Patrick E. Steadman

Performing label-fusion-based segmentation using multiple automatically generated templates.

Classically, model‐based segmentation procedures match magnetic resonance imaging (MRI) volumes to an expertly labeled atlas using nonlinear registration. The accuracy of these techniques are limited due to atlas biases, misregistration, and resampling error. Multi‐atlas‐based approaches are used as a remedy and involve matching each subject to a number of manually labeled templates. This approach yields numerous independent segmentations that are fused using a voxel‐by‐voxel label‐voting procedure. In this article, we demonstrate how the multi‐atlas approach can be extended to work with input atlases that are unique and extremely time consuming to construct by generating a library of multiple automatically generated templates of different brains (MAGeT Brain). We demonstrate the efficacy of our method for the mouse and human using two different nonlinear registration algorithms (ANIMAL and ANTs). The input atlases consist a high‐resolution mouse brain atlas and an atlas of the human basal ganglia and thalamus derived from serial histological data. MAGeT Brain segmentation improves the identification of the mouse anterior commissure (mean Dice Kappa values (κ = 0.801), but may be encountering a ceiling effect for hippocampal segmentations. Applying MAGeT Brain to human subcortical structures improves segmentation accuracy for all structures compared to regular model‐based techniques (κ = 0.845, 0.752, and 0.861 for the striatum, globus pallidus, and thalamus, respectively). Experiments performed with three manually derived input templates suggest that MAGeT Brain can approach or exceed the accuracy of multi‐atlas label‐fusion segmentation (κ = 0.894, 0.815, and 0.895 for the striatum, globus pallidus, and thalamus, respectively). Hum Brain Mapp 34:2635–2654, 2013.

Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion

Recurrent deletions at the 22q11.2 locus have been established as a strong genetic risk factor for the development of schizophrenia and cognitive dysfunction. Individuals with 22q11.2 deletions have a range of well-defined volumetric abnormalities in a number of critical brain structures. A mouse model of the 22q11.2 deletion (Df(16)A+/−) has previously been utilized to characterize disease-associated abnormalities on synaptic, cellular, neurocircuitry, and behavioral levels. We performed a high-resolution MRI analysis of mutant mice compared with wild-type littermates. Our analysis revealed a striking similarity in the specific volumetric changes of Df(16)A+/− mice compared with human 22q11.2 deletion carriers, including in cortico-cerebellar, cortico-striatal and cortico-limbic circuits. In addition, higher resolution magnetic resonance imaging compared with neuroimaging in human subjects allowed the detection of previously unknown subtle local differences. The cerebellar findings in Df(16)A+/− mice are particularly instructive as they are localized to specific areas within both the deep cerebellar nuclei and the cerebellar cortex. Our study indicates that the Df(16)A+/−mouse model recapitulates most of the hallmark neuroanatomical changes observed in 22q11.2 deletion carriers. Our findings will help guide the design and interpretation of additional complementary studies and thereby advance our understanding of the abnormal brain development underlying the emergence of 22q11.2 deletion-associated psychiatric and cognitive symptoms.

MRI-detectable changes in mouse brain structure induced by voluntary exercise.

Physical exercise, besides improving cognitive and mental health, is known to cause structural changes in the brain. Understanding the structural changes that occur with exercise as well as the neuroanatomical correlates of a predisposition for exercise is important for understanding human health. This study used high-resolution 3D MR imaging, in combination with deformation-based morphometry, to investigate the macroscopic changes in brain structure that occur in healthy adult mice following four weeks of voluntary exercise. We found that exercise induced changes in multiple brain structures that are involved in motor function and learning and memory including the hippocampus, dentate gyrus, stratum granulosum of the dentate gyrus, cingulate cortex, olivary complex, inferior cerebellar peduncle and regions of the cerebellum. In addition, a number of brain structures, including the hippocampus, striatum and pons, when measured on MRI prior to the start of exercise were highly predictive of subsequent exercise activity. Exercise tended to normalize these pre-existing differences between mice.

The Effectiveness of a Student Volunteer Program for Research in a Pediatric Emergency Department

BACKGROUND Emergency Department (ED) student-based research assistant programs have been shown to be effective in enrolling patients when the students receive university course credit or pay. However, the impact on research outcomes when university students act as volunteers in this role is relatively unknown. OBJECTIVES The main objective of this study was to determine how often potentially eligible children were accurately identified by volunteer research assistants for enrollment into prospective research in the ED. We also examined the frequency of successful enrollments and the accuracy of data capture. METHODS This was a prospective cross-sectional study of university student volunteer research assistant performance in a tertiary care pediatric ED between March 2011 and July 2013. The participants primary role was to screen and facilitate enrollment of ED patients into clinical research. For each volunteer, we recorded demographics, number of screenings, enrollments, and data capture accuracy. RESULTS Over five 6-month sessions, 151 student volunteers participated. Of these, 77.3% were female, 58.8% were undergraduate students, and 61.1% were interested in medical school. Student volunteers accurately screened 11,362/13,067 (87.0%) children, and they accurately identified 4407/4984 (88.4%) potentially eligible children for study enrollment. Of the 3805 eligible for enrollment exclusively by the students, 3228 (84.8%) families/children consented and completed all study procedures. Furthermore, students correctly entered 11,660/12,567 (92.8%) data points. CONCLUSIONS Utilizing university student volunteers to facilitate research enrollment in the ED is effective and allows for the capture of a high percentage of potentially eligible patients into prospective clinical research studies.

Implementation of a volunteer university student research assistant program in an emergency department: the nuts and bolts for success.

Prospective research studies often advance clinical practice in the emergency department (ED), but they can be costly and difficult to perform. In this report, we describe the implementation of a volunteer university student research assistant program that provides students exposure to medicine and clinical research while simultaneously increasing the capacity of an EDs research program. This type of program provides 15 hours per day of research assistant coverage for patient screening and enrolment for minimal risk research studies, and screening for higher risk studies. The latter is true without the added burden or costs of co-administering university course credit or pay for service, which are common features of most of these types of programs currently in operation. We have shown that our volunteer-based program is effective for an EDs research success as well as for its student participants. For other EDs interested in adopting similar programs, we provide the details on how to get such a program started and highlight the structure and non-monetary incentives that facilitate a programs ongoing success.

A highly specific pattern of volumetric brain changes due to 22q11.2 deletions in both mice and humans.

A highly specific pattern of volumetric brain changes due to 22q11.2 deletions in both mice and humans

Characteristics and outcomes of Canadian MD/PhD program graduates: a cross-sectional survey

BACKGROUND Combined MD/PhD programs provide a structured path for physician-scientist training, but assessment of their success within Canada is limited by a lack of quantitative data. We collected outcomes data for graduates of Canadian MD/PhD programs. METHODS We developed and implemented a Web-based survey consisting of 41 questions designed to collect outcomes data for Canadian MD/PhD program alumni from 8 Canadian universities who had graduated before September 2015. Respondents were categorized into 2 groups according to whether they had or had not completed all training. RESULTS Of the 186 eligible alumni of MD/PhD programs, 139 (74.7%) completed the survey. A total of 136/138 respondents (98.6%) had completed or were currently completing residency training, and 66/80 (82%) had completed at least 1 postgraduate fellowship. Most (58 [83%]) of the 70 respondents who had completed all training were appointed as faculty at academic institutions, and 37 (53%) had been principal investigators on at least 1 recent funded project. Among the 58 respondents appointed at academic institutions, 44/57 (77%) dedicated at least 20% of their time to research, and 25/57 (44%) dedicated at least 50% to research. During their combined degree, 102/136 respondents (75.0%) published 3 or more first-author papers, and 133/136 (97.8%) matched with their first choice of specialty. The median length of physician-scientist training was 13.5 years. Most respondents graduated with debt despite having been supported by Canadian Institutes of Health Research MD/PhD studentships. INTERPRETATION Most Canadian MD/PhD program alumni pursued careers consistent with their physician-scientist training, which indicates that these programs are meeting their primary objective. Nevertheless, our findings highlight that a minority of these positions are research intensive; this finding warrants further study. Our data provide a baseline for future monitoring of the output of Canadian MD/PhD programs.

Assessing Individual Neuronal Activity Across the Intact Brain: Using Hybridization Chain Reaction (HCR) to Detect Arc mRNA Localized to the Nucleus in Volumes of Cleared Brain Tissue

Arc (activity‐regulated cytoskeleton‐associated protein) is an immediate early gene that may be used to label recently active neurons. Arc is transcribed following neuronal activity, and its mRNA is then rapidly transported to dendrites. This feature allows nuclear‐localized Arc mRNA to define ensembles of recently active neurons in systems or circuit neuroscience. However, typical in situ hybridization techniques severely constrain the thickness of the tissue specimen (typically 20‐µm brain slices). Here, we describe a protocol for visualizing intranuclear Arc mRNA in large (4 × 4 × 3 mm) volumes of intact mouse brain tissue. We combined a tissue clearing protocol (iDISCO+) with an advanced in situ hybridization technique (hybridization chain reaction [HCR]) to detect nuclear‐localized Arc mRNA in whole, intact brain regions without the need for brain sectioning or reconstruction. We successfully applied this protocol to image ensembles of neurons of the basolateral amygdala in mice that are active following the recall of a conditioned fear memory.

Training the next generation of Canadian Clinician-Scientists: charting a path to success

Clinician-scientists are physicians with training in both clinical medicine and research that enables them to occupy a unique niche as specialists in basic and translational biomedical research. While there is widespread acknowledgement of the importance of clinician-scientists in todays landscape of evidence-based medical practice, training of clinician-scientists in Canada has been on the decline, with fewer opportunities to obtain funding. With the increasing length of training and lower financial compensation, fewer medical graduates are choosing to pursue such a career. MD-PhD programs, in which trainees receive both medical and research training, have the potential to be an important tool in training the next generation of clinician-scientists; however, MD-PhD trainees in Canada face barriers that include an increase in medical school tuition and a decrease in the amount of financial support. We examined the available data on MD-PhD training in Canada and identified a lack of oversight, a lack of funding and poor mentorship as barriers experienced by MD-PhD trainees. Specific recommendations are provided to begin the process of addressing these challenges, starting with the establishment of an overseeing national body that would track long-term outcome data for MD-PhD trainees. This national body could then function to implement best practices from individual programs across the country and to provide further mentorship and support for early-career physician-scientists. MD-PhD programs have the potential to address Canadas growing shortage of clinician-scientists, and strengthening MD-PhD programs will help to effect positive change.