Invented by Li-Huei Tsai, Anthony James Martorell, Ho-Jun Suk, Ed Boyden, Massachusetts Institute of Technology

Dementia is a debilitating condition that affects millions of people worldwide. It is a progressive disease that affects memory, thinking, and behavior, and can severely impact a person’s quality of life. As the population ages, the prevalence of dementia is expected to increase, making it a significant public health concern. The market for systems and methods for preventing, mitigating, and/or treating dementia is rapidly growing, with new technologies and treatments being developed to address this issue. The market for systems and methods for preventing, mitigating, and/or treating dementia is diverse, with a range of products and services available to address different aspects of the disease. These include pharmaceuticals, medical devices, cognitive training programs, and lifestyle interventions. Pharmaceutical companies are investing heavily in developing drugs that can slow down or even reverse the progression of dementia. Some of these drugs target the underlying causes of the disease, such as the accumulation of beta-amyloid plaques in the brain. Medical devices are also being developed to help people with dementia manage their symptoms. These include wearable devices that monitor vital signs and alert caregivers if there are any changes in the person’s condition. Other devices, such as smart home technology, can help people with dementia live independently for longer by automating tasks and providing reminders. Cognitive training programs are another area of the market that is growing rapidly. These programs are designed to help people with dementia maintain their cognitive abilities and improve their quality of life. They typically involve exercises that challenge the person’s memory, attention, and problem-solving skills. Some programs also incorporate physical exercise, which has been shown to have a positive impact on brain health. Lifestyle interventions are also an important part of the market for systems and methods for preventing, mitigating, and/or treating dementia. These include changes to diet and exercise habits, as well as social and cognitive stimulation. Studies have shown that people who engage in regular physical activity, eat a healthy diet, and stay socially active are less likely to develop dementia. Overall, the market for systems and methods for preventing, mitigating, and/or treating dementia is expected to continue growing in the coming years. As the population ages, the demand for effective treatments and interventions will only increase. The development of new technologies and treatments will be critical in addressing this issue and improving the lives of people with dementia and their caregivers.

The Massachusetts Institute of Technology invention works as follows

Devices and systems for treating Alzheimer’s or dementia in a patient in need thereof.” In one example of non-invasive delivery of combined auditory and vision stimuli, the frequency is between 20 Hz and 60 Hz and, more specifically, 40 Hz. This induces synchronized gamma waves in at least one region of the brain of the subject. According to different treatment and exposure protocols combined auditory-visual stimulation (as opposed auditory or visual stimulus alone) promotes microglia responses in the medial frontal cortex (mPFC). In general, combined auditory-visual stimulation causes a microglia clustering in the mPFC, visual cortex and auditory cortex.

Background for Systems and Methods for Preventing, Mitigating, and/or Treating Dementia

Alzheimer?s disease (AD), a neurodegenerative progressive disease, is characterized by a gradual decline in memory and reasoning. It is the most prevalent form of dementia, affecting one in eight over 65s, and is the sixth-leading cause of death in America. This progressive neurodegenerative disease is expected to grow by 40% over the next 10 years.

Histopathologically, AD may be characterized by the accumulation of amyloid plaques comprising the amyloid-? (A?) The tau protein is used to make peptides and neurofibrillary (NFT) tangles. The A? The normal physiological function of peptide, a 36-43 amino acid protein, is unknown. The A? The A? C-terminal fragment? C-terminal fragment? peptide production. Normal conditions allow the A? The soluble A? In AD patients, however, the A? peptide appears to aggregate into higher-order species to form soluble oligomers and insoluble plaques in a concentration-dependent manner. This aggregation could lead to many neurotoxic effects, including disruption of brain metabolism, neuroinflammation and reduced functional connectivity. It may also cause synaptic loss and neuronal death, or the formation of NFTs.

The relationship between concentration and neuronal activity has been shown to be fundamental. The relationship between A? The first was the treatment of organotypic slices from Tg mice that overexpress APP with tetrodotoxin. This decreased neuronal activities and, subsequently, AP levels. Picrotoxin treatment had the opposite effect, resulting in increased neuronal activity. Dynamic modulation A? In vivo, neuronal activity has also been used to demonstrate the dynamic modulation of A? The most severe plaque deposits in AD patients may be aligned with brain regions that are consistently active, also known as the “default-mode network.

At the moment, AD is incurable and there are no treatments that can stop its progression. They may be palliative or have many side effects. Preventative and/or Therapeutic Strategies targeting the A? A? In clinical trials, immunotherapy and inhibitions of? and? secretases have proven to be toxic or ineffective in reducing AD pathology. The lack of cognitive benefits in clinical trials with amyloid beta (e.g. bapineuzumab), has led to the failure of these trials. Clinical trials of gamma-secretase inhibiters (e.g. semagacestat), which worsen cognitive deficits, have failed. Even existing medications such as acetylcholinesterase inhibiters (e.g. donepezil, rivastigmine), and N-methyl D-aspartate receptor antagonists (e.g. memantine), demonstrate only mild cognitive improvements.

As disclosed in U.S. Patent Application Ser. No. No. In the patent (hereafter incorporated by reference in full), inducing synchronized oscillations of gamma in the brain through visual or auditory stimulation results in reduced amyloid loads and morphological change in certain brain regions. “The Inventors are aware and appreciate that there is a continuing need for dementia and Alzheimer’s treatment methods that target circuit-wide diseases affecting multiple brain centres that are responsible for memory, learning, and higher-order functions.

In light of the above, the present disclosure relates to at least a part to combined visual and auditory stimuli that induce gamma waves in the brains of a subject using various techniques referred herein generally as ‘Gamma ENtrainment Using sensory stimuli (GENUS)? The combined auditory and visually stimuli disclosed herein (e.g. visual and auditory GENUS), unexpectedly, generates physiological and behavioral effects not seen with either visual or auditory GENUS. The positive effects of combined auditory-visual GENUS on the brain are not limited to the auditory cortex and hippocampus, but also include inducing a clustering response of microglia in the medial frontal cortex and reducing the amyloid burden throughout the neocortex. The combined effects of auditory and vision GENUS can be observed within a short period of time (on the order weeks) of exposure or treatment.

In one aspect, this disclosure discloses devices, methods and systems that can be used to treat dementia or Alzheimer’s Disease in a patient. The method involves non-invasively delivering combined visual and auditory stimuli with a frequency between 20 Hz and 60 Hz in order to induce synchronized Gamma oscillations within at least one region of the brain of the patient. In some embodiments the dementia is related to AD, vascular, frontal-temporal, Lewy Body, or age-related cognitive decline. “The subject can be either a person or an animal.

In some embodiments the combined auditory-visual stimuli has a frequency between 35 Hz and 45 Hz or about 40 Hz.

In some embodiments, non-invasively delivering combined visual and auditory stimuli induces periodic spiking responses in 5% or more of the recording sites in the at least one cortical region selected from the auditory (AC), visual (VC), hippocampus and medial prefrontal (mPFC). In certain embodiments, non-invasively delivering a combined auditory and vision stimuli induces a local field potential at 40 Hz or more in the medial prefrontal cortex (mPFC).

In some embodiments the non-invasively delivered combined auditory/visual stimuli increase microglial responses in at least one cortical region. The cortex region can include the neocortex as well as the AC, VC, HPC and mPFC. In certain embodiments, microglial responses are induced in mPFC. In some embodiments the microglial responses are induced across multiple cortex regions. In some embodiments the microglial reaction is induced throughout the neocortex.

In some embodiments the increasing microglial responses comprises of at least one of the following effects: increasing the number of microglia in 25 micrometers from an amyloid plaque, increasing microglia body diameter, decreasing microglial project length and increasing microglia count. In one embodiment, increasing microglial responses include an increase of at least 10% to 50% in the microglia body diameter. In one embodiment, an increasing microglial reaction is a decrease of at least 10%, 20-30%, 40-50% in the microglial projection. In one embodiment, increasing microglial responses includes an increase of at least 10%, 20-30%, 40-50% in the number of microglia cells.

In some embodiments, an increasing microglial reaction is observed after non-invasively delivering auditory and/or visual stimuli for 1, 2, 3, 5, 6, 7, 8, 9 or 10 consecutive days.

In some embodiments, non-invasively delivering combined audio and visual stimuli includes reducing amyloid deposits in at least one cortical region, selected from the neocortex and any of the AC, VC, HPC and mPFC. The cortex region can include the neocortex as well as the AC, VC, HPC and mPFC. In certain embodiments, microglial responses are induced in mPFC. In some embodiments the microglial responses are induced across multiple cortex regions. In some embodiments the microglial reaction is induced throughout the entire neocortex.

In an embodiment, reducing amyloid plates consist of at least 5, 10, 15, 25, 30, 35, forty, fifty, five-fifty, or sixty percent reduction in plaque size. In one embodiment, the reducing plaques amyloid is at least 5, 10, 15, 25, 30, 35, forty, fifty, five, or sixty percent reduction in number.

In some embodiments, an increasing microglial reaction is observed after non-invasively delivering auditory and/or visual stimuli for 1, 2, 3, 5, 6, 7, 8, 9 or 10 consecutive days.

In certain embodiments, non-invasively delivering a combined auditory-visual stimulus comprises reducing a amount of amyloid? (A?) (A?) The cortex region can include the neocortex as well as the AC, VC, HPC and mPFC. In certain embodiments, microglial responses are induced in mPFC. In some embodiments the microglial responses are induced across multiple cortex regions. In some embodiments the microglial reaction is induced throughout the entire neocortex.

In one embodiment, the amount of A is reduced by at least 5, 10, 15, 20, 25, 30, 35, 40, 45. 50. 55. or 60%. The amount of A? In some embodiments the AP peptide includes at least one isoform of A?1-40 peptide or A?1-42 peptide. In some embodiments the A? A? The peptide A? peptide.

In some embodiments, an increasing microglial reaction is observed after non-invasively delivering auditory and/or visual stimuli for 1, 2, 3, 5, 6, 7, 8, 9 or 10 consecutive days.

The disclosure also provides a method of treating Alzheimer’s or dementia in a patient by delivering non-invasively to the patient a combined stimuli, which includes the visual and sound stimuli aligned synchronously, and which induces synchronized gamma waves in at least a brain region. The synchronized oscillations lead to an improvement in cognitive function.

In some embodiments the visual stimulation comprises repeated 12.5ms on and 12.5ms off light. In some embodiments the optogenetic stimulus is a light emitting diode of 40-80W power. In some embodiments the auditory stimulation is a tone of 10 kHz played at a frequency of 40 Hz, with a duty-cycle ranging from about 4% to 80%. In some embodiments the visual stimulus is a 40 Hz light that flickers for 10 seconds with a duty-cycle of between 10% and 80%.

In some embodiments the visual and auditory stimuli are synchronized. In some embodiments the visual stimulus is out of phase with the auditory stimuli by?180 degrees to 0 or 0 to 180.

Click here to view the patent on Google Patents.