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Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. Epub 2019 Mar 14 PubMed.
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One of the earliest events in Alzheimer's disease is a decrease of blood flow (Iturria-Medina et al., 2016), which will reduce both the nutrient supply to neurons and amyloid removal. It is fascinating, therefore, that the auditory stimulus used in this study leads to a 50-100 percent increase in blood vessel diameter in auditory cortex and hippocampus (as assessed by the position of the basal lamina around vessels), which would be expected to greatly increase blood flow.
It would be interesting to know whether the authors measured arteriole or capillary diameters, and whether live imaging could be used to see the time course of this change in vivo. I look forward to further work demonstrating that this result can be reproduced by other groups and establishing the mechanism of the effect.
References:
Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC, Alzheimer’s Disease Neuroimaging Initiative. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun. 2016 Jun 21;7:11934. PubMed.
View all comments by David AttwellWashington University
This is very interesting. I was fascinated by the visual stimulus data a couple years ago, and now the same by the auditory stimulus. This paper goes into a lot of detail to counter the hypothesis that changes in neuronal activity driving a suppression in Aβ production.
I agree with the authors’ argument that is likely a clearance effect and not activity. First, they detect changes in microglia and astrocytes that are consistent with a clearance mechanism. Second, GENUS reduces pathology in seven days. I find it difficult to believe activity would have a rapid effect in reducing plaques that fast, whereas enhanced clearance could be that rapid. Third, GENUS worked in their exogenous tau seeding experiment; altered activity could affect seeding, I guess, but the more likely explanation is enhanced clearance.
That several modalities at 40Hz are capable of suppressing AD-related pathology is very exciting. It suggests that the underlying mechanism can be engaged via multiple routes that could reach beyound just visual and auditory cortex. Adding to that, combined auditory/visial stimulation had wider effects than in just the auditory and visual cortex; since these cortical areas are not the hardest hit in AD, it is promising that either multiple modalities could be employed or combinations could be used to have a broader impact across the brain to reduce pathology.
View all comments by John CirritoHarvard Medical School
This new study is an elegant tour de force linking neural network function to the cognitive and pathological features of AD. Although application to humans remains to be established, the protean effects of gamma entrainment using auditory and visual stimulation are impressive, with improved memory, reduction of amyloid and tau pathology, and effects on microglia, astrocytes and vascular function in AD and FTD mouse models. The reduction in amyloid load from auditory stimulation appears to dissipate seven days following the end of the stimulation period, suggesting that sustained treatment might be necessary. It would be of interest to investigate this with longer-term treatment regimens to know if a more durable therapeutic response could be achieved.
A surprising finding was that changes in pathology and behavior could not be explained by overall changes in neuronal firing rate, suggesting that some other higher-order function of gamma entrainment, perhaps number or type of neurons entrained, might be relevant. Another interesting observation is that the effects of gamma entrainment on Aβ pathology are mediated, at least in part, by microglial activation. How gamma stimulation, but not other neuronal firing patterns, regulate microglial biology and induce Aβ clearance is an important question.
I anticipate that it will not be long before we know whether this intervention is effective in humans with MCI or AD.
View all comments by Bruce YanknerMake a Comment
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