Development and implementation of a case-based collaborative learning flipped classroom preclinical neurology course.

This paper describes the development, content, structure, and implementation of a case-based collaborative learning, flipped classroom, integrated preclinical neurology, neuroanatomy, and neuroscience course for first year medical students at Harvard Medical School. We report the methods for pre-class preparation, in-class instruction, and evaluation; student feedback with respect to content, teaching method, and learning environment; and several lessons learned regarding how to optimize preparatory and in-class learning in a case-based flipped classroom course.

Transformation of Undergraduate Medical Education in 2023.

This Viewpoint discusses potential shifts in teaching and learning for undergraduate medical education with the advent of artificial intelligence tools.

Advanced Integrated Science Courses: Building a Skill Set to Engage With the Interface of Research and Medicine.

Scientific research has been changing medical practice at an increasing pace. To keep up with this change, physicians of the future will need to be lifelong learners with the skills to engage with emerging science and translate it into clinical care. How medical schools can best prepare students for ongoing scientific change remains unclear. Adding to the challenge is reduced time allocated to basic science in curricula and rapid expansion of relevant scientific fields. A return to science with greater depth after clinical clerkships has been suggested, although few schools have adopted such curricula and implementation can present challenges. The authors describe an innovation at Harvard Medical School, the Advanced Integrated Science Courses (AISCs), which are taken after core clerkships. Students are required to take 2 such courses, which are offered in a variety of topics. Rather than factual content, the learning objectives are a set of generalizable skills to enable students to critically evaluate emerging research and its relationship to medical practice. Making these generalizable skills the defining principle of the courses has several important advantages: it allows standardization of acquired skills to be combined with diverse course topics ranging from basic to translational and population sciences; students can choose courses and projects aligned with their interests, thereby enhancing engagement, curiosity, and career relevance; schools can tailor course offerings to the interests of local faculty; and the generalizable skills delineate a unique purpose of these courses within the overall medical school curriculum. For the 3 years AISCs have been offered, students rated the courses highly and reported learning the intended skill set effectively. The AISC concept addresses the challenge of preparing students for this era of rapidly expanding science and should be readily adaptable to other medical schools.

The Harvard Medical School Pathways Curriculum: Reimagining Developmentally Appropriate Medical Education for Contemporary Learners.

As the U.S. health care system changes and technology alters how doctors work and learn, medical schools and their faculty are compelled to modify their curricula and teaching methods. In this article, educational leaders and key faculty describe how the Pathways curriculum was conceived, designed, and implemented at Harvard Medical School. Faculty were committed to the principle that educators should focus on how students learn and their ability to apply what they learn in the evaluation and care of patients. Using the best evidence from the cognitive sciences about adult learning, they made major changes in the pedagogical approach employed in the classroom and clinic. The curriculum was built upon 4 foundational principles: to enhance critical thinking and provide developmentally appropriate content; to ensure both horizontal integration between courses and vertical integration between phases of the curriculum; to engage learners, foster curiosity, and reinforce the importance of student ownership and responsibility for their learning; and to support students' transformation to a professional dedicated to the care of their patients and to their obligations for lifelong, self-directed learning.The practice of medicine is rapidly evolving and will undoubtedly change in multiple ways over the career of a physician. By emphasizing personal responsibility, professionalism, and thinking skills over content transfer, the authors believe this curriculum will prepare students not only for the first day of practice but also for an uncertain future in the biological sciences, health and disease, and the nation's health care system, which they will encounter in the decades to come.

Noninvasive Brain Stimulation in Epilepsy.

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

Precise Identification of Cell and Tissue Features Important for Histopathologic Diagnosis by a Whole Slide Imaging System.

BACKGROUND: Previous studies have demonstrated the noninferiority of pathologists' interpretation of whole slide images (WSIs) compared to microscopic slides in diagnostic surgical pathology; however, to our knowledge, no published studies have tested analytical precision of an entire WSI system. METHODS: In this study, five pathologists at three locations tested intra-system, inter-system/site, and intra- and inter-pathologist precision of the Aperio AT2 DX System (Leica Biosystems, Vista, CA, USA). Sixty-nine microscopic slides containing 23 different morphologic features suggested by the Digital Pathology Association as important to diagnostic pathology were identified and scanned. Each of 202 unique fields of view (FOVs) had 1-3 defined morphologic features, and each feature was represented in three different tissues. For intra-system precision, each site scanned 23 slides at three different times and one pathologist interpreted all FOVs. For inter-system/site precision, all 69 slides were scanned once at each of three sites, and FOVs from each site were read by one pathologist. To test intra- and inter-pathologist precision, all 69 slides were scanned at one site, FOVs were saved in three different orientations, and the FOVs were transferred to a different site. Three different pathologists then interpreted FOVs from all 69 slides. Wildcard (unscored) slides and washout intervals were included in each study. Agreement estimates with 95% confidence intervals were calculated. RESULTS: Combined precision from all three studies, representing 606 FOVs in each of the three studies, showed overall intra-system agreement of 97.9%; inter-system/site agreement was 96%, intra-pathologist agreement was 95%, and inter-pathologist agreement was 94.2%. CONCLUSIONS: Pathologists using the Aperio AT2 DX System identified histopathological features with high precision, providing increased confidence in using WSI for primary diagnosis in surgical pathology.

Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions.

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.

Fostering Student-Faculty Partnerships for Continuous Curricular Improvement in Undergraduate Medical Education.

PROBLEM: A number of medical schools have used curricular reform as an opportunity to formalize student involvement in medical education, but there are few published assessments of these programs. Formal evaluation of a program's acceptability and use is essential for determining its potential for sustainability and generalizability. APPROACH: Harvard Medical School's Education Representatives (Ed Reps) program was created in 2015 to launch alongside a new curriculum. The program aimed to foster partnerships between faculty and students for continuous and real-time curricular improvement. Ed Reps, course directors, and core faculty met regularly to convey bidirectional feedback to optimize the learning environment in real time. OUTCOMES: A survey to assess the program's impact was sent to students and faculty. The majority of students (202/222; 91.0%) reported Ed Reps had a positive impact on the curriculum. Among faculty, 35/37 (94.6%) reported making changes to their courses as a result of Ed Reps feedback, and 34/37 (91.9%) agreed the program had a positive impact on the learning environment. Qualitative feedback from students and faculty demonstrated a change in school culture, reflecting the primary goals of partnership and continuous quality improvement (CQI). NEXT STEPS: This student-faculty partnership demonstrated high rates of awareness, use, and satisfaction among faculty and students, suggesting its potential for local sustainability and implementation at other schools seeking to formalize student engagement in CQI. Next steps include ensuring the feedback provided is representative of the student body and identifying new areas for student CQI input as the curriculum becomes more established.

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy.

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Third International Congress on Epilepsy, Brain, and Mind: Part 2.

Epilepsy is both a disease of the brain and the mind. Here, we present the second of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Humanistic, biologic, and therapeutic aspects of epilepsy, particularly those related to the mind, were discussed. The extended summaries provide current overviews of epilepsy, cognitive impairment, and treatment, including brain functional connectivity and functional organization; juvenile myoclonic epilepsy; cognitive problems in newly diagnosed epilepsy; SUDEP including studies on prevention and involvement of the serotoninergic system; aggression and antiepileptic drugs; body, mind, and brain, including pain, orientation, the "self-location", Gourmand syndrome, and obesity; euphoria, obsessions, and compulsions; and circumstantiality and psychiatric comorbidities.

Physiological consequences of abnormal connectivity in a developmental epilepsy.

OBJECTIVE: Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. METHODS: We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. RESULTS: Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. INTERPRETATION: Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions.

The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development.

Mutations in GPR56, a member of the adhesion G protein-coupled receptor family, cause a human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Magnetic resonance imaging (MRI) of BFPP brains reveals myelination defects in addition to brain malformation. However, the cellular role of GPR56 in oligodendrocyte development remains unknown. Here, we demonstrate that loss of Gpr56 leads to hypomyelination of the central nervous system in mice. GPR56 levels are abundant throughout early stages of oligodendrocyte development, but are downregulated in myelinating oligodendrocytes. Gpr56-knockout mice manifest with decreased oligodendrocyte precursor cell (OPC) proliferation and diminished levels of active RhoA, leading to fewer mature oligodendrocytes and a reduced number of myelinated axons in the corpus callosum and optic nerves. Conditional ablation of Gpr56 in OPCs leads to a reduced number of mature oligodendrocytes as seen in constitutive knockout of Gpr56. Together, our data define GPR56 as a cell-autonomous regulator of oligodendrocyte development.