Véronique Bohbot, PhD / Dr. Glen Jickling

Associate Professor, Department of Psychiatry-Faculty of Medicine, McGill University / Clinical neurologist, Assistant Professor, Faculty of Medicine and Dentistry, University of Alberta, Edmonton
Researcher of the month: 
Dec 2017

Véronique Bohbot, PhD

John R. & Clara M. Fraser Memorial Award Recipient
Associate Professor, Department of Psychiatry
Associate Member, Department of Neurology and Neurosurgery
Faculty of Medicine, McGill University

Trailblazer

The work of Véronique Bohbot focuses on everything to do with the hippocampus. Part of the limbic system, this seahorse-shaped region of the brain is small, but it plays a pivotal role in vital functions, such as learning, memory, spatial navigation and memory for our life events.

“If you understand what’s specific about the hippocampus, then you have an application to a number of neurological and psychiatric disorders,” says Bohbot, Associate Professor at the McGill University Department of Psychiatry and Researcher at the Douglas Institute, Montreal. “Many neuropsychiatric diseases are associated with atrophy in the hippocampus, including post-traumatic stress disorder, depression and schizophrenia.”

Hippocampal atrophy also plays an important role in neurodegenerative diseases, such as Alzheimer’s.

Bohbot’s research has focused on differentiating types of memory, early detection of and interventions for Alzheimer’s disease, the intertwined roles of the hippocampus and caudate nucleus in navigation, the role of progesterone in hippocampal function in women, and more. She and her coworkers were first to discover the existence of theta waves recorded in the hippocampus of epilepsy patients, an 8-Hertz rhythm, known to be critical for learning and memory in rodents.

“We’ve made of lot of groundbreaking discoveries that have advanced science,” she says.

Bohbot is an expert in the field of spatial memory and navigation. She received her PhD training in psychology and cognitive neuroscience in Dr. Lynn Nadel’s laboratory at the University of Arizona. Nadel was first to theorize that the hippocampus was responsible for cognitive mapping – the brain’s ability to acquire, store, and recall information about the relative location of objects in our environment. The theory was borne out of an initial discovery by John O’Keefe, who won a Nobel Prize for showing the importance of hippocampal neurons in place localization.

Nadel’s work significantly influenced her career. “He taught me how there’s a precise role for the hippocampus in memory. He was the first person to generate a full theory about the specific role of the hippocampus, distinct from other types of memory dependent on other regions of the brain. That knowledge is fundamental to all of the discoveries that I’ve made.”

Bohbot extended Nadel’s teachings on the distinctions between different memory systems in the human brain. She was first to show that, when it comes to spatial memory, the hippocampus competes with another region of the brain, called the caudate nucleus, in ways that may influence the development of neuropsychiatric and neurodegenerative diseases.

“There’s a negative correlation in the sense that, when one area grows, the other shrinks,” she says. “When people use their caudate nucleus, we can actually measure atrophy in the hippocampus.”

People use the hippocampus to create a mental map of their surroundings. This map functions like an internal GPS, helping people to form a birds’ eye view of their environment, so they can figure out where they are and how to navigate to where they need to go.

“Without a cognitive map, you can’t devise shortcuts,” she explains. “If, one day, you’re driving to work and the road is blocked, because of construction, then you can use your cognitive map to get around it.”

Over time, when we continually travel the same path or perform the same function, at some point, it becomes a habit and we navigate on autopilot. The autopilot involves making an action, such as a right turn, in response to a stimulus, e.g. at the tall, white building. The series of stimulus-response associations, or autopilot, are dependent on the caudate nucleus taking over. It records and stores information, forming habits, so your brain can automatize complex tasks.

Bohbot cites an example of how the caudate nucleus functions. When she needed to drive a colleague to the airport, she was concerned that her brain would go on autopilot, so she asked her colleague to remind her to turn west at a specific exit to head toward the airport, because she was used to turning east at that particular junction to drive home from work.

Sure enough, when they got lost in conversation, her colleague had to interrupt her to warn her that she was on the lane to take the exit going east and had to get into the other lane to go west.

“This example illustrates well the extent to which our caudate nucleus can dominate our behaviour and have us adopt a familiar route when we are on autopilot, even when that’s not where we want to go,” she says. Thankfully, Bohbot recognized the risk of taking a familiar route and warned her colleague, who was not on autopilot, so that he could indicate the western exit in time.

“That's why we can’t use both systems at the same time. You are either operating out of habit or you’re not.”

In 2017, Bohbot and Dr. Greg West of the Université de Montréal showed in a series of studies that the way that young adults, aged 18 to 30, navigate through action video games, i.e., first-person shooter games, such as Call of Duty, decreases the amount of grey matter in their hippocampus over time when they use their caudate nucleus.

That’s because action video games involve immediate rewards, which promote the caudate nucleus. In addition, the players who use their caudate nucleus while playing action video games relied on in-game GPS mapping systems to navigate instead of using their cognitive-mapping skills. This study showed for the first time that a real-life activity can lead to shrinkage of the hippocampus in participants using their caudate nucleus.

The researchers found that 3D platform video games, such as Super Mario Bros, that encouraged cognitive mapping actually increased grey matter in the hippocampus.

When Bohbot and her team first detected a larger caudate nucleus on the MRI scans of response learners in 2007, who rely on autopilot rather than cognitive mapping to navigate their environment, “I jumped up and down, I was so excited,” she says. This was the very first study showing that a bias for stimulus-response learning in healthy young adults could be explained by structural differences in their brain.

“Engaging the caudate nucleus on an everyday basis comes at a cost to the hippocampus. That makes us think, maybe that’s what happens in patients with Alzheimer’s disease. They have a larger caudate nucleus, and atrophy in the hippocampus follows.”

Bohbot assembled a highly qualified research team to find out whether increasing hippocampal size with specific spatial memory exercises developed in her laboratory, over the last 12 years, might prevent shrinkage of the hippocampus and delay the progression of Alzheimer’s disease in high-risk patients with mild cognitive impairment. They were able to complete a small pilot study, however, Bohbot’s all four CIHR grants were up for renewal in 2016 in the midst of the CIHR reforms that negatively affected 88% of laboratories across Canada. Bohbot’s application for renewal of her CIHR funding for a larger-scale trial was denied, despite receiving top 100% scores from three reviewers. Without financial support, the project has faltered.

In another line of study, Bohbot used her custom-made tasks to detect which healthy older adult participants used their caudate nucleus, in order to identify those with atrophy of the hippocampus and neighbouring entorhinal cortex, which are predictors of future clinical diagnosis of Alzheimer’s disease. One CIHR reviewer wrote that there was no point in doing the research on early detection of patients at risk for the disease, because Alzheimer’s has no cure.

“And yet, the whole world is looking for ways to intervene early, because interventions fail when the disease has progressed to an advanced stage,” she observes.

Bohbot’s research findings show that people who exercise their cognitive-mapping skills have a larger hippocampus, better overall cognition and a lower risk of developing Alzheimer’s disease. Based on these results, Bohbot strongly believes that exercising cognitive mapping skills will be protective against other neurological and psychiatric disorders.

Dr. Glen Jickling
Clinical neurologist, Assistant Professor,
Faculty of Medicine and Dentistry, University of Alberta, Edmonton

Unraveling mysteries of the immune response in stroke

“I’ve always been an inquisitive person and liked going deeper into problems,” says Glen Jickling, a clinical neurologist and Assistant Professor at the Faculty of Medicine and Dentistry, University of Alberta, Edmonton. “I enjoy being in the lab environment, asking questions, and doing projects to answer them.”

Jickling studies how the immune system responds to stroke and other severe brain injuries. 

A born-and-raised Albertan, he grew up in Calgary, where his father taught biology at a local high school. Early exposure to science led him to pursue undergraduate studies in biochemistry and medical school at the University of Alberta, Edmonton.

During a summer rotation, Jickling began to work with patients at the U of A stroke clinic. He became involved in a number of research projects there during his residency training in neurology.

“That’s what started my interest in stroke,” he says.  

He went on to a neurology fellowship at the University of California at Davis in Sacramento to develop his research interests. He studied how genes are expressed or “switch on” in the immune system when someone has a stroke. Expressed genes or RNA are an essential piece of the body’s protein-building machinery.

“I liked the fact that it was clinically relevant,” he says. 

The project opened his eyes to new ways of looking at complex disorders. He took a job as an assistant professor at UC Davis and, over the next 8 years, continued to focus on RNA expression in stroke.

Jickling wants to figure out whether the immune system can be tweaked to better prevent stroke and to reduce brain injury when stroke occurs.He discovered how to use RNA expression as a biomarker – a biochemical tool – to identify whether a person has had an ischemic stroke. Some biomarkers of RNA expression can identify the cause of stroke, e.g., a heart, blood vessel, or other problem, he says.

Knowing what causes stroke is important, because that information guides treatment decisions, he says. In about 35% of patients, the cause of stroke is unknown.

“Stroke is not always easy to identify quickly, because it’s often mimicked by other diseases, such a migraine, brain tumour or seizure. Having a stroke biomarker could help an emergency doctor rapidly identify someone with stroke and get them to treatment they urgently need.”

Tiny immune regulators

Aside from untangling diagnostic challenges, Jickling is searching for new avenues of stroke treatment.

MicroRNA have the potential to control how the body’s immune system reacts to stroke in a healthy way. MicroRNA are a group of small RNAs that regulate gene expression. They regulate when the immune system kicks into action to repair stroke damage and shutting it down when repairs are no longer needed.

In some people, an overly active immune system may worsen stroke outcome by breaking down blood vessel walls or disrupting the blood-brain barrier, causing more bleeding into an already damaged brain.

“The immune response is tightly regulated,” says Jickling. “If it switches on too much or too little, it’s not helping. You need to find a balance.”

Jickling’s research has identified immune system components that, when activated after stroke, can predict who will have excessive bleeding 24 hours after treatment with the blood-thinner tPA.

“With biomolecular markers, we can get even more precise as to what’s going on in someone’s body at the time of stroke and give better estimates of bleeding risk,” he says.

Forging ahead

In 2016, Jickling received the Derek Denny-Brown Young Neurological Scholar Award in Clinical Science. The highest and most prestigious award of the American Neurological Association, it honours mid-career neuroscientists who have made outstanding contributions to the prevention, diagnosis and treatment of neurological disease.

He returned to the University of Alberta in 2016. “Some of the best stroke care in the world happens here. In terms of developing biomarkers, that’s a huge benefit.”

Work on RNA expression in stroke continues in his laboratory at the University of Alberta, where he is developing a biomarker that will pinpoint atrial fibrillation as the cause of stroke and pursuing microRNA projects. 

When it comes to research, Jickling is “increasingly amazed at how complicated things are and how much there is to learn about how a disease process occurs.”

Basic science research is very useful. We need to understand how things work and what mechanisms underlie disease to develop better treatments.   By keeping research questions focused directly on what’s going in a patient Dr Jickling is optimistic that better stroke prevention and care will be delivered to Canadians.

glenj@ualberta.ca