Browsing by Author "Dunn, Jeffrey F."

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    Assessment of the Efficacy of MRI for Detectionof Changes in Bone Morphology in a MouseModel of Bone Injury
    (Wiley, 2013-07-11) Taha, May A; Manske, Sarah; Kristensen, Erika; Taiani, Jaymi; Krawetz, Roman; Wu, Ying; Ponjevic, Dragana; Matyas, John; Boyd, Steven; Rancourt, Derrick; Dunn, Jeffrey F.
    Purpose To determine whether magnetic resonance imaging (MRI) could be used to track changes in skeletal morphology during bone healing using high-resolution micro-computed tomography (μCT) as a standard. We used a mouse model of bone injury to compare μCT with MRI. Materials and Methods Surgery was performed to induce a burr hole fracture in the mouse tibia. A selection of biomaterials was immediately implanted into the fractures. First we optimized the imaging sequences by testing different MRI pulse sequences. Then changes in bone morphology over the course of fracture repair were assessed using in vivo MRI and μCT. Histology was performed to validate the imaging outcomes. Results The rapid acquisition with relaxation enhancement (RARE) sequence provided sufficient contrast between bone and the surrounding tissues to clearly reveal the fracture. It allowed detection of the fracture clearly 1 and 14 days postsurgery and revealed soft tissue changes that were not clear on μCT. In MRI and μCT the fracture was seen at day 1 and partial healing was detected at day 14. Conclusion The RARE sequence was the most suitable for MRI bone imaging. It enabled the detection of hard and even soft tissue changes. These findings suggest that MRI could be an effective imaging modality for assessing changes in bone morphology and pathobiology.
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    The Effect of Transcranial Direct Current Stimulation on GABA and Glx in Children During Motor Learning
    (2019-06-07) Nwaroh, Chidera; Harris, Ashley D.; Kirton, Adam; Bray, Signe L.; Condliffe, Elizabeth G.; Dunn, Jeffrey F.
    Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain activity. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity but there is little information about the underlying mechanisms. Additionally, studies have shown that tDCS can affect local levels of GABA and glutamate both of which are associated with skill acquisition and plasticity. This study aimed to quantify changes in GABA and Glx in response to 5 consecutive days of anodal tDCS or high definition tDCS targeting the M1 in children. Our results suggest HD-tDCS elicits a neurochemical response that is different from anodal tDCS despite resulting in similar motor enhancements. Additionally, we identified a relationship between left sensorimotor cortex GABA and improvements in motor performance. Overall, our results suggest that the developing brain responds differently to tDCS when compared to adult literature.
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    Evaluating endogenous repair of focal cartilage defects in C57BL/6 and MRL/MpJ mice using 9.4 T magnetic resonance imaging: A pilot study
    (Elsevier, 2015-01-09) Mak, J.; Leonard, C.; Foniok, T.; Rushforth, D.; Dunn, Jeffrey F.; Krawetz, R.
    The use of magnetic resonance imaging (MRI) for evaluating joint injuries is often considered superior to radiography due to the capacity of MRI for visualizing both soft and hard tissues. While longitudinal studies regarding cartilage repair have been undertaken on patients and in larger animal models, a method has yet to be developed for mouse cartilage to be repeatedly and non-invasively evaluated over time. The aim of this pilot study was to investigate if morphological changes following a focal cartilage injury in mice could be measured by 9.4T magnetic resonance imaging. Focal cartilage defects were induced in the left knee of 4-6weeks old C57BL/6 and MRL/MpJ mice. At endpoints 0, 2, and 4weeks post-injury, legs were dissected out and imaged ex vivo. The defect could be detected by MRI immediately after injury, appearing as a hyperintense focal point and with size similar to that of the surgical tool used. Defects were visible in both strains up to 4weeks post-injury, although signal intensity decreased over time. One C57BL/6 in particular, displayed extensive fibrosis in the patellar tendon at 4weeks as assessed by histology, while the MR images of the same animal displayed a clear, structural distinction between the patella and the new tissue growth. Overall, our results suggest that MRI could be used for longitudinal studies in murine cartilage injury models to evaluate certain characteristics of repair not detectable through histology.
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    Expanding the Potential Therapeutic Options for Remote Ischemic Preconditioning: Use in Multiple Sclerosis
    (Frontiers Media, 2018-06-19) Cámara-Lemarroy, Carlos Rodrigo; Metz, Luanne M.; Smith, Eric Edward; Dunn, Jeffrey F.; Yong, Voon Wee E.
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    Functional Near-Infrared Spectroscopy Reveals Reduced Interhemispheric Cortical Communication after Pediatric Concussion
    (Mary Ann Liebert, 2015-06-01) Ubran, Karolina J.; Barlow, Karen M.; Jimenez, Jon J.; Goodyear, Bradley G.; Dunn, Jeffrey F.
    Concussion, or mild traumatic brain injury (mTBI), is a growing concern, especially among the pediatric population. By age 25, as many as 30% of the population are likely to have had a concussion. Many result in long-term disability, with some evolving to postconcussion syndrome. Treatments are being developed, but are difficult to assess given the lack of measures to quantitatively monitor concussion. There is no accepted quantitative imaging metric for monitoring concussion. We hypothesized that because cognitive function and fiber tracks are often impacted in concussion, interhemispheric brain communication may be impaired. We used functional near-infrared spectroscopy (fNIRS) to quantify functional coherence between the left and right motor cortex as a marker of interhemispheric communication. Studies were undertaken during the resting state and with a finger-tapping task to activate the motor cortex. Pediatric patients (ages 12–18) had symptoms for 31–473 days, compared to controls, who have not had reported a previous concussion. We detected differences between patients and controls in coherence between the contralateral motor cortices using measurements of total hemoglobin and oxy-hemoglobin with a p < 0.01 (n = 8, control; n = 12 mTBI). Given the critical need for a quantitative biomarker for recovery after a concussion, we present these data to highlight the potential of fNIRS coupled with interhemispheric coherence analysis as a biomarker of concussion injury.
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    Investigating the Relationship Between Cortical Grey Matter Hypoxia and Disability in Multiple Sclerosis
    (2020-06-24) Evans, Taelor; Dunn, Jeffrey F.; Yong, Voon Wee; Kuipers, Hedwich Fardau; Pike, G. Bruce
    Multiple sclerosis (MS) is a progressive neurological disease characterized by inflammation and neurodegeneration. These pathological processes may be mediated by hypoxia, or reduced oxygenation. Thus, hypoxia may contribute to disability and therapeutic outcomes in MS. Near-infrared spectroscopy (NIRS) non-invasively measures absolute cortical oxygenation and can be used to quantify hypoxia. The goal of this thesis was to characterize the prevalence of grey matter (GM) hypoxia in people with MS (PwMS) using NIRS and to relate hypoxia to disability and treatment with disease-modifying therapies (DMTs). Results indicate that 30% of PwMS exhibit hypoxia, which is unexpectedly more common in patients treated with DMTs than untreated subjects. However, no clear association between hypoxia and physical or cognitive disability was observed. Therefore, GM hypoxia may reflect subclinical disease activity, although this needs to be explored. Overall, this thesis validates that NIRS bears potential for clinical use as an adjunctive imaging modality in MS.
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    Local metabolic rate during whole body vibration
    (American Physiological Society, 2013-03-14) Friesenbichler, Bernd; Nigg, Benno M; Dunn, Jeffrey F.
    Whole body vibration (WBV) platforms are currently used for muscle training and rehabilitation. However, the effectiveness of WBV training remains elusive, since scientific studies vary largely in the vibration parameters used. The origin of this issue may be related to a lack in understanding of the training intensity that is imposed on individual muscles by WBV. Therefore, this study evaluates the training intensity in terms of metabolic rate of two lower-extremity muscles during WBV under different vibration parameters. Fourteen healthy male subjects were randomly exposed to 0 (control)-, 10-, 17-, and 28-Hz vibrations while standing upright on a vibration platform. A near-infrared spectrometer was used to determine the gastrocnemius medialis (GM) and vastus lateralis (VL) muscles' metabolic rates during arterial occlusion. The metabolic rates during each vibration condition were significantly higher compared with control for both muscles (P < 0.05). Each increase in vibration frequency translated into a significantly higher metabolic rate than the previous lower frequency (P < 0.05) for both muscles. The current study showed that the local metabolic rate during WBV at 28 Hz was on average 5.4 times (GM) and 3.7 times (VL) of the control metabolic rate. The substantial changes in local metabolic rate indicate that WBV may represent a significant local training stimulus for particular leg muscles.
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    Magnetic Resonance Imaging of Tumor Growth and Leukocyte Infiltration in Brain Tumors after Stimulation of the Innate Immune System
    (2018-06-26) Yang, Run Ze; Yong, Voon Wee; Dunn, Jeffrey F.; Pike, G. Bruce; Kelly, John James Patrick
    Glioblastoma (GBM) is one of the deadliest brain cancers, and immunotherapy may be a promising treatment option. One of the challenges with immunotherapy in GBM is the lack of biomarkers that can be used to detect treatment response early on during treatment. The goal of this thesis is to use MRI to determine whether vitamin B3 (niacin) can suppress GBM growth, and develop a MRI method capable of detecting whether niacin stimulates monocyte trafficking to the brain tumor. We used human and animal derived brain tumor initiating cells for the studies. We used conventional anatomical MRI to show that niacin is capable of reducing tumor growth in the mouse. We showed that innate immune cells can be labeled by ferumoxytol, an iron based MRI contrast agent. This can be used to detect the effects of the innate immune stimulating drugs (Amphotericin B and niacin) in a mouse model of GBM. This is done by intravenously injecting ferumoxytol, and then quantifying iron changes in the tumor with susceptibility MRI. We expanded upon our results to investigate the mechanism of the iron changes after ferumoxytol injection. We used clodronate liposomes to deplete monocytes in the blood and Kupffer cells in the liver and showed that there is minimal passive leakage of ferumoxytol into the tumor, suggesting that ferumoxytol must be carried into the tumor by a phagocytic cell such as monocytes. We implemented another method of measuring ferumoxytol, quantitative susceptibility mapping (QSM), and used it in conjunction with T2* mapping to investigate whether the magnitude of ferumoxytol enhancement is related to future tumor control in niacin treated animals. We found that the degree of ferumoxytol enhancement is directly related to niacin’s ability to control tumor growth, with high ferumoxytol enhancement corresponding to smaller tumors. This thesis showed that niacin treatment can reduce tumor growth by stimulating monocytes. In addition, using ferumoxytol to track the innate immune system is a promising imaging tool to aid the assessment of immunotherapy treatment response in GBM.
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    Postictal behavioural impairments are due to a severe prolonged hypoperfusion/ hypoxia event that is COX-2 dependent
    (eLife Sciences Publications Ltd, 2016-11-22) Farrell, Jordan; Gaxiola-Valdez, Ismael; Wolff, Marshal; David, Laurence; Dika, Haruna; Geeraert, Bryce; Wang, X Rachel; Singh, Shaily; Spanswick, Simon; Dunn, Jeffrey F.; Antle, Michael; Federico, Paolo; Teskey, G Campbell
    Abstract 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.
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    A Tale of Two Methods: Combining Near-Infrared Spectroscopy with MRI for Studies of Brain Oxygenation and Metabolism
    (Kluwer, 2014-03-22) Dunn, Jeffrey F.; Nathoo, Nabeela; Yang, Runze
    Combining magnetic resonance imaging (MRI) with near-infrared spectroscopy (NIRS) leads to excellent synergies which can improve the interpretation of either method and can provide novel data with respect to measuring brain oxygenation and metabolism. MRI has good spatial resolution, can detect a range of physiological parameters and is sensitive to changes in deoxyhemoglobin content. NIRS has lower spatial resolution, but can detect, and with specific technologies, quantify, deoxyhemoglobin, oxyhemoglobin, total hemoglobin and cytochrome oxidase. This paper reviews the application of both methods, as a multimodal technology, for assessing changes in brain oxygenation that may occur with changes in functional activation state or metabolic rate. Examples of hypoxia and ischemia are shown. Data support the concept of reduced metabolic rate resulting from hypoxia/ischemia and that metabolic rate in brain is not close to oxygen limitation during normoxia. We show that multimodal MRI and NIRS can provide novel information for studies of brain metabolism.
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    The pre-ictal state in focal epilepsy
    (2011) Slone, Edward; Federico, Paolo; Dunn, Jeffrey F.
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    Training the Brain to Survive Stroke
    (Public Library of Science, 2012-09-13) Dunn, Jeffrey F.; Wu, Ying; Zhao, Zonghang; Srinivasan, Sathya; Natah, Sirajedin
    Background: 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. Methods and Findings: Rats were exposed to hypoxia (3 weeks living at K an atmosphere). After acclimation, capillary density was measured morphometrically and was increased by 30% in the cortex. Novel implantable oxygen sensors showed that partial pressure of oxygen in the brain was increased by 40% in the normal cortex. Infarcts were induced in brain with 1 h reversible middle cerebral artery occlusions. After ischemia (48 h) behavioural scores were improved and T2 weighted MRI lesion volumes were reduced by 52% in acclimated groups. There was a reduction in inflammation indicated by reduced lymphocytes (by 27–33%), and ED1 positive cells (by 35–45%). Conclusions: It is possible to stimulate a natural adaptive mechanism in the brain which will reduce damage and improve outcome for a given ischemic event. Since these adaptations occur after factors such as HIF-1a have returned to baseline, protection is likely related more to morphological changes such as angiogenesis. Such pre-conditioning, perhaps with exercise or pharmaceuticals, would not necessarily reduce the incidence of stroke, but the severity of damage could be reduced by 50%.
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    Understanding disease processes in multiple sclerosis through magnetic resonance imaging studies in animal models
    (Elsevier, 2014-04-24) Nathoo, Nabeela; Yong, V. Wee; Dunn, Jeffrey F.
    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 ofthe 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.
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    Using magnetic resonance imaging in animal models to guide drug development in multiple sclerosis
    (2013-11-21) Nathoo, Nabeela; Yong, V Wee; Dunn, Jeffrey F.; Beketskaia, Maria
    Major advances are taking place in the development of therapeutics for multiple sclerosis (MS), with a move past traditional immunomodulatory/immunosuppressive therapies toward medications aimed at promoting remyelination or neuroprotection. With an increase in diversity of MS therapies comes the need to assess the effectiveness of such therapies. Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the effectiveness of MS therapeutics in clinical trials. As all new therapeutics for MS are tested in animal models first, it is logical that MRI be incorporated into preclinical studies assessing therapeutics. Here, we review key papers showing how MR imaging has been combined with a range of animal models to evaluate potential therapeutics for MS. We also advise on how to maximize the potential for incorporating MRI into preclinical studies evaluating possible therapeutics for MS, which should improve the likelihood of discovering new medications for the condition.