Soula M, Martín-Ávila A, Zhang Y, Dhingra A, Nitzan N, Sadowski MJ, Gan WB, Buzsáki G. Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice. Nat Neurosci. 2023 Apr;26(4):570-578. Epub 2023 Mar 6 PubMed.

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Comments

  1. This is a very important paper that unfortunately gives us disappointing news about this potential new therapeutic approach of gamma stimulation. Findings like these are an important reminder of why we need to have replication studies.

    I think this does suggest that the effect, if real, is very dependent on the specific context of the experimental condition. I do think this finding casts some doubt on gamma stimulation as a viable intervention. We won't know for sure either way until the large-scale trials are completed, but this paper shows that the field needs to gain a better understanding of how and when this technique works before engaging in expensive trials. 

    The most important lack of replication to me is the failure to robustly entrain brain rhythms, but this might be something that depends a great deal on the specific AD mouse model implemented.

    View all comments by Bryce Mander

  2. Alzheimer’s disease therapeutics remains one of the most unmet medical needs. Therefore, the scientific community should encourage and support any explorative treatment approaches. Even though the conclusions of the current study disagree with previously published high-order brain area entrainment, Aβ load reduction, and microglial activation, the high individual variability of plaque load at the transition age in the strains used may be one of the main reasons for the discrepancy in the treatment efficacy. A longer time of light exposure should be explored.

    We have obtained preliminary data indicating that treatment for one hour per day and continued for one month significantly enhanced the cognitive abilities of young mice (6 months) but not old mice (15 months). We think the mechanism of cognitive enhancement can be better explained using the environmental enrichment theory, and that the younger mice receive the most benefit from this enrichment of sensory stimulation.

    This paper will reignite exciting debates on the validity and mechanisms of 40 Hz light flicker treatments.

    View all comments by Sheng-Tao Hou

  3. This study brings up interesting questions about the mechanisms involved in the effects of gamma light stimulation, including whether entrainment of native gamma oscillations plays a role. This study concludes that 40 Hz light stimulation likely does not entrain native gamma oscillations.

    Like applying a drug to cells is different from endogenous signaling mechanisms, stimulation is not the same as native brain activity. There may be some confusion in the field on this point, because the word entrainment is used in the literature in two ways: to mean entrainment to a sensory stimulus, as prior studies of sensory stimuli have used it, or entrainment of endogenous oscillations, as this paper used the term. The mechanisms by which gamma stimulation affects Alzheimer’s pathology and how modulation of neural activity plays a role are an active area of investigation.  

    Several studies from multiple groups have found that gamma light stimulation reduces Aβ and improves cognition in mice. Shen et al. found that gamma light flicker reduces Aβ levels and identified signaling mechanisms involved in APP processing to reduce Aβ (Shen et al., 2022). Examining gamma flicker effects in a model of cerebral ischemia, Zheng et al. show gamma light flicker improves cognitive function and protects hippocampal neurons, and these changes may arise from enhanced presynaptic plasticity (Zheng et al., 2020). Several other studies from different labs have shown gamma sensory stimulation reduces Aβ pathology and improves cognition in different experimental contexts which complement those from the Tsai lab (Adaikkan et al., 2019; Martorell et al., 2019; Park et al., 2020, 2022; Tian et al., 2021). 

    This study from Soula et al. has several important differences from prior work. For example, while ELISA to assess Aβ is typically measured in fresh tissue, this study used fixed tissue, which may reduce sensitivity. As another example, this study assessed plaques and microglia after visual stimulation only and at different time points after visual stimulation than in prior studies. Prior work showed that Aβ levels change as a function of time after stimulation. Indeed, the modality of stimulation and time of assay relative to stimulation are important variables.

    Many important questions remain, perhaps most importantly—will gamma light stimulation, or other forms of gamma stimulation, provide therapeutic benefit in patients with Alzheimer’s disease? Several studies in patients have shown gamma sensory stimulation is safe and feasible in humans (Chan et al., 2022; Cimenser et al., 2021; He et al., 2021). In fact, studies have used sensory flicker in human subjects for basic research for decades (a few examples: Galambos et al., 1981; Krolak-Salmon et al., 2003; Norcia et al., 2015). 

    Prior studies of gamma sensory stimulation are too short or small to draw conclusions about treatment efficacy in Alzheimer’s disease. A large pivotal trial is needed to rigorously answer this question. Because gamma sensory stimulation has been shown to be safe and feasible in humans and has beneficial effects in many animal studies, human clinical trials are warranted.  

    References:

    Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.

    Chan D, Suk HJ, Jackson BL, Milman NP, Stark D, Klerman EB, Kitchener E, Fernandez Avalos VS, de Weck G, Banerjee A, Beach SD, Blanchard J, Stearns C, Boes AD, Uitermarkt B, Gander P, Howard M 3rd, Sternberg EJ, Nieto-Castanon A, Anteraper S, Whitfield-Gabrieli S, Brown EN, Boyden ES, Dickerson BC, Tsai LH. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. PLoS One. 2022;17(12):e0278412. Epub 2022 Dec 1 PubMed.

    Cimenser A, Hempel E, Travers T, Strozewski N, Martin K, Malchano Z, Hajós M. Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients. Front Syst Neurosci. 2021;15:746859. Epub 2021 Sep 24 PubMed.

    Galambos R, Makeig S, Talmachoff PJ. A 40-Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2643-7. PubMed.

    He Q, Colon-Motas KM, Pybus AF, Piendel L, Seppa JK, Walker ML, Manzanares CM, Qiu D, Miocinovic S, Wood LB, Levey AI, Lah JJ, Singer AC. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease. Alzheimers Dement (N Y). 2021;7(1):e12178. Epub 2021 May 13 PubMed.

    Krolak-Salmon P, Hénaff MA, Tallon-Baudry C, Yvert B, Guénot M, Vighetto A, Mauguière F, Bertrand O. Human lateral geniculate nucleus and visual cortex respond to screen flicker. Ann Neurol. 2003 Jan;53(1):73-80. PubMed.

    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.

    Norcia AM, Appelbaum LG, Ales JM, Cottereau BR, Rossion B. The steady-state visual evoked potential in vision research: A review. J Vis. 2015;15(6):4. PubMed.

    Park SS, Park HS, Kim CJ, Baek SS, Park SY, Anderson C, Kim MK, Park IR, Kim TW. Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice. J Appl Physiol (1985). 2022 Apr 1;132(4):1054-1068. Epub 2022 Feb 24 PubMed.

    Park SS, Park HS, Kim CJ, Kang HS, Kim DH, Baek SS, Kim TW. Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer's disease. Alzheimers Res Ther. 2020 May 20;12(1):62. PubMed.

    Shen Q, Wu X, Zhang Z, Zhang D, Yang S, Xing D. Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β-amyloid load in Alzheimer's disease model. Aging Cell. 2022 Mar;21(3):e13573. Epub 2022 Feb 23 PubMed.

    Tian T, Qin X, Wang Y, Shi Y, Yang X. 40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice. J Alzheimers Dis. 2021;84(3):983-993. PubMed.

    Zheng L, Yu M, Lin R, Wang Y, Zhuo Z, Cheng N, Wang M, Tang Y, Wang L, Hou ST. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun. 2020 Jun 15;11(1):3012. PubMed.

    View all comments by Annabelle Singer

  4. In this paper, the authors tested if one hour of 40 Hz flickering light entrained gamma frequencies in the hippocampus and reduced amyloid levels and plaque burden. These findings were previously shown by Iaccarino et al. in 5xFAD transgenic mice, with one hour of stimulation reducing amyloid levels by 45-55 percent and reducing amyloid plaque burden, an extraordinary reduction in amyloid (particularly plaques) after a one-hour intervention. Iaccarino et al. had also found that microglia had increased co-localization with amyloid plaques.

    In a rigorous set of experiments using 5xFAD mice, Soula et al. failed to replicate these findings.  The discrepancy may be due to a much larger number of animals used for the experiments in Soula et al. versus Iaccarino et al. 

    Soula et al. did find that stimulation with slower delta frequencies (4 Hz) entrained neurons in the hippocampus, an important observation since optogenetically stimulated frequencies in the delta range (0-4 Hz) have been shown to reduce amyloid (Kastanenka et al., 2017, 2019). 

    Noninvasive acoustic stimulation of slow oscillations during sleep has been shown, and may be a potential non-invasive intervention, to reduce amyloid levels in the brain, although more work is needed.  Overall, this paper is an important contribution to the field.  Future studies are needed to test the benefits of light and acoustic stimulation to reduce AD pathology.

    References:

    Kastanenka KV, Hou SS, Shakerdge N, Logan R, Feng D, Wegmann S, Chopra V, Hawkes JM, Chen X, Bacskai BJ. Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer's Disease. PLoS One. 2017;12(1):e0170275. Epub 2017 Jan 23 PubMed.

    Kastanenka KV, Calvo-Rodriguez M, Hou SS, Zhou H, Takeda S, Arbel-Ornath M, Lariviere A, Lee YF, Kim A, Hawkes JM, Logan R, Feng D, Chen X, Gomperts SN, Bacskai BJ. Frequency-dependent exacerbation of Alzheimer's disease neuropathophysiology. Sci Rep. 2019 Jun 20;9(1):8964. PubMed.

    View all comments by Brendan Lucey

  5. This appears to be a careful and well-controlled paper to investigate the role of 40 Hz flickering light on gamma oscillations and amyloid pathology/neuroinflammation in two different mouse models of AD. 

    This follows on a very high-impact paper showing remarkable effects in mouse brain, and subsequent translation to human studies. I'm honestly surprised that we haven't seen 20+ papers investigating this approach, as it is so simple to reproduce by almost any lab with access to mice, and it would completely change how we treat patients with AD.

    The paper by Soula et al. demonstrates negative results, which always begs the question of whether the exact methods were followed. The expertise of the team, however, suggests that their results should not be dismissed. I applaud the investigators for their rigor.

    View all comments by Brian Bacskai

  6. We appreciate Dr. Buzsaki’s interest in our work, where we and many others have shown that 40 Hz sensory stimulation ameliorates Alzheimer's pathology (Shen et al., 2022; Iaccarino et al., 2016; Singer et al., 2018; Park et al., 2020; Park et al., 2022; Martorell et al., 2019; Adaikkan et al., 2019; Cimenser et al., 2021). We agree with the authors that native gamma oscillations and the steady-state oscillations evoked by 40 Hz sensory stimulation are likely distinct neurophysiological phenomena. 

    While the mechanisms mediating the various physiological, biological, and biochemical effects remain to be explored, it is important that experiments replicate the methodology and animal conditions described in previous studies. Soula et al. reported a number of unconventional methodologies, including combining different genotypes for statistical analysis in IHC experiments and using AD cohorts that lack amyloid.

    It would be important to know how the mice were handled for experiments in this paper that seem to cause a stress response, when we and others report no changes in stress in mice or human patients (Adaikkan et al., 2019; Garza et al., 2019; Chan et al., 2022). We also note the promising amyloid ELISA quantification that, despite not reaching statistical significance, shows trends for amyloid attenuation following 40 Hz stimulation (e.g., p=0.096 and p=0.089), a finding that prevailed even though the authors used quantification on fixed tissue.

    Overall, we welcome the field's continued interest in our work, which along with other groups has shown cognitive benefits (Park et al., 2022; Martorell et al., 2019; Adaikkan et al., 2019; Cimenser et al., 2021; He et al., 2021; Chan et al., 2022) in mouse models and human subjects via its extension to clinical studies. The approach has received the FDA’s Breakthrough Device designation for digital therapeutics in Alzheimer’s dementia. We welcome additional studies to further define the molecular mechanisms involved in modulating neuronal oscillations to treat Alzheimer's pathology.

    References:

    Shen Q, Wu X, Zhang Z, Zhang D, Yang S, Xing D. Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β-amyloid load in Alzheimer's disease model. Aging Cell. 2022 Mar;21(3):e13573. Epub 2022 Feb 23 PubMed.

    Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.

    Singer AC, Martorell AJ, Douglas JM, Abdurrob F, Attokaren MK, Tipton J, Mathys H, Adaikkan C, Tsai LH. Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc. 2018 Aug;13(8):1850-1868. PubMed.

    Park SS, Park HS, Kim CJ, Kang HS, Kim DH, Baek SS, Kim TW. Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer's disease. Alzheimers Res Ther. 2020 May 20;12(1):62. PubMed.

    Park SS, Park HS, Kim CJ, Baek SS, Park SY, Anderson C, Kim MK, Park IR, Kim TW. Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice. J Appl Physiol (1985). 2022 Apr 1;132(4):1054-1068. Epub 2022 Feb 24 PubMed.

    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.

    Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.

    Cimenser A, Hempel E, Travers T, Strozewski N, Malchano Z, Hajos M. Randomized controlled trial of gamma sensory stimulation treatment maintains functional ability and decreases sleep fragmentation in Alzheimer’s disease patients. Alzheimer’s & Dementia, 31 December 2021 Alzheimer’s & Dementia

    Garza KM, Zhang L, Borron B, Wood LB, Singer AC. Gamma Visual Stimulation Induces a Neuroimmune Signaling Profile Distinct from Acute Neuroinflammation. J Neurosci. 2020 Feb 5;40(6):1211-1225. Epub 2019 Dec 23 PubMed.

    He Q, Colon-Motas KM, Pybus AF, Piendel L, Seppa JK, Walker ML, Manzanares CM, Qiu D, Miocinovic S, Wood LB, Levey AI, Lah JJ, Singer AC. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease. Alzheimers Dement (N Y). 2021;7(1):e12178. Epub 2021 May 13 PubMed.

    Chan D, Suk HJ, Jackson BL, Milman NP, Stark D, Klerman EB, Kitchener E, Fernandez Avalos VS, de Weck G, Banerjee A, Beach SD, Blanchard J, Stearns C, Boes AD, Uitermarkt B, Gander P, Howard M 3rd, Sternberg EJ, Nieto-Castanon A, Anteraper S, Whitfield-Gabrieli S, Brown EN, Boyden ES, Dickerson BC, Tsai LH. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. PLoS One. 2022;17(12):e0278412. Epub 2022 Dec 1 PubMed.

    View all comments by Li-Huei Tsai

  7. In terms of research methods, this study seems to be no different from existing MIT research. Nevertheless, if you think about why the results were different from previous studies, in addition to the potential sources of discrepant results in the discussion section, uncontrolled aversion behavior of mice might have contributed to the discrepant results. Aversion behavior may reduce gamma entrainment and thus amyloid clearance. The 40 Hz power spectral density (PSD) value in the current study was lower than that in Iaccarino et al. ( 2016). In addition, lack of statistical power may be involved. Further studies with a well-powered sample may be needed.

    References:

    Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.

    View all comments by Ki Woong Kim

  8. This is a well-designed study that advances current knowledge on the role and mechanism of noninvasive brain stimulation to entrain brain rhythms toward the development of novel treatments for neurodegenerative diseases and cognitive enhancement. 

    First, the study did not show any significant difference in the mean values of Aβ deposition in the 40 Hz group compared to the control. Still, the group mean values in the 40 Hz group tended to be smaller than the control group. This raises the question whether there was not enough power to detect a statistical significance. It would be very helpful to repeat these experiments using effect sizes based on this study, and with the necessary sample sizes that would detect a significant difference should it exist. This is especially encouraged by the difference they found in one of the cohorts.

    Second, the lack of entrainment of gamma oscillations beyond the visual cortex, and its attribution to the fact that the flickering light may not be salient to the mouse, is very interesting. This finding is consistent with the perspective in human studies that noninvasive brain stimulation—or at least some of forms—could be best value when combined with behavioral interventions which typically require motivation and engagement on behalf of the participant, such as cognitive remediation.

    This important study highlights the need to conduct more studies of this nature to address variability across samples and to conduct well-powered experiments with large samples. Moreover, it highlights also the value of conducting translational experiments that would carefully design and match preclinical and clinical experiments via close collaboration between bench and bedside researchers.

    View all comments by Tarek Rajji

  9. It is always good to check published work by redoing experiments as part of advancing your own work. However, Soula et al. should not have expected to see any changes in Aβ burden away from the visual cortex, because Iaccarino et al. showed that light stimulation only affected the visual cortex. That group's follow-on study combined auditory and visual stimulation at 40 Hz, which led to changes in Aβ burden in the auditory cortex, in the visual cortex, and—interestingly—a little bit of hippocampus and a little bit of prefrontal cortex. My quick read of Soula et al. says that the authors may have misinterpreted those results. Other groups, including mine, have reproduced Iaccarino et al.'s results with both light and sound (Bobola et al., 2020).

    References:

    Bobola MS, Chen L, Ezeokeke CK, Olmstead TA, Nguyen C, Sahota A, Williams RG, Mourad PD. Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo. Brain Stimul. 2020 Jul - Aug;13(4):1014-1023. Epub 2020 Apr 1 PubMed.

    View all comments by Pierre Mourad

  10. 40 Hz sensory stimulation has been suggested as a potential noninvasive treatment for Alzheimer’s disease. Although this approach sounds simple, the implementation to produce reliable results is not trivial. In their latest study, Buzsaki and his colleagues have reported that in two AD mouse models, either acute (one hour) or chronic (seven days) 40 Hz light stimulation could not significantly modify AD pathology (Aβ loads and microglial morphology) (but see Extended Data Fig. 2d). They also showed that wild-type mice avoid 40 Hz visual stimulation, which continuously increases cholinergic signals in the hippocampus. 

    Compared to previous studies, what might explain this discrepancy? We do not know. To answer this question, we need to clarify multiple questions: for example, how similar or different is their exact 40 Hz stimulation protocol, compared to previous studies? What if a multisensory 40 Hz stimulation is applied? How about the procedures of histological evaluations, which often rely on arbitrary parameters? How about microglial morphology in deep cortical layers, not just superficial layers? In the future, it would be important to develop and adopt novel technologies to assess AD pathology across brain regions in vivo longitudinally.

    In addition, rather than arguing based simply on p-values, it is more constructive to compare the effect size too. What sample size is required for future studies?

    Finally, since mice avoided their 40 Hz visual stimulation environment, it may be interesting to analyze how AD mice behave during treatment in future studies. In a human study, 40 Hz stimulation treatment can modify sleep (Cimenser et al., 2021). In mouse experiments, it may be important to report when (light or dark phase?) a treatment is applied and to assess how their behavior changes outside the treatment period. In a chronic treatment condition, it is possible that what mice do outside the treatment period might make a difference.

    An important study always raises many questions for further investigation, as is the case here.

    References:

    Cimenser A, Hempel E, Travers T, Strozewski N, Martin K, Malchano Z, Hajós M. Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients. Front Syst Neurosci. 2021;15:746859. Epub 2021 Sep 24 PubMed.

    View all comments by Shuzo Sakata

  11. There is a growing interest in evaluating the potential of patterned noninvasive brain stimulation to impact Alzheimer’s disease pathology and learning and memory. Several recent studies showed promising results in various animal models of AD and human AD patients. Specifically, gamma visual sensory stimulation induces gamma entrainment in occipital visual areas and several other brain areas in human scalp EEG (He et al., 2021; Zhang et al., 2021; Chan et al., 2021; Zibrandtsen et al., 2020; Lee et al., 2021; Lahijanian et al., 2021; Agger et al., 2022), as well as in the visual cortex and hippocampus in animal models (Iaccarino et al., 2016; Adaikkan et al., 2019; Zheng et al., 2020). Further, gamma stimulation reduces amyloid levels, provides other protective effects, and improves learning and memory (Iaccarino et al., 2016; Adaikkan et al., 2019; Shen et al., 2022; Park et al., 2020, 2022; Yao et al., 2020; Tian et al., 2021; Lin et al., 2021; Kim et al., 2022). 

    In contrast, the recent paper by Soula et al. reports that gamma stimulation did not induce native gamma entrainment or reduce amyloid levels in AD mouse models. It is important to note key methodological differences that may have impacted the outcomes of these experiments. For example, although not fully clear, it appears that Soula et al. conducted experiments during animals’ dark cycles based on the method described in the study, while all previously published experiments performed experiments during the light cycle. Even so, this study showed a trend toward reduced amyloid pathology after gamma stimulation, though the results are not significant. Further, Soula et al. also showed sensory evoked local field potential and single-unit responses, albeit weakly, in the cortex and/or hippocampus.

    In order to better examine the differences between these results and those previously reported, examining the neural coherence across brain areas and other neuropathology measures, including tau phosphorylation, neurodegeneration and gene expression changes in neuronal and glial cells after acute or chronic gamma stimulation administered during the dark, would provide further insights. Nonetheless, the study by Soula et al. provides insights into potential differences from stimulation that is conducted during the dark cycle versus during the light cycle. It is also of note that animals handle visual sensory stimuli slightly differently between the dark and light cycles; thus, whether the aversive behavioral response that they observed, which is again different from previous findings, could be due to differences in brain state and neuromodulatory system associated with circadian rhythm requires further investigation. It has been demonstrated, for instance, that repeated sensory-evoked gamma administration improves sleep/circadian clock mechanisms and amyloid pathology (Yao et al., 2022). In humans, gamma stimulation improved sleep measures (Cimenser et al., 2021; Chan et al., 2022) 

    I agree with Li-Huei Tsai’s assessment that “native gamma oscillations, and the steady-state oscillations evoked by 40 Hz sensory stimulation, are likely distinct neurophysiological phenomena.” In fact, we previously articulated, “it would be interesting to know the extent of mechanistic similarity between spontaneous, optogenetics-induced, and sensory-evoked gamma” (Adaikkan et al., 2021). The study by Soula et al. takes an important step toward understanding the differences between sensory-evoked and native gamma oscillations. Future studies are required to describe the cell, molecular, and neurophysiological mechanisms involved in regulating neuronal oscillations to improve the outcomes of Alzheimer's disease.

    References:

    Adaikkan C, Tsai LH. Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. Epub 2019 Dec 10 PubMed.

    Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.

    Chan D, Suk HJ, Jackson BL, Milman NP, Stark D, Klerman EB, Kitchener E, Fernandez Avalos VS, de Weck G, Banerjee A, Beach SD, Blanchard J, Stearns C, Boes AD, Uitermarkt B, Gander P, Howard M 3rd, Sternberg EJ, Nieto-Castanon A, Anteraper S, Whitfield-Gabrieli S, Brown EN, Boyden ES, Dickerson BC, Tsai LH. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. PLoS One. 2022;17(12):e0278412. Epub 2022 Dec 1 PubMed.

    Cimenser A, Hempel E, Travers T, Strozewski N, Martin K, Malchano Z, Hajós M. Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients. Front Syst Neurosci. 2021;15:746859. Epub 2021 Sep 24 PubMed.

    Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.

    Zibrandtsen IC, Agger M, Kjaer TW. Gamma Entrainment in a Large Retrospective Cohort: Implications for Photic Stimulation Therapy for Alzheimer's Disease. J Alzheimers Dis. 2020;75(4):1181-1190. PubMed.

    Lee K, Park Y, Suh SW, Kim SS, Kim DW, Lee J, Park J, Yoo S, Kim KW. Optimal flickering light stimulation for entraining gamma waves in the human brain. Sci Rep. 2021 Aug 10;11(1):16206. PubMed.

    Zheng L, Yu M, Lin R, Wang Y, Zhuo Z, Cheng N, Wang M, Tang Y, Wang L, Hou ST. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun. 2020 Jun 15;11(1):3012. PubMed.

    Lahijanian M, Aghajan H, Vahabi Z, Afzal A. Gamma Entrainment Improves Synchronization Deficits Caused by Dementia. bioRxiv. October 3, 2021 bioRxiv

    Agger MP, Carstensen MS, Henney MA, Hansen LS, Baandrup AO, Nguyen M, Petersen PM, Madsen KH, Kjær TW. Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light. J Alzheimers Dis. 2022;88(1):335-344. PubMed.

    He Q, Colon-Motas KM, Pybus AF, Piendel L, Seppa JK, Walker ML, Manzanares CM, Qiu D, Miocinovic S, Wood LB, Levey AI, Lah JJ, Singer AC. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease. Alzheimers Dement (N Y). 2021;7(1):e12178. Epub 2021 May 13 PubMed.

    Shen Q, Wu X, Zhang Z, Zhang D, Yang S, Xing D. Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β-amyloid load in Alzheimer's disease model. Aging Cell. 2022 Mar;21(3):e13573. Epub 2022 Feb 23 PubMed.

    Kim SH, Park SS, Kim CJ, Kim TW. Exercise with 40-Hz light flicker improves hippocampal insulin signaling in Alzheimer disease mice. J Exerc Rehabil. 2022 Feb;18(1):20-27. Epub 2022 Feb 24 PubMed.

    Park SS, Park HS, Kim CJ, Kang HS, Kim DH, Baek SS, Kim TW. Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer's disease. Alzheimers Res Ther. 2020 May 20;12(1):62. PubMed.

    Park SS, Park HS, Kim CJ, Baek SS, Park SY, Anderson C, Kim MK, Park IR, Kim TW. Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice. J Appl Physiol (1985). 2022 Apr 1;132(4):1054-1068. Epub 2022 Feb 24 PubMed.

    Tian T, Qin X, Wang Y, Shi Y, Yang X. 40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice. J Alzheimers Dis. 2021;84(3):983-993. PubMed.

    Park Y, Lee K, Park J, Bae JB, Kim SS, Kim DW, Woo SJ, Yoo S, Kim KW. Optimal flickering light stimulation for entraining gamma rhythms in older adults. Sci Rep. 2022 Sep 16;12(1):15550. PubMed.

    Yao Y, Ying Y, Deng Q, Zhang W, Zhu H, Lin Z, Zhang S, Ma J, Zhao Y. Non-invasive 40-Hz Light Flicker Ameliorates Alzheimer's-Associated Rhythm Disorder via Regulating Central Circadian Clock in Mice. Front Physiol. 2020;11:294. Epub 2020 Apr 24 PubMed.

    Zhang Y, Zhang Z, Luo L, Tong H, Chen F, Hou ST. 40 Hz Light Flicker Alters Human Brain Electroencephalography Microstates and Complexity Implicated in Brain Diseases. Front Neurosci. 2021;15:777183. Epub 2021 Dec 13 PubMed.

    Lin Z, Hou G, Yao Y, Zhou Z, Zhu F, Liu L, Zeng L, Yang Y, Ma J. 40-Hz Blue Light Changes Hippocampal Activation and Functional Connectivity Underlying Recognition Memory. Front Hum Neurosci. 2021;15:739333. Epub 2021 Dec 16 PubMed.

    Chan D, Suk HJ, Jackson B, Milman NP, Stark D, Beach SD, Tsai LH. Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease. J Intern Med. 2021 Nov;290(5):993-1009. Epub 2021 Jun 22 PubMed.

    View all comments by Chinnakkaruppan Adaikkan

  12. I noticed that the visual response in this paper is relatively small, with only a small, narrow band increase at 40Hz (Fig 4C). Light flicker should be a sensory stimulus that elicits a strong response. So even if the V1 can't follow such a 40Hz entrainment, the power of other frequency bands should increase. I wonder whether such a small visual response is due to the aversion behavior of animals used in the experiments of this paper?

    However, for such a small visual response, the authors have found some improvement after 40 Hz stimulation and a statistically significant reduction in Aβ42 in V1. (Quote: "We note that some histopathological and ELISA measures showed some improvement after 40-Hz stimulation, and decrease of Aβ42 in V1 reached statistical significance.")

    References:

    Huang P, Xiang X, Chen X, Li H. Somatostatin Neurons Govern Theta Oscillations Induced by Salient Visual Signals. Cell Rep. 2020 Nov 24;33(8):108415. PubMed.

    View all comments by Ji Hu

  13. I like this study, especially the within-one animal comparison of microglia before and after light stimulation.

    Furthermore, the results show that it is necessary to better understand the underlying mechanisms of neuronal network aberrations in AD. With this knowledge, we might be able to more precisely interfere and fine tune and restore proper oscillations in AD.

    In my opinion we need to think about possibilities for how to apply optogenetics/chemogenetics in humans in the long run. These tools might give us the opportunity to precisely manipulate oscillations in specific brain regions, like the hippocampus.

    View all comments by Martin Fuhrmann

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