A clinical trial is exploring the use of magnetic brain stimulation on people with MS to activate specialised brain cells to repair and regrow myelin.
How a new clinical trial is aiming to improve the lives of people with multiple sclerosis
myelin
Anxiety and PTSD linked to increased myelin in brain’s gray matter
An fMRI scan of the brain of a military veteran with PTSD, showing gray matter regions with increased myelin CREDIT UCSF image by Linda Chao
A recent study links anxiety behavior in rats, as well as post traumatic stress disorder (PTSD) in military veterans, to increased myelin — a substance that expedites communication between neurons — in areas of the brain associated with emotions and memory.
The results, reported by scientists at the University of California, Berkeley, and UC San Francisco (UCSF), provide a possible explanation for why some people are resilient and others vulnerable to traumatic stress, and for the varied symptoms — avoidance behavior, anxiety and fear, for example — triggered by the memory of such stress.
If, as the researchers suspect, extreme trauma causes the increased myelination, the findings could lead to treatments — drugs or behavioral interventions — that prevent or reverse the myelin production and lessen the aftereffects of extreme trauma.
Myelin is a layer of fatty substances and proteins that wraps around the axons of neurons — essentially, the insulation around the brain’s wiring — to facilitate long-distance transmission of signals and, thus, communication between distant areas of the brain. The inner regions of the brain look white — in fact, they are referred to as “white matter” — because of the myelin encasing the many large bundles of axons there.
But the new study finds increased myelination of axons in so-called “gray matter,” where most of the cell bodies of neurons reside and most of the wiring is less insulated with myelin. The extra myelination was found primarily in areas associated with memory.
Researchers at the San Francisco Veterans Affairs Medical Center conducted brain MRI scans of 38 veterans — half with PTSD, half without — and found an increase in myelination in the gray matter of those with PTSD compared to that seen in the brains of those not suffering from PTSD.
Colleagues at UC Berkeley, meanwhile, discovered a similar increase in myelination in the gray matter of adult rats subjected to an acute stressful event. While not all rats showed long-term effects from the stress — just as not all traumatized veterans develop PTSD — those that did had increased myelination in specific areas of the brain associated with particular symptoms of stress that was identical to what UCSF physicians found in veterans with PTSD.
Both veterans with PTSD and stressed rats that exhibited avoidance behavior, for example, had increased myelination in the hippocampus, often thought of as the seat of memory. Those exhibiting a fear response had increased myelination in the amygdala, which plays a key role in our response to strong emotions, such as fear or pleasure. Those suffering from anxiety had increased myelination in the dentate gyrus, a region critical to learning and memory.
“The combination of these studies in rats with our population of veterans with post traumatic stress disorders is, to me, really exciting,” said senior author Dr. Thomas Neylan, director of the Posttraumatic Stress Disorders (PTSD) Clinic and the Stress and Health Research Program at the San Francisco VA. “At least it’s another mechanism to think about as we develop new treatments. If we see enduring ability to shape myelin content in an adult brain, maybe treatments will help reverse this. That’s where we want to go next with this.”
People — and rats — vary in their response to stress
The correlation between the symptoms and the region of myelination was discovered because UC Berkeley researchers subjected the rats to a battery of more than a dozen tests to assess their specific behavioral response to acute stress.
“We understand that there’s a lot of individual variation in humans, but with rats, they’re genetically identical, so you think when you expose them to stress you’re going to get the same response,” said senior author Daniela Kaufer, UC Berkeley professor of integrative biology. “But the response is extremely variable. They sort of fall into groups, such that some are really resilient, and some are vulnerable. And the ones that are vulnerable are vulnerable in different ways: Some show avoidance behavior, and some show fear learning problems, and some show startle responses that are exaggerated.”
According to Neylan, similar individuality is seen in people with PTSD. The new study suggests that the specific symptoms are related to which areas of the brain are being newly myelinated.
“There’s a lot of heterogeneity across different people with PTSD; it’s not one size fits all. Every PTSD patient generally has a mix of different symptoms,” said Neylan, professor-in-residence in psychiatry at the UC San Francisco Weill Institute for Neurosciences. “Some people are very avoidant. Some people are very hyperreactive. The idea is that if you can show that these different symptom clusters have different neural circuitry, it might actually lead us closer to subtyping people in a way that we could be more targeted in our treatment.”
The researchers, who published their results in December 2021 in the journal Translational Psychiatry, show that stress produces more of the brain’s glial cells, called oligodendrocytes, which wrap around the axons of neurons and make the myelin. The increased myelin produced by these new oligodendrocytes could affect the speed of connections between neurons, making some connections hyperresponsive.
“In the gray matter of your cortex, most of the dendrites and axons — the projections that come out of the neurons that help establish communications with other neurons — can form thousands of connections, and most of them are unmyelinated,” Neylan said. “But if experience leads you to start to lay down myelin to strengthen certain connections, let’s say your ability to respond quickly to a fearful stimulus, you can speed up that circuit, but you lose the kind of broader adaptive flexibility that you normally would have with mostly unmyelinated axons and dendrites. People with PTSD become almost like a one-note musician — they really know how to respond to fear. But that enhanced, quick response to fear may diminish their adaptive flexibility for non-fear-type behavior.”
Acute stress boosts oligodendrocytes
In 2014, Kaufer and her UC Berkeley colleagues discovered that rats subjected to acute stress produced more oligodendrocytes in the brain’s gray matter — specifically, in the hippocampus. She proposed that this led to increased myelination of axons, potentially interfering with the speed at which signals traveled between different areas of the gray matter of the brain, such as the hippocampus and the amygdala. The new study bolsters that theory.
Neylan was intrigued by the 2014 findings and contacted Kaufer, and they’ve been collaborating ever since. Neylan teamed up with Linda Chao, UCSF professor of radiology, who developed a way to image myelin in the gray matter of the brain, and several years ago scanned the brains of 38 veterans who had experienced severe trauma, some with and some without PTSD.
At the time, scientists looking for changes in myelination related to brain disorders were focused on the cortex’s white matter, which is mostly myelinated. In multiple sclerosis, for example, an autoimmune attack destroys myelin in the white matter. Kaufer was perhaps the first to find evidence of increased myelination in the gray matter associated with disease.
Chao and Neylan did find increased myelination of neurons in the gray matter of veterans with PTSD, but not in those without PTSD. The worse the symptoms, the greater the myelination.
This led Kaufer and first author Kimberly Long, now a UCSF postdoctoral fellow, to see if they could also find increased myelin in gray matter after acute trauma in rats. After they focused on the specific symptoms of individual rats with PTSD, they found a correlation between symptoms and myelination in specific regions of the gray matter.
Chao subsequently reanalyzed the brain scans of her earlier group of 38 veterans and found the same correlation: Specific symptoms were associated with myelination in one region of gray matter, but not others.
Long and Kaufer then employed a type of viral gene therapy to rev up a transcription factor, called olig1, that increases the production of oligodendrocytes from stem cells in the gray matter. When Long injected the virus into the dentate gyrus of rats, the researchers found that this boosted the number of oligodendrocytes and generated symptoms of avoidance, even without any stress.
“The next question was, ‘If I change oligodendrocyte genesis, am I going to change behavior?” Kaufer said. “The beginning of an answer is here in this paper — it’s yes. And now, there’s a lot more to do to really understand that.”
Neylan, Chao and Kaufer are collaborating on further studies, including looking for increased myelin in the brains of PTSD patients who have died, improving fMRI imaging of myelin in the brain, investigating the effects of chronic stress on the brain connections of rats, and using new high-resolution imaging to study the myelin deposition in gray matter.
The work was supported by a grant from National Institute of Mental Health of the National Institutes of Health (R01MH115020).
Other co-authors of the paper were undergraduates Yurika Kazama, Vivian Roan, Rhea Misra, Anjile An, Kelsey Hu, and Claire Toth and doctoral student Jocelyn Breton of UC Berkeley; UCLA undergraduate Lior Peretz; University of Arizona undergraduate Dyana Muller; University of British Columbia (UBC) doctoral student William Casazza; UBC professor Sara Mostafavi; Boston University neurologist Dr. Bertrand Huber; and researcher Steven Woodward of the VA Palo Alto Health Care System.
Autism-linked gene, if deleted, results in less myelin
Myelin, a sheath of insulation around nerves that enables electrical impulses to efficiently travel through the central nervous system, is diminished in mice that have a gene deletion associated with autism spectrum disorder, new research finds.
Scientists at The University of Texas Health Science Center at San Antonio (also referred to as UT Health San Antonio) reported the discovery in the journal Molecular Psychiatry on Nov. 5. In mice the team deleted one copy of a gene, Tbx1, that is encoded in the chromosome 22q11.2 region linked to impaired cognition.
“Variants of this gene, Tbx1, are associated with autism spectrum disorder, intellectual disability and many other developmental issues,” said Noboru Hiroi, PhD, professor of pharmacology at UT Health San Antonio. “These ultra-rare variants are found in only a few families in the world.”
The researchers observed that Tbx1 deletion significantly impacted cognitive speed of mice on two tests: the Morris water maze, which challenges spatial memory, and attentional set shifting, which taxes cognitive flexibility.
Collaborating with scientists at Tohoku University in Japan who performed whole-brain magnetic resonance imaging (MRI) studies, the Texas scientists sought to learn which brain regions had altered white matter. Robust changes were seen only in the fimbria, a band of nerve fibers that connect various brain regions with the hippocampus, the latter of which is a key center of learning and memory.
“That is a very regionally specific deficit,” Dr. Hiroi said. The team confirmed the findings through electron microscopy.
In analyzing the slower cognition exhibited by the mice, the researchers hypothesized that myelin, the sheath of fat and protein that increases conduction of impulses across nerves, was negatively impacted.
Indeed, mice lacking one Tbx1 copy did not have as many cells called oligodendrocytes. These are the cells that manufacture myelin.
“This negatively affected the production of the building blocks of myelin, which resulted in these mice not having enough protective fibers,” Dr. Hiroi said. “Without the myelin sheath, you don’t have speedy signal conductance between brain regions.”
The study is limited in the sense that researchers cannot compare the speed of mice on a pair of tests with actual cognition in humans. But in the case of understanding gene copy number variants in developmental and psychiatric disorders, both mouse and human studies are important in advancing knowledge, Dr. Hiroi said.
“In a mouse model, we identified structural changes in the brain and a specific gene that, when deficient, is responsible for those changes,” he said. “Tbx1 is only one of many genes implicated in autism and schizophrenia, but this mechanistic basis we found, this impaired myelination, can be tested for generalizability in other copy number variants and ultra-rare variants.”
Funding is by three institutes of the U.S. National Institutes of Health (NIH). They are the National Institute of Mental Health (NIMH), the National Institute on Deafness and Other Communication Disorders (NIDCD) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Dr. Hiroi is appointed in the departments of pharmacology, cellular and integrative physiology and cell systems and anatomy at UT Health San Antonio.
Multiple Sclerosis -Strategies for the regeneration of myelin
Impaired repair of chronic lesions in neuronal cholesterol mutants (NcKO). The mutants form less myelin (brown), and the proliferation of oligodendrocytes (green) is reduced. CREDIT MPI for Experimental Medicine/ Berghoff
The degradation and regeneration of myelin sheaths characterise neurological disorders such as multiple sclerosis. Cholesterol is an indispensable component of myelin sheaths. The cholesterol for the regenerated myelin sheaths must therefore either be recycled from damaged myelin or produced again locally. In a recent study, scientists at the Max Planck Institute for Experimental Medicine in Göttingen, led by Gesine Saher, found that in the case of chronic damage, unlike in acute damage, hardly any cholesterol is recycled. Instead, the new production of cholesterol determines the efficiency of the repair. Unexpectedly, not only the myelin-forming cells themselves but also nerve cells make an important contribution to regeneration. Cholesterol synthesis in nerve cells ensures the replenishment of newly myelin-forming cells. This could impact the therapeutic success for myelin disorders such as multiple sclerosis.
When lesions develop in myelin disorders such as multiple sclerosis, the cholesterol- and lipid-rich insulating layer around the nerve fibres is lost. In order to prevent permanent damage, the now unmyelinated nerve fibres must be protected again as quickly as possible by newly regenerated myelin. In the acute phase of the disorder, defective myelin is abundant. Cholesterol is taken up from defective myelin by phagocytes and reprocessed and made available to the myelin-forming cells. This repair process often proceeds quickly and smoothly in younger patients.
However, the longer the disorder lasts, the less efficient this critical process becomes. Phagocytes of the brain can turn into foam cells that are no longer involved in the recycling of cholesterol. The chronic and repeated degradation of myelin sheaths eventually leaves nerve fibres permanently unmyelinated. Degenerated myelin and cholesterol are thus scarce in chronic lesions. “We suspected that in the low-cholesterol environment of chronic lesions, the production of this important lipid kicks in”, explains lead researcher Gesine Saher from the Max Planck Institute for Experimental Medicine in Göttingen.
Cholesterol from nerve cells promotes the regeneration of myelin-forming cells
Saher and her working group are investigating the role of cholesterol and other lipids in the nervous system under both physiological and pathological conditions. Together with an international team of researchers, they have now investigated which of the body’s own processes contribute to repair after chronic myelin disease.
In their study, the researchers examined nerve cells (neurons) from pharmacological and genetic mouse models with myelin defects. Neurons normally cover the majority of their cholesterol demand by uptake of lipid-rich lipoproteins with only little synthesis. In acute lesions, cholesterol production in nerve cells is even further reduced. “The fact that the neurons from the chronic disorder models boost the production of cholesterol was completely surprising”, reports Stefan Berghoff, former coworker of Gesine Saher and first author of the study.
In order to investigate the relevance of this observation, the researchers genetically inactivated the synthesis of cholesterol in neurons and in the myelin-forming cells (oligodendrocytes) of mice. In the neuronal and oligodendroglial mutants, the regeneration of myelin sheaths was severely reduced in chronic lesions. However, unlike in glial mutants, neuronal cholesterol also enhanced the proliferation of oligodendrocyte progenitor cells. Treatment with a cholesterol-enriched diet had a similarly positive effect on these progenitor cells. “We assume that neurons provide this extra production of cholesterol”, says Berghoff. “This benefits all other cells in chronic lesions, which have greatly reduced their own production of cholesterol”.
Although acute and chronic lesions and their endogenous repair mechanisms differ greatly, the availability and management of cholesterol and other lipids ultimately makes a considerable contribution to the efficiency of regeneration. “The challenge of the next studies will be to develop therapy concepts for patients with myelin disorders in which acute and chronic lesions can be treated simultaneously”, says Saher, leader of the research team.
UCalgary scientists discover a new way to battle multiple sclerosis
University of Calgary scientists Andrew Caprariello, Ph.D., left, and Dr. Peter Stys, professor at the Cumming School of Medicine, are challenging conventional thinking about the root cause of multiple sclerosis. Cumming School of Medicine
Ridiculous. That’s how Andrew Caprariello says his colleagues described his theory about multiple sclerosis (MS) back when he was doing his PhD in Ohio.
Caprariello’s passion to explore controversial new theories about MS propelled him to seek out a postdoctoral fellowship with a like-minded thinker, whom he found in University of Calgary’s Dr. Peter Stys, a member of the Hotchkiss Brain Institute at the Cumming School of Medicine(CSM).
The collaboration paid off. Caprariello, Stys and their colleagues have scientific proof published in the Proceedings of the National Academy of Sciences (PNAS) that their somewhat radical theory has merit. “I’ve always wondered ‘what if’ MS starts in the brain and the immune attacks are a consequence of the brain damage,” says Caprariello, PhD, and lead author on the study.
Currently, MS is considered to be a progressive autoimmune disease. Brain inflammation happens when the body’s immune system attacks a protective material around nerve fibers in the brain called myelin. Conventional thinking is that rogue immune cells initially enter the brain and cause myelin damage that starts MS.
“In the field, the controversy about what starts MS has been brewing for more than a decade. In medical school, I was taught years ago that the immune attack initiates the disease. End of story,” says Stys, a neurologist and professor in the Department of Clinical Neurosciences at the CSM. “However, our findings show there may be something happening deeper and earlier that damages the myelin and then later triggers the immune attacks.”
To test the theory, the research team designed a mouse model of MS that begins with a mild myelin injury. In this way, researchers could mirror what they believe to be the earliest stages of the disease.
“Our experiments show, at least in this animal model, that a subtle early biochemical injury to myelin secondarily triggers an immune response that leads to additional damage due to inflammation. It looks very much like an MS plaque on MRI and tissue examination,” says Stys. “This does not prove that human MS advances in the same way, but provides compelling evidence that MS could also begin this way.”
With that result, the researchers started to investigate treatments to stop the degeneration of the myelin to see if that could reduce, or stop, the secondary autoimmune response.
“We collaborated with researchers at the University of Toronto and found that by targeting a treatment that would protect the myelin to stop the deterioration, the immune attack stopped and the inflammation in the brain never occurred,” says Stys. “This research opens a whole new line of thinking about this disease. Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”
It can be very hard to find funding to investigate an unconventional theory. The research team was funded by the Brain and Mental Health Strategic Research Fund, established by the Office of the Vice-President (Research) at UCalgary to support innovative, interdisciplinary studies within the Brain and Mental Health research strategy.
“We chose high-risk, novel projects for these funds to support discoveries by teams who did not have the chance to work together through conventional funding sources,” said Ed McCauley, PhD, vice-president (research). “The MS study shows the potential of brain and mental health scholars to expand capacity by tapping into new approaches for conducting research. Their work also exemplifies the type of interdisciplinary research that is propelling the University of Calgary as an international leader in brain and mental health research.”