The level of tissue oxygenation provides information related to the balance between oxygen delivery, oxygen utilization, tissue reactivity and morphology during physiological conditions. Tissue partial pressure of oxygen (PtO(2)) is influenced by the use of anesthesia or restraint. These factors may impact the absolute level of PtO(2). In this study we present a novel fiber optic method to measure brain PtO(2). This method can be used in unanesthetized, unrestrained animals, provides absolute values for PO(2), has a stable calibration, does not consume oxygen and is MRI compatible. Brain PtO(2) was studied during acute hypoxia, as well as before and after 28 days of high altitude acclimatization. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It is comprised of a fiber optic probe with a tip containing material that fluoresces with an oxygen dependent lifetime. Brain PtO(2) declines by 80% and 76% pre- and post-acclimatization, respectively, when the fraction of inspired oxygen declines from 0.21 to 0.08. In addition, a linear relationship between brain PtO(2) and inspired O(2) levels was demonstrated r(2)=0.98 and r(2)=0.99 (pre- and post-acclimatization). Hypoxia acclimatization resulted in an increase in the overall brain PtO(2) by approximately 35%. This paper demonstrates the use of a novel chronically implanted fiber optic based sensor for measuring absolute PtO(2). It shows a very strong linear relationship in awake animals between inspired O(2) and tissue O(2), and shows that there is a proportional increase in PtO(2) over a range of inspired values after exposure to chronic hypoxia.

Open-bore MRI scanners allow joint soft tissue to be imaged over a large, uninterrupted range of flexion. Using an open-bore scanner, 3D para-sagittal images of the posterior cruciate ligament (PCL) were collected from seven healthy subjects in unloaded, recumbent knee extension and flexion. PCL length was measured from one 2D MRI slice partition per flexion angle, per subject. The anterior surface of the PCL lengthened significantly between extension and flexion (p<0.001). Conversely, the posterior surface did not. Changes were not due to the PCL moving relative to the 2D slice partition; measurements made from 3D reconstructions, which compensated for PCL movement, did not differ significantly from measurements made from 2D slice partitions. In a second experiment, videos of knee flexion were made by imaging two subjects at several flexion angles. Videos allowed soft tissue tracking; examples are included. In a third experiment, unloaded knees of seven healthy, recumbent subjects were imaged at extension and at 40°, 70°, 90°, 100°, 110° and 120° flexion. The distance between PCL attachments increased between extension and 100°, and then decreased (p<0.001). The anterior surface of the PCL lengthened over the flexion angles measured (p<0.01). The posterior surface of the PCL lengthened between extension and 40° and then shortened (p<0.001). Both attachment separation and anterior surface length increased dramatically between extension and 40°, but varied less afterwards. Results indicate that PCL dynamics differ between terminal extension and active function sub-arcs. Also, attachment separation cannot predict the lengthening of all parts of the PCL, nor can lengthening of one part of the PCL predict the lengthening of another part. A potential connection between lengthening and loading is discussed. We conclude that low-field MRI can assess ligament lengthening during flexion, and that the dynamics of the PCL for any given region and sub-arc should be measured directly.

Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4 T MRI on rats prior to and following soman exposure. T2 images were taken at least 24 h prior, 1 h and 18-24 h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18-24 h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18-24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18-24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p < 0.001). These findings indicate there is regionally specific neurodegeneration 24 h after exposure to soman. The high correlation between T2 relaxivity and histopathology supports the use of T2 as a marker of injury.

Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.

Non-invasive quantitative imaging of cerebral oxygen metabolism (CMRO2) in small animal models is crucial to understand the role of oxidative metabolism in healthy and diseased brains. In this study, we developed a multimodal method combining near-infrared spectroscopy (NIRS) and MRI to non-invasively study oxygen delivery and consumption in the cortex of mouse and rat models. The term CASNIRS is proposed to the technique that measures CMRO2 with ASL and NIRS. To determine the reliability of this method, CMRO2 values were compared with reported values measured with other techniques. Also, the sensitivity of the CASNIRS technique to detect changes in CMRO2 in the cortex of the animals was assessed by applying a reduction in core temperature, which is known to reduce CMRO2. Cerebral blood flow (CBF) and CMRO2 were measured in five mice and five rats at a core temperature of 37 °C followed by another measurement at 33 °C. CMRO2 was 7.8 ± 1.8 and 3.7 ± 0.9 (ml/100 g/min, mean ± SD) in mice and rats respectively. These values are in good agreement with reported values measured by 15O PET, 17O NMR, and BOLD fMRI. In hypothermia, we detected a significant decrease of 37% and 32% in CMRO2 in the cortex of mice and rats, respectively. Q10 was calculated to be 3.2 in mice and 2.7 in rats. In this study we showed that it is possible to assess absolute values of metabolic correlates such as CMRO2, CBF and oxygen extraction fraction (OEF) noninvasively in living brain of mice and rats by combining NIRS with MRI. This will open new possibilities for studying brain metabolism in patients as well as the many mouse/rat models of brain disorders.

Protein expression for 384 total and post-translationally modified proteins was assessed in 871 CLL and MSBL patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteomics identified six recurrent signatures that were highly prognostic of survival and time to first or second treatment at three levels: individual proteins, when grouped into 40 functionally related groups (PFGs), and systemically in signatures (SGs). A novel SG characterized by hairy cell leukemia like proteomics but poor therapy response was discovered. SG membership superseded other prognostic factors (Rai Staging, IGHV Status) and were prognostic for response to modern (BTK inhibition) and older CLL therapies. SGs and PFGs membership provided novel drug targets and defined optimal candidates for Watch and Wait vs. early intervention. Collectively proteomics demonstrates promise for improving classification, therapeutic strategy selection, and identifying novel therapeutic targets.

Heart rate variability (HRV) is a popular tool to quantify autonomic function. However, this typically requires an expensive 3-12 lead electrocardiogram (ECG) and BioAmp system. This investigation sought to determine the validity and reliability of an OpenBCI cyton biosensing board (open source) for accurately quantifying HRV.

Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage (ICH). As a regulator of inflammation and lipid metabolism, Liver X receptor (LXR) has the potential to alter microglia/macrophage (M/M) phenotype, and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes. To support potential clinical translation, the benefits of enhanced LXR signalling are examined in experimental ICH.

There are exciting new advances in multiple sclerosis (MS) resulting in a growing understanding of both the complexity of the disorder and the relative involvement of grey matter, white matter and inflammation. Increasing need for preclinical imaging is anticipated, as animal models provide insights into the pathophysiology of the disease. Magnetic resonance (MR) is the key imaging tool used to diagnose and to monitor disease progression in MS, and thus will be a cornerstone for future research. Although gadolinium-enhancing and T2 lesions on MRI have been useful for detecting MS pathology, they are not correlative of disability. Therefore, new MRI methods are needed. Such methods require validation in animal models. The increasing necessity for MRI of animal models makes it critical and timely to understand what research has been conducted in this area and what potential there is for use of MRI in preclinical models of MS. Here, we provide a review of MRI and magnetic resonance spectroscopy (MRS) studies that have been carried out in animal models of MS that focus on pathology. We compare the MRI phenotypes of animals and patients and provide advice on how best to use animal MR studies to increase our understanding of the linkages between MR and pathology in patients. This review describes how MRI studies of animal models have been, and will continue to be, used in the ongoing effort to understand MS.

Multiple sclerosis (MS) has a significant inflammatory component and may have significant gray matter (GM) pathophysiology. Brain oxygenation is a sensitive measurement of the balance between metabolic need and oxygen delivery. There is evidence that inflammation and hypoxia are interdependent. In this paper, we applied novel, implanted PO2 sensors to measure hypoxia in cortical and cerebellar GM, in an inflammation-induced mouse model of MS.

Accelerometers are being increasingly incorporated into neuroimaging devices to enable real-time filtering of movement artifacts. In this study, we evaluate the reliability of sway metrics derived from these accelerometers in a standard eyes-open balance assessment to determine their utility in multimodal study designs. Ten participants equipped with a head-mounted accelerometer performed an eyes-open standing condition on 7 consecutive days. Sway performance was quantified with 4 standard metrics: root-mean-square (RMS) acceleration, peak-to-peak (P2P) acceleration, jerk, and ellipse area. Intraclass correlation coefficients (ICC) quantified reliability. P2P in both the mediolateral (ICC = 0.65) and anteroposterior (ICC = 0.67) planes yielded the poorest reliability. Both ellipse area and RMS exhibited good reliability, ranging from 0.76 to 0.84 depending on the plane. Finally, jerk displayed the highest reliability with an ICC value of 0.95. Moderate to excellent reliability was observed in all sway metrics. These findings demonstrate that head-mounted accelerometers, commonly found in neuroimaging devices, can be used to reliably assess sway. These data validate the use of head-mounted accelerometers in the assessment of motor control alongside other measures of brain activity such as electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS).

Concussion, or mild traumatic brain injury (mTBI), accounts for ∼80% of all TBIs across North America. The majority of mTBI patients recover within days to weeks; however, 14-36% of the time, acute mTBI symptoms persist for months or even years and develop into persistent post-concussion symptoms (PPCS). There is a need to find biomarkers in patients with PPCS, to improve prognostic ability and to provide insight into the pathophysiology underlying chronic symptoms. Recent research has pointed toward impaired network integrity and cortical communication as a biomarker. In this study we investigated functional near-infrared spectroscopy (fNIRS) as a technique to assess cortical communication deficits in adults with PPCS. Specifically, we aimed to identify cortical communication patterns in prefrontal and motor areas during rest and task, in adult patients with persistent symptoms. We found that (1) the PPCS group showed reduced connectivity compared with healthy controls, (2) increased symptom severity correlated with reduced coherence, and (3) connectivity differences were best distinguishable during task and in particular during the working memory task (n-back task) in the right and left dorsolateral prefrontal cortex (DLPFC). These data show that reduced brain communication may be associated with the pathophysiology of mTBI and that fNIRS, with a relatively simple acquisition paradigm, may provide a useful biomarker of this injury.

Atrophy has become a clinically relevant marker of progressive neurodegeneration in multiple sclerosis (MS). To better understand atrophy, mouse models that feature atrophy along with other aspects of MS are needed. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to determine the extent of atrophy in a model of inflammation-associated central nervous system pathology. High-resolution magnetic resonance imaging (MRI) and atlas-based volumetric analysis were performed to measure brain regional volumes in EAE mice. EAE brains were larger at peak clinical disease (days 14-16) compared to controls, with affected regions including the cerebellum, hippocampus, and corpus callosum. Following peak clinical disease, EAE mice exhibited significant loss of volume at chronic long-term disease duration (day 66+). Atrophy was identified in both white and grey matter regions including the cerebral cortex, cerebellum, hippocampus, corpus callosum, basal forebrain, midbrain, optic tract, and colliculus. Histological analysis of the atrophied cortex, cerebellum, and hippocampus showed demyelination, and axonal/neuronal loss. We hypothesize this atrophy could be a result of inflammatory associated neurodegenerative processes, which may also be involved in MS. Using MRI and atlas-based volumetrics, EAE has the potential to be a test bed for treatments aimed at reducing progressive neurological deterioration in MS.

Nerve agent exposure can cause debilitating neurological damage even with treatment. Currently accepted treatments involve attenuating the cholinergic crisis and seizure onset but do not focus directly on neuroprotection. Hence, there is a need for improved treatments to reduce neurological deficits. It is important to understand the pathophysiology of nerve agent mediated injury in order to identify effective treatment targets. Nerve agent-induced seizures are believed to be the main contributor to the neuropathology. Recently seizures have been shown to cause vascular changes that may actually attenuate neurological damage. This study evaluated the effect of soman-induced convulsive seizures on the relationship between CNS oxygen consumption and supply. To simultaneously assess changes in oxygenation and perfusion, rats were implanted with permanently fixed fiber-optic tissue oxygen sensing probes in the motor cortex and imaged with continuous arterial spin labelling MRI to measure cerebral blood flow. Baseline tissue oxygen tension (ptO2) and cerebral blood flow (CBF) were measured in isoflurane anaesthetized rats at least one day prior to soman or saline exposure. Rats were pretreated with HI-6 dimethansulfonate and atropine methyl nitrate (125 mg/kg and 20 mg/kg; intraperitoneal) followed by a convulsive dose of soman (90 μg/kg; subcutaneous) or equal volume of saline. Three additional treatments of HI-6/AMN were administered to improve survival. At 1.5 -hs after exposure, ptO2 and cerebral blood flow measurements were conducted. There was a significant decrease in CBF 1.5 -hs following soman exposure but no change in ptO2 was found. When we correlated ptO2 and CBF, for a given ptO2, there was lower CBF following soman exposure. This may indicate metabolism is inhibited, possibly because of mitochondrial impairment, therefore reducing oxygen demand. These data show hypoperfusion in brain following soman exposure which would be expected to contribute to soman-related neuropathology.

Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable.

Presently, little can be done to repair brain tissue after stroke damage. We hypothesized that the mammalian brain has an intrinsic capacity to adapt to low oxygen which would improve outcome from a reversible hypoxic/ischemic episode. Acclimation to chronic hypoxia causes increased capillarity and tissue oxygen levels which may improve the capacity to survive ischemia. Identification of these adaptations will lead to protocols which high risk groups could use to improve recovery and reduce costs.

With the rapid increase in new fNIRS users employing commercial software, there is a concern that many studies are biased by suboptimal processing methods. The purpose of this study is to provide a visual reference showing the effects of different processing methods, to help inform researchers in setting up and evaluating a processing pipeline. We show the significant impact of pre- and post-processing choices and stress again how important it is to combine data from both hemoglobin species in order to make accurate inferences about the activation site.

Brain tumor–initiating cells (BTICs) drive glioblastoma growth through not fully understood mechanisms. Here, we found that about 8% of cells within the human glioblastoma microenvironment coexpress programmed cell death 1 (PD-1) and BTIC marker. Gain- or loss-of-function studies revealed that tumor-intrinsic PD-1 promoted proliferation and self-renewal of BTICs. Phosphorylation of tyrosines within the cytoplasmic tail of PD-1 recruited Src homology 2–containing phosphatase 2 and activated the nuclear factor kB in BTICs. Notably, the tumor-intrinsic promoting effects of PD-1 did not require programmed cell death ligand 1(PD-L1) ligation; thus, the therapeutic antibodies inhibiting PD-1/PD-L1 interaction could not overcome the growth advantage of PD-1 in BTICs. Last, BTIC-intrinsic PD-1 accelerated intracranial tumor growth, and this occurred in mice lacking T and B cells. These findings point to a critical role for PD-1 in BTICs and uncover a nonimmune resistance mechanism of patients with glioblastoma to PD-1– or PD-L1–blocking therapies.

Mild traumatic brain injury (mTBI) is a debilitating but extremely common form of brain injury that affects a substantial number of people each year. mTBI is especially common in children and adolescents. Our understanding of mTBI pathophysiology is limited, and there is currently no accepted marker for disease severity. A potential marker for disease severity may be cerebrovascular dysfunction. Recent findings have implicated cerebrovascular alteration as an important component of mTBI and suggest it contributes to the development of persistent, long-term symptoms. In this paper, we conducted two studies to investigate whether mTBI affects venous drainage patterns in the central nervous system using alterations in the size of venous sinuses as a marker of changes in drainage. Using a closed head vertical weight-drop model and a lateral impact injury model of mTBI, we imaged and quantified the size of three major draining vessels in the adolescent rat brain using 9.4T MRI. Areas and volumes were quantified in the superior sagittal sinus and left and right transverse sinuses using images acquired from T2w MRI in one study and post-gadolinium T1w MRI in another. Our results indicated that the three venous sinuses were significantly larger in mTBI rats as compared to sham rats 1-day post injury but recovered to normal size 2 weeks after. Acutely enlarged sinuses post-mTBI may indicate abnormal venous drainage, and this could be suggestive of a cerebrovascular response to trauma.