A man in his 30s or 40s undergoes transcranial magnetic stimulation therapy (TMS) in a psychiatric clinic to control depression or anxiety EMT concept. (© Yistocking - stock.adobe.com)
Table of Contents
In a nutshell
This dual-target brain stimulation treatment for depression works faster than traditional methods by targeting two brain regions at once.
The accelerated 5-day schedule could provide quicker relief for severely depressed patients, particularly those in crisis.
Because it doesn’t require complex equipment, more clinics could offer this depression treatment, making it more accessible to patients
CAMBRIDGE, England — Depression affects about one in 20 adults, and while treatments like antidepressants and talk therapy help many people, they fail to work for nearly a third of patients. For these individuals with treatment-resistant depression, finding effective treatment becomes increasingly urgent. Now, an innovative brain stimulation approach could help these patients feel better in just five days, according to promising research from scientists at the University of Cambridge and their colleagues in China.
The treatment uses repetitive transcranial magnetic stimulation (TMS), which applies magnetic pulses to the brain through a device placed against the scalp. This non-invasive technique has been used for years to treat depression, but traditional approaches require daily visits over 20-30 days — a schedule that can be challenging for many patients, especially those in crisis or with limited access to treatment centers.
“The treatment works faster because, by targeting two areas of the brain implicated in depression, we’re effectively correcting imbalances in two import processes, getting brain regions ‘talking’ to each other correctly,” explains University of Cambridge Professor Valerie Voon, who led the UK side of the study, in a statement.
How Does Dual-Region TMS Work?
Depression involves an imbalance in brain activity — some regions show too little activity while others are overactive. The standard TMS treatment, approved by both UK’s NICE and the FDA, targets an underactive region on the left side of the brain called the dorsolateral prefrontal cortex. This area helps regulate emotions and plays a role in thinking and memory. When it’s underactive, people often experience common depression symptoms like low mood and difficulty concentrating.
The new approach adds stimulation to a second region on the right side of the brain called the orbitofrontal cortex (OFC). This area helps us process rewards and negative experiences. In depression, this region tends to be overactive, which may explain why depressed individuals often focus more on negative experiences and have trouble feeling pleasure from activities they usually enjoy.
Treatment-resistant depression creates significant challenges beyond the immediate symptoms. Patients often face higher medical costs, have more difficulty maintaining work and relationships, and experience a higher risk of suicide. Current options for these patients are limited. While treatments like electroconvulsive therapy can be effective, they often require hospitalization and can have significant side effects. This is why finding faster-acting, less invasive treatments is crucial.
TMS emerged as a depression treatment in the 1980s, offering a new approach that doesn’t require medication or surgery. The treatment uses magnetic pulses similar in strength to those used in MRI machines but focused on specific brain regions. Unlike medications that affect the entire brain, TMS can target particular areas that aren’t functioning optimally in depression. However, traditional TMS treatment schedules can be challenging – patients typically need to visit a clinic every weekday for 4-6 weeks, making it difficult for those who work, live far from treatment centers, or need rapid improvement.
A patient undergoes transcranial magnetic stimulation (TMS) therapy at a psychiatric facility to treat depression or anxiety. (© Yistocking – stock.adobe.com)
Testing Dual-Region TMS On Depression Patients
The study design was carefully planned to test whether this new approach made a difference. Beyond just measuring if patients felt better, the researchers used brain imaging to understand how the treatment affected brain function. They conducted detailed scans before and after treatment to see how different brain regions communicated with each other.
The 75 study participants were all receiving stable doses of antidepressant medication but hadn’t improved despite at least six weeks of treatment. Many also had anxiety symptoms and were taking anti-anxiety medications, reflecting the complex nature of real-world depression treatment. This is important because previous studies often excluded such patients, making it harder to know if treatments would work in typical clinical settings.
The researchers divided participants into three groups. One group received the new two-region treatment, another got the standard single-region treatment plus a placebo, and the third received only placebo treatments. For the placebo or “sham” treatments, researchers tilted the coil for one site and placed it over a different area for the other site, delivering very weak pulses that created similar sensations without affecting the brain.
Depression severity was measured using the Hamilton Rating Scale for Depression, a comprehensive assessment that looks at 24 different aspects of depression. These include not just mood but also physical symptoms like sleep problems, appetite changes, and energy levels, as well as thoughts about death or suicide. This detailed assessment helped ensure that improvements weren’t limited to just one aspect of depression.
Promising Results: Rapid Improvement
Researchers found that nearly half of those receiving the two-region treatment felt better immediately after the five-day course, compared to just 18.2% of the single-region group and 4.3% of the placebo group. “Patients frequently reported experiencing ‘lighter and brighter’ feelings as early as the second day of treatment,” said co-author Dr. Hailun Cui from Fudan University.
The rapid improvement seen in the two-region treatment group is particularly significant. In traditional depression treatments, including standard TMS, it often takes several weeks to see significant improvement. The fact that nearly half of patients showed major improvement after just five days suggests this approach might help patients feel better when they most need it.
Brain scans revealed how the treatment affected communication between different brain regions. The two-region treatment appeared to help normalize communication between brain areas involved in emotional processing and reward. Think of it as helping different parts of the brain work together more effectively – like improving the signal between different members of an orchestra so they can play in harmony.
Safety and Tolerability
Four weeks after treatment, about 60% of participants in both active treatment groups showed significant improvement, compared to 22% in the placebo group. This suggests that while the two-region treatment works faster, both active treatments can be effective over time. Researchers measured improvement using a standardized depression rating scale that looks at various symptoms including mood, sleep problems, and suicidal thoughts.
The treatment proved generally safe, though not without discomfort. About half of the two-region treatment group reported pain at the treatment site, compared to 9% of the single-region group. Mild to moderate headaches occurred in about 19% of all participants. Despite this discomfort, no participants dropped out of the study, suggesting they found the treatment tolerable.
“This new treatment has demonstrated a more pronounced – and faster – improvement in response rates for patients with major depressive disorder,” says Dr. Yanping Shu from the Guizhou Mental Health Centre. “It represents a significant step forward in improving outcomes, enabling rapid discharge from hospitals for individuals with treatment-resistant depression.”
Future Outlook
Looking ahead, this treatment could change how we help people with severe depression. The ability to deliver effective treatment in just five days could make it easier for patients to complete the full course of therapy. It might also help reduce hospitalization times or even prevent the need for hospitalization in some cases. The treatment’s accessibility without specialized equipment means it could potentially be offered in more locations, making it available to patients who might otherwise have limited access to advanced treatments.
The researchers are particularly interested in understanding why some patients responded better than others. They’re now studying whether certain types of depression symptoms might predict who will benefit most from this approach. They’re also exploring the optimal timing for any follow-up sessions that might be needed to maintain improvement.
Points of Contention
Readers should consider these important limitations when evaluating the findings of this study:
Short-Term vs. Long-Term Effects
Immediate Impact: The dual-region treatment showed rapid improvement within five days, but long-term effectiveness compared to standard TMS treatment still requires further evaluation.
Delayed Response: Some participants in single-region treatments improved gradually, suggesting a potentially different trajectory or delayed response to standard TMS treatments.
Dosage and Frequency Differences
Unequal Treatment Intensity: Participants receiving the dual-region treatment were exposed to more pulses overall (25% more stimulation), raising the question of whether improved outcomes were due to the dual-region approach itself or simply higher cumulative stimulation.
Real-World Applicability
Patient Selection and Medication Use: Participants remained on antidepressants and anti-anxiety medications, which reflects clinical realities but may influence or confound results. Real-world patients might vary significantly from the study sample, affecting generalizability.
Imaging and Biological Mechanisms
Mechanistic Clarity Needed: The study suggests connectivity changes between specific brain regions might underlie improvements, but causality remains speculative. Further research is required to clarify these mechanisms clearly.
Absence of a Single OFC-only Group
Limited Clarity on OFC Contribution: Without a group receiving stimulation to only the orbitofrontal cortex (OFC), it’s difficult to isolate the OFC’s individual contribution to improvements, complicating conclusions about why dual-region stimulation might be more effective.
Spontaneous Improvement and Placebo Effect
Placebo Improvement Observed: Some placebo group patients also improved, indicating the possibility of spontaneous remission, placebo effects, or attention effects from treatment environments, complicating interpretation of results.
Need for Replication and Expansion
Preliminary Study Nature: With a relatively small sample size, this pilot study requires replication with larger participant numbers and diverse populations to confirm findings robustly.
Funding and Support Issues to Consider:
Institutional and Governmental Funding
The study received funding from multiple sources, including government agencies and institutional grants from both the UK and China. While generally indicative of credibility, government-funded studies can still carry implicit expectations or biases towards showcasing positive outcomes or emphasizing national or institutional research excellence.
Absence of Industry Funding
Notably, the funding sources listed (Medical Research Council UK, National Natural Science Foundation of China, and local health commissions in Guizhou) are primarily public institutions rather than commercial entities. This is typically reassuring, but even publicly funded studies may have implicit pressures to report promising results that justify future public investments.
Potential Biases from International Collaboration
Collaboration between the UK and Chinese institutions could introduce subtle pressure for positive findings to maintain collaborative relationships or secure future joint funding. Though speculative, it’s worth considering given the cross-national prestige attached to successful outcomes.
Commercialization and Accessibility
While the researchers suggest that their method could be adopted widely without expensive neuronavigation equipment, real-world implementation costs, training, and ongoing equipment maintenance can limit accessibility. These practical considerations are often not fully addressed in studies funded by academic or governmental sources focused primarily on theoretical or clinical efficacy.
Future Funding Expectations
With pilot studies such as this one, there’s typically an underlying expectation of using promising results to secure additional funding. This may encourage a subtle bias towards reporting positive preliminary findings, although not explicitly stated in the publication.
These points do not imply unethical practice or deliberate bias by the researchers but rather highlight the importance of understanding how funding sources and institutional support might subtly shape research design, reporting, and interpretation.
Paper Summary
Methodology
The study used a double-blind, randomized controlled design where neither patients nor assessors knew who received which treatment. Researchers used the EEG 10-20 system to position the TMS coil, delivering either active or sham stimulation to specific brain regions. The dual-site group received inhibitory stimulation to the right OFC followed by excitatory stimulation to the left dlPFC, with sessions separated by 5-minute intervals. Each participant received 20 total sessions over five days.
Results Breakdown
The primary measure of improvement was the change in depression scores on the Hamilton Rating Scale for Depression (HRSD-24). Both active treatment groups showed significant improvement compared to sham at 4 weeks. The dual-site group demonstrated faster response rates and better daily depression scores by day 5. Brain imaging showed specific changes in neural connectivity, particularly between the OFC and other regions involved in depression.
Funding and Disclosures
The research was supported by multiple institutions including the Medical Research Council, Wolfson College, National Natural Science Foundation of China, and various other Chinese research funds. The authors reported no conflicts of interest.
Publication Information
Published in Psychological Medicine (2024), authored by Hailun Cui and colleagues from the University of Cambridge and multiple Chinese institutions. The study was registered with ChiCTR (Identifier: ChiCTR2100049002) and conducted from June 2021 to February 2022, with follow-up completed by April 2022.