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A large real-world study shows that fMRI-guided targeting can meaningfully improve response rates in accelerated TMS for treatment-resistant depression, while standard-targeted TMS remains a meaningful option.
If you've been fighting depression for years and watched medication after medication fail to lift it, the exhaustion and frustration are real. You've probably read about newer treatments and wondered whether any of them would actually work for you, and whether the personalized approaches are worth the extra cost and complexity.
Transcranial magnetic stimulation (TMS) has been FDA-approved for depression since 2008, and the field has evolved substantially in recent years. New accelerated protocols deliver a full treatment course in five days rather than six weeks, and some clinics have added functional MRI to personalize where the treatment is targeted for each patient.
This article walks through what a recently released naturalistic study of 195 patients can tell you about fMRI-guided accelerated TMS: how much it improves outcomes, when standard targeting is still effective, and how the treatment compares to other options. Individual results vary.
Note: A recent naturalistic study of 195 patients found that adding fMRI-guided targeting to accelerated iTBS treatment improved response rates from 62.2% to 77.5% (propensity-matched analysis). Both approaches produced meaningful outcomes in a cohort with an average of more than five failed medication trials. Individual results vary. Book a free consultation to find out if you're a candidate.
A recent naturalistic study analyzed outcomes from 195 adults with treatment-resistant depression who received accelerated TMS between 2018 and 2025. These were not carefully selected research participants. They were patients seeking treatment in a clinical setting, many with multiple failed medication trials and complex medical histories.
The study compared two groups: 115 patients received fMRI-guided targeting to personalize their treatment, while 80 patients received standard scalp-based targeting using the Beam F3 method, which estimates location based on skull landmarks.
After statistical adjustment that accounted for baseline differences between groups, patients who received fMRI-guided targeting were 2.3 times more likely to respond to treatment. The propensity-matched response rate went from 62.2% with standard targeting to 77.5% with fMRI guidance.Put another way: for every 6-7 patients who receive fMRI-guided treatment, one additional person achieves significant symptom relief compared to standard targeting.
Percentage of patients achieving clinical response within one month. Both approaches showed strong effectiveness.
To appreciate why personalized targeting might make such a difference, we need to understand a bit about how TMS works and what it's trying to accomplish.
Depression isn't caused by a single brain region "malfunctioning." Instead, it involves disrupted communication between multiple brain networks. One of the most important connections is between the dorsolateral prefrontal cortex (DLPFC), located behind your forehead and involved in executive function, emotion regulation, and decision-making, and the subgenual cingulate cortex (SGC), a deeper region that tends to be overactive in depression.
Think of these regions like two cities connected by a highway. In depression, this highway becomes underactive—the DLPFC isn't properly regulating the SGC's emotional processing. TMS works by stimulating specific spots in the DLPFC to strengthen this connection.
Personalization matters because everyone's brain is organized slightly differently. The exact location of the DLPFC that connects most strongly to the SGC varies from person to person.
The DLPFC is a relatively large brain region that is responsible for many functions, so the "ideal" spot to stimulate within the DLPFC to reach the SGC could be a very different location for you than for someone else.
fMRI (functional magnetic resonance imaging) allows clinicians to map your brain's specific connectivity patterns. During a roughly 20-minute scan, patients simply rest while the MRI measures spontaneous fluctuations in brain activity—seeing how your brain naturally communicates with itself.
The analysis identifies which locations in your DLPFC show the strongest anti-correlation (negative functional connectivity) with the SGC. This is your personalized target: the precise spot where stimulation is most likely to influence the depression-related network.
The DLPFC is a large region with many subregions that do similar, overlapping functions. Most areas of the left DLPFC contribute in lesser and greater degrees to the function of controlling depression. The small spot that is the most anti-correlated with SGC is particularly dedicated to this function, and is the most potent spot to stimulate. However, if you stimulate just about anywhere in the left DLPFC, you will likely get some degree of benefit.
The Beam F3 method relies on this fact for treating many patients effectively without imaging. This method uses skull measurements to estimate where the DLPFC is located, similar to how a tailor might use standard measurements to estimate clothing fit. It accounts for head size variations but doesn't capture the individual differences in where specific brain networks are located.
Traditional TMS for depression uses daily sessions over four to six weeks, a significant time commitment. Accelerated TMS compresses this into five days, with 8–10 sessions per day spaced approximately 50 minutes apart. It uses a specific stimulation pattern called intermittent theta-burst stimulation (iTBS), delivers a full treatment course in one week, and enables faster onset of therapeutic effect than traditional protocols.
This acceleration is based on established neuroscience. The brain undergoes neuroplastic changes, or physical rewiring of neural connections, in response to TMS. Multiple daily sessions may reinforce these changes more effectively than sessions spread over weeks. It's similar to how studying with short breaks can be more effective than spreading study sessions far apart. Neural pathways are strengthened while they're still active from the previous session.
Here's what the study found in practical terms.
Overall effectiveness
When researchers used propensity score matching (a statistical technique that creates "matched pairs" of similar patients who differed primarily in whether they received fMRI guidance) the benefits became clearer:
This represents 2.3 times higher odds of response, which means that for every six to seven patients who receive fMRI-guided treatment, one additional person achieves significant symptom relief compared to standard targeting. In practical terms, if 100 patients were treated with fMRI guidance instead of standard targeting, approximately 15 additional people would experience significant improvement.
Interestingly, the second best predictor of treatment outcome (after fMRI guidance) was the number of previous antidepressant trials. More prior medication failures predicted lower response rates—highlighting how critical new treatment options like aTMS are for truly treatment-resistant cases.
Age, sex, baseline severity, and history of other brain stimulation treatments didn't significantly predict outcomes, suggesting that aTMS with fMRI guidance may work across a broad range of patient profiles.
Treatment was generally well-tolerated, with no patients discontinuing due to adverse events. Common side effects in the study included headache (61% fMRI-guided, 45% standard), fatigue (31% fMRI-guided, 30% standard), and treatment-emergent anxiety (15% fMRI-guided, 7% standard).
Most side effects resolved quickly, often within the treatment week itself. For patients who experience treatment-emergent anxiety that persists, adding right-hemisphere stimulation to target the anxiety-related circuit has been documented as a management approach in the literature and is one option available in accelerated TMS programs. Individual results vary.
The study also reported one patient who died by suicide two days after treatment. This patient had been identified as high-risk at baseline with a prior history of suicide gestures, and after review by three board-certified psychiatrists, the death was determined to be unrelated to direct TMS effects. This case underscores the importance of ongoing safety monitoring after intensive treatment, particularly for patients who may perceive it as a last-resort intervention.
This study addresses a critical question facing the field: Is the added complexity and cost of fMRI-guided targeting worth it?
The answer from this data appears to be yes—with some important caveats:
Not everyone has access to fMRI-guided TMS, and insurance coverage for TMS varies significantly between standard and accelerated protocols.The technology requires:
If fMRI-guided targeting isn't available in your area, this study's findings remain encouraging: standard accelerated TMS still produced a 62-66% response rate, which compares favorably to most antidepressant medications and traditional TMS protocols.
This wasn't a carefully selected research population - these were real patients seeking treatment in a clinical setting.
📊 Context Matters
These outcomes are particularly impressive because this population represents highly treatment-resistant depression. After 4-5 failed medication trials, the expected response rate to a new medication is typically only 10-15%. Achieving a 73% response rate in this population demonstrates the potential of accelerated TMS as a game-changing intervention.
1. Real-world data: Unlike highly controlled clinical trials that exclude patients with comorbidities, this study included the messy reality of clinical practice—patients with multiple diagnoses, prior treatment failures, and varying clinical presentations.
2. Large sample size: With 195 patients, this is one of the largest reports of accelerated TMS outcomes to date.
3. Sophisticated statistics: The researchers used propensity score matching to create "apples-to-apples" comparisons between groups that differed in baseline characteristics.
1. Not a randomized trial: Patients chose whether to receive fMRI guidance (often based on insurance coverage, schedule constraints, or personal preference). While statistical matching helps, unmeasured confounding factors could still influence results.
2. Potential placebo enhancement: Patients receiving fMRI guidance knew they were getting "advanced" personalized treatment, which might enhance placebo response.
3. Temporal bias: fMRI guidance was introduced midway through data collection, so later patients had different treatment experiences than earlier ones.
4. Single-site study: Results from one specialized clinic may not generalize to all settings.
The gold standard for confirming these findings would be a randomized controlled trial where patients are assigned to fMRI-guided vs. standard targeting. Such a trial is currently underway (NCT07043738), and results are eagerly awaited.
This study represents an important step toward what researchers call "precision psychiatry"—tailoring treatments to individual brain architecture rather than using one-size-fits-all approaches.
The concept builds on decades of neuroscience research showing that:
fMRI-guided TMS exemplifies this paradigm. Rather than stimulating a generic "depression region," it identifies and targets the specific circuit dysfunction present in your particular brain.
These response rates are best understood alongside other treatment-resistant depression options.
Depression is a time-sensitive condition. Symptoms have real costs in relationships, work, and quality of life, so a treatment that produces results in days rather than weeks or months represents a meaningful advance. Individual results vary.
What About Treatment Durability?
One question this study doesn't fully answer: How long do these improvements last?
The outcomes were measured within one month of treatment completion. While this demonstrates rapid and robust initial response, longer-term follow-up data will be crucial for understanding durability.
Preliminary evidence from other accelerated TMS studies suggests that:
This is an area where ongoing research is needed, and where personalized approaches (like fMRI-guided maintenance targeting) may prove valuable.
This study opens several exciting research directions:
Symptom-specific targeting: Rather than just targeting "depression," could we identify distinct targets for specific symptoms like anxiety, anhedonia (inability to feel pleasure), or cognitive dysfunction?
Biomarker development: Can baseline brain connectivity patterns predict who will respond best to treatment?
Multi-target protocols: Should some patients receive stimulation to multiple sites based on their specific symptom profile?
Optimization of fMRI acquisition: What's the minimum scan time needed? How does scanner quality affect target selection?
Integration with other treatments: How does aTMS combine with psychotherapy, medications, or other neuromodulation approaches?
In this study, standard-targeted accelerated TMS produced a 62.2% response, while fMRI-guided targeting reached 77.5%. These results are better than most traditional treatments for depression. What’s more, improvement typically occurs within days to weeks rather than months, and the treatment is effective even in patients who have tried more than five prior antidepressant medications.
If you are considering treatment, both fMRI-guided and standard-targeted protocols are options worth discussing with a treatment team, based on your specific circumstances, prior treatment history, and access to fMRI-guided providers.
Cognitive FX offers fMRI-guided accelerated intermittent theta burst TMS for patients with treatment-resistant depression. The protocol shares the core design elements described in the study above: functional MRI targeting of the individualized DLPFC-SGC connection, an accelerated schedule delivered over five consecutive days, and intermittent theta burst stimulation as the pulse pattern.
What the protocol involves. Treatment starts with a functional MRI scan and a clinical intake with the CFX psychiatric team. The neuroscientist and prescribing physician review the fMRI in-house to identify the specific coordinate in the DLPFC with the strongest anti-correlation to the SGC in that patient. That coordinate becomes the individualized treatment target. Over the following five consecutive days, patients receive 10 iTBS sessions per day, spaced approximately 50 minutes apart, for 50 sessions total. FDA-approved neuronavigation is used to place the coil on the exact target every session.
How this differs from standard rTMS. Standard rTMS uses a single scalp-based coordinate applied to every patient, spread over four to six weeks of daily sessions. Cognitive FX's protocol uses each patient's own fMRI to identify the individualized target, and compresses the full treatment course into five days. The protocol is off-label for depression (all TMS use for post-concussion syndrome or other conditions is off-label). For depression, standard rTMS is the FDA-approved indication, but many clinics including Cognitive FX offer accelerated iTBS protocols where clinical evidence supports it.
What the cost and format look like. The current fMRI-guided accelerated iTBS treatment at Cognitive FX is priced between $9,000 and $12,000 for the full five-day course. This is generally self-pay, as insurance coverage for accelerated fMRI-guided protocols is limited. Standard rTMS delivered over four to six weeks is often covered by insurance after failure of multiple antidepressants, and CFX can help patients understand their options.
Who is a candidate. The treatment is appropriate for adults with treatment-resistant depression, defined as depression that has not responded to at least two adequate trials of antidepressant medications. The DeSouza study cohort included patients with an average of more than five prior medication failures, so this treatment approach is being applied to patients with substantial treatment resistance.
Who is not a candidate. Cognitive FX does not offer this treatment to patients with metallic implants in the head or neck (including cochlear implants, aneurysm clips, or internal pulse generators), patients with a history of seizures or high seizure risk, patients who are pregnant, or patients in acute psychiatric crisis requiring immediate hospitalization. Bipolar patients may be candidates but require careful individual assessment. During the free consultation, the clinical team reviews each patient's medical history and symptom picture to determine fit before treatment is scheduled.
How it integrates with other care. The accelerated iTBS protocol addresses one component of depression treatment: brain network dysfunction identifiable on imaging. Many patients also benefit from continued psychotherapy, medication management with their existing prescriber, and other supportive care. The treatment is not a replacement for these; it is a targeted intervention that can be combined with them.
How the treatment is scheduled. The process starts with a free consultation with the Cognitive FX team. The consultation reviews your medical history, prior treatments, current symptoms, and treatment preferences to determine whether the fMRI-guided approach is likely to fit your case. If treatment is appropriate, the intake team coordinates the pre-treatment scan, the five-day intensive schedule, travel logistics for out-of-state patients, and follow-up care. Individual results vary.
This study adds compelling real-world evidence that fMRI-guided targeting improves outcomes for accelerated TMS in depression. The 15-point improvement in response rate (from 62% to 77.5%) is clinically meaningful and statistically robust.
However, the finding that standard targeting still produced 62-66% response rates is equally important. For the millions of people suffering from treatment-resistant depression, even standard accelerated TMS represents a rapid, effective, and well-tolerated option—particularly for those who've exhausted multiple medication trials.
The ideal scenario, of course, is making fMRI-guided approaches widely accessible. But in the meantime, we can take comfort that accelerated TMS protocols show strong effectiveness regardless of targeting method.
Studies like this help clarify both the value of precision approaches and the reality that standard-targeted TMS is still meaningfully effective. The 15-point improvement in matched response rate (from 62.2% to 77.5%) is clinically meaningful and statistically significant. For patients who have access to fMRI-guided treatment, the added personalization is worth considering. For patients whose only option is standard-targeted accelerated TMS, the outcomes in this study cohort suggest the treatment is still a strong candidate.
For patients with treatment-resistant depression, accelerated TMS with or without fMRI guidance may offer benefits where previous treatments have not. Individual results vary.
If persistent depression hasn't responded to multiple medication trials, fMRI-guided accelerated iTBS may help. Take our brief assessment to see if you're a candidate, schedule a free consultation, or call us at 385-334-6093 to speak with our team. Individual results vary.
Dr. Mark D. Allen holds a Ph.D. in Cognitive Science from Johns Hopkins University and received post-doctoral training in Cognitive Neuroscience and Functional Neuroimaging at the University of Washington. As a co-founder of Cognitive Fx, he played a pivotal role in establishing the unique and exceptional treatment approach. Dr. Allen is renowned for his pioneering work in adapting fMRI for clinical use. His contributions encompass neuroimaging biomarkers development for post-concussion diagnosis and innovative research into the pathophysiology of chronic post-concussion symptoms. He's conducted over 10,000 individualized fMRI patient assessments and crafted a high-intensity interval training program for neuronal and cerebrovascular recovery. Dr. Allen has also co-engineered a machine learning-based neuroanatomical discovery tool and advanced fMRI analysis techniques, ensuring more reliable analysis for concussion patients.
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Published peer-reviewed research shows that Cognitive FX treatment leads to meaningful symptom reduction in post-concussion symptoms for 77% of study participants. Cognitive FX is the only PCS clinic with third-party validated treatment outcomes.
READ FULL STUDY