendors (GE, Siemens, Philips). These scanners were located at two research institutions. Ten healthy subjects were scanned. On each scanner, the subject underwent two scan sessions, each of which included three TRUST scans, to evaluate the intrasession and intersession reproducibility of Yv . Each scanner was also equipped with a capnograph device to record the EtCO2 of the subject during the MRI scan. We found no significant bias in Yv measurements across the three scanners (P = 0.18). The measured Yv values on the three scanners were also strongly correlated with each other (intraclass correlation coefficients > 0.85, P < 0.001). The intrasession and intersession coefficients of variation of Yv were less than 4% and showed no significant difference among the scanners. In addition, our results revealed that (1) within the same subject, Yv increased with EtCO2 at a rate of 1.24 ± 0.17%/mmHg (P < 0.0001), and (2) across different subjects, individuals with a higher EtCO2 had a higher Yv , at a rate of 0.94 ± 0.36%/mmHg (P = 0.01). These results suggest that (1) the standardized TRUST sequences had similar accuracies and reproducibilities for the quantification of Yv across the scanners, and (2) recording of EtCO2 may be a useful complement to Yv measurement to account for CO2 -related physiological fluctuations in Yv in multisite, multivendor studies.

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Alterations in motor functional connectivity in Neonatal Hypoxic Ischemic Encephalopathy.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is the result of global hypoxic-ischemic brain injury in neonates due to asphyxia during birth and is one of the most common causes of severe, long-term neurologic deficits in children. Methods: Resting state fMRI (rs-fMRI) was used to assess potential functional disruptions in the primary and association motor areas in HIE neonates (n = 16) compared to healthy controls (n = 11). RESULTS: Results demonstrate reduced intra-hemispheric resting state functional connectivity (rs-FC) between primary motor regions (upper extremity and facial motor regions) as well as reduced inter-hemispheric rs-FC in the HIE group. In addition, HIE neonates demonstrated increased rs-FC between motor regions and frontal, temporal and parietal cortices but decreased rs-FC with the cerebellum. DISCUSSION: These preliminary results provide initial evidence for the disruption of functional communication with the motor network in neonates with HIE. Further studies are necessary to both validate these findings in a larger dataset as well as to determine if rs-fMRI measurements collected at birth may have the potential to serve as a prognostic marker in addition to the traditional combination of clinical measurements and conventional MRI.

Prospective motion detection and re-acquisition in diffusion MRI using a phase image-based method-Application to brain and tongue imaging.

PURPOSE: To develop an image-based motion-robust diffusion MRI (dMRI) acquisition framework that is able to minimize motion artifacts caused by rigid and nonrigid motion, applicable to both brain and tongue dMRI. METHODS: We developed a novel prospective motion-correction technique in dMRI using a phase image-based real-time motion-detection method (PITA-MDD) with re-acquisition of motion-corrupted images. The prospective PITA-MDD acquisition technique was tested in the brains and tongues of volunteers. The subjects were instructed to move their heads or swallow, to induce motion. Motion-detection efficacy was validated against visual inspection as the gold standard. The effect of the PITA-MDD technique on diffusion-parameter estimates was evaluated by comparing reconstructed fiber tracts using tractography with and without re-acquisition. RESULTS: The prospective PITA-MDD technique was able to effectively and accurately detect motion-corrupted data as compared with visual inspection. Tractography results demonstrated that PITA-MDD motion detection followed by re-acquisition helps in recovering lost and misshaped fiber tracts in the brain and tongue that would otherwise be corrupted by motion and yield erroneous estimates of the diffusion tensor. CONCLUSION: A prospective PITA-MDD technique was developed for dMRI acquisition, providing improved dMRI image quality and motion-robust diffusion estimation of the brain and tongue.

Early Stage Longitudinal Subcortical Volumetric Changes following Mild Traumatic Brain Injury.

Objective: To investigate early brain volumetric changes from acute to 6 months following mild traumatic brain injury (mTBI) in deep gray matter regions and their association with patient 6-month outcome.Methods: Fifty-six patients with mTBI underwent MRI and behavioral evaluation at acute (<10 days) and approximately 1 and 6 months post injury. Regional volume changes were investigated in key gray matter regions: thalamus, hippocampus, putamen, caudate, pallidum, and amygdala, and compared with volumes from 34 healthy control subjects. In patients with mTBI, we further assessed associations between longitudinal regional volume changes with patient outcome measures at 6 months including post-concussive symptoms, cognitive performance, and overall satisfaction with life.Results: Reduction in thalamic and hippocampal volumes was observed at 1 month among patients with mTBI. Such volume reduction persisted in the thalamus until 6 months. Changes in thalamic volumes also correlated with multiple symptom and functional outcome measures in patients at 6 months.Conclusion: Our results indicate that the thalamus may be differentially affected among patients with mTBI, resulting in both structural and functional deficits with subsequent post-concussive sequelae and may serve as a biomarker for the assessment of efficacy of novel therapeutic interventions.

Alterations in the whole brain network organization after prenatal ethanol exposure.

BACKGROUND: People with fetal alcohol spectrum disorder (FASD) often have structural or functional alterations of the central nervous system, including changes in brain network organization. These have been associated with neuropsychological deficits, but outcomes are not consistent across studies. We used a rat model of FASD to assess brain network alterations in males and females following ethanol exposure during a prenatal period similar to the first half of gestation in humans. METHODS: Pregnant Long Evans rats were given an ethanol-containing or isocaloric non-ethanol diet from gestation day 6 to 20. Resting-state functional magnetic resonance imaging was performed on offspring in young adulthood. Graph theoretical analysis was used to assess properties associated with the whole brain network organization, with a focus on segregation, integration, and small-world organization-a feature which allows specialized local information processing (segregation) and simultaneously efficient global information sharing (integration). RESULTS: Ethanol-exposed females showed a significant decrease in small-worldness compared with control females or with ethanol-exposed males. Compared to control females, the proportion of animals with atypically high path length (1 standard deviation higher than the grand average) was significantly higher in ethanol-exposed females, indicating that the alteration in small-world organization is driven by decreased network integration. No significant effects were seen in males. CONCLUSION: The results revealed that prenatal ethanol exposure disrupts the balance between network segregation and integration in young adult female rats. The whole brain network is less integrated after ethanol exposure in the females, suggesting wide-spread reduction of long-range regional communication.

Nicotinamide Mononucleotide Administration Prevents Experimental Diabetes-Induced Cognitive Impairment and Loss of Hippocampal Neurons.

Diabetes predisposes to cognitive decline leading to dementia and is associated with decreased brain NAD+ levels. This has triggered an intense interest in boosting nicotinamide adenine dinucleotide (NAD+) levels to prevent dementia. We tested if the administration of the precursor of NAD+, nicotinamide mononucleotide (NMN), can prevent diabetes-induced memory deficits. Diabetes was induced in Sprague-Dawley rats by the administration of streptozotocin (STZ). After 3 months of diabetes, hippocampal NAD+ levels were decreased (p = 0.011). In vivo localized high-resolution proton magnetic resonance spectroscopy (MRS) of the hippocampus showed an increase in the levels of glucose (p < 0.001), glutamate (p < 0.001), gamma aminobutyric acid (p = 0.018), myo-inositol (p = 0.018), and taurine (p < 0.001) and decreased levels of N-acetyl aspartate (p = 0.002) and glutathione (p < 0.001). There was a significant decrease in hippocampal CA1 neuronal volume (p < 0.001) and neuronal number (p < 0.001) in the Diabetic rats. Diabetic rats showed hippocampal related memory deficits. Intraperitoneal NMN (100 mg/kg) was given after induction and confirmation of diabetes and was provided on alternate days for 3 months. NMN increased brain NAD+ levels, normalized the levels of glutamate, taurine, N-acetyl aspartate (NAA), and glutathione. NMN-treatment prevented the loss of CA1 neurons and rescued the memory deficits despite having no significant effect on hyperglycemic or lipidemic control. In hippocampal protein extracts from Diabetic rats, SIRT1 and PGC-1α protein levels were decreased, and acetylation of proteins increased. NMN treatment prevented the diabetes-induced decrease in both SIRT1 and PGC-1α and promoted deacetylation of proteins. Our results indicate that NMN increased brain NAD+, activated the SIRT1 pathway, preserved mitochondrial oxidative phosphorylation (OXPHOS) function, prevented neuronal loss, and preserved cognition in Diabetic rats.

White Matter Alterations in Fmr1 Knockout Mice during Early Postnatal Brain Development.

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability ascribed to the autism spectrum disorder. Studies with FXS patients have reported altered white matter volume compared to controls. The Fmr1 knockout (KO) mouse, a model for FXS, showed evidence of delayed myelination during postnatal brain development. In this study, we examined several white matter regions in the male Fmr1 KO mouse brain compared to male wild-type (WT) mice at postnatal days (PND) 18, 21, 30, and 60, which coincide with critical stages of myelination and postnatal brain development. White matter volume, T2 relaxation time, and magnetization transfer ratio (MTR) were measured using magnetic resonance imaging and myelin content was determined with histological staining of myelin. Differences in the developmental accumulation of white matter and myelin between Fmr1 KO and WT mice were observed in the corpus callosum, external and internal capsules, cerebral peduncle, and fimbria. Alterations were more predominant in the external and internal capsules and fimbria of Fmr1 KO mice, where the MTR was lower at PND 18, then elevated at PND 30, and again lower at PND 60 compared to the corresponding regions in WT mice. The pattern of changes in MTR were similar to those observed in myelin staining and could be related to the altered protein synthesis that is a hallmark of FXS. While no significant changes in white matter volumes and T2 relaxation time between the Fmr1 KO and WT mice were observed, the altered pattern of myelin staining and MTR, particularly in the external capsule, reflecting the abnormalities associated with myelin content is suggestive of a developmental delay in the white matter of Fmr1 KO mouse brain. These early differences in white matter during critical developmental stages may contribute to altered brain networks in the Fmr1 KO mice.

Functional Connectivity and Metabolic Alterations in Medial Prefrontal Cortex in a Rat Model of Fetal Alcohol Spectrum Disorder: A Resting-State Functional Magnetic Resonance Imaging and in vivo Proton Magnetic Resonance Spectroscopy Study.

Prenatal ethanol exposure alters brain structure, functional connectivity, and behavior in humans and rats. Behavioral changes include deficits in executive function, which requires cooperative activity between the frontal cortices and other brain regions. In this study, we analyzed the functional connectivity and neurochemical levels of the prefrontal cortex (PFC) using resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) in ethanol-exposed (Eth) and control (Ctr) rats. Pregnant Long-Evans rats were fed a liquid diet containing ethanol (2.1-6.46% v/v ethanol) from gestational days 6 to 21 (Eth). Ctr animals received an isocaloric, isonutritive liquid diet. In young adulthood, male and female offspring underwent in vivo MRI using a 7.0-Tesla system. 1H-MRS from the PFC and whole brain rsfMRI were obtained on the animals. Seed-based functional connectivity analysis was performed with seeds placed in the PFC, matching the voxel of MRS. Male, but not female, Eth rats showed less functional connectivity between PFC and dorsal striatum than Ctr animals. In Eth males glucose levels were significantly lower, and in Eth females lower levels of phosphorylcholine but an increased gamma-aminobutyric acid/glutamate ratio were observed in the PFC compared with Ctr animals. Prenatal ethanol alters brain metabolism and functional connectivity of the PFC in a sex-dependent manner.

Association of Patient Self-Reported Shoulder Scores to Quantitative and Semiquantitative MRI Measures of Rotator Cuff Intramuscular Fatty Infiltration: A Pilot Study.

OBJECTIVE. The purpose of this study was to determine the relationship of supraspinatus fat fraction and Goutallier grade to the American Shoulder and Elbow Surgeons (ASES) score in cohorts of older adults with painful full-thickness supraspinatus tendon (SST) tear and control subjects. SUBJECTS AND METHODS. Seventeen control subjects and 15 study participants with painful full-thickness SST tear were prospectively recruited (mean age ± SD, 63.0 ± 10.1 years and 62.6 ± 9.0 years, respectively). Study participants received shoulder MRI and completed ASES questionnaires at one time. Goutallier grade was assessed on T1-weighted MRI. Fat fraction was measured on 6-point Dixon MRI. Body mass index (BMI) was determined. Descriptive, correlation, reliability, and regression analyses were performed. RESULTS. The control and painful full-thickness SST tear cohorts differed in mean supraspinatus fat fraction (3.3% ± 1.4% and 7.3 ± 5.9%, respectively; p = 0.024) and Goutallier grade (0.4 ± 0.5 and 0.9 ± 0.7, respectively; p = 0.022). Fat fraction (p = 0.014) and Goutallier grade (p = 0.017) showed a significant inverse association with ASES score only in the SST tear cohort. The association of BMI to ASES score was significant only in the control group (p = 0.036). The correlation between BMI and fat fraction were different for the two groups (control cohort, r = 0.676 and p = 0.003; SST tear cohort, r = 0.124 and p = 0.687). Fat fraction showed strong interobserver reliability (intraclass correlation coefficient, 0.903); Goutallier grade showed poor interobserver reliability (κ = 0.178). CONCLUSION. The association of ASES score and supraspinatus fat fraction or Goutallier grade differs between patients with painful full-thickness SST tear and control subjects without symptoms. Although fat fraction shows strong reliability, Goutallier grade should be regarded cautiously because of suboptimal reproducibility. Our results also suggest that painful full-thickness SST tear alters the correlation between supraspinatus fat fraction and BMI as compared with control subjects.

Quantification of shoulder muscle intramuscular fatty infiltration on T1-weighted MRI: a viable alternative to the Goutallier classification system.

BACKGROUND: Quantification of rotator cuff intramuscular fatty infiltration is important for clinical decision-making in patients with rotator cuff tear. The semi-quantitative Goutallier classification system is the most commonly used method, but has limited reliability. Therefore, we sought to test a freely available fuzzy C-means segmentation software program for reliability of the quantification of shoulder intramuscular fatty infiltration on T1-weighted MR images and for correlation with fat fraction by six-point Dixon MRI. MATERIALS AND METHODS: We performed a prospective cross-sectional study to measure visible intramuscular fat area percentage on oblique sagittal T1 MR images by fuzzy C-means segmentation and fat fraction maps by six-point Dixon MRI for 42 shoulder muscles. Intra- and inter-observer reliability were determined. Correlative analysis for fuzzy C-means and six-point Dixon intramuscular fatty infiltration measures was also performed. RESULTS: We found that inter-observer reliability for the quantification of visible intramuscular fat area percentage by fuzzy C-means segmentation and fat fraction by six-point Dixon MRI was 0.947 and 0.951 respectively. The intra-observer reliability for the quantification of visible intramuscular fat area percentage by fuzzy C-means segmentation and fat fraction by six-point Dixon MRI was 0.871 and 0.979 respectively. We found a strong correlation between fuzzy C-means segmentation and six-point Dixon techniques; r = 0.850, p < 0.001 by individual muscle; and r = 0.977, p < 0.002 by study subject. CONCLUSION: Quantification of intramuscular fatty infiltration by fuzzy C-means segmentation on T1-weighted sequences demonstrates excellent reliability and strong correlation with fat fraction by six-point Dixon MRI. Quantitative fuzzy C-means segmentation is a viable alternative to the semi-quantitative Goutallier classification system.

Effects of Early Alcohol Exposure on Functional Organization and Microstructure of a Visual-Tactile Integrative Circuit.

BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) often have deficits associated with multisensory processing. Because ethanol (EtOH) disrupts activity-dependent neuronal plasticity, a process that is essential for refining connections during cortical development, we hypothesize that early alcohol exposure results in alterations in multisensory cortical networks, which could explain the multisensory processing deficits seen in FASD. Here, we use a gyrencephalic animal model to test the prediction that early alcohol exposure alters the functional connectivity and microstructural features of the rostral posterior parietal cortex (PPr), a visual-tactile integrative area. METHODS: Ferrets were exposed to moderate doses of EtOH during the brain growth spurt period. Functional connectivity and microstructural features were assessed using resting-state functional magnetic resonance imaging and ex vivo diffusion kurtosis imaging (DKI), respectively, when the animals reached juvenile age and adulthood, respectively. RESULTS: While the whole brain volume was smaller in alcohol-treated animals, the relative size of the frontal brain area was larger when compared to control animals. Altered functional connectivity was observed in alcohol-treated animals, where increased connectivity was observed between PPr and the region that provides its major visual inputs (the caudal portion of the parietal cortex), but not with the region that provides its major somatosensory inputs (tertiary somatosensory cortex). DKI revealed reduced microstructural tissue complexity in all investigated sensory areas of alcohol-treated animals. CONCLUSIONS: In this study, we observed alterations in cortical functional connectivity and microstructural integrity in a cortical area involved in multisensory processing in a ferret FASD model. These findings indicate an alteration in cortical networks that may be related to the multisensory processing deficiencies observed in FASD.

Modulation of working memory load distinguishes individuals with and without balance impairments following mild traumatic brain injury.

OBJECTIVES: Balance and gait deficits can persist after mild traumatic brain injury (TBI), yet an understanding of the underlying neural mechanism remains limited. The purpose of this study was to investigate differences in attention network modulation in patients with and without balance impairments 2-8 weeks following mild TBI. METHODS: Using functional magnetic resonance imaging, we compared activity and functional connectivity of cognitive brain regions of the default mode, central-executive and salience networks during a 2-back working memory task in participants with mild TBI and balance impairments (n = 7, age 47 ± 15 years) or no balance impairments (n = 7, age 47 ± 15 years). RESULTS: We first identified greater activation in the lateral occipital cortex in the balance impaired group. Second, we observed stronger connectivity of left pre-supplementary motor cortex in the balance impaired group during the working memory task, which was related to decreased activation of regions within the salience and central executive networks and greater suppression of the default mode network. CONCLUSIONS: Results suggest a link between impaired balance and modulation of cognitive resources in patients in mTBI. Findings also highlight the potential importance of moving beyond traditional balance assessments towards an integrative assessment of cognition and balance in this population.

Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms.

Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

Toward the Development of a Flexible Mesoscale MRI-compatible Neurosurgical Continuum Robot.

Brain tumor, be it primary or metastatic, is usually life threatening for a person of any age. Primary surgical resection which is one of the most effective ways of treating brain tumors can have tremendously increased success rate if the appropriate imaging modality is used for complete tumor resection. Magnetic resonance imaging (MRI) is the imaging modality of choice for brain tumor imaging because of its excellent soft-tissue contrast. MRI combined with continuum soft robotics has immense potential to be the next major technological breakthrough in the field of brain cancer diagnosis and therapy. In this work, we present the design, kinematic, and force analysis of a flexible spring-based minimally invasive neurosurgical intracranial robot (MINIR-II). It is comprised of an inter-connected inner spring and an outer spring and is connected to actively cooled shape memory alloy spring actuators via tendon driven mechanism. Our robot has three serially connected 2-DoF segments which can be independently controlled due to the central tendon routing configuration. The kinematic and force analysis of the robot and the independent segment control were verified by experiments. Robot motion under forced cooling of SMA springs was evaluated as well as the MRI compatibility of the robot and its motion capability in brainlike gelatin environment.

Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats.

Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

Noncontrast-enhanced peripheral venography using velocity-selective magnetization preparation and transient balanced SSFP.

PURPOSE: To develop a three-dimensional (3D) noncontrast-enhanced (NCE) peripheral magnetic resonance venography (MRV) method and demonstrate its feasibility in vivo. METHODS: The proposed MRV pulse sequence consisted of a velocity-selective (VS) inversion preparation module, inversion delay time (TI), fat inversion pulse, and 3D balanced steady-state free precession (bSSFP) dummy excitations and readout. The VS preparation module inverted arterial blood, which recovered close to zero magnetization during TI. The TI and the number of dummy excitations (Nnum ) were numerically optimized for maximizing vein-to-background contrast and tested in a healthy subject. The proposed MRV of the entire peripheral system, using four-station acquisition, was performed in six healthy subjects and three peripheral artery patients. RESULTS: The numerical optimization yielded TI = 350 ms and Ndum = 40, which was supported by the largest vein contrast among the parameters chosen around the optima on in vivo venograms. Four-station peripheral MRV using the optimized parameters well visualized all major deep veins with high vein-to-background contrast. The relative vein contrast ratios were 0.80 ± 0.08, 0.75 ± 0.07, and 0.84 ± 0.06 against the arteries, muscle, and fat, respectively. CONCLUSION: The proposed NCE MRV using VS preparation and transient bSSFP can generate high-contrast peripheral venograms directly with a single acquisition.

In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine.

PURPOSE: This study evaluated the longitudinal metabolic alterations after neonatal hypoxia-ischemia (HI) in rats and tested the neuroprotective effect of acetyl-L-carnitine (ALCAR) using in vivo proton short-TE Point-RESolved Spectroscopy method. METHODS: Rice-Vannucci model was used on 7-day-old Sprague-Dawley rats. Data were acquired from contralateral and ipsilateral cortex and hippocampus, respectively at 4 time points (24-h, 72-h, 7-days, 28-days) post-HI. The effect of subcutaneous administration of ALCAR (100 mg/kg) immediately after HI, at 4-h, 24-h, and 48-h post-HI was determined. RESULTS: Significant reductions in glutathione (P < 0.005), myo-inositol (P < 0.002), taurine (P < 0.001), and total creatine (P < 0.005) were observed at 24-h postinjury compared with the control group in the ipsilateral hippocampus of the HI rat pups. ALCAR-treated-HI rats had lower levels of lactate and maintained total creatine at 24-h and had smaller lesion size compared with the HI only rats. CONCLUSION: Severe oxidative, osmotic stress, impaired phosphorylation, and a preference for anaerobic glycolysis were found in the ipsilateral hippocampus in the HI pups at 24-h postinjury. ALCAR appeared to have a neuroprotective effect if administered early after HI by serving as an energy substrate and promote oxidative cerebral energy producing and minimize anaerobic glycolysis.