Links in a brain
Functional connectivity is unlocking new knowledge about diseases
Mapping the brain’s activity while the body is at rest may provide a window into disease processes and ideas for early detection that today remain untapped. More than 15 years after functional connectivity MRI (fcMRI) first demonstrated at The Medical College of Wisconsin that the brain is never truly at rest, two alumni are carrying the torch for this re-emerging technology, including a former graduate student partially credited for its discovery.
Bharat Biswal, PhD ’96
James S. Hyde, PhD, the James S. Hyde Professor of Biophysics and Director of the College’s National Biomedical EPR Center, had just published the first ever paper on functional magnetic resonance imaging (fMRI) of the sensorimotor system in human brain when Bharat Biswal, PhD ’96, enrolled at the Medical College under his tutelage. Dr. Hyde had noticed that the noise in the fMRI data was unusually high and seemed to be coming from the brain itself. When the time came for Biswal to select a dissertation topic, Dr. Hyde suggested he study this high level of noise.
The results were spectacular. They discovered that the noise was indeed physiological and depended on neurological activity. Moreover, coherent patterns of this “physiological noise” in the brain revealed regions that had long been considered to be members of known brain systems.
Their discovery of (and ensuing publication on) fcMRI in 1995 was met with some controversy, although several other investigators soon replicated their findings. Interest increased steadily over the last decade and a half as it became apparent that a new way had been found to investigate brain function based on previously unknown brain physiology.
“Like a typical graduate student, the first concern was to get the work published and just to obtain my PhD,” Dr. Biswal said. “While I was aware that the finding was quite novel and pretty interesting, I had thought that if a few groups would find the methods useful, that would be great.”
As it turns out, the National Institutes of Health paid attention, and has supported Dr. Biswal, now Associate Professor of Radiology at the University of Medicine & Dentistry of New Jersey, in his research. The NIH also announced the Human Connectome Project in 2010, committing $40 million to understanding connective pathways in the human brain.
Age-, and sex-related variations detected in functional connectivity using seed-based correlation analyses. The first column depicts group-level Resting State Functional Connectivity maps for three representative “default mode” seeds. The seed ROIs (regions of interest) are shown as white circles. The second and third column depict voxels exhibiting age- and sex-related variations (modeled as covariates). “Male” refers to significantly greater connectivity in males; similarly, “female” refers to significantly greater connectivity in females. “Older” refers to significantly increasing connectivity with increasing age, whereas “younger” refers to significantly increasing connectivity with decreasing age. “Pos”, positive functional connectivity; “neg”, negative functional connectivity.
Matter that matters
Neuroscience has been dominated by studies of gray matter, the workhorse of the brain composed of neurons responsible for our thoughts and actions. Connectivity, however, shines light on white matter, the slender fibers that act as the electrical cabling to link brain regions both structurally and functionally. fcMRI involves measurements made in gray matter in the absence of any stimulus or task that, paradoxically, provide information about connectivity. It is based on physiological fluctuations that were found by the Medical College investigators to exist in all gray matter regions. Regions of gray matter that exhibit similar patterns of fluctuations (i.e., are correlated) are said to be connected.
“The brain is always working, and in the regions of the brain that are connected functionally, the neurons oscillate and fire together in a unique pattern,” said Christopher Pawela, PhD ’08, Assistant Professor of Plastic Surgery and of Biophysics at the Medical College, who also trained under Dr. Hyde. “We can, with MRI, detect this common oscillation and thereby map connected regions in the brain that are functionally connected.”
This is accomplished by observing the changes in blood flow that occur during neuronal activity. Regions of the brain do not have to be structurally connected to have functional connectivity, and a structural connection does not necessarily signify a functional link. This is an observation noted in Dr. Biswal’s paper, “Toward discovery science of human brain function,” published March 9, 2010, in the Proceedings of the National Academy of Sciences.
In December, his findings were cited as the second most significant research advance in 2010 by the National Institute of Mental Health. His research is based on the 1,000 Functional Connectomes Project he oversees, which collects existing fcMRI data from centers worldwide to create an open resource for mapping and understanding brain function.
The database currently includes information from more than 1,400 participants, and Dr. Biswal is working to organize it in a standard format to allow researchers to download the data sets as well as search based on demographic information. Already, it has led Dr. Biswal and his collaborators to demonstrate the presence of a universal functional architecture in the brain and evidence that variations in connectivity follow demographic patterns. There is optimism in the field that this growing body of information will be the basis for eventual translation to clinical applications.
fMRI BOLD activation and resting-state connectivity maps of the rodent sensorimotor system. Figure a is the fMRI task induced brain activation map from direct radial nerve stimulation of the right upper forelimb. The displayed images are located -2.90 mm from bregma. Figures b,c,d are maps resulting from resting-state functional connectivity analysis in normal control rats. In figure b the reference voxels were placed in the right sensorimotor thalamus (SMT). In figure c the reference region was placed in the right primary/secondary motor areas (M1/M2). In figure d the reference region placed was placed in the right caudate putamen CP. (a) is an activation map with a voxel threshold at P = 0.005; (b), (c), and (d) are resting-state maps (0.35 threshold) from representative reference regions marked by asterisks. Results from 15 rats are averaged. Figure e shows a simplified flowchart displaying the brain-system connections involved in the motor and sensory networks in the rodent brain as defined by prior histological studies. Regions listed in the cortex include the M1/M2 and primary/secondary sensory areas (S1, S2). The corpus callosum (CC) contains the highest number of connections to the cortex. The SMT includes the ventral posterior medial thalamic nucleus/ventral posterior lateral thalamic nucleus (VP), the posterior thalamic nucleus (PO), and the ventral lateral thalamic nucleus (VL). The CP and globus pallidus (GP) are included as parts of the basal ganglia.
“A careful characterization of a universal, or gender-, or age-specific architecture may help clinicians to use individual subjects’ specifications to rapidly identify for any differences with a composite architecture of healthy subjects in the same age range,” Dr. Biswal said. “If differences are found, a more thorough and personalized assessment could be done.”
Mental and physical health uses
Researchers foresee a bevy of potential uses for fcMRI. The technology might someday help provide more definitive diagnoses for mental health disorders, such as schizophrenia or bipolar disorder. It may aid in understanding the development and progression of post-traumatic stress disorder and attention deficit hyperactivity disorder as well as evaluate the effect of treatment.
Functional connectivity imaging could possibly be used to determine whether a person in a coma has lost all cognitive faculties or if they have awareness and lack only the ability to physically respond. The brain’s response to anesthesia is another application being explored.
While fMRI has had little clinical success outside of surgery planning for brain tumor excision, fcMRI may be better positioned to provide information that guides clinical decisions, Dr. Pawela said.
“Hopefully, functional connectivity MRI could be a tool that may be missing within the toolbox, so we can try to study some of these disorders,” he said.
At the Medical College, colleagues Shi Jiang Li, PhD, Professor of Biophysics, and Piero Antuono, MD, Professor of Neurology, are using fcMRI in an attempt to discover markers based on altered brain connections for identifying individuals at risk for developing Alzheimer’s disease before symptoms occur. Their scans of healthy subjects, those with mild cognitive disorder and those with Alzheimer’s may help determine the effectiveness of medications for halting or reversing disease progression and the best time to intervene.
Alumni branches in family tree
The robust research effort in fMRI and now fcMRI can be traced to the close-knit network of scientists who have trained in the Medical College’s Department of Biophysics, particularly with Dr. Hyde as a mentor. The alumni of this program often collaborate and form bonds that help further research and careers, Dr. Pawela said.
“Former students of Dr. Hyde’s are like family, and former students from Biophysics at the Medical College have kind of a bond,” he said. “We get along, and have gone through shared experiences and we see each other regularly.”
Christopher Pawela, PhD ’08
An international meeting is how Dr. Pawela met Dr. Biswal, and their connection as alumni engendered their collaboration to advance fcMRI research. They recently co-founded the peer-reviewed journal Brain Connectivity and serve as co-editors-in-chief. Dr. Pawela also chaired the Second International Conference on Resting-State Functional Brain Connectivity held in September at the Medical College, which included a key presentation by Dr. Biswal on his connectome project.
Dr. Pawela entered this field as a graduate student mentored by Dr. Hyde and built upon the work of Dr. Biswal and those who followed. He demonstrated that functional connectivity existed in rats and other mammals and was thus not just a phenomenon of higher order cognition. This finding is important since drug development and other therapeutic options typically have origins in animal models.
Now on the Medical College of Wisconsin faculty, Dr. Pawela is interested in how the brain changes in response to damage of the peripheral nervous system, and fcMRI provides a unique view of brain plasticity. His research shows that in the case of nerve damage, for example, from a severed digit or injury to the brachial plexus during a child’s birth, there are connectivity changes that occur in the brain. Recovering more complete function in the body will likely require treatment that addresses not just nerve repair but also the brain’s wiring and response, he said.
“We are trying to think about the brain and body as one system, not just independent components,” Dr. Pawela said. “We are trying to create a paradigm shift in the way people think about injury. It’s not a closed system. How does the brain interpret this change and what are the ways in which we can actually help the brain heal itself, because the brain changes as well as the nerves.”
With the field advancing so quickly, it is difficult to determine when a true impact might be felt by health care providers and patients. There is a great deal of research needed, but the accessibility of the technology (fcMRI will soon be included in the software packages of most major scanner manufacturers) may expedite things.
“Is fcMRI something that is going to be deployed in the clinic tomorrow?” Dr. Pawela asked. “I don’t know, but it could be.”
Journal of record
Medical College of Wisconsin alumni Christopher Pawela, PhD ’08, and Bharat Biswal, PhD ’96, have together founded the journal of record for researchers and clinicians interested in all aspects of brain connectivity. Published bi-monthly by Mary Ann Liebert, Inc., Brain Connectivity launched this February and will include original peer-reviewed papers, review articles, discussions and product/technology reviews.
“The hope is that a new journal of brain connectivity will foster greater research interest in this area,” Dr. Biswal said. “Another aim is to bring together researchers currently working on all aspects of brain connectivity in order to help accelerate the field with increased dialogue.”
Brain Connectivity will follow the progress of the National Institutes of Health’s Human Connectome Project and other similar initiatives worldwide. Dr. Biswal and Dr. Pawela share the role of editor-in-chief of the journal. Dr. Pawela hopes the journal will help ensure the scientific field grows properly and consistently.
“It is certainly a hot area of science right now,” Dr. Pawela said. “Our goal with the journal and with meetings is to help steer the field so that it doesn’t become a pseudoscience, that there is some directionality and some purpose, as well as common language across the field.
“We are at the Wild West stage right now, I would call it, so it is an exciting time, but it is also a dangerous time, and we want to make sure the technology is applied in the appropriate way.”
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