Pinpointing Target Regions for Brain Stimulation in Treatment-Resistant Depression

Post by Natalia Ladyka-Wojcik

The takeaway

This is the first large-scale randomized controlled trial to demonstrate the importance of pinpointing target regions involved in depression with magnetic resonance imaging (MRI) for treatment with transcranial magnetic stimulation (TMS). Treatment benefits can last longer than we previously understood - up to six months after TMS. 

What's the science?

Although antidepressants and psychotherapies are effective treatment methods for many people with severe major depressive disorder, some individuals have treatment-resistant depression and may benefit from therapeutic neuromodulation, such as repetitive transcranial magnetic stimulation (rTMS). rTMS for depression has been popular for the past several decades, but – critically – no data is available to support its long-term effectiveness (beyond 1-3 months). Moreover, rTMS is traditionally applied to the same site on the scalp such that individual differences in the brain circuits involved in depression may not be accounted for. A more recent approach called connectivity-guided intermittent theta burst stimulation (cgiTBS), may provide longer-lasting treatment effects than standard rTMS by personalizing the targets to each individual’s brain circuitry using MRI data. This month in Nature Medicine, Morriss and colleagues directly compared the efficacy of both therapeutic neuromodulation approaches in a multi-center, randomized controlled trial for treatment-resistant depression over 26 weeks.

How did they do it?

Participants in this study were randomly assigned to receive 20 sessions of either rTMS or cgiTBS over four to six weeks. For both groups, sessions involved placing an electromagnetic coil against the scalp to deliver magnetic pulses that can alter activity in brain circuits thought to be involved in depression. The authors pinpointed the precise location of a brain region involved in depression (the left dorsolateral prefrontal cortex) for each participant by collecting structural or functional MRI (think brain anatomy vs. brain activity) for those undergoing rTMS or cgiTBS, respectively. cgiTBS coordinates were based on the correlation between brain activity of the left dorsolateral prefrontal cortex and the right anterior insula. Crucially, a computerized tracking system, called Neuronavigation, allowed them to deliver the treatment consistently across all 20 sessions, reducing the variability in stimulation at each session. To determine if participants showed a long-lasting reduction in depression symptoms following rTMS or cgiTBS, they administered a widely used depression assessment scale at the start of the study, and later at 8, 16, and 26 weeks.

What did they find?

This study provides large-scale evidence for both rTMS and cgiTBS as effective interventions for treatment-resistant depression. Both groups showed a similar and large average decrease in symptom scores on the depression assessment scale at the 8-week follow-up compared to the start of the study and both groups maintained lower symptom scores on average at the 26-week follow-up. Participants experienced improvements in quality of life despite previously not responding to other treatment approaches for depression, with over two-thirds having reported feeling better by session 20 of stimulation. Importantly, a third of participants across both rTMS and cgiTBS groups showed a 50% drop in depression symptoms, with a fifth of participants maintaining this drop even after 26 weeks. The authors also found that participants who completed fewer than 20 stimulation sessions of either rTMS or cgiTBS showed less improvement in their depressive symptoms at the 26-week follow-up. Together, these findings demonstrate that personalizing the targeted brain sites (via either functional or structural means) for TMS using MRI in patients with treatment-resistant depression can result in long-lasting reductions of depression symptoms, even beyond what has previously been assessed in the literature. 

What's the impact?

This study is the first large-scale trial to find evidence that MRI-guided TMS (both rTMS and cgiTBS) is an effective, long-lasting approach for treatment-resistant depression. Given that around a third of all people with major depressive disorder experience treatment-resistant depression which does not respond to antidepressants and psychotherapies, the results of this study highlight the need to establish MRI-guided TMS as a standard treatment approach in these cases.  

Access the original scientific publication here.

Firing in Rhythm: Simultaneous Ripples Across Distant Brain Regions Facilitate the Integration of Brain Signals

Post by Rachel Sharp

The takeaway

When high-frequency brain waves, known as “ripples”, occur simultaneously across different brain regions, they help integrate signals between these regions through coordinated neural activity. These findings support the hypothesis that ripples play an important role in helping our brains combine complex information across distant brain regions.

What's the science?

How do individual elements of a neural event occurring at different locations across the brain unify into a cohesive mental experience? The “binding-by-synchrony” hypothesis suggests that high-frequency ripples synchronize across brain regions, forming integrated networks of neural activity. Ripples have been shown to synchronize, and have even been shown to organize cell firing in rodents, but the impact of synchronized rippling across distant brain regions in humans is still unknown. This week in PNAS, Verzhbinsky and colleagues test the impact of simultaneous rippling on the integration of neural signals across different brain areas in humans. To do this, the authors used implanted microelectrodes spanning distances of up to 16mm (a US dime is 17.9 mm in diameter) in regions of the cortex used to execute movements and process language.

How did they do it?

The authors implanted four Utah Arrays (a group of 96 microelectrodes with the ability to record spatially accurate neural activity) into the cortex of three participants. They then recorded activity from these electrodes for each patient, over several hours, during both wake and sleep, and analyzed how selected neurons changed their firing rates in response to ripple activity detected by neighboring electrodes. After collecting the full recordings from each participant, the authors analyzed the rate at which ripples co-occurred, whether or not co-firing increased across brain regions when those regions were co-rippling, and whether co-rippling neurons across different regions were better able to predict the firing patterns of other neurons, compared to non-co-rippling neurons. To examine this, they categorized individual neurons as either “predicting drivers (B)” or “predicted targets (A)”. They measured the extent to which firing patterns in B neurons predicted observed firing patterns in A neurons when the surrounding neurons were co-rippling.

What did they find?

The authors found that brain regions that experienced co-rippling also experienced greater integration of neural firing across patients, brain regions, and brain states (wake vs. sleep). They also found that neurons were more likely to fire in synchrony with co-occurring ripples, which was correlated with the ability of neurons to predict another neuron’s firing patterns. This finding supports the idea that networks of neurons distributed across different brain regions synchronize through simultaneous high-frequency ripples. Neurons in co-rippling regions are more likely to fire together, and to exhibit predictive firing patterns. Ultimately, their findings supported the “binding-by-synchrony” hypothesis, showing evidence for networks of co-firing neurons across brain regions, enhanced by simultaneous ripple activity. 

What's the impact?

This study found that simultaneous ripples improve connections between both nearby and distant neurons in the human brain. These ripples were able to organize firing across large groups of neurons, showing the importance co-occurring ripples may have on integrating complex neural events, even when they occur in different brain regions. This integration of neural events helps us achieve complex cognition, organize our thoughts, and make appropriate decisions. Understanding the biological mechanism that drives neural integration gives us another clue to deciphering the puzzle of complex human perception and cognition.

A New Way Forward: Psychedelic Therapy for the Treatment of Mental Illness

Post by Laura Maile 

The need for effective treatments for mental illness

An estimated 26% of adults in the United States suffer from depression, anxiety, or other related mental health disorders, and around 20% of patients don’t respond to standard treatments. Major depressive disorder (MDD) is a substantial public health burden, with an estimated $210 billion burden every year in the US alone. Drug treatments for MDD usually require weeks to reach effective levels, and many who take such treatments do so indefinitely. Along with the adverse side effects reported for many drugs used to treat depression and anxiety, the cost burden to patients and the public highlights the critical need for improved treatments. 

What are psychedelics?

There are many synthetic and naturally occurring substances categorized as “psychedelics,” which are defined by their ability to alter consciousness, perception, cognition, and mood, usually through action at serotonin receptors. Classic psychedelics including psilocybin, mescaline, N, N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) bind to a variety of receptors, but exert their psychoactive effects by binding to a specific type of serotonin receptor, the 5-HT2A receptor, which is mostly located on excitatory neurons in the cortex. Binding to these specific serotonin receptors leads to intracellular signaling cascades that ultimately lead to synaptic plasticity and increased activity of neurons in regions of the brain associated with cognition, attention, emotion regulation, and sensory perception. Scientists don’t yet fully understand the specific mechanisms that lead to the acute effects of the psychedelic experience, nor the long-term effects of their use in treating mental health disorders.  

What’s the current state of research on psychedelic psychotherapy?

There have been several studies that support the high therapeutic potential of psychedelics in the treatment of depression, anxiety, alcohol-use disorder, substance-use disorder, and post-traumatic stress disorder. Evidence comes from both surveys of psychedelic self-administration and small-scale clinical investigations with controlled administration and medical supervision, usually in conjunction with psychological support or therapy before, during, and after the treatment sessions. In 2021, Davis and colleagues published a randomized clinical trial of 24 participants with MDD, showing that just two treatment sessions of psychotherapy-assisted administration of psilocybin led to significant improvement in symptoms in 71% of participants, and full remission in 54% of participants one month later. Ross and colleagues demonstrated similar findings in another small-scale randomized placebo-controlled trial focusing on the treatment of anxiety and depression in cancer patients. In this study, between 60-80% of patients saw continued relief from anxiety and depression symptoms 6.5 months following a single dose of psilocybin combined with psychotherapy. Another study published in 2022 by Holze and colleagues tested the effects of LSD psychotherapy in 42 participants with anxiety, both with and without a life-threatening illness. In this study, participants experienced two treatment sessions with LSD and two with placebo, and most experienced reduced anxiety and depression symptoms 16 weeks later. Overall, this research suggests that psychedelic therapy can be effective in treating mental illness, even after just a couple of treatments.

Results from a randomized clinical trial (von Rotz et al., 2022)

What does the future look like?

Recent studies in rodents indicate that some of the beneficial effects of psychedelics for depression treatment may depend on the TrkB receptor, not serotonin receptors. More research is needed to understand further the mechanism of action that underlies the beneficial effects of psychedelics. One concern regarding psychedelic therapy is the potential side effects - more research is needed to determine whether existing psychedelic drugs can be chemically altered to target receptors that will limit the hallucinogenic effects while maintaining the beneficial antidepressant effects. While past clinical trials have indicated the potential benefits of using psychedelics to treat mental illness, additional large-scale randomized clinical trials are needed to ensure the safety and efficacy of using various psychedelic drugs for treatment-resistant depression, anxiety, and other mental illnesses, especially for individuals already taking medications like antidepressants. These include studies on 5-MeO-DMT, a component of Sonoran Desert Toad venom that produces an intense psychedelic experience that lasts between 5-20 minutes, which is much shorter than the hours-long effects of LSD and psilocybin.  

The takeaway

Reviews of many recent clinical studies indicate that psychedelics have huge potential as an alternative treatment for depression, anxiety, and other mental health disorders. When administered in a safe environment in combination with psychotherapy, psychedelics can result in long-term reductions in depression and anxiety symptoms, with few adverse effects reported. More large-scale clinical trials are needed to assess the safety and efficacy of these treatments in a more diverse pool of patients. The research and development of approved psychedelics is an important ongoing effort that may have substantial impacts on the personal, social, and economic burdens of mental health disorders worldwide.    

References +

Carhart-Harris et al. Psylocibin with psychological support for treatment-resistant depression: an open label feasbility study. 2016. The Lancet Psychiatry.

Davis AK et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. 2021. JAMA Psychiatry.

DiVito AJ et al. Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review. 2020. Mol Biol Rep.

Holze F et al. Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study. 2022. Biological Psychiatry.

Kocak, D.D., Roth, B.L. Examining psychedelic drug action. 2024. Nat. Chem.

McClure-Begley et al. The promises and perils of psychedelic pharmacology for psychiatry. 2022. Nat Rev Drug Discov.

Moliner R et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. 2023. Nature Neuroscience.

Ross S et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. 2016. J Psychopharmacol.

Von Rotz et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. 2022. eClinical Medicine.