This innovative study by Kashyap and colleagues (2024) explored a potential new treatment approach for early-stage Alzheimer's disease (AD) using personalized transcranial magnetic stimulation (TMS).
The researchers investigated whether targeting specific brain networks using neuroimaging-guided theta burst stimulation could help patients with early AD. This approach is particularly noteworthy as it represents a non-invasive treatment option that could complement existing AD medications, with potentially fewer side effects than current treatments. The study emerges at a crucial time in AD research, as while new treatments like anti-amyloid monoclonal antibodies have shown promise, they often come with significant side effects and limitations. The researchers hypothesized that by using precise, personalized brain stimulation, they might be able to influence dysfunctional brain networks and improve cognitive function.
Method
The study involved 10 participants with early-stage, biomarker-confirmed AD, all of whom met specific inclusion criteria including a Mini Mental Status Examination score above 24 and a Clinical Dementia Rating of 0.5-1. Each participant underwent detailed brain imaging using a 3T Siemens Skyra Scanner to identify dysfunctional large-scale brain networks. The imaging protocol included T1-weighted images, resting-state functional MRI, and diffusion tensor imaging, providing a comprehensive view of brain structure and connectivity.
The treatment protocol was particularly sophisticated, using the MagVenture TMS Therapy system with a B65-coil-FDA cleared coil. Participants received five daily sessions over two weeks, with each daily session consisting of three separate stimulation periods targeting different brain regions. A key feature of the protocol was the use of intermittent theta burst stimulation (iTBS), delivered at 80% of each participant's resting motor threshold. Each stimulation session involved 3-pulse 50 Hz bursts with 40 trains and an inter-train interval of 8 seconds, totaling 1,200 pulses per target. This resulted in 18,000 pulses per day and a total of 90,000 pulses over the entire treatment course.
The targeting strategy was particularly innovative: one target area (right temporal area G dorsal - RTGd) was common across all participants, while two additional targets were personalized based on each participant's brain connectivity patterns. These targets were selected using sophisticated analysis of functional connectivity anomalies, with researchers choosing areas showing three or more standard deviations from normal connectivity patterns. The Localite Navigator system provided real-time feedback for precise targeting during treatment sessions.
Results
The primary finding was improvement in attention scores, with participants showing significant gains on the RBANS attention index (average improvement of 9.7 points, p = 0.01). Story memory, a component of immediate memory, also showed improvement in 70% of participants, though this didn't reach statistical significance. The study did not detect significant changes in the targeted brain networks' connectivity patterns when comparing pre- and post-treatment measurements. While the treatment was generally well-tolerated, three participants couldn't complete the RTGd stimulation due to facial twitching or anxiety, though they continued treatment at other target locations. Most side effects were mild and transient, with no serious adverse events reported.
Implications
The results suggest that personalized TMS could potentially serve as a safe, non-invasive treatment option for early-stage AD. The improvement in attention scores is particularly encouraging, as cognitive enhancement is a key goal in AD treatment. While the lack of changes in brain connectivity patterns raises questions about the mechanism of action, the cognitive improvements suggest the treatment may work through pathways not captured by the study's imaging measures. The findings also highlight the potential value of personalized medicine approaches in neurodegenerative disease treatment, suggesting that individual brain connectivity patterns might guide therapeutic interventions.
Design Strengths
The study broke new ground by combining several innovative elements: it used precise neuroimaging guidance for targeting, employed a personalized approach to treatment, and focused on early-stage AD patients with confirmed biomarkers. The researchers also used sophisticated brain mapping techniques based on the Human Connectome Project, allowing for more precise targeting than traditional TMS approaches. The comprehensive cognitive testing and careful monitoring of adverse effects provided valuable safety data. The use of biomarker-confirmed AD patients from a community neurology clinic enhanced the study's clinical relevance, while the sophisticated imaging and analysis protocols ensured high-quality data collection.
Design Limitations
Several limitations should be considered when interpreting the results. The small sample size (10 participants) and lack of a control group make it difficult to definitively attribute improvements to the treatment. The study population was also quite homogeneous, consisting entirely of white, highly educated participants. The six-week follow-up period may have been too short to capture the full effects of the intervention. Additionally, the need for multiple daily treatments over several hours could present practical challenges for clinical implementation. The researchers noted that the jaw twitching associated with RTGd stimulation led to suboptimal dosing in some participants, which could have affected outcomes. The study also didn't assess immediate post-treatment effects on cognition or fMRI, potentially missing important short-term changes. Further research with larger, more diverse populations, longer follow-up periods, and comparison groups would help validate these preliminary findings and better understand the treatment's mechanisms of action.
Glossary
AD: Alzheimer's disease, a progressive neurodegenerative condition characterized by amyloid plaques and neurofibrillary tangles in the brain.
amyloid plaques: Abnormal protein deposits found in the brains of Alzheimer's patients that interfere with normal brain function.
biomarker: A measurable indicator that can be used to determine the presence or progression of a disease, in this case specific proteins that indicate Alzheimer's disease.
CDR: Clinical Dementia Rating, a numeric scale used to quantify the severity of dementia symptoms.
fc-rs-fMRI: functional connectivity resting state functional magnetic resonance imaging, a technique that measures brain activity patterns while a person is at rest.
HCP: Human Connectome Project, a comprehensive mapping of human brain networks that provides detailed information about brain region connections.
iTBS: Intermittent theta burst stimulation, a specialized form of transcranial magnetic stimulation that delivers short bursts of magnetic pulses.
LSBNs: Large-scale brain networks, interconnected regions of the brain that work together to perform specific functions.
MMSE: Mini Mental Status Examination, a standardized test used to assess cognitive function.
neurofibrillary tangles: Abnormal accumulations of tau protein inside brain cells, characteristic of Alzheimer's disease.
RBANS: Repeatable Battery for the Assessment of Neuropsychological Status, a standardized test measuring various aspects of cognitive function.
RTGd: Right temporal area G dorsal, a specific region of the brain targeted in this study.
TMS: Transcranial magnetic stimulation, a non-invasive technique that uses magnetic fields to stimulate specific areas of the brain.
Google Illuminate Discussion
Listen to a great discussion of the December 2024 Frontiers in Neuroscience article "Open label pilot of personalized, neuroimaging-guided theta burst stimulation in early-stage Alzheimer’s disease?"created using Google Illuminate.
Theta Burst Stimulation Transcript
Host: So, we're talking about Alzheimer's, a tough disease, but this paper suggests a really interesting new approach to treatment. It's all about using brain scans to personalize a type of brain stimulation.
Guest: Exactly. It's a precision medicine approach, targeting specific areas of the brain affected by Alzheimer's.
Host: Personalized brain zaps? Sounds intense!
Guest: Not quite zaps, more like a gentle nudge. It's called theta burst stimulation, or TBS.
Host: Okay, gentle nudge. But how do they even know where to nudge?
Guest: That's where the brain scans come in. They use fMRI to pinpoint the problem areas.
Host: So, Alzheimer's messes with brain networks, right? Big, interconnected areas that work together.
Guest: Precisely. And current treatments, while helpful, don't really address the network disruptions directly.
Host: So this new method tries to fix the broken connections?
Guest: Exactly. It's like rewiring the brain, but non-invasively.
Host: This fMRI, it shows how different parts of the brain talk to each other, right?
Guest: Yes, it maps the brain's functional connectivity. They look for areas with abnormal connections.
Host: And then they zap those areas with TBS?
Guest: They use a technique called intermittent theta burst stimulation, iTBS. It's a specific pattern of magnetic pulses.
Host: And it's personalized, so each patient gets a unique treatment plan?
Guest: Absolutely. One common target area, plus two others personalized to each patient's brain scan.
Host: So, they did a small study, right? Ten people?
Guest: A pilot study, yes. To test the feasibility and safety of the approach.
Host: And did it work? Did they see improvements in brain connectivity?
Guest: Not significantly in the primary outcome measure, no. But there was a surprising improvement in attention.
Host: Interesting. So the brain networks didn't change much, but their attention got better?
Guest: That's the unexpected finding. It suggests the treatment might have broader effects than initially anticipated.
Host: So, no major side effects?
Guest: No serious adverse events. The most common was facial twitching, which is manageable.
Host: So, a small study, some unexpected results, and manageable side effects. What's the next step?
Guest: A larger, sham-controlled trial. To really see if this is a genuine treatment effect.
Host: Why might attention improve without major changes in brain networks?
Guest: Maybe the stimulation had indirect effects on other networks. Or maybe the study wasn't long enough to see network changes.
Host: And the small sample size is a limitation, right?
Guest: Definitely. And the lack of a sham group makes it hard to be certain about the results.
Host: But this approach is pretty innovative, right? Using brain scans to personalize treatment?
Guest: Absolutely. It's a precision medicine approach that could revolutionize how we treat Alzheimer's.
Host: So, what's the future of this research?
Guest: Larger, more rigorous trials are needed. And exploring different stimulation parameters.
Host: So, a promising start, but more research is needed. It's a fascinating approach, though.
Guest: Definitely. It shows the potential of personalized brain stimulation in neurodegenerative diseases.
Host: That was a great discussion! Thanks so much.
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