Memories Unravelled
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In 1953, Henry Molaison underwent an experimental surgery known as bilateral temporal lobectomy to treat the severe epilepsy he had been experiencing. His surgeon removed his medial temporal lobe, including a structure known as the hippocampus—a part of the brain involved in the storage of long-term memory—in hopes of curing the condition. While Molaison emerged from the surgery no longer facing chronic seizures, he could not retain any new information and had lost his ability to form memories. Despite his memory loss, Molaison’s surgery would allow researchers to contribute invaluable information to the field of neuroscience.

To this day, scientists struggle with understanding the inner workings of the memory process. Through the development of more advanced technology and different molecular approaches to the topic, researchers have been able to make major strides in further elucidating the mechanisms behind our minds. In particular, neurological research in McGill has brought about some of the most revolutionary and exciting findings that have helped further our understanding of this mysterious organ and its roles in forming memories.
Brenda Milner, a Canadian neuropsychologist working at the Montreal Neurological Institute (MNI), was one researcher who contributed extensively to the study of memory by examining the effects of Molaison’s surgery on his brain. Specifically, she investigated the cause of his inability to retain any short-term memories and convert them into long-term memories, despite retaining his long-term memories from before the operation. Short-term memories are formed just after processing an incident, and can only store around seven items for a short period of time, compared to long-term memories that can store vast amounts of information for infinite periods of time.

Milner and her doctoral advisor, Donald Hebb, speculated that the other side of Molaison’s hippocampus—the unoperated side—was probably damaged in some way as well, a condition known as a bilateral lesion. Their hypothesis was confirmed years later when an autopsy was carried out on a similar patient’s brain. The hippocampus tissue on the unoperated side in the second patient was, in fact, damaged and wasting away.

However, it was Milner’s behavioural studies on Molaison that served as the breakthrough point for her. By encouraging him to participate in a set of rigorous experiments, Milner investigated the extent of his inability to form long-term memories. First, she sent Molaison through a maze, where he had to learn to navigate through trial and error. Molaison showed no improvement with three days of practice. Next, she challenged him with a sensorimotor task, where he had to draw a star guided by the reflection of his hand. The task became easier with practice, and within three days of repeating the drawing, Molaison’s performance was perfect—although he could not recall ever having completed the task before.

“He had absolutely no memory of all these trials he had been through,” Milner said in a previous interview with the McGill Journal of Medicine. “There was a total dissociation between his experience and his excellent performance.”

From these behavioural studies, Milner concluded that there are multiple memory systems, which she divided into episodic memory—the recall of autobiographical events, as well as procedural memory, which is the memory for performing an action—the same memory system Molaison used to improve during his drawing activity.
Despite Milner’s discoveries, it would take time and the development of technology beyond behavioural science until further breakthroughs in memory research could be made. These achievements included the development of magnetic resonance imaging (MRI) during the 1970s and functional magnetic resonance imaging (fMRI) in the 1990s.

Both technologies harness radio waves to form images of the body, providing researchers with the unprecedented ability to visualize the interior of the brain. Stephen Frey and Marilyn Jones-Gotman are two McGill professors who used fMRIs to advance their research. Before her retirement in 2009, Jones-Gotman used fRMIs to take images of the brain in different situations— such as comparing pleasant and unpleasant sensory stimuli—with the intent to further her understanding of how the brain responds to stimulus.
Also advancing this field of study is Karim Nader, a professor at McGill who is working on elucidating the mechanisms behind long-term memory storage. Moving beyond Milner, who used a human model, he is looking into how recalled memories can be changed and even erased, by studying memories in rats.

“When a memory is retrieved, it is transformed into a vulnerable state in which it can be lost, changed or strengthened depending on the experimental manipulation,” Nader states on his laboratory website. “We have been asking questions at the behavioural, physiological, and molecular levels of [memory] analysis [through studying rats].”

Nader’s lab research in 2000 showed that if a memory of fear is reactivated, these long-term and previously stable memories become unstable once more. It’s up to the brain to make new proteins in order to store these reactivated memories again. Using a type of medication known as a beta-blocker, his team discovered that they could prevent the re-storage of these memories—essentially erasing them. This finding has given rise to exciting possibilities for developing a treatment for post-tramautic stress disorder (PTSD) patients.
Similarly, Sylvain Williams, an associate professor of psychiatry at McGill, is trying to gain a better understanding of how the hippocampus functions in forming memories at the molecular level. With the development of a technology known as optogenetics, which allows researchers to control genetically modified neurons with light signals, the lab is able to monitor the neural activity of live animals.

Previously in 1954, scientists began to measure brain activity through theta waves and frequencies. These waves are responsible for processing and storing memories of various types of information depending on the behavioural activity, where longer beta and gamma waves are produced during deep sleep, and shorter theta waves are produced during conversations and while learning.

While researchers previously believed that these waves passed through the hippocampus region in strictly one direction, Williams’ team is investigating the possibility that they can actually move in both directions.

“There are many other different kinds of neurons and projections that have not been described in the hippocampus,” Williams said. “In order for us to understand how the hippocampus works and how information is treated, [...] we need to find first all these circuits, characterize them, and understand them.”

To produce these theta waves, a host of different neurons are involved. Williams’ lab is studying a type of neurotransmitter called gamma-aminobutyric acid (GABA). In 2014, his team discovered that when GABA neurons in the subiculum—the last region of the chain of information flow in the hippocampus—are activated, they can actually move in the reverse direction to affect previous regions in the hippocampus.

“[Scientists previously] thought information was passed out passively to the hippocampus and then the subiculum,” Williams said. “But [now] this is not so, because the subiculum may also control how the information is treated in the preceding regions.”

The team is currently trying to figure out whether these GABA neurons play different roles depending on the types of activities. Using optogenetics, the researchers are pushing the boundaries of previous studies with animal models. They are actually able to compare the neural activity of rats that are exploring, sitting, or dreaming.

“We show [that] it does occur, and is very important in […] sleep,” Williams said. “[This] really provides [a] new perspective on information processing in the hippocampus, [and] suggests that it’s more complicated than we expected. The way information is processed in the hippocampus has to be looked at again using our data as a backbone.”
Looking Ahead
The field of neuroscience and neuropsychology has made huge leaps in understanding the mechanisms by which memory functions, aided and abetted by the rise of technology. From crude operations on humans without a complete understanding of the different parts of the brain, to fine-tuning the genetic make-up of single neurons to manipulate the hippocampus of rats, Montreal continues to serve as a hub for researchers who are further advancing the process of unraveling the mysterious processes of memories.

Currently, the Language and Memory Laboratory at McGill coordinates research from a variety of Montreal-based investigators, with the goal of advancing studies in memory formation. Directed by Debra Titone, the Canada Research Chair of Cognitive Neuroscience of Language and Memory, the lab uses a vast array of cognitive neuroscience and imaging techniques to compare normal and disordered populations, such as those suffering from schizophrenia.

Scientists have just scraped the surface of uncovering the many neurons involved in processing memories. The continued development of technology, and insights gained through studying animal models, has enabled researchers to accumulate a knowledge base from which today’s scientists can apply their studies to investigate diseases of human memory.