- New study shows ‘exquisitely’ organized network interactions in the adolescent brain underpin attention processing
In Headlines on May 26, 2016
Vaibhav Diwadkar, Ph.D.
Dynamic brain network interactions in the healthy adolescent brain are remarkably more sophisticated and sensitive to attention demand than has been previously demonstrated.
That is one takeaway from a seminal publication led by Pranav Jagtap, a fourth-year medical student in the Wayne State University School of Medicine’s Department of Psychiatry and Behavioral Neurosciences. His paper on “Effective Connectivity of Ascending and Descending Frontal-thalamic Pathways During Sustained Attention: Complex Brain Network Interactions in Adolescence,” is slated for the June issue of the journal Human Brain Mapping and demonstrates “the beautiful and exquisite functional optimization of the adolescent brain,” said Vaibhav Diwadkar, Ph.D., associate professor and senior author on the study.
In the study, the investigative team collected functional magnetic resonance imaging, or fMRI, signals in a group of healthy adolescents (11 to 19 years old) during a sustained attention task. Sustained attention is the ability to maintain focus or remain vigilant for long periods of time. Impaired attention often emerges in adolescence, and is observed across multiple psychiatric illnesses, most obviously in attention deficit hyperactivity disorder. Understanding attention mechanisms in the healthy adolescent brain is of particularly high clinical relevance. The team’s focus on this behavioral domain reflects a search for discovering brain network mechanisms, that if identified might inform understanding of many of these clinical syndromes.
“Sustained attention and vigilance are foundational elements of behavioral function, and a pre-requisite for many more complex behaviors. Moreover, the demands of sustained attention vary, sometimes being very intense and sometimes being very light,” said Dr. Diwadkar said, who co-directs the department’s Brain Imaging Research Division.
“Of course, the brain can implement sophisticated behaviors like sustained attention, largely because it is itself a complex network. In the past, imaging studies have typically focused on characterizing isolated activity of brain regions. Yet, it is now widely accepted that it is only through sophisticated discovery of network connectivity between regions that we can understand mechanisms of complex behavior. Discovering this connectivity is a non-trivial problem; yet this process of discovery is crucial if we are to understand how the brain ‘works.’ This was the major thrust of this work,” he added.
The sustained attention task used in the study varied attention demand and induced dynamics in fMRI signals across multiple brain regions. Changes in the fMRI signal contain information about the brain’s network interactions that can be recovered using complex analytic methods. The team focused on interactions between the prefrontal cortex and the thalamus, two brain regions previously shown to have important roles in sub-serving attention. The thalamus has been called the ‘gateway’ to the cortex, and signals from the thalamus are fed upward to cortical regions such as the prefrontal cortex for more elaborate processing. “However, the cortex can modify how the thalamus functions through descending inputs. Thus there is presumed to be a sophisticated interplay between these ascending (thalamus to prefrontal cortex) and descending (prefrontal cortex to thalamus) pathways,” Dr. Diwadkar said.
To understand network dynamics between these regions, the team quantitatively modeled fMRI signals using complex effective connectivity analyses that estimate causal interactions between brain regions. “These methods are considered one of the highest standards for network analyses of fMRI data,” Dr. Diwadkar said.
The team showed that the effective connectivity of the ascending thalamus to prefrontal pathway is not differentially affected by the varying demands of the sustained attention task, reaffirming that the ascending pathway is a gateway that appropriately sends information upward without filtering. However, the effective connectivity of the descending prefrontal to thalamus pathway showed increased connectivity when attention demand is high.
“Remarkably, even in adolescence, network interactions from the cortex to the thalamus are highly sensitive to the difficulty of the task, dynamically increasing connectivity in the face of increased attention demand. That we observed this in the adolescent brain speaks to the complexity with which the brain dynamically implements behavior, and demonstrates the beautiful organization of network interactions. This is a highly elegant revelation,” he said.
The team is extending the analytic approaches in support of discovering brain network dysfunction in adolescent and adult clinical syndromes, including obsessive-compulsive disorder.
”Understanding how the brain implements behavior is a remarkable challenge, and many of the problems in understanding neuropsychiatric syndromes are linked to solving this challenge. Our efforts in the Brain Imaging Research Division are directed at applying sophisticated analytic approaches toward unraveling many of these difficult questions. We are hopeful that our explorations will illuminate some understanding of mechanisms of typical brain network interactions, and how impairments in these contribute to the emergence of psychiatric syndromes,” Dr. Diwadkar said
The research was supported by grants from the National Institute of Mental Health (MH68680 and MH59299), the National Alliance for Research on Schizophrenia and Depression, the Children’s Research Center of Michigan, the Children’s Hospital of Michigan Foundation, the Prechter Pediatric Bipolar Program World Heritage Foundation, the Cohen Neuroscience Endowment and the Lycaki-Young Fund from the State of Michigan. Additional support was provided by a Summer Medical Student Research Fellowship given by the WSU School of Medicine to Jagtap, and a Career Development Chair and Charles H. Gershenson Distinguished Faculty Fellowship to Dr. Diwadkar from the WSU Office of the President.
- Dr. Lisak elected to second term on DMC Foundation Board
In Headlines on May 24, 2016
Robert Lisak, M.D.
Robert Lisak, M.D., F.A.A.N., F.R.C.P., professor of Neurology and of Immunology and Microbiology for the Wayne State University School of Medicine, was recently re-elected to the DMC Foundation’s Board of Directors.
This will be Dr. Lisak’s second three-year term on the board.
Formerly known as the Health & Wellness Foundation, the DMC Foundation was created in 2010 to receive part of the charitable assets transferred from the Detroit Medical Center following its sale to Vanguard Health Systems, which became a part of Tenet Healthcare Corp. in October 2013.
The foundation, which has awarded hundreds of thousands of dollars in grants, is dedicated to promoting the well-being of the general public in the metropolitan Detroit area through the support of health-related research, education and community benefit activities.
The organization is overseen by a 15-member board.
- Student wins AOA fellowship to conduct research on brain tumors
In Headlines on May 24, 2016
A Wayne State University School of Medicine first-year medical student is one of only 53 students nationwide selected for a prestigious fellowship to conduct medical research in the lab of a mentor this summer.
Ankush Chandra, of the Class of 2019, received the 2016 Carolyn L. Kuckein Student Research Fellowship from the Alpha Omega Alpha Honor Medical Society.
The fellowship provides Chandra $5,000 to conduct research during the summer and $1,000 for travel to present the results at a national or international meeting. Chandra will conduct his research in the laboratory of Manish Kumar Aghi, Ph.D., M.D., professor of Neurosurgery for the University of California San Francisco. Dr. Aghi specializes in adult brain tumors. As principal investigator at the UCSF Brain Tumor Research Center, his research interests include glioblastoma angiogenesis, mechanisms of glioblastoma resistance to anti-angiogenic therapy, and experimental glioblastoma therapies like oncolytic viruses.
“While I am still uncertain about the field of medicine I would like to practice, I am driven toward procedure-based fields,” said Chandra, who was born in New York. “I have had a long-term interest in the neurosciences, and thus I am exploring neurology, neurosurgery, neuro-oncology, neuro-radiation oncology and interventional neurology.”
His research project is titled “Characterization of Binding Sites Implicated in Cross Activation of c-Met/B1 Integrin in Bevacizumab-Resistant Glioblastoma.” Glioblastomas are often considered the most malignant of brain tumors.
“Glioblastoma is a model disease that stimulates my interest. What really interests me about this tumor is its intricacies of this tumor,” he said. “This tumor has a well-orchestrated mechanism of invasion that lets it become intimately imbedded into the normal neural tissue. This makes it difficult to treat and surgically remove. … This tumor becomes resistance to therapy and develops an even more aggressive and invasive phenotype.”
Data from the lab he will be joining has identified molecules that are unregulated and cross link to provide resistance in glioblastoma to treatment with bevacizumab, a drug that slows the growth of new blood vessels and is used to treat certain cancers. He is interested in investigating specific sites of the two molecules that could lead to development of small molecule inhibitors to overcome the resistance.
Chandra has prior experience in cancer and neuroscience research. As an undergraduate at Boston University, he conducted research in the laboratory of Hengye Man, M.D., Ph.D., associate professor of Biology, and completed a senior thesis that investigated the role of clathrin-mediated endocytosis in neuronal development. After graduating, he conducted two years of full-time research in the Eichler Lab at Harvard Medical School/Massachusetts General Hospital, investigating molecular mechanisms underlying white matter leukodystrophies. His research was published in the October 2015 edition of the Journal of Neuroscience. During the thesis year of his master’s degree at Boston University Chandra worked for Merrimack Pharmaceuticals, testing biologics that targeted specific tumor or tumor cells expressing a specific biomarker.
“This research work really developed and shaped my interest in research targeted therapies for different types of cancers, especially hard-to-treat cancers such as glioblastoma,” he said. “While we know so much about the brain, there’s much more we don’t know. The brain is a very mysterious organ that behaves uniquely.”
Chandra credits his mother’s diagnosis with cancer when he was in ninth grade as the “initial spark” to pursue research and medicine. She has since been in full remission and cancer free since 2005.
“While we have discovered and developed many advanced therapies for cancer, millions of people still die from this disease each year. It has been commonly found across all cancers that tumors tend to become resistant to chemotherapy and become invasive,” he said. “This field is very exciting as we are able to use molecular biology approaches to understand the mechanism of resistance and target specific sites to overcome the resistance. Such therapies have proven to be more effective as adjuvant therapy alongside chemotherapy than chemotherapy alone.”
- Dr. Terlecky leaving for new Seton Hall medical school
In Headlines on May 24, 2016
Stanley Terlecky, Ph.D.
Stanley Terlecky, Ph.D., associate professor of Pharmacology and associate dean of Biomedical Graduate Programs for the Wayne State University School of Medicine, is leaving for a new position at Seton Hall University.
Dr. Terlecky has accepted the position of associate dean and chair of Biomedical Graduate Studies and Basic Science Medical Education for the new medical school under development at Seton Hall University. His last day with the WSU School of Medicine will be June 14.
“A member of our faculty since 1998, Dr. Terlecky has overseen a very strong graduate program since his appointment as associate dean in 2013, and is responsible for considerable contributions to the School of Medicine, particularly in the Interdisciplinary Biomedical Sciences program,” said Jack D. Sobel, M.D., dean of the School of Medicine. “We have indeed been fortunate to have in Dr. Terlecky a powerful advocate for graduate students in the biomedical sciences.”
“It is a wonderful challenge to try to help build a new medical school,” Dr. Terlecky said. “I have so enjoyed these 18 years at Wayne State. I hope that I have given back half of what I have received. It will be very difficult to leave all of the friends and colleagues I have made over the years.”
The move will see Dr. Terlecky return to his East Coast roots. Originally from New York, he has family in the area and his two oldest children attend Drexel University in Philadelphia. His wife, Laura J. Terlecky, an executive secretary for the WSU Technology Committee in the Office of the Vice President for Research, will remain with WSU for another year while their two youngest children complete middle school and high school, respectively.
Dr. Terlecky has had a longstanding interest in graduate student training. He mentored several doctoral students in his own laboratory and served on the dissertation committees of many others. He assisted in the development of the school’s M.D./Ph.D. program and was involved in a number of initiatives to increase graduate student recruitment.
- School of Medicine hosts Michigan Physiological Society annual meeting
In Headlines on May 23, 2016
Patrick Mueller, Ph.D., speaks at the meeting.
From left, Erica Wehrwein, Ph.D., with poster winners Brandon Coughlin, Kiera Fisher, Hannah Marti, Shibandri Das, Dean Bakoulas, Mohamad El-Chami and Naveen Sharma.
From left, Erica Wehrwein, Ph.D., with oral presentation winners Ankita Jayakumar, Janice Diaz-Ortero, Kevin Gordish, Ph.D., and Monica McCullough. Not pictured: Amanda Shoemaker and Kevin Steelman.
More than 170 physiologists from 16 universities and research institutions gathered at the Wayne State University School of Medicine to participate in the third annual Michigan Physiological Society Meeting, held May 12-13 in Scott Hall. The meeting was hosted by the School of Medicine’s Department of Physiology.
“The meeting’s success was reflected by the involvement of more than twice as many participants as the previous year’s meeting, and by the generous support donated by several departments, school and administrative units at Wayne State University and participating universities and colleges across Michigan,” said Patrick Mueller, Ph.D., associate professor of Physiology.
Dr. Mueller assumed the role of MPS president during the business portion of the annual meeting, and thanked the organizing committee, including the Department of Physiology’s Joanne Kaiser and Christine Cupps, for their critical role in the meeting’s success
In association with the main meeting, a high school science teachers’ workshop sponsored by the American Physiological Society was held. The workshop provided concurrent and overlapping training sessions for local high school teachers interested in physiology education and training for their students. Department of Physiology Chair Jian-Ping Jin, M.D., Ph.D., and WSU Vice President for Research Stephen Lanier, Ph.D., spoke at the meeting’s opening session, acknowledging the importance of the integrative physiology research in education and health happening in Michigan.
The main meeting included four oral sessions and two poster sessions representing more than 80 trainees, including graduate, undergraduate and high school students, postdoctoral fellows, early stage investigators and established investigators.
“Because of the tremendous financial support for the meeting, the society was able to recognize several trainees based on their outstanding poster and oral presentations,” Dr. Mueller said.
Shibandri Das (Wayne State University, mentor: Noreen Rossi, M.D.)
Hannah Marti (Michigan Technological University)
Kiera Fisher (Michigan State University)
Dean Bakoulas, (Wayne State University, mentor: Patrick Mueller, Ph.D.)
Brandon Coughlin (Michigan State University)
Mohamad El-Chami, (Wayne State University, mentor: Jason Mateika, Ph.D.)
Janice Diaz-Ortero (Michigan State University)
Kevin Gordish, PhD, (Henry Ford Hospital and Wayne State University, mentor: William Beierwaltes, Ph.D.)
Ankita Jayakumar, (Henry Ford Hospital and Wayne State University; mentor: Pablo Ortiz, Ph.D.)
Amanda Shoemaker and Kevin Steelman (Central Michigan University)
- Neurology resident presents retinal biology in Huntingon's disease breakthrough at world's largest neurology meeting
In Headlines on May 20, 2016
Marissa Dean, M.D.
Detroit Medical Center-Wayne State University Neurology Chief Resident Marissa Dean, M.D., a 2012 graduate of the WSU School of Medicine, presented the results of a groundbreaking study examining retinal biology in patients with Huntington’s disease at the recently concluded American Academy of Neurology’s 68th annual meeting, held in Vancouver.
Using 3D-Optical Coherence Tomography, WSU neurologists performed macular segmentation in patients with Huntington’s disease and in age-matched healthy control patients. The results showed that several individual layers of the retina were thicker in patients with the disease than in the age-matched controls, most notably in the layers where mutant protein is known to cause transcriptional dysregulation.
“This is the first in-vivo study in Huntington’s disease demonstrating localization of mutant Huntingtin protein in the retina, and opens up a huge area of investigation in developing biomarkers in Huntington’s disease,” said Omar Khan, M.D., professor and chair of the WSU Department of Neurology, the study’s principal investigator. “Translational research in neurodegenerative disorders is a key area of focus in our department. Our residents regularly participate in research, which is exemplified by the dedication and commitment of Dr. Dean, who is committed to a career in movement disorders.”
Navid Seraji-Bozorgzad, M.D., assistant professor of Neurology and the department’s residency director, who was the study co-principal investigator, said “Dr. Dean’s presentation at the meeting was one of 15 platform presentations made by a neurology resident at the world’s largest neurology meeting, attended by more than 15,000 neurologists from all over the world. This speaks volumes to the quality of our trainees and preparing the next generation of clinician-scientists.”
Huntington’s disease is a uniformly fatal neurodegenerative disorder caused by polyglutamine expansions in the Huntingtin protein. The condition eventually leads to symptoms affecting muscle coordination, and resulting in abnormal movements and mental decline. Almost 30,000 Americans are diagnosed with Huntington’s disease and another 200,000 are considered at risk. Symptoms typically appear between the ages of 30 and 50, and progressively worsen during a period of 10 to 20 years.
The Department of Neurology is undertaking a new study led by co-principal investigators Dr. Khan and Dr. Seraji-Bozorgzad to investigate MRI-PET biomarkers in Huntington’s disease. They anticipate initiating clinical trials adopting an “antisense oligonucleotide” approach to silence the mutant gene.
“Our goal is to have a premier clinical and translational research center at Wayne State University in neurodegenerative disorders, and our work in Huntington’s disease is a step in that direction,” Dr. Khan said.