Sensory Stimulation Systems


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Name: Sensory Stimulation Systems
Synonyms: GENUS, Gamma entrainment using sensory stimuli, GammaSense Stimulation
Therapy Type: Combination, Procedural Intervention
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Cognito Therapeutics, Inc.


Sensory Stimulation Systems, and GENUS, refer to a non-invasive procedure, i.e., a "digital therapeutic," being developed by Cognito Therapeutics. The company developed a wearable GammaSense Stimulation device, which delivers sensory stimuli at gamma band frequency in order to entrain gamma oscillations in the brain. An LED light flashing at 40 Hz for one hour was reported to boost gamma power in the visual (V1), prefrontal, and somatosensory cortices, and hippocampal CA1. It also increases synchronization between V1 and the other regions. A second paradigm combines light and sound at 40 Hz to strengthen gamma oscillations throughout the auditory cortex, hippocampus, and medial prefrontal cortex.

In 5XFAD, APPPS1, and wild-type mice, one hour of light-based GENUS reportedly halved Aβ levels, and one week of GENUS in 6-month-old 5XFAD mice cut amyloid plaque load by two-thirds. In TauP301S, this regimen cut phosphorylated tau by 40 percent (Iaccarino et al., 2016).

Neuron numbers were maintained in TauP301S mice for three weeks with GENUS starting at 7.5 months of age, when neurodegeneration begins in this model. In the inducible p25 neurodegeneration mouse model, six weeks of GENUS preserved neuron number and cortical thickness. In both models, GENUS maintained neuronal expression of genes affecting synaptic transmission and vesicle trafficking, protected DNA, increased the density of mushroom spines, and improved performance in the Morris water maze. In all models tested, GENUS lowered microgliosis and inflammatory gene expression, while increasing internalization of Aβ (Adaikkan et al., 2019). The combination of light and sound at 40 Hz in 6-month-old 5XFAD mice had similar effects to light alone, but reached more brain areas (Martorell et al., 2019).

In other studies, 40 Hz light flicker or ultrasound was reported to improve cognitive function, enhance presynaptic plasticity, and activate microglia to reduce Aβ plaque load (Park et al., 2020; Zheng et al., 2020; Bobola et al., 2020). A separate study linked acoustic stimulation to lowered amyloid plaques and increased microglial numbers in the hippocampi of 5XFAD mice (Lee et al., 2018).

In one study using 40 Hz optogenetic stimulation, hippocampal gamma waves and spatial memory changed, but plaque load did not. In another, plaques grew; memory was not assessed (Etter et al., 2019Wilson et al., 2020). In one study, native gamma oscillation entrainment, amyloid lowering, and microglial activation were not replicated (Soula et al., 2023).

For reviews, see McDermott et al., 2018Adaikkan and Tsai, 2020Manippa et al., 2023).


In a brief pilot study conducted in Europe, without Cognito Therapeutics, 10 days of 40 Hz light therapy, administered for two hours per day, did not affect amyloid load, as measured by PiB PET, in 10 AD patients (Ismail et al., 2018).

In April 2018, Cognito Therapeutics began a Phase 1 trial called Overture to evaluate the GammaSense device in 60 people with AD or mild cognitive impairment due to AD. Participants received one hour of combined 40 Hz auditory and visual stimulation, or a sham treatment, daily for six months at home, with a follow-up visit one month later to assess safety. The primary outcome was ADAS-Cog, CDR-SB, and MADCOMS scores, with ADCS-ADL and MMSE and amyloid imaging as secondary outcomes. The trial took place at six sites in the U.S. and ran until August 2021.

In March 2021, results of the sham-controlled phase were presented at AD/PD. Forty-six participants received active stimulation, 28 sham. There were no serious adverse events, but more participants on active stimulation complained of tinnitus. In each group, 28 percent of participants dropped out. The trial missed all three primary outcomes. On secondary outcomes, the stimulation group showed an 84 and 83 percent slowing of decline on ADCS-ADL and MMSE, respectively. Active treatment was associated with a 61 percent slowing of whole-brain atrophy. There was no effect on hippocampal volume. Of the 53 people who finished the six-month regimen, 44 continued to a one-year, open-label extension (Apr 2021 conference news).

In May 2018, a second Phase 1 study called Etude began comparing dosing paradigms for auditory and visual GENUS in 20 people with AD or mild cognitive impairment due to AD. These included one hour once per day, one hour twice per day, one hour every other day, and 30 or 120 minutes twice per day. The primary outcomes were amyloid PET and safety; secondary, ADAS-Cog. The trial was to be completed in November 2019; no results have been reported.

From November 2018 to February 2020, a third study called Flicker evaluated the tolerability of a combined audio-visual stimulation for one hour per day in 10 people with AD. Five participants received eight weeks of GENUS; five received four weeks of no intervention followed by four weeks of intervention. There was no placebo/sham.

As reported at AD/PD 2021, the study first tested escalating brightness and loudness. Most people tolerated full intensity stimulation. Overall, participants completed 95 percent of sessions. No severe treatment-related adverse events were reported. Some participants reported dizziness, headaches, or tinnitus; one person’s hearing loss worsened. In exploratory measures, EEG detected gamma entrainment in many brain areas. Gamma power was the same after four weeks treatment, and weakened after eight. Strengthened brain connectivity was detected at eight weeks between the posterior cingulate and precuneus, two regions in the default mode network that is disrupted in AD. Brain amyloid and CSF Aβ or tau did not change after eight weeks, although CSF levels of many cytokines changed (Apr 2021 conference news).

Two other studies of gamma entrainment were conducted at MIT, with results also presented at AD/PD 2021. These studies used an easel-mounted array of lights and speakers, rather than the GammaSense device. One began in April 2019 and involved 46 healthy adults and 26 older people with mild AD. EEG monitoring was used to optimize stimulation parameters during 30-60 minute sessions. The 40 Hz light/sound stimulation increased gamma waves in most brain areas, while triggering no headaches, vision or hearing changes, or seizures.

A second study began in August 2019 to evaluate the effects of daily stimulation in 15 people with mild AD. Participants were randomized to active or sham stimulation for one hour daily using the same light/speaker array at home for six or nine months. The primary outcomes measured device usage and adverse events. Other outcomes included cognition, function, neuropsychiatric symptoms, blood levels of amyloid, tau, and neurofilament light, EEG changes, structural and functional MRI, sleep time and efficiency, and physical activity. After the first period, all participants had the option to continue on active settings for six or nine months. In this study, data collection was paused at three months due to the COVID pandemic. Preliminary results found daily stimulation resulted in better sleep by one month. At three months, active treatment strengthened functional MRI connectivity in brain circuits involved in vision and memory, improved performance on a face-name-matching test, and may have slowed loss of hippocampal volume. Participants reportedly could not tell if they received active or sham stimulation (Apr 2021 conference news). Results of GENUS studies were subsequenctly published (Chan et al., 2022).

In January 2021, Cognito's GammaSense stimulation device received breakthrough status from the FDA. 

In October 2022, the University of Tennessee Medical Center in Knoxville started enrolling 20 people with Alzheimer's disease into an open-label study of an eight-week course of one hour per day of treatment with an audio/visual gamma stimulation device by Cognito. The primary outcome assesses cortical visual processing; the study will run until December 2023. 

In December 2022, Cognito Therapeutics began enrolling for a Phase 3 trial in 345 people with Alzheimer’s disease. They are to be randomized to either active or sham treatment lasting one hour per day for up to a year, using a sensory stimulation device called GS120. Primary outcomes are change from baseline at 12 months on the ADCS-ADL and change from baseline at 12 months on the combined statistical test (CST) of the ADCS-ADL and MMSE. The trial is being run at 38 sites across the U.S., and is expected to be complete in 2025.

For details on trials of this approach, see and

Last Updated: 09 Mar 2023


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News Citations

  1. Does Synchronizing Brain Waves Bring Harmony?

Research Models Citations

  1. 5xFAD (B6SJL)
  2. Tau P301S (Line PS19)

Paper Citations

  1. . The Effect of 40-Hz Light Therapy on Amyloid Load in Patients with Prodromal and Clinical Alzheimer's Disease. Int J Alzheimers Dis. 2018;2018:6852303. Epub 2018 Jul 30 PubMed.
  2. . 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.
  3. . Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.
  4. . Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.
  5. . 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.
  6. . 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.
  7. . Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun. 2020 Jun 15;11(1):3012. PubMed.
  8. . 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.
  9. . 40 Hz acoustic stimulation decreases amyloid beta and modulates brain rhythms in a mouse model of Alzheimers disease. BioRxiv. August 20, 2018. BioRxiv.
  10. . Optogenetic gamma stimulation rescues memory impairments in an Alzheimer's disease mouse model. Nat Commun. 2019 Nov 22;10(1):5322. PubMed.
  11. . Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer's disease pathology. Sci Rep. 2020 Sep 22;10(1):15456. PubMed.
  12. . 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.
  13. . Gamma Band Neural Stimulation in Humans and the Promise of a New Modality to Prevent and Treat Alzheimer's Disease. J Alzheimers Dis. 2018;65(2):363-392. PubMed.
  14. . Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. Epub 2019 Dec 10 PubMed.
  15. . Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review. Neuropsychol Rev. 2023 Mar 6; PubMed.

Other Citations

  1. APPPS1

External Citations


Further Reading


  1. . Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. Epub 2019 Dec 10 PubMed.
  2. . Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study. J Alzheimers Dis. 2023;92(2):653-665. PubMed.
  3. . An update on the use of gamma (multi)sensory stimulation for Alzheimer's disease treatment. Front Aging Neurosci. 2022;14:1095081. Epub 2022 Dec 15 PubMed.
  4. . Episodic memory effects of gamma frequency precuneus transcranial magnetic stimulation in Alzheimer's disease: A randomized multiple baseline study. J Neuropsychol. 2022 Nov 9; PubMed.
  5. . Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans. Front Aging Neurosci. 2022;14:1010765. Epub 2022 Oct 6 PubMed.
  6. . Optogenetic neuromodulation with gamma oscillation as a new strategy for Alzheimer disease: a narrative review. J Yeungnam Med Sci. 2022 Feb 14; PubMed.
  7. . Non-invasive auditory brain stimulation for gamma-band entrainment in dementia patients: An EEG dataset. Data Brief. 2022 Apr;41:107839. Epub 2022 Jan 19 PubMed.
  8. . 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.
  9. . 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.