Jan 25, 2022

Toronto Scientists Hunting for the Perfect Rhythm to Beat Depression Blues

researchers in the lab
By Amanda Ferguson

When it comes to finding a long-lasting treatment for depression, a team of Toronto scientists say it could come down to finding the perfect rhythm.

The approach, under development by scientists at the University of Toronto’s Temerty Faculty of Medicine, Sinai Health and the Centre for Addiction and Mental Health (CAMH), has nothing to do with music and everything to do with tweaking an existing form of brain stimulation therapy.

Graham Collingridge

One component of the project is led by Graham Collingridge, director of the Tanz Centre for Research in Neurodegenerative Diseases at Temerty Medicine who is a neuroscientist and senior investigator at Lunenfeld-Tanenbaum Research Institute (LTRI) at Sinai Health, alongside LTRI staff scientist John Georgiou.

The two are part of a team of Toronto researchers recently awarded a $950,000 grant by Bell Let’s Talk and Brain Canada to improve the technology and test it on volunteer adult patients.

The research centres around transcranial magnetic stimulation, or TMS, a form of brain stimulation therapy that’s been shown to hold enormous promise in helping patients with treatment-resistant depression. The approach uses a device to deliver pulses of magnetic stimulation to the prefrontal cortex, a part of the brain associated with mood regulation.

Collingridge and Georgiou are using brain stimulation with mice to determine whether changing the spacing or tempo of the pulses to the brain could ultimately deliver long-lasting relief from depression symptoms.

“The pattern of stimulation is vital,” said Collingridge, who also a professor of physiology at Temerty Medicine. “It has been recently discovered that instead of applying the rhythm within a short space of time, you have a break for a few minutes and then repeat the stimulation, the effect on synapses in the brain is stronger and longer-lasting.”

The research focuses on a process called long-term potentiation, in which a brief period of intense neuronal activity leads to a long-lasting increase in the strength of connections between the nerve cells.

Evelyn Lambe

Long-term potentiation was discovered by European scientists Tim Bliss and Terje Lømo, based on the influential hypothesis of the Canadian psychologist Donald Hebb; knowledge of how it is induced was then used to develop the TMS patterns used to treat depression today.

“The ability to rapidly test this new stimulus paradigm in human subjects is based on over 30 years of fundamental research in the field of LTP,” Collingridge said. “It’s impossible to overestimate the importance of basic research for the development of improved treatments for human conditions.”

Georgiou said that by optimizing the patterns of stimulation, the team hopes to produce stronger and longer-lasting LTP that in turn should translate into a persistent antidepressant effect.

In order to find the perfect pattern, Collingridge and Georgiou are collaborating with Evelyn Lambe, an associate professor of physiology at Temerty Medicine, who is leading work on optimizing the stimulus parameters in the prefrontal cortex, the region targeted by TMS in patients, as part of the Bell Let’s Talk Brain Canada research grant.

"The goal is to optimize treatment to rebuild connections between neurons essential for mood regulation," said Lambe. Her lab's work investigating the impact of social isolation on the brain has become increasingly relevant to mental health during the COVID19 pandemic. "Social isolation and other stressors wear us down by impairing brain function at the cellular level," Lambe notes.

Tarek Rajji
Sanjeev Sockalingam

Tarek Rajji, who is a professor of psychiatry at Temerty Medicine and executive director of the Toronto Dementia Research Alliance, as well as chief of the adult neurodevelopment and geriatric psychiatry division at CAMH, will adapt the optimized stimulation parameters to humans using TMS and electroencephalograhy. His team will examine which pattern of stimulation leads to better brain plasticity in the frontal lobes of adults with acute depression.

Throughout the project, Sanjeev Sockalingam, professor of psychiatry at Temerty Medicine and a clinician-scientist and vice president education at CAMH, will lead the knowledge translation component of the work. This will involve mental health clinicians, people with lived/living experience and families working with researchers from the start of the project.

“The integrated approach involving clinicians and service users will help us co-create knowledge that gets to people who can use it faster and more effectively,” said Sockalingam.

The project arose from earlier work and conversations among Rajji and Collingridge around links between dementia and depression, funded by Temerty Medicine, the Tanz Centre and Toronto Dementia Research Alliance. The pair hope to apply their work on optimizing TMS protocols for dementia, in addition to depression.