BHI core faculty members Drs. Michal Schnaider Beeri, David Zald, and Andrew Westbrook shared insights on a recent study investigating transcranial magnetic stimulation (TMS) as a potential treatment to slow cognitive decline in Alzheimer’s Disease. The study focuses on targeting a key brain network involved in memory, which is typically impacted early in the disease.
Michal Schnaider Beeri, PhD
Director, Herbert and Jacqueline Krieger Klein Alzheimer’s Research Center at the BHI
The Herbert and Jacqueline Krieger Klein Professor of Neurology, Robert Wood
Johnson Medical School
This study utilized transcranial magnetic stimulation (TMS) to trigger electrical signals in brain regions associated with memory, the primary cognitive domain affected by Alzheimer’s disease. The small-scale study included 18 older adults who received weekly TMS treatments for 52 weeks, and 14 who received a placebo. Results showed that the TMS group demonstrated improvements in several cognitive tests compared to the placebo group.
The study’s main strength lies in its novelty. For decades, Alzheimer’s therapeutic research has focused on amyloid and tau pathology, showing success in clearing these proteins but yielding limited cognitive benefits for patients. Therefore, therapeutic approaches targeting other aspects of brain function, such as activating impaired neuronal networks, are welcome. Another crucial advantage is the minimal adverse events reported, especially when compared to the newly FDA-approved monoclonal antibody drugs for Alzheimer’s disease, which can cause significant side effects known as ARIA (amyloid-related imaging abnormalities), manifesting as brain inflammation and/or microbleeds.
The study’s primary limitations include its small sample size, its single-site nature rather than being a multi-center study, and the lack of assessment of biological markers such as brain MRI measures and blood biomarkers for Alzheimer’s and other dementias. This is particularly significant because recent evidence strongly suggests that new Alzheimer’s therapies have their greatest beneficial effects on individuals with low pathology, in other words those at the earliest stages of the disease process.
The article does not specify what is the region that was activated. It is also unclear at what dementia stage these patients were.
Andrew Westbrook, PhD
Assistant Professor, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School (RWJMS)
Center for Advanced Human Brain Imaging Research (CAHBIR) at the BHI
The trial was motivated by an emerging hypothesis that the mechanisms of Alzheimer’s disease pathology include aberrant balance of excitatory versus inhibitory neurotransmission and the putative impact of TMS on excitation-inhibition balance. There are lots of hypotheses about the paths by which Alzheimer’s disease affects neuronal and cognitive function. So, even if excitation-inhibition balance does play a role, TMS is unlikely to address all the underlying mechanisms of the disease. That said, the current results are in line with this emerging hypothesis implicating excitation-inhibition balance in Alzheimer’s and also suggests that TMS may be clinically useful. The fact that the study reports beneficial effects on cognition over a long period (a full year) and also that the study design was placebo-controlled are all strengths.
A weakness of the study is that it is unclear how much of the results reflect a placebo effect. TMS blinding can be very difficult to achieve, and so it is conceivable that study participants knew if they were in an active versus a placebo treatment group. Also, the effects of TMS on brain function can be non-specific – a single TMS pulse can have widespread effects on brain function, so it is unclear how much a clinically-relevant effect depends on targeting specific brain systems as opposed to a more general effect of TMS on brain function.
David Zald, PhD
Director, Center for Advanced Human Brain Imaging Research (CAHBIR) at the BHI Henry Rutgers Term Professor of Psychiatry, Rutgers Robert Wood Johnson Medical School (RWJMS)
The demonstrated safety profile of TMS enhances enthusiasm for the development of these techniques. One thing that is frustrating in reading the reporting on this small trial, is that the NBC news article leaves out a lot of important details, like where they were targeting and precisely how they were personalizing the targeting. From another source, it appears that they were targeting the default mode network (although precisely which regions within this large-scale distributed brain network was not articulated. Treatment tailored to each study participant was created via single-pulse TMS combined with EEG based on transcranial evoked potentials and patient MRI data.
Hopefully, future studies will be able to replicate these effects in a larger-scale study, with observable effects on neuroimaging markers of disease progression.
