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Sensory Stimulation Systems

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Overview

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, Parkinson's Disease, Down's Syndrome
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Not Regulated), Down's Syndrome (Not Regulated)
Company: Cognito Therapeutics, Inc.

Background

Sensory Stimulation Systems, and GENUS, refer to a noninvasive procedure, i.e., a "digital therapeutic," being developed by Cognito Therapeutics. The company developed a wearable GammaSense Stimulation device. It pairs headphones and opaque glasses to deliver light and sound 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 combination of light and sound at 40 Hz has been shown to strengthen gamma oscillations throughout the auditory cortex, hippocampus, and medial prefrontal cortex. Gamma oscillations play a role in sensory processing, cognition, and memory consolidation, and are weakened in AD.

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 (Singer et al., 2018Park 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). Multisensory 40 Hz stimulation was reported to increase glymphatic clearance of Aβ in the same model (Murdock et al., 2024), and to restore hippocampal synaptic potentiation in rat models (Yang et al., 2023). Other reported effects of 40 Hz light flicker in AD preclinical models include increased expression of cytokines that regulate microglia (Garza et al., 2020; Prichard et al., 2023), normalization of circadian rhythms, altered APP processing, and improved effects of exercise on cognition (Yao et al., 2020; Shen et al., 2022; Park et al., 2022).

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 other negative studies, native gamma oscillation entrainment, amyloid lowering, and microglial activation were not replicated (Soula et al., 2023; Yang and Lai, 2023). Transgenic AD rats increased their activity, but did not improve cognition, after light and sound stimulation (Bentley and Broussad, 2024).

For reviews, see McDermott et al., 2018Adaikkan and Tsai, 2020Manippa et al., 2022; Blanco-Duque et al., 2024).

Devices that offer 40 Hz light and sound stimulation are sold directly to consumers. Evidence for their claimed uses is sparse.

Findings

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 its CogTx-001 GammaSense stimulation device in 60 people with AD or mild cognitive impairment due to AD. Devices were calibrated for each participant and EEG-verified to elicit 40 Hz steady-state gamma oscillations. 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 five sites in the U.S. and ran until August 2021.

In March 2021, results 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). Published results on the first 22 participants reported a decrease in nighttime activity. Active treatment was reported to result in stabilization on the ADCS-ADL, compared to a decline in the sham group (Cimenser et al., 2021). Complete results were published after peer review (Hajós et al., 2024). Additional analysis of MRI data suggested reduced white matter atrophy and myelin content loss, especially in the entorhinal cortex (Da et al., 2024). Results of the open-label extension were presented at the March 2024 AD/PD conference. Adherence was 80 percent, with no new adverse events of tinnitus or headache reported. ADCS-ADL scores were stable in the 15 continuously treated patients. The seven patients who started on placebo showed a trend toward slowing of decline in the ADCS-ADL and loss of brain volume after switching to active treatment. Progression modeling implied a disease-modifying effect.

In May 2018, a second Phase 1 study called Etude began comparing dosing paradigms for auditory and visual stimulation with the GammaSense device 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 by March 2022; 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 mild cognitive impairment due to AD. Five participants received eight weeks of GammaSense stimulation; five received four weeks of no intervention followed by four weeks of intervention. There was no placebo/sham. This investigator-initiated trial was conducted at Emory University, and sponsored by Cognito. 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). Nine of the 10 participants chose to enter a one-year, open-label extension.

Two other studies of gamma entrainment were conducted at MIT, with results also presented at AD/PD (April 2021 conference news). These studies used an easel-mounted array of lights and speakers, not 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 both studies were subsequently published (Chan et al., 2022).

Seven participants in these studies entered the open-label extension. At the 2024 AD/PD conference, results were reported on three late-onset and two early onset AD patients, who completed treatment for a total of 30 months. Induction of 40 Hz neural activity was sustained, but brain connectivity was reduced. The properties of circadian rhythms improved compared to baseline; hippocampal volume loss slowed compared to historical controls. In the late-onset patients only, cognitive scores stabilized, with a preservation of performance on the MMSE, CDR-SB compared to historical controls.

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

In July 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 Cognito’s GammaSense device. The primary outcome assesses cortical visual processing; the study will run until December 2025.

In December 2022, Cognito Therapeutics began enrolling for a Phase 3 trial in 345 people with AD. 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 on the combined statistical test (CST) of the ADCS-ADL and MMSE. In mid-2023, the trial increased enrollment to 530, and later added a one-year open-label extension. It is being run at 68 sites across the U.S., and is expected to be complete in 2025.

In December 2022, a new feasibility study began at MIT, enrolling 50 people with mild AD for six months of one hour daily, at-home stimulation, with a sham control. This study uses the easel-mounted GENUS device developed at MIT, and also will test a vibrating device that delivers 40 Hz tactile stimulation (see Suk et al., 2023). Primary outcomes are 40 Hz brain entrainment, safety, functional connectivity by fMRI, and AD-related inflammation biomarkers based on RNA sequencing in blood. Other outcomes include changes in the microbiome, sleep/wake patterns, and a cognitive testing battery. Participants will have the option of continuing the regimen for one year in an open-label extension. Completion is anticipated in September 2024.

In January 2024, MIT and MGH researchers began a prevention trial. It plans to enroll 50 cognitively normal people with cerebral amyloid deposits to a one-year, one-hour daily at-home treatment with the easel-mounted GENUS device, against a primary outcome of change in brain amyloid on PET. Other outcomes are to be change in tau-PET, structural and functional MRI, EEG, night-time activity, blood biomarkers of AD, and compliance. A substudy will assess CSF biomarkers of amyloid and tau. The study also plans to measure changes in CSF flow, white matter and myelination by diffusion MRI, neuropsychiatric symptoms, gamma oscillations, sleep, activity levels and adverse events. Completion is planned for May 2026. This trial offers a one-year, open-label extension.

At Emory University, a Parkinson’s trial began in May 2024. This study will enroll 28 PD patients who have problems walking, for six months treatment with a commercially available stimulation device from the Canadian company MindAlive Inc. Primary outcomes are compliance and adverse events; the study will also assess general symptoms and specifically freezing of gait, as well as CSF biomarkers of amyloid and inflammation.  

MIT investigators are also running safety, feasibility, and optimization trials of GENUS in people with PD, and with Down's syndrome.

For details on trials of this approach, see clinicaltrials.gov.

Last Updated: 08 May 2024

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References

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. . 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.
  3. . Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease. Front Neurol. 2024;15:1343588. Epub 2024 Mar 6 PubMed.
  4. . Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease. J Alzheimers Dis. 2024;97(1):359-372. PubMed.
  5. . 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.
  6. . Vibrotactile stimulation at gamma frequency mitigates pathology related to neurodegeneration and improves motor function. Front Aging Neurosci. 2023;15:1129510. Epub 2023 May 18 PubMed.
  7. . Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.
  8. . Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.
  9. . 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.
  10. . Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc. 2018 Aug;13(8):1850-1868. PubMed.
  11. . 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.
  12. . Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun. 2020 Jun 15;11(1):3012. PubMed.
  13. . 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.
  14. . 40 Hz acoustic stimulation decreases amyloid beta and modulates brain rhythms in a mouse model of Alzheimers disease. BioRxiv. August 20, 2018. BioRxiv.
  15. . Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature. 2024 Mar;627(8002):149-156. Epub 2024 Feb 28 PubMed.
  16. . Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease. Eur J Neurosci. 2023 Sep;58(6):3402-3411. PubMed.
  17. . 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.
  18. . Brain rhythms control microglial response and cytokine expression via NF-κB signaling. Sci Adv. 2023 Aug 9;9(32):eadf5672. PubMed.
  19. . 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.
  20. . 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.
  21. . 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.
  22. . Optogenetic gamma stimulation rescues memory impairments in an Alzheimer's disease mouse model. Nat Commun. 2019 Nov 22;10(1):5322. PubMed.
  23. . Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer's disease pathology. Sci Rep. 2020 Sep 22;10(1):15456. PubMed.
  24. . 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.
  25. . Chronic Visual Stimulation with LED Light Flickering at 24, 40, or 80 Hz Failed to Reduce Amyloid β Load in the 5XFAD Alzheimer's Disease Mouse Model. eNeuro. 2023 Aug;10(8) Print 2023 Aug PubMed.
  26. . Multimodal Gamma Stimulation Improves Activity but not Memory in Aged Tgf344-AD Rats. Curr Alzheimer Res. 2024 Mar 5; PubMed.
  27. . 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.
  28. . Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. Epub 2019 Dec 10 PubMed.
  29. . 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.
  30. . Audiovisual gamma stimulation for the treatment of neurodegeneration. J Intern Med. 2024 Feb;295(2):146-170. Epub 2023 Dec 19 PubMed.

Other Citations

  1. APPPS1

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  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.
  10. . Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice. Sci Transl Med. 2024 Mar 6;16(737):eadf4601. PubMed.
  11. . BrainWAVE: A Flexible Method for Noninvasive Stimulation of Brain Rhythms across Species. eNeuro. 2023 Feb;10(2) Print 2023 Feb PubMed.