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News Article | October 26, 2016

DETROIT - Researchers in the Wayne State University School of Medicine's Department of Psychiatry and Behavioral Neurosciences will use a new five-year, $3.2 million grant from the National Institute of Mental Health to explore the underlying mechanisms of impaired learning and memory in schizophrenia from the perspective of brain plasticity, function and network dynamics. The NIMH defines schizophrenia as a chronic and disabling mental disorder that affects how a person thinks, feels and behaves, including loss of reality due to hallucinations, delusions, unusual or dysfunctional ways of thinking, and agitated body movements. People with the condition also have difficulty beginning or sustaining activities, focusing or paying attention, or remembering information immediately after learning it. About 1 percent of the U.S. population -- approximately 2.2 million people -- have schizophrenia, but the neurobiology of the illness remains poorly understood. Principal Investigator and Associate Professor Jeffrey Stanley, Ph.D., and Co-Principal Investigator and Professor Vaibhav Diwadkar, Ph.D., lead the study "Advancing innovative brain imaging to detect altered glutamate modulation and network dynamics in schizophrenia," which was funded on its first submission. The study is the first to combine functional MRI (fMRI) and complex analyses of brain imaging data with innovative measurement of the brain's functional neurochemistry using functional magnetic resonance spectroscopy (fMRS). "While fMRI data are somewhat 'distant' from fundamental neurobiological processes because the signal relies on blood flow that is correlated with -- but distinct from -- neurophysiological and neuro-chemical events, in developing fMRS we are able to measure and quantify changes in hippocampal glutamate in the brain. We have an imaging technique that may provide more direct information about functional changes in the brain," Dr. Stanley said. The combination of approaches will provide objective biological markers of this poorly understood illness. The team plans to explore interventions that may eventually normalize the abnormal markers. "This is a longer-term goal but is central to our collective aims," he added. The duo co-directs the department's Brain Imaging Research Division, which encompasses about 40 staff and student trainees involved in multiple areas of research, including imaging studies into obsessive compulsive disorder, mood disorders, borderline personality disorder, ADHD and reading disabilities, and more. The division has published extensively in the areas of schizophrenia and psychosis in the last seven years, with research supported by the NIMH, the Brain and Behavior Research Foundation, and other private foundations. "Because the pathophysiology of schizophrenia remains obscure, our efforts have been in the area of innovative image analyses and methods development. Schizophrenia is fundamentally a disorder that disrupts cognitive and memory processing, psychological processes that depend on normal communication between brain regions" Diwadkar said. "Therefore, using fMRI, we have primarily been interested in how brain regions fail to 'communicate' appropriately during basic processing. Several of these investigations have zeroed in on the dorsal prefrontal cortex, or dPFC, and the hippocampus, two brain regions that are particularly implicated in the illness. The dPFC has been particularly implicated with regard to the dopamine hypothesis of schizophrenia; the hippocampus has been implicated with regard to the glutamate hypothesis of the illness. "Using complex network analyses of fMRI signals, we have established that in schizophrenia, the dPFC and the hippocampus are characterized by abnormal interactions during associative memory and learning. This is notable because associative memory and learning are related to hippocampal glutamate. Therefore, our fMRI results provide some manner of convergence with neuro-chemical hypotheses of the illness. The addition of fMRS is a logical methodological and scientific extension of these earlier studies, and is entirely unique." The researchers compare their current work to the implications of a biomarker like hypercholesterolemia for cardiac disease, once poorly understood as recently as 60 years ago. "Today, managing cholesterol is a widely accepted treatment pathway in cardiac disease," Diwadkar said. "In many ways, biological psychiatry is in its infancy, yet to better treat neuropsychiatric conditions, understanding the brain is imperative. There is no other organ in the body to which psychiatric illnesses can be related as they can be to dysfunctional processes in the brain." The project, while of substantial scientific and clinical significance, also spotlights the department's dual aims of research and clinical excellence and outreach, and will increase its recruitment possibilities, he said. The department's clinic for Treatment and Research in Behavioral Health located in the Tolan Park Medical Building is likely the only of its kind in Detroit focused on serving patients with schizophrenia and psychosis. "Wayne State is also one of the few places that has the expertise -- personnel like Drs. Stanley and Diwadkar -- and infrastructure to carry out this innovative work that, in real time, can measure brain chemistry and function/whole brain network function/dysfunction," said Department of Psychiatry and Behavioral Neurosciences Chair and Professor David Rosenberg, M.D. "Dr. Stanley is an internationally recognized physicist, and this is his second R01 as a principal investigator. Dr. Diwadkar is a renowned cognitive neuroscientist, with worldwide collaborations." The research relies on the clinical support of Psychiatry's Vice Chair for Clinical Services Alireza Amirsadri, M.D., and Vice Chair for Education and Resident Training Richard Balon, M.D., with recruitment efforts aided by Assistant Professor Luay Haddad, M.D., and Professor Manuel Tancer, M.D. The team's research endeavors have also been supported by the department and its chair, Rosenberg, and involves members of the division's core research and recruitment team, including Dalal Khatib, Patricia Thomas, Usha Rajan, Caroline Zajac-Benitez, Asadur Chowdhary and Ashley Burgess, and the clinic team of Ed Mischel, Albert Pizzuti, Jaclynne Burns, and numerous other clinicians and social workers. The grant number for this project is HD089875. Wayne State University is one of the nation's pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit

Song J.,Imaging Research | Hynynen K.,Sunnybrook Health Science Center
IEEE Transactions on Biomedical Engineering | Year: 2010

A hemispherical-focused, ultrasound phased array was designed and fabricated using 1372 cylindrical piezoelectric transducers that utilize lateral coupling for noninvasive transcranial therapy. The cylindrical transducers allowed the electrical impedance to be reduced by at least an order of magnitude, such that effective operation could be achieved without electronic matching circuits. In addition, the transducer elements generated the maximum acoustic average surface intensity of 27 W/cm 2. The array, driven at the low (306-kHz) or high frequency (840-kHz), achieved excellent focusing through an ex vivo human skull and an adequate beam steering range for clinical brain treatments. It could electronically steer the ultrasound beam over cylindrical volumes of 100-mm in diameter and 60-mm in height at 306 kHz, and 30-mm in diameter and 30-mm in height at 840 kHz. A scanning laser vibrometer was used to investigate the radial and length mode vibrations of the element. The maximum pressure amplitudes through the skull at the geometric focus were predicted to be 5.5 MPa at 306 kHz and 3.7 MPa at 840 kHz for RF power of 1 W on each element. This is the first study demonstrating the feasibility of using cylindrical transducer elements and lateral coupling in construction of ultrasound phased arrays. © 2009 IEEE.

Chan R.W.,University of Toronto | Ramsay E.A.,Imaging Research | Cheung E.Y.,University of Waterloo | Plewes D.B.,University of Toronto | Plewes D.B.,Imaging Research
Magnetic Resonance in Medicine | Year: 2012

Fast imaging applications in magnetic resonance imaging (MRI) frequently involve undersampling of k-space data to achieve the desired temporal resolution. However, high temporal resolution images generated from undersampled data suffer from aliasing artifacts. In radial k-space sampling, this manifests as undesirable streaks that obscure image detail. Compressed sensing reconstruction has been shown to reduce such streak artifacts, based on the assumption of image sparsity. Here, compressed sensing is implemented with three different radial sampling schemes (golden-angle, bit-reversed, and random sampling), which are compared over a range of spatiotemporal resolutions. The sampling methods are implemented in static scenarios where different undersampling patterns could be compared. Results from point spread function studies, simulations, phantom and in vivo experiments show that the choice of radial sampling pattern influences the quality of the final image reconstructed by the compressed sensing algorithm. While evenly undersampled radial trajectories are best for specific temporal resolutions, golden-angle radial sampling results in the least overall error when various temporal resolutions are considered. Reduced temporal fluctuations from aliasing artifacts in golden-angle sampling translates to improved compressed sensing reconstructions overall. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Boyd N.F.,Ontario Cancer Institute | Martin L.J.,Ontario Cancer Institute | Bronskill M.,Imaging Research | Yaffe M.J.,Imaging Research | And 5 more authors.
Journal of the National Cancer Institute | Year: 2010

Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate X-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography. © 2010 The Author.

Boyd N.F.,Campbell University | Boyd N.F.,Ontario Cancer Institute | Martin L.J.,Campbell University | Martin L.J.,Ontario Cancer Institute | And 2 more authors.
Breast Cancer Research | Year: 2011

Variations in percent mammographic density (PMD) reflect variations in the amounts of collagen and number of epithelial and non-epithelial cells in the breast. Extensive PMD is associated with a markedly increased risk of invasive breast cancer. The PMD phenotype is important in the context of breast cancer prevention because extensive PMD is common in the population, is strongly associated with risk of the disease, and, unlike most breast cancer risk factors, can be changed. Work now in progress makes it likely that measurement of PMD will be improved in the near future and that understanding of the genetics and biological basis of the association of PMD with breast cancer risk will also improve. Future prospects for the application of PMD include mammographic screening, risk prediction in individuals, breast cancer prevention research, and clinical decision making. © 2010 BioMed Central Ltd.

Chopra R.,Imaging Research | Chopra R.,University of Toronto | Vykhodtseva N.,Brigham and Women's Hospital | Hynynen K.,Imaging Research | Hynynen K.,University of Toronto
ACS Chemical Neuroscience | Year: 2010

Pulsed ultrasound exposures of brain tissue in the presence of microbubble contrast agents have been shown to achieve transient focal disruption of the blood-brain barrier without significant damage to surrounding brain tissue. The effects of overall exposure duration on the extent of blood-brain barrier disruption was studied in these experiments to determine operating conditions for increasing the amount of therapeutic agents delivered to the brain. Exposures at 1.08 MHz ranging from 0.2 to 0.8 MPa in amplitude were delivered transcranially to the brains of rabbits and rats for durations ranging from 30 to 1200 s. The amount of signal enhancement on contrast-enhanced T1-weighted MR images were used to quantify the extent of blood-brain barrier disruption, and histological evaluation of the exposed regions was performed to evaluate the impact on brain tissue. A subset of four rats underwent weekly exposures for 3 weeks to evaluate the feasibility of repeat sonications to the brain. The results suggest that exposures less than 180 s in duration are associated with a low probability of irreversible damage to brain tissue at pressure amplitudes of 0.38 MPa. Although exposures greater than 300 s were associated with an increase in the proportion of irreversible damage, this may be acceptable for chemotherapy delivery, where the therapeutic goal is tissue destruction. Repeat exposures to the brain were feasible but resulted in evidence of focal brain damage in 50% of animals. © 2010 American Chemical Society.

Wright C.,Imaging Research | Wright C.,University of Toronto | Hynynen K.,Imaging Research | Hynynen K.,University of Toronto | And 2 more authors.
Investigative Radiology | Year: 2012

Objectives: To characterize the ability of high-intensity focused ultrasound to achieve thrombolysis in vitro and investigate the feasibility of this approach as a means of restoring blood flow in thrombus-occluded arteries in vivo. Materials and Methods: All experiments were approved by the Institutional Animal Care Committee. Thrombolysis was performed with a 1.51-MHz focused ultrasound transducer with pulse lengths of 0.1 to 10 milliseconds and acoustic powers up to 300 W. In vitro experiments were performed with blood clots formed from rabbit arterial blood and situated in 2-mm diameter tubing. Both single location and flow bypass recanalization experiments were conducted. In vitro clot erosion was assessed with 30-MHz ultrasound, with debris size measured with filters and a Coulter counter. In vivo clots were initiated in the femoral arteries of rabbits (n = 26). Cavitation signals from bubbles formed during exposure were monitored. In vivo flow restoration was assessed with 23-MHz Doppler ultrasound. Results: At a single location, in vitro clot erosion volumes increased with exposure power and pulse length, with debris size reducing with increasing pulse length. Flow bypass experiments achieved 99.2% clot erosion with 1.1% of debris above 0.5 mm in size. In vivo, 10 milliseconds pulses were associated with bleeding, but at 1 millisecond, it was feasible to achieve partial flow restoration in 6of the 10 clots with only 1of the 10 showing evidence of bleeding. In all cases, thrombolysis occurred only in the presence of cavitation. Conclusion: High-intensity focused ultrasound thrombolysis is feasible as a means of restoring partial blood flow in thrombus-occluded arteries in the absence of thrombolytic agents. The potential for bleeding with this approach requires further investigation. © 2012 by Lippincott Williams & Wilkins.

Schad K.C.,Imaging Research | Schad K.C.,University of Toronto | Hynynen K.,Imaging Research | Hynynen K.,University of Toronto
Physics in Medicine and Biology | Year: 2010

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment is difficult as bioeffects can occur outside of the target region. Spatial control of bubbles can be achieved by ultrasound-induced conversion of liquid perfluorocarbon droplets to gas bubbles. This study was undertaken to determine the acoustic parameters for bubble production by droplet conversion and how it depends on the acoustic conditions and droplet physical parameters. Lipid-encapsulated droplets containing dodecafluoropentane were manufactured with sizes ranging from 1.9 to 7.2 μm in diameter and diluted to a concentration of 8 × 106 droplets mL-1. The droplets were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure under flow conditions through an acoustically transparent vessel. The sonications were 10 ms in duration at frequencies of 0.578, 1.736 and 2.855 MHz. The pressure threshold for droplet conversion was measured with an active transducer operating in pulse-echo mode and simultaneous measurements of broadband acoustic emissions were performed with passive acoustic detection. The results show that droplets cannot be converted at low frequency without broadband emissions occurring. However, the pressure threshold for droplet conversion decreased with increasing frequency, exposure and droplet size. The pressure threshold for broadband emissions was independent of the droplet size and was 2.9, 4.4 and 5.3 MPa for 0.578, 1736 and 2.855 MHz, respectively. In summary, we have demonstrated that droplet conversion is feasible for clinically relevant sized droplets and acoustic exposures. © 2010 Institute of Physics and Engineering in Medicine.

News Article | March 4, 2016

Inside our brains nerve cells signal each other using neurotransmitters including carbon monoxide (CO) and nitric oxide (NO) gases. Besides sharing a number of biological and chemical characteristics, CO and NO work together in regulating many physiological processes including vasodilatation, and immune reaction. Accurate and quantitative measurements of their physiological levels have been seen to result in meaningful findings and the focus of many previous studies. However their similarities have prevented such effort from cracking the entangled bond between CO and NO. A research team from the Center for Neuroscience Imaging Research within the Institute for Basic Science Center (IBS) has devised a precise and fast responding tool that for the first time, enables completely separate and simultaneous, in-vivo measurements of CO and NO gases. The IBS team has monitored their levels in real time during a seizure event and confirmed that CO and NO are closely involved in the activation of neuronal cells. The dual sensor is an amperometric microdevice, which is an electrical detection tool that is able to discern one specific molecule in a pool of many substances and count its concentration. What makes this so special is that the IBS device packs two separate sensors–one for CO, the other for NO exclusively–which can record in real time into a 300-µm probe, roughly twice the diameter of a human hair. The probe is a construction of a 76-µm and a 50-µm platinum wires encased in thin, pulled glass capillary. The sensing tips of the probe are made of one gold and one platinum layers electroplated onto platinum substrates electrochemically etched to create recessed pores, resulting in a greater surface area (thus a higher sensitivity) for CO/NO detection. The fluorinated xerogel covering the tip prevents other biological interferents from obstructing the probe and allows the CO/NO gases to pass through selectively. With miniaturized size and tapered needle-like shape, the dual sensor allowed the IBS team to record CO/NO within tissue during an acute seizure. Immediately after probe insertion, the IBS team was able to monitor almost dynamic changes in CO/NO levels. Seizures have three distinct phases: initiation, propagation and termination. The dual sensor probe was able to record clearly defined changes in CO/NO levels which changed in accordance to the seizure's phase changes. Dr. Minah Suh of the research group said, "Subsequent further study needs to be performed for the clarification of a correlation between each seizure type and the associated pattern of CO/NO changes." Dr. Suh added "Further studies will help to give more insights into the function and response of these neurotransmitters, laying the foundation for therapeutic applications for neuronal diseases." Explore further: Scrutinising the tip of molecular probes More information: Yejin Ha et al. Insertable Fast-Response Amperometric NO/CO Dual Microsensor: Study of Neurovascular Coupling During Acutely Induced Seizures of Rat Brain Cortex, Analytical Chemistry (2016). DOI: 10.1021/acs.analchem.5b04288

News Article | September 13, 2016

Research from Indiana University has found that structured block-building games improve spatial abilities in children to a greater degree than board games. The study, which appears in the journal Frontiers in Psychology, measured the relative impact of two games -- a structured block-building game and a word-spelling board game -- on children’s spatial processing. Such processing includes mental rotation, which involves visualizing what an object will look like after it is rotated. The research lends new support to the idea that such block games might help children develop spatial skills needed in science- and math-oriented disciplines. It is also the first study to use neuroimaging to explore the effects of block building on brain activity, saidSharlene Newman, a professor in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, who led the research. "Block play changed brain activation patterns," Newman said. "It changed the way the children were solving the mental rotation problems; we saw increased activation in regions that have been linked to spatial processing only in the building blocks group." The structured block-building game used for the study was called "Blocks Rock"; the board game was Scrabble. The research builds upon previous studies that have shown that children who frequently participate in activities such as block play, puzzles and board games have higher spatial ability than those who participate more in activities such as drawing, riding bikes, or playing with trucks and sound-producing toys. It is also demonstrates that training on one visuospatial task can transfer to other tasks. In this instance, training on the structured block-building game resulted in transfer to mental rotation performance. "Other studies look solely at behavioral changes, such as the improved performance on measures of spatial ability," Newman said. "We're actually scanning the brain." To conduct the study, IU researchers placed 28 8-year-olds in a magnetic resonance imaging scanner before and after playing one of the two games. Play sessions were conducted for 30 minutes over the course of five days. To create an equal distribution of spatial ability between the two groups from the start, the children were divided evenly according to several categories that have been linked to differences in spatial ability: gender, age, musical training, mathematical skill and socio-economic status. The two groups of 14 children also took a mental rotation test while inside the scanner, both before and after playing the games. The test -- a longstanding measure of spatial visualization and analysis -- presents two versions of the same letter, and the children had to decide whether the second letter was simply a rotated version of the same letter or a rotated mirror image of that letter. There were no differences in mental rotation performance between the two groups in either the brain activation or performance during the first rotation test and scan. But the block play group showed a change in activation in regions linked to both motor and spatial processing during the second scan. The group who played board games failed to show any significant change in brain activation between the pre- and post-game scans, or any significant improvement on the mental rotation test results. Insofar as the spatial abilities of 8-year-olds are still developing, Newman said the change from the first scan to the second scan might reflect a shift in the strategy used to solve the mental rotation problems. In other words, as children develop their spatial abilities, they may move from a piecemeal strategy in which they analyze the internal relations or parts of an image to a holistic strategy in which the image as a whole is mentally rotated. "The block play group showed a change in activation in regions linked to both motor and spatial processing," Newman added. "This raises the possibility that the block play group changed how they were performing the mental rotation task after training." Ultimately, Newman, who in other work has explored the relationship between math and spatial reasoning, hopes that such findings will help students struggling with math and other disciplines. "Any way you can improve a child's mathematical competence, whether through block-building or any other method, that's where my interest lies," she said. Newman is also the director of the IU Imaging Research Facility and associate vice provost of undergraduate education at IU Bloomington. Other IU researchers on the study were Mitchell Hansen, an undergraduate student, and Arianna Gutierrez, a research associate who was an undergraduate at the time of the study. Both are members of the IU Bloomington Department of Psychological and Brain Sciences.

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