During the five years before people develop the first clinically recognized signs of multiple sclerosis (MS), they are up to four times more likely to be treated for nervous system disorders such as pain or sleep problems. They are 50 per cent more likely to visit a psychiatrist, according to new research from the University of British Columbia.
The study, the largest-ever effort to document symptoms of people before they know they have MS, could enable physicians to diagnose the disease – and thus start treating it – earlier, therefore possibly slowing the damage it causes to the brain and spinal cord.
MS results from the body’s immune system attacking myelin, the fatty material that insulates neurons and enables rapid transmission of electrical signals. When myelin is damaged, communication between the brain and other body parts is disrupted, leading to vision problems, muscle weakness, difficulty with balance and coordination, and cognitive impairments.
Because the symptoms are varied, often associated with other disorders, and can be transitory, diagnosing MS can be a challenge. Confirmation of the disease usually is done by magnetic resonance imaging (MRI), a test of nerve impulses, or an examination of spinal fluid.
Canada has one of the highest rates of MS in the world for reasons that elude scientists.
The researchers, led by Helen Tremlett, a Professor in the Division of Neurology at UBC, examined the health records of 14,000 people with multiple sclerosis from B.C., Saskatchewan, Manitoba and Nova Scotia between 1984 and 2014 and compared them to the health records of 67,000 people without the disease.
Tremlett and former postdoctoral fellow José Wijnands found that fibromyalgia, a condition involving widespread musculoskeletal pain, was more than three times as common in people who were later diagnosed with MS, and irritable bowel syndrome was almost twice as common.
Two other conditions with markedly higher rates among people to be diagnosed with MS are migraine headaches and any mood or anxiety disorder, which includes depression, anxiety and bipolar disorder.
The higher rates of those illnesses also correspond with higher use of medications for musculoskeletal disorders, nervous system disorders, and disorders of the genito-urinary tract, along with antidepressants and antibiotics.
The study, published in Multiple Sclerosis Journal, provides definitive evidence that MS can be preceded by early symptoms – known as a prodrome – that aren’t considered “classic” manifestations of the disease, like blurred vision or numbness or weakness in the limbs. As recently as 2000, medical textbooks asserted that MS did not have a prodrome.
“The existence of such ‘warning signs’ are well-accepted for Alzheimer’s disease and Parkinson’s disease, but there has been little investigation into a similar pattern for MS,” said Tremlett, a Canada Research Chair in Neuroepidemiology and Multiple Sclerosis and member of the Djavad Mowafaghian Centre for Brain Health. “We now need to delve deeper into this phenomenon, perhaps using data-mining techniques. We want to see if there are discernible patterns related to sex, age, or the ‘type’ of MS they eventually develop.”
PhD student Inbar Fischer Credit Tel Aviv University
A groundbreaking study from Tel Aviv University enhances our understanding of the biological mechanisms behind genetically based autism. It mainly focuses on mutations in the SHANK3 gene, which are responsible for nearly one million autism cases worldwide. Based on these findings, the research team applied a genetic treatment that improved the functioning of cells affected by the mutation, paving the way for future therapies for SHANK3-related autism.
The study was led by the lab of Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University.
Prof. Barak: “Autism is a common neurodevelopmental disorder affecting 1-2% of the global population, with one in every 36 boys in the U.S. diagnosed. Its causes include environmental, genetic, and social factors, such as advancing parental age at conception. In my lab, we focus on the genetic causes of autism, particularly mutations in the SHANK3 gene. This gene is vital for the protein that binds receptors in neurons, essential for receiving chemical signals that enable neuron communication. Damage to SHANK3 can disrupt this communication, impairing brain development and function. Our study aims to explore previously unknown mechanisms through which SHANK3 mutations affect brain development, leading to autism.”
Specifically, the research team focused on two components in the brain that have not yet been studied extensively in this context: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce. Myelin tissue is a fatty layer that insulates nerve fibres (axons), similar to the insulating layer that coats electrical cables. When the myelin is faulty, the electrical signals transmitted through the axons may leak, disrupting the message transmission between brain regions and impairing brain function.
The team employed a genetically engineered mouse model for autism, introducing a mutation in the Shank3 gene that mirrors the mutation found in humans with this form of autism. Inbar Fischer: “Through this model, we found that the mutation causes a dual impairment in the brain’s development and proper function: first, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for the binding and functioning of receptors that receive chemical signals (neurotransmitters and others) from neighbouring cells. This means that the defective protein associated with autism disrupts message transmission to these vital support cells. Secondly, when the function and development of oligodendrocytes is impaired, their myelin production is also disrupted. The faulty myelin does not properly insulate the neuron’s axons, thereby reducing the efficiency of electrical signal transmission between brain cells and the synchronization of electrical activity between different brain parts. In our model, we found myelin impairment in multiple brain areas and observed that the animals’ behaviour was adversely affected.”
The researchers then sought a method for fixing the damage caused by the mutation, hoping to develop a treatment for humans ultimately. Inbar Fischer: “We obtained oligodendrocytes from the brain of a mouse with a Shank3 mutation and inserted DNA segments containing the normal human SHANK3 sequence. Our goal was to allow the normal gene to encode a functional and normal protein, which would perform its essential role in the cell by replacing the defective protein. To our delight, following treatment, the cells expressed the normal SHANK3 protein, enabling the construction of a functional protein substrate to bind the receptors that receive electrical signals. In other words, the genetic treatment we had developed repaired the oligodendrocytes’ communication sites, essential for the cells’ proper development and function as myelin producers.”
To validate findings from the mouse model, the research team generated induced pluripotent stem cells from the skin cells of a girl with autism caused by a SHANK3 gene mutation identical to that in the mice. From these stem cells, they derived human oligodendrocytes with the same genetic profile. These oligodendrocytes displayed impairments similar to those observed in their mouse counterparts.
Prof. Barak concludes: “In our study, we discovered two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and, consequently, damage to the myelin they produce. These findings have important implications – both clinical and scientific. Scientifically, we learned that defective myelin played a significant role in autism and identified the mechanism causing the damage to myelin. Additionally, we revealed a new role for the SHANK3 protein: building and maintaining a functional binding substrate for receptors critical for message reception in oligodendrocytes (not just in neurons). We discovered that contrary to the prevailing view, these cells play essential roles in their own right, far beyond the support they provide for neurons — often seen as the leading players in the brain. In the clinical sphere, we validated a gene therapy approach that led to significantly improved development and function of oligodendrocytes derived from the brains of mice modelling autism. This finding offers hope for developing genetic treatment for humans, which could enhance the myelin production process in the brain. Furthermore, recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding the brain mechanisms underlying autism and paves the way for future treatment development.
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.
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.
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