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Gamma Waves therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710538/
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Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role
Artemis Traikapi* and Nikos Konstantinou

 Department of Rehabilitation Sciences, Faculty of Health Sciences, Cyprus University of
Technology, Limassol, Cyprus
Despite decades of research, Alzheimer’s Disease (AD) remains a lethal neurodegenerative disorder for
which there are no effective treatments. This review examines the latest evidence of a novel and newly
introduced perspective, which focuses on the restoration of gamma oscillations and investigates their
potential role in the treatment of AD. Gamma brain activity (∼25–100 Hz) has been well-known for its role
in cognitive function, including memory, and it is fundamental for healthy brain activity and intra-brain
communication.
Aberrant gamma oscillations have been observed in both mice AD models and human AD
patients.
A recent line of work demonstrated that gamma entrainment, through auditory and visual sensory
stimulation, can effectively attenuate AD pathology and improve cognitive function in mice models
of the disease.
The first evidence from AD patients indicate that gamma entrainment therapy can reduce loss of
functional connectivity and brain atrophy, improve cognitive function, and ameliorate several
pathological markers of the disease. Even though research is still in its infancy, evidence suggests that
gamma-based therapy may have a disease-modifying effect and has signified a new and promising era in
AD research.
Introduction
Alzheimer’s Disease (AD) is a slowly progressing, lethal neurodegenerative disorder and the most
prevalent form of dementia accounting for 60–80% of the total dementia cases worldwide (Alzheimer’s
Association, 2020).
The core pathological hallmarks and the most dominant hypotheses of AD are the extracellular
plaque accumulation formed by amyloid beta (Aβ), and intracellular neurofibrillary tangles
composed of phosphorylated tau protein. Both pathologies cause a broad variety of neurotoxic
cascades and massive loss of neurons and synapses in the cerebral cortex and hippocampus
(Bloom, 2014).
Even though scientific knowledge has increased enormously and our understanding of the pathological
mechanisms involved in AD have been well-identified, clinical trials that have targeted these mechanisms
have not succeeded in identifying effective methods to treat or reverse the disease (Fan et al., 2020).
Considering the alarming rise and the tremendous personal, social, and financial burden of AD, scientists
have tried to move away from the well-recognized hypotheses. AD pathogenesis has recently been
explored from different perspectives, such as infection, cerebral vasoconstriction and prion transmission
(Jeong et al., 2018; Seminara et al., 2018; Tian et al., 2019), offering new insights into the potential
treatments of AD.
A recent pioneering approach targets brain waves to treat AD pathology. Brain oscillations, particular
gamma oscillations, are altered in AD patients and animal models of the disease (e.g., Jelles et al.,
2008; Klein et al., 2016). On that basis, a novel approach investigates the effectiveness of a therapy
based on modulation of neuronal gamma oscillations using sensory inputs, and its potential therapeutic
role, signifying a new and promising era in AD research. In this review, we summarize the status of
research on the potential therapeutic effect of gamma entrainment in mice models of AD and human
patients.
Aberrant Gamma Neural Activity in Alzheimer’s Disease: Evidence From Animal Studies
Gamma waves are the fastest brainwaves in the human brain, produced by synchronized electrical pulses
from masses of neurons communicating with each other, resonating between approximately 25 and 100
Hz (Hughes, 2008). Several human studies have investigated their role in object representation and visual
feature binding (Tallon-Baudry and Bertrand, 1999) as well as in higher cognitive functions (van Vugt et
al., 2010; Miller et al., 2018; Griffiths et al., 2019). Gamma rhythms have been recorded ubiquitously
across the human brain. They are being widely encountered in the visual system (Murty et al.,
2018; Zhigalov et al., 2021) in addition to different cortical and subcortical brain structures (e.g., Cohen et
al., 2009; van der Werf et al., 2010; Manabe and Mori, 2013). What is more, it has been suggested that
gamma-band synchronization supports fundamental functions critical for various cognitive
processes (Bosman et al., 2014). All this evidence reveals gamma oscillations’ multifunctionality, which
supports a wide range of both sensory and higher cognitive functions (for further information on gamma
oscillations, please see Bosman et al., 2014; Cannon et al., 2014; Fries, 2015; Cole and Voytek, 2017).
Mounting evidence suggests that gamma rhythms are also prominent in the hippocampus, playing a
crucial role in memory functions (e.g., Colgin and Moser, 2010; Carr et al., 2012; Buzsáki, 2015). It is,
therefore, not surprising, that disorders characterized by memory impairment, such as AD, are
associated with aberrant activity of gamma oscillations (Mably and Colgin, 2018).
The presence of gamma oscillations has been identified in vivo in the hippocampus and the
entorhinal cortex of healthy rodents (Penttonen et al., 1998), while changes in this brain
activity have been evident in several rodent models of AD. In fact, Klein et al. (2016) reported
changes in rodents’ gamma oscillations in the entorhinal cortex at an early stage of the disease.
Another study found impaired theta-gamma cross-frequency coupling in the hippocampus before
plaque formation, in 1-month old transgenic mice (Goutagny et al., 2013). Verret et al.
(2012) identified that both AD patients and transgenic mice presented dysfunctions on the parvalbumin
cells and inhibitory synaptic activity which resulted in aberrant gamma oscillatory activity and cognitive
disfunction. Restoring the levels of the interneuron-specific and parvalbumin cells sodium channel
proteins had profound and beneficial effects on gamma brain activity and cognitive function.
Goutagny et al. (2013) indicated that the reduction of slow gamma activity (25–50 Hz) in the
hippocampal area CA1 can result in impaired memory function. Similar findings were reported
by Mably et al. (2017) who demonstrated that decreased gamma activity in mice models of AD can
result in memory dysfunction. Cumulatively, current evidence suggests that gamma brain activity is
decreased in mice models of the disease, causing cognitive dysfunction. The exact mechanisms
responsible for this alteration are not known, however, it has been suggested that synaptic and neuronal
functions are affected by either soluble Aβ or its fibrillary forms (Walsh and Selkoe, 2004),
contributing to network alterations (Palop and Mucke, 2016). In rodents, these changes are reported to
appear before plaques formation (Iaccarino et al., 2016; Etter et al., 2019).
Evidence that aberrant gamma activity and cognitive dysfunction arise in mice models of AD
before the accumulation of amyloid plaques provides convincing evidence that abnormalities in
gamma brain oscillations may represent an early biomarker for AD (Goutagny et al., 2013; Mably
and Colgin, 2018). Nevertheless, the question of whether the aberrant gamma oscillations activity is
responsible for the observed cognitive impairment in AD patients or if it is just another by-product of the
disease pathology, which produces the cognitive symptoms, remains to be answered. Additionally, it is
unclear whether inducing gamma oscillations in transgenic mice can affect AD pathophysiology and
cognition. It has been shown, however, that steady-state brain gamma oscillations can be stimulated or
driven by sensory stimulation (e.g., Ross et al., 2013) and that neuronal activity has the potential to
modulate the Aβ load (Cirrito et al., 2005; Bero et al., 2011).
The Effects of Gamma Stimulation in Mice
In light of accumulating evidence, recent studies demonstrated that restoration of gamma oscillations has
the potential to alleviate AD pathology and cognitive function in mice. Iaccarino et al. (2016) used a non-
invasive brain stimulation technique to manipulate gamma brainwaves. Specifically, the authors used
light flicker stimulation at three different frequencies (20, 40, 80 Hz), constant light or dark, and random
flicker to treat the pathology of 5XFAD mice.
After only 1 h of light flicker stimulation stimulation the authors observed reduction of Aβ levels in
visual cortex by almost 60%, compared with dark controls. Another critical finding was the
transformation of microglial morphology consistent with increased phagocytic activity and the elevation of
microglia/Aβ interactions.
These effects were specific to the 40 Hz light exposure as neither constant light nor 20 Hz, 80 Hz or
random flicker led to significant changes in mice pathology. After treating 5XFAD mice for 1 h daily over 7
days, the investigators found that 40 Hz visual stimulation significantly decreased both soluble and
insoluble Aβ1–40 and Aβ1–42 levels and reduced the accumulated amyloid pathology in visual cortex
by almost 67%, compared with dark controls. Finally, they observed reduction of the tau tangles in a
mouse model of tauopathy, indicating the generalization of 40 Hz stimulation effect to other pathogenic
proteins. Interestingly, these findings were replicated in several mice models, including WT, 5XFAD, and
APP/PSI (i.e., mice genetically engineered to exhibit specific AD pathologies; for reviews see Elder et al.,
2010; Oblak et al., 2021), suggesting that the effects are not specific to one animal model.
In a more recent study Martorell et al. (2019) presented mice models of AD with noise stimuli at 8 Hz, 40
Hz, 80 Hz and random stimulation tones for 1 h, daily, for 7 days. The authors reported that only 40 Hz
stimulation produced similar with Iaccarino et al. (2016) results, that extended from the primary auditory
cortex to the hippocampus and were accompanied by memory improvements. When the authors
combined the auditory with the visual (A + V) 40 Hz stimulation they observed reduction of
amyloid dispositions not only to the primary sensory cortices and the hippocampus, but also to
the medial prefrontal cortex and within the whole neocortex. Amyloid reduction was frequency-
specific, as it was observed only at 40 Hz but not at 8 Hz, 80 Hz or at random A + V frequency stimulation.
Additionally, the authors observed profound glial responses after the concurrent A + V 40 Hz
stimulation to the aforementioned areas, vs. visual or auditory stimulation alone and no
stimulation controls. Finally, from a study of the same research group (Adaikkan et al., 2019), it became
evident that 40 Hz visual stimulation entrains gamma oscillatory activity not only to the visual cortex but
also to the hippocampus, the prefrontal and the somatosensory cortices. In addition, gamma activity was
not enhanced only at local networks but also between these areas, indicating that 40 Hz light stimulation
improves inter-area communication, whereas 80 Hz stimulation did not produce similar results.
Finally, the authors delivered 40 Hz visual stimulation or no stimulation to tau P301S mice for 22
days. It was found that prolonged daily 40 Hz visual stimulation had a neuroprotective effect, in
terms of reduction of neuronal and synaptic loss in broad brain areas, which was accompanied by
cognitive improvements.
Overall, these studies provided evidence that inducing gamma oscillations through sensory 40 Hz
stimulation has the potential to ameliorate several of AD’s key neuropathologies, such as amyloid
plaques, neurofibrillary tangles (ovillos neurofibrilares – Estructuras anormales localizadas en
varias partes del cerebro y compuestas de agrupaciones densas de filamentos helicoidales
apareados (neurofilamentos y microtúbulos), and neuronal and synaptic loss, in several mice
models of AD. While the exact mechanisms under which the observed changes occurred remain to be
determined, these findings raised the interesting question of whether an increase in gamma frequency
neural activity in humans can be a promising strategy to alleviate AD’s pathological changes and hence,
to restore patients’ cognitive deficits. In any case, generalization of these 40 Hz protocols has gained
interest and it is currently a promising avenue (McDermott et al., 2018).
In view of the above findings, Yao et al. (2020) used light stimulation to investigate its effect on circadian
rhythm in AD mice models. The authors used APP/PSI mice models of AD and their non-transgenic wild-
type (WT) littermates and randomly divided them into no-stimulation or 40 Hz light therapy groups.
They found that 40 Hz light flicker for 1 h, daily, for a 30 day period, ameliorated circadian rhythm
disorder (difficulty falling asleep, waking up during the sleep cycle or waking up too early and
being unable to fall back to sleep) compared to the no-stimulation condition, which is suggested to
represent a primary component of the causal pathway, which leads to AD pathogenesis and accelerates
its progression (Vanderheyden et al., 2018). Furthermore, the authors observed induced gamma activity
in visual cortex and reduction of Aβ and tau production in the hypothalamus of the APP/PSI mice.
Additionally, they reported an increase of key clock proteins expression (e.g., BMAL1, CLOCK,
and PER2), and a restoration of the hypothalamus electrophysiological changes. Importantly, the
30-days light therapy proved safe, leading to no adverse side effects to mice’s physiological status. These
effects were evident only in the APP/PSI mice that received the 40 Hz light treatment but no such effects
were found in the no-stimulation condition. Taken together, this evidence suggests that 40 Hz sensory
stimulation may also have the potential to treat the circadian rhythm disorder presented in AD
(Homolak et al., 2018; Phan and Malkani, 2019; Pak et al., 2020).
Bobola et al. (2020) examined whether it is possible to safely alleviate AD pathophysiology in mice
models, and hence to replicate the work of Iaccarino et al. (2016), using transcranial focused ultrasound
pulsed at 40 Hz. The authors used 40 Hz ultrasound without contrast agents and observed microglia
activation that co-localized with amyloid plaques after just 1 h of application, as compared to sham
stimulation on age-matched mice. After 5 days of transcranial ultrasound therapy, the mice’s Aβ
burden reduced by almost 50% in the ultrasound exposed brain and by 28% in the CA1 area, in
contrast to sham therapy. These results compare closely with those observed by medications applied to
mice models for substantially prolonged time periods (Bhattacharya et al., 2014; Chandra and Pahan,
2019). Overall, even though the application of 40 Hz transcranial ultrasound did not lead to the
generalization of the effects throughout the brain as with the combination of auditory and visual sensory
stimulation by Martorell et al. (2019), the results demonstrated that it is a safe and effective intervention
and further research is needed in this area.
The aforementioned findings provide compelling evidence on the positive effects of audiovisual sensory
gamma stimulation on AD pathology in mice. Additionally, it should be noted that Zhen et al.
(2017) demonstrated that neuropathological changes and cognitive function can also be alleviated
through gamma burst magnetic stimulation, delivered via deep-brain reachable low field magnetic
stimulation (i.e., a non-invasive technique designed to intervene with the brain’s neuronal activity), in mice
models of the disease. Following the robust animal data, research is now focusing on investigating
whether these findings would translate into human AD patients.
Sensory Gamma Frequency Stimulation in Alzheimer’s Disease Patients
The accumulating evidence on gamma entrainment through visual and auditory stimulation in mice was a
major stride toward establishing the importance of gamma brain waves, particularly at 40 Hz, in the
amelioration of AD neuropathology. The research on the therapeutic efficacy of gamma sensory
stimulation in AD patients, although still in its infancy, provides encouraging data. Clements-Cortes et al.
(2016) evaluated the effects of 40 Hz sound stimulation vs. non-rhythmic visual stimulation in AD patients.
The study indicated that somatosensory stimulation, via a device (i.e., NextWave chair) which produced
40 Hz sound waves through six speakers, had a significant effect on the cognitive function of patients with
mild to moderate AD, in contrast with the visual stimulation which involved nature pictures displayed on a
television screen. While patients’ gamma brain activity or possible changes on AD pathology were not
assessed, this study provided solid evidence regarding the efficacy of gamma-based treatment in AD.
More recently, Suk et al. (2020) developed a light and noise delivery device and stimulated at 40 Hz
cognitively healthy, AD, and epileptic patients while their electrophysiological responses were recorded.
The concurrent audiovisual stimulation was proved safe in all subject groups, including the epileptic
patients, while induced highly coordinated 40 Hz oscillations. Even though patients’ cognitive abilities
were not examined, this study provided preliminary evidence regarding the safety and feasibility of 40 Hz
sensory stimulation in AD patients.
To investigate the efficacy of sensory stimulation as a novel disease modifying therapy in AD
patients, Chan et al. (2021) conducted a longitudinal, placebo-controlled trial. Specifically, 15 patients with
mild AD were recruited and divided into experimental and control groups. Both groups were given the
same sensory stimulation device to use at home for 1 h daily. The devise was programmed to deliver
constant white light and noise to the control group and synchronized audiovisual stimulation at 40 Hz to
the active group. AD patients who received real auditory and visual stimulation treatment daily, over a
period of 3 months, presented reduced loss of functional connectivity, improved memory performance and
ameliorated sleep markers in relation to controls. Additionally, the active group showed less brain atrophy
and more importantly did not show further hippocampal atrophy or ventricular expansion in relation to the
control group, indicating a possible delay in the disease progression. In the same manner, He et al.
(2021) recruited 10 patients with prodromal AD who received daily 40 Hz audiovisual sensory stimulation
for 1 h over the course of 4 or 8 weeks. Even though, control group or sham stimuli were not included for
comparison reasons, the study indicated that the treatment was safe and resulted in improved functional
connectivity in the default mode network and altered cytokines and immune factors in the cerebrospinal
fluid. Overall, both studies provided compelling evidence that gamma-based therapy, through visual and
auditory stimulation, may have a disease modifying effect and may be used to alleviate AD
pathology. Table 1 summarizes the clinical studies that applied gamma frequency brain stimulation in AD
patients.
Table 1
TABLE 1. Summary of clinical studies that applied gamma frequency brain stimulation to Alzheimer’s
Disease (AD) patients.
Gamma Frequency Non-Invasive Brain Stimulation in Alzheimer’s Disease Patients
Sensory brain stimulation is currently the most commonly used technique to change brain waves activity
in AD research. However, there are other approaches available which allow interference with brain activity
and stimulate in desirable frequencies. Among these, transcranial alternating current stimulation (tACS), a
non-invasive brain stimulation technique, has been proposed as an alternative technique to sensory
stimulation and has the potential to result in stronger effects (Strüber and Herrmann, 2020). TACS
delivers sinusoidal alternating electric currents over cortical areas of interest, at specific frequencies,
entraining cortical oscillations at these frequencies. Hence, it has the potential to modulate cognitive
functions that are related with the applied frequencies (for reviews please see Paulus, 2011; Herrmann et
al., 2013).
Kehler et al. (2020) examined whether 40 Hz stimulation over the left dorsolateral prefrontal cortex,
through tACS, could improve cognitive function in AD patients. Eleven patients with mild to moderate AD
received two 30-min stimulation sessions per day, accompanied by cognitive exercises, for four
consecutive weeks (active group) while six patients received cognitive exercises alone, for 4 weeks
(control group). Memory improvements were observed in both groups, however, these
improvements were maintained only to the active group at the follow up, at the 1-month post-
treatment assessment.
In a recent study, a single session of 40 Hz tACS over Pz (an area overlying the medial parietal
cortex and the precuneus) showed significant improvements on patients’ episodic memory
performance and restoration of intracortical connectivity measures of cholinergic
neurotransmission. – BUENON
The effect was evident in the AD patients who received the 40 Hz tACS, compared to sham exposure
(Benussi et al., 2021). Even though the effects of 40 Hz tACS in AD underlying pathology were not
considered, these results provide preliminary evidence that gamma frequency stimulation through non-
invasive techniques may also have the potential to alleviate cognitive symptoms in AD patients.
Increasing evidence suggests that tACS at gamma frequencies can effectively modulate a variety of
cognitive functions in healthy and neuropsychiatric patients, demonstrating strong clinical potential for the
inducement of gamma oscillations in AD (for a review please see Strüber and Herrmann, 2020).
Most recently, Liu et al. (2021) employed repetitive transcranial magnetic stimulation (TMS), a non-
invasive brain stimulation technique that induces a pulsing electric current to the brain, which allows
focused stimulation of the cerebral cortex, and demonstrated the clinical efficacy of 40 Hz in improving
cognitive impairments in AD (for reviews on the use of TMS in AD see Nardone et al., 2014; Liao et al.,
2015; Cheng et al., 2018; Taylor et al., 2019). The authors recruited 37 AD patients divided into active and
sham TMS groups who received 12 sessions of 40 Hz TMS bilaterally at the angular gyrus, over the
course of 4 weeks, and found significant cognitive improvement which lasted for up to 8 weeks in
relation to sham stimulation. – BUENON.
The authors also reported that 40 Hz TMS stimulation led to prevention of gray matter volume
loss, and modulated gamma activity in the temporoparietal cortex as measured with power
spectral density analysis of the resting-state electroencephalography (EEG) recordings, while at
the same time increased local, long-range, and dynamic connectivity within the brain, enhancing
information flow and integration. Importantly, the intervention was proven safe with no side effects.
Accordingly, TMS might also have the potential to promote gamma rhythm synchronization, providing a
novel non-pharmacological intervention for AD.
The non-invasive brain stimulation techniques provide the benefit of selecting specific brain areas for
stimulation. Even though up to date no specific area has been identified as ideal to provide the most
beneficial effects, it is suggested that several areas or pathways that are known to be negatively affected
in AD, could provide potential targets. On that basis, by targeting these areas, crucial for normal cognitive
function brain connections and pathways could be strengthened or rescued (e.g., stimulating the
precuneus to alleviate abnormal functional connectivity in the default mode network) leading to cognitive
improvements (Heath et al., 2018).
Discussion and Future Directions
Gamma oscillations reflect a fundamental brain process, critical for healthy intra-brain communication and
cognitive functions, especially memory, and, if disturbed, results in cognitive disfunction (Başar, 2013).
Decreased gamma brain activity has been observed in both mice models of AD and human patients.
Evidence, indicating aberrant gamma brain rhythms in mice, before the accumulation of amyloid
plaques (Goutagny et al., 2013; Iaccarino et al., 2016) has drawn scientific interest toward the
investigation of their role in AD pathology and their potential role in its treatment. Etter et al.
(2019) showed that restoration of gamma oscillations in the hippocampus by optogenetic gamma
stimulation of parvalbumin neurons is sufficient to rescue memory loss in mice without decrease of plaque
load. In that respect, it is evident that gamma brain waves play a crucial role in memory function that
appears to be independent from plaque accumulation.
Whether the observed disruption in gamma brain activity is responsible for the cognitive impairment in AD,
or if it is just another outcome of the disease’s pathology remains to be answered. However, the
entrainment of this brain activity and the consequent impact on the disease’s pathology has gained
interest and has signified a new and promising era in AD research. Even though the investigations are still
at their infancy, evidence suggests that restoration of gamma oscillations, through auditory and visual
gamma stimulation, may have the potential to ameliorate AD pathology and improve cognition. The first
evidence regarding the effectiveness of 40 Hz gamma entrainment through sensory stimulation in human
patients (Chan et al., 2021; He et al., 2021), supports the notion regarding the essential role that gamma
brain activity plays in AD pathology. In addition to sensory stimulation, scientists have investigated the
effects of 40 Hz stimulation using other techniques that allow interference with brain activity and stimulate
at desirable frequencies. For instance, non-invasive methods, such as transcranial alternating current
stimulation and transcranial magnetic stimulation have been used generating positive results. On that
basis, the new and promising research area of investigating the potential of gamma stimulation as a
disease modifying therapeutic for AD, has emerged.
Cumulatively, current evidence from mice and human studies points toward investigating 40 Hz-based
protocols as potential treatment for AD. Nevertheless, it should be noted that while the frequency-specific
effect (i.e., 40 Hz) has been evident in mice studies (Iaccarino et al., 2016; Adaikkan et al., 2019; Martorell
et al., 2019), the same remains to be determined in humans. Preliminary data from AD patient studies, do
provide evidence about the potential therapeutic efficacy of 40 Hz entrainment. However, it remains
unclear if these effects are specific to 40 Hz or can be seen using other gamma-based protocols. On that
basis, it would be crucial in the future to compare 40 Hz stimulation with other gamma-range protocols, to
determine whether the unique and profound effects of gamma stimulation are frequency-specific in
humans.
A second interesting question that remains to be answered, is whether gamma stimulation targeting
directly brain areas and connections that have been negatively affected by AD pathophysiology (e.g., the
default mode network; Palop and Mucke, 2016), or cortical areas associated with the hippocampus, will
be sufficient to restore gamma rhythms, AD pathology, and patients’ cognitive function. Finally, while
several functions are attributed to gamma oscillations, such us their essential role in supporting
fundamental circuit functions and cortical signal transmissions across the brain (Bosman et al., 2014),
results from mice studies (Iaccarino et al., 2016; Adaikkan et al., 2019; Martorell et al., 2019) imply
possible unappreciated mechanisms of action. In these studies, it is suggested that 40 Hz gamma
stimulation can effectively attenuate mice pathology (i.e., Aβ and tau load; synapses and
connectivity loss; cognitive function) by inducing profound glial responses and offering
neuroprotection. It would be interesting therefore, to investigate the role of gamma oscillations in the
recruitment of neuronal and glial responses, as well as in the modification of plasticity proteins. In contrast
to mice studies, in humans, the observed improvements in patients’ cognitive functions have been
attributed to the enhancement of gamma rhythm activity within the brain, which allows the information flow
and integration (Liu et al., 2021). The effects of gamma stimulation on patients’ amyloid and tau burden as
well as on microglial responses remain to be seen.
While gamma brain activity in AD patients is well-studied, the exact relationship between AD pathology
and changes in gamma activity is yet inconclusive. Reduced gamma activity has been detected in AD
patients (e.g., Stam et al., 2002; Başar et al., 2016) and has even been suggested as a potential
biomarker for Mild Cognitive Impairment and AD (Murty et al., 2021). However, a number of studies have
reported elevated gamma activity in AD patients (van Deursen et al., 2008; Başar et al., 2017). Although
this contradictory observations may stem from various experimental parameters (Byron et al., 2021), a
recent study demonstrated that changes in gamma brain activity might be dependent on the degree of
amyloid burden (Gaubert et al., 2019). Hence, it is important for future studies to correlate AD pathology
with changes in gamma oscillations (Byron et al., 2021) as well as to clarify the role that the degree of
pathogenesis plays in gamma brain activity.
Further, although accumulated evidence indeed supports the idea that induction of gamma oscillations
can modify AD pathology, several challenges and inconsistencies of this therapeutic approach remain. An
important aspect for consideration is that cortical gamma rhythms can be induced via various
mechanisms, such as the interneuron gamma (ING) and the pyramidal-interneuron gamma
(PING; Tiesinga and Sejnowski, 2009; Buzsáki and Wang, 2012) and hence, outcomes and mechanisms
of action may vary depending on the method used to increase gamma activity. For instance, Wilson et al.
(2020) applied 40 Hz optogenetic stimulation in the basal forebrain parvalbumin neurons of mice models
of AD and observed an increase of amyloid burden across several brain regions. As different methods of
stimulation can lead to distinct molecular and cellular responses, thus implicating different mechanisms of
action, it is of paramount importance to investigate which induction methods have beneficial or detrimental
effects on patients’ pathology. Further research is needed to uncover these limitations in addition to well-
designed clinical trials in which different ranges of gamma frequencies will be investigated.
Finally, considering that stimuli which can modulate gamma brain activity in humans are abundant in the
environment (e.g., visual and auditory stimuli, such as human speech; Towle et al., 2008), an interesting
question for future research is whether the effects of 40 Hz stimulation are specific to the stimulation
protocols employed in the aforementioned studies or gamma brain activity can also be modulated by
environmental sensory stimulation, such as everyday speech. Moreover, if indeed gamma sensory
stimulation can alter brain gamma activity (e.g., Murty et al., 2018; Chan et al., 2021; Liu et al., 2021),
such abundance of gamma sensory stimulation in the environment raises questions about how the brain
protects interference by such stimuli.
In conclusion, the recent evidence on the potential therapeutic effects of gamma frequency stimulation in
AD suggests that while induction of gamma oscillations is an important and promising approach for AD
pathology alleviation, several issues remain to be addressed and much work remains to be done to
establish whether this emerging field will lead to the development of novel AD therapeutic interventions.
Author Contributions
AT and NK contributed to the conception and design of the study. AT wrote the first manuscript. NK
contributed to the manuscript revision. Both authors approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those
of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that
may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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HASTA AQUÍ 22-03-2023

Small studies of 40-hertz sensory stimulation confirm safety, suggest Alzheimer’s benefits
MIT researchers report early-stage clinical study results of tests with noninvasive 40-hertz light
and sound treatment.
David Orenstein | Picower Institute for Learning and Memory
Publication Date:
December 13, 2022
PRESS INQUIRIES
Caption:
Picower Institute scientists are testing whether sensory stimulation of the brain's 40-hertz "gamma"
frequency rhythm can treat Alzheimer's disease. Part of the study involves scanning the brains of study
volunteers with magnetic resonance imaging.
Credits:
Photo: David Orenstein/Picower Institute
A pair of early-stage clinical studies testing the safety and efficacy of 40-hertz sensory stimulation to treat
Alzheimer’s disease has found that the potential therapy was well-tolerated, produced no serious adverse
effects, and was associated with some significant neurological and behavioral benefits among a small
cohort of participants.
“In these clinical studies we were pleased to see that volunteers did not experience any safety issues and
used our experimental light and sound devices in their homes consistently,” says Li-Huei Tsai, the Picower
Professor in the the Picower Institute for Learning and Memory at MIT and senior author of the Dec.
1 paper describing the studies in PLoS ONE. “While we are also encouraged to see some significant
positive effects on the brain and behavior, we are interpreting them cautiously, given our study’s small
sample size and brief duration. These results are not sufficient evidence of efficacy, but we believe they
clearly support proceeding with more extensive study of 40-hertz sensory stimulation as a potential
noninvasive therapeutic for Alzheimer’s disease.”
In three studies spanning 2016-19, Tsai’s lab discovered that exposing mice to light flickering or sound
clicking at the gamma-band brain rhythm frequency of 40 hertz — or employing the light and sound
together — produced widespread beneficial effects. Treated mice modeling Alzheimer’s disease
pathology experienced improvements in learning and memory; reduced brain atrophy, neuron and
synapse loss; and showed lower levels of the hallmark Alzheimer’s proteins amyloid beta and
phosphorylated tau compared to untreated controls. The stimulation appears to produce these effects by
increasing the power and synchrony of the 40-hertz brain rhythm, which the lab has shown profoundly
affects the activity of several types of brain cells, including the brain’s vasculature.
Study designs
Based on those encouraging results, Diane Chan, a neurologist at Massachusetts General Hospital and a
postdoc in Tsai’s lab, led the two new clinical studies at MIT. One set of tests, a “phase 1” study, enrolled
43 volunteers of various ages, including 16 people with early-stage Alzheimer’s, to confirm that exposure
to 40-hertz light and sound was safe and to test whether it increased 40-hertz rhythm and synchrony after
a few minutes of exposure, as measured with EEG electrodes. The study also included two patients with
epilepsy at the University of Iowa who consented to having measurements taken in deeper brain
structures during exposure to 40-hertz sensory stimulation while undergoing epilepsy-related surgery.
The second set of tests, a “phase 2A” pilot study, enrolled 15 people with early-stage Alzheimer’s disease
in a single-blinded, randomized, controlled study to receive exposure to 40-hertz light and sound (or non-
40-hertz “sham” stimulation for experimental controls) for an hour a day for at least three months. They
underwent baseline and follow-up visits including EEG measurements during stimulation, MRI scans of
brain volume, and cognitive testing. The stimulation device the volunteers used in their homes (a light
panel synchronized with a speaker) was equipped with video cameras to monitor device usage.
Participants also wore sleep-monitoring bracelets during their participation in the trial.
The phase 2A trial launched just before the onset of the Covid-19 pandemic in 2020, causing some
participants to become unable to undergo follow-ups after three months. The study therefore only reports
results through a four-month period.
Study results
In the phase 1 study, volunteers filled out a questionnaire on side effects, reporting a few minor but no
major adverse effects. The most common was feeling “sleepy or drowsy.” Meanwhile, measurements
taken with EEG scalp electrodes clustered at frontal and occipital sites showed significant increases in 40-
hertz rhythm power at each cortical site among cognitively normal younger and older participants as well
as volunteers with mild Alzheimer’s. The readings also demonstrated significant increase in coherence at
the 40-hertz frequency between the two sites. Between the two volunteers with epilepsy, measurements
showed significant increases in 40-hertz power in deeper brain regions such as the gyrus rectus,
amygdala, hippocampus, and insula, with no adverse events, including seizures.
In the phase 2A study, neither treated nor control volunteers reported serious adverse events. Both
groups used their devices 90 percent of the time. The eight volunteers treated with 40-hertz stimulation
experienced several beneficial effects that reached statistical significance compared to the seven
volunteers in the control condition. Control participants exhibited two signs of brain atrophy as expected
with disease progression: reduced volume of the hippocampus and increased volume of open spaces, or
ventricles. Treated patients did not experience significant changes in these measures. Treated patients
also exhibited better connectivity across brain regions involved in the brain’s default mode and medial
visual networks, which are related to cognition and visual processing respectively. Treated patients also
exhibited more consistent sleep patterns than controls.
Neither the treatment nor control groups showed any differences after just three months on most cognitive
tests, but the treatment group did perform significantly better on a face-name association test, a memory
task with a strong visual component. The two groups, which were evenly matched by age, gender, APOE
risk gene status, and cognitive scores, differed by years of education, but that difference had no
relationship to the results, the researchers wrote.
“After such a short time we didn’t expect to see significant effects on cognitive measures, so it was
encouraging to see that, at least on face-name association, the treatment group did perform significantly
better,” Chan says.
In PLOS ONE the researchers concluded: “Overall, these findings suggest that 40Hz GENUS has positive
effects on AD-related pathology and symptoms and should be studied more extensively to evaluate its
potential as a disease-modifying intervention for AD.”
After the study ended all participants were permitted to continue using the devices set to provide the 40-
hertz stimulation.
The MIT team is now planning new clinical studies to test whether 40-hertz sensory stimulation may be
effective in preventing the onset of Alzheimer’s in high-risk volunteers, and is launching preliminary
studies to determine its therapeutic potential for Parkinson’s disease and Down syndrome. Cognito
Therapeutics, an MIT spinoff company co-founded by Tsai and co-author Ed Boyden, the Y. Eva Tan
Professor of Neurotechnology at MIT, has launched phase 3 trials of 40-hertz sensory stimulation as an
Alzheimer’s treatment using a different device.
Tsai, Boyden, and co-author Emery N. Brown, the Edward Hood Taplin Professor of Computational
Neuroscience and Medical Engineering at MIT, are among the co-founders of MIT’s Aging Brain Initiative,
which has advanced this collaboration and other neurodegeneration research at MIT.
In addition to Tsai, Chan, Boyden, and Brown, the study’s other authors are Ho-Jun Suk, Brennan
Jackson, Noah Milman, Danielle Stark, Elizabeth Klerman, Erin Kitchener, Vanesa S. Fernandez Avalos,
Gabrielle de Weck, Arit Banerjee, Sara D. Beach, Joel Blanchard, Colton Stearns, Aaron D. Boes, Brandt
Uitermarkt, Phillip Gander, Matthew Howard III, Eliezer J. Sternberg, Alfonso Nieto-Castanon, Sheeba
Anteraper, Susan Whitfield-Gabrieli, and Bradford C. Dickerson.
Funding for the study came from sources including the Robert A. and Renee E. Belfer Family Foundation,
the Ludwig Family Foundation, the JPB Foundation, the Eleanor Schwartz Charitable Foundation, the
Degroof-VM Foundation, the Halis Family Foundation, and David B Emmes, Gary Hua and Li Chen, the
Ko Han Family, Lester Gimpelson, Elizabeth K. and Russell L. Siegelman, Joseph P. DiSabato and Nancy
E. Sakamoto, Alan and Susan Patricof, Jay L. and Carroll D Miller, Donald A. and Glenda G. Mattes, the
Marc Haas Foundation, Alan Alda, and Dave Wargo.
An Hour of Light and Sound a Day Might Keep Alzheimer’s at Bay
Playing a flashing white light and a trilling sound reversed signs of Alzheimer’s in mice. Researchers are
now trying it in humans
 By Angus Chen on March 14, 2019
There is no cure for Alzheimer’s disease. Although a few drugs manage temporarily certain cognitive
symptoms of the illness, none can stop or meaningfully slow its progression. “We really don’t have much
to offer people,” says Shannon Macauley, a neuroscientist at Wake Forest School of Medicine. Virtually all
new treatments have failed in clinical trials. But new research is looking beyond drugs to see what relief
might come from a simple LED light and a speaker.
Bathing patients in flashing light and pulsing sounds both tuned to a frequency of 40 hertz might reverse
key signs of Alzheimer’s in the brain, according to a paper published in Cell on Thursday. “I think it’s an
absolutely fascinating paper to be honest,” says Macauley, who was not involved in this work. “It’s a very
provocative idea. It’s noninvasive and easy and low cost, potentially, so if it were to come to fruition in
humans—that’s fabulous.”
Still, all this is a big if, Macauley acknowledges. The work was done in mice with genetic alterations that
doomed them to develop key symptoms and pathology of Alzheimer’s disease. One batch of mice formed
neurofibrillary tangles inside their neurons—dysfunctional knots of a protein called tau that can lead to the
cell’s death. Another batch of the mice developed amyloid beta plaques—sticky heaps of protein that dam
the flow of communication between neurons. All the mice also had a third hallmark of the disease—
irregular brain activity in the gamma range of brain waves that oscillate between 30 and 100 times a
second.
In 2015 neuroscientist Li-Huei Tsai, director at The Picower Institute for Learning and Memory at
Massachusetts Institute of Technology, was working on an experiment to manipulate that brain activity by
flashing a white light at these mice. Like light strobes, our brains flicker. Brain waves are generated when
large groups of neurons oscillate on and off together. Neurons encode our thoughts and actions and
senses in this rhythmic electrical flutter. So when Tsai tuned her light to flash 40 times a second, or 40
hertz, and flickered it at the mice, their brains flickered back—generating gamma waves at a
corresponding 40 hertz. Then, something unexpected happened.
When Tsai dissected the mice brains afterward, the amount of amyloid plaques and tau tangles in the
mice that saw the light had plummeted. “It was the most remarkable thing,” Tsai says. “The light flicker
stimulation triggers a tremendous microglia response. These are the brain’s immune cells that clear cell
debris and toxic waste including amyloid. They’re impaired in Alzheimer’s disease, but [the light] seems to
restore their abilities.”
This clearing-out process only happened in the visual cortex where the brain processes light
information. To get these effects to penetrate deeper into the brain, she added a clicking sound
like a dolphin’s chirrup that also had a 40-hertz frequency. When the mice sat in a room with both
the flashing light and the droning sound for an hour day, seven days in a row, amyloid plaques
and tau tangles began falling in not just the audio and visual cortices but the prefrontal cortex and
the hippocampus as well. “This was one of the big jumps in the new paper,” Macauley says.
“These are the learning and memory centers of the brain. And there was about a 40 or 50 percent
decrease in amyloid and tau levels. It’s an absolutely impressive feat.” – BUENON -
BUENISIMOOOOOOO
That showed when Tsai put the mice through a set of cognitive tests. In one, where the mice were given a
familiar and an unfamiliar object to explore, mice that didn’t get the treatment acted as though they’d
never seen the familiar object. “That shows some memory problems,” Tsai says. Mice that saw the light
and heard the sound spent about two thirds of the time that untreated mice did examining the familiar
object. “It was unbelievable,” Tsai says. “This is the first time we’ve seen that this noninvasive stimulation
can improve cognitive function. It’s not a drug or an antibody or anything, it’s just light and sound.”
One possible explanation for this is brains with Alzheimer’s have irregular, often hyperactive, neurons,
says Jorge Palop, a neurologist at the University of California, San Francisco, who did not work on the
study. By providing the brains with a steady and regular beat, the repeating light and sound might work as
a kind of metronome for brain activity. “This could be like resetting the mice every day and correcting
some of this abnormal activity that they have,” he says. “Then downstream of that are all these beneficial
effects.”
All of this is still at the level of speculation. Researchers simply do not know why these brain waves,
specifically ones rising from light and sound stimulation at 40 hertz and no other frequencies, can lead to
a reversal of Alzheimer’s disease symptoms. “That’s a mystery,” says Terrence Town, a neuroscientist, at
the University of Southern California who was not involved with the work. It’s also not clear if these
beneficial effects would appear or if 40 hertz is the “magic” frequency in humans, he says.
Tsai is already working on answering those questions. In human studies underway at Cognito
Therapeutics, a start-up she founded with her colleague Ed Boyden, she says light and sound seem to
increase gamma waves in healthy participants without negative side effects. “Nobody gets sick or even
complains about it,” Tsai says. “But to see a [therapeutic] effect in humans, you’ll have to wait a long time.
If this approach has an impact, the experiment could easily take five years to have some conclusive
answer.”
Can flickering light and sound treat Alzheimer’s?

Share on PinterestCould flickering lights and sounds help scientists treat Alzheimer’s? Perchek
Industrie/EyeEm/Getty Images
 Research in mice has hinted that light and sound flickering at 40 hertz (Hz) could help treat
Alzheimer’s disease by restoring connectivity in the brain and mobilizing the immune
system against toxic proteins.
 Now, a pilot study involving people with early Alzheimer’s suggests that this novel
approach is safe and tolerable.
 The research also provides preliminary evidence that sensory flicker may restore brain
connectivity and modify the immune system in people with the disease.
The vast number of nerve cells in the human brain — about 86 billionTrusted Source of them according to
one estimate — appear to coordinate their activities by firing in synchrony.
One particular firing frequency, at about 40 pulses per second (40 Hz) in the gamma frequency range,
plays a pivotal role in brain functions, such as conscious awareness, perception, and memory.
Neuroscientists have discovered, for example, that on the rare occasions when people become aware
that they are dreaming, known as lucid dreaming, the strength of electrical oscillations at 40 Hz intensifies
in their brains.
There is also some evidenceTrusted Source that stimulating a sleeping volunteer’s brain with a weak
electric field pulsing at low gamma frequencies can induce lucid dreams.
Other researchTrusted Source has found that the brains of people who practice some forms of meditation,
which involves highly focused attention, have an unusually strong gamma signal during meditation and
“instructed mind-wandering” practices.
Conversely, scientists have found disruptions in the gamma range in several neurological
disorders, including Alzheimer’s diseaseTrusted Source.
“There is evidence that gamma activity is altered in people with dementia,” said Annabelle Singer, Ph.D.,
a neuroscientist at the Georgia Institute of Technology and Emory University in Atlanta.
“Exactly how gamma changes depends on what brain regions are measured and what the participant is
doing — like during a task vs. awake but resting,” she added.
Alzheimer’s disease is an incurable, degenerative form of dementia that damages parts of the brain that
play a role in thought, memory, and language.
The early stages, known as mild cognitive impairment (MCI), involve relatively mild loss of memory.
However, the later stages include debilitating symptoms, such as getting lost in once familiar places, poor
judgment, and changes in mood and personality.
The Centers for Disease Control and Prevention (CDC) estimate that in 2020, 5.8 millionTrusted
Source people in the United States were living with Alzheimer’s.
Sensory flicker as a treatment?
Dr. Singer and her colleagues in the Wallace H. Coulter Department of Biomedical Engineering at Georgia
Tech and Emory University are developing a novel approach to treating the disease that involves light and
sound pulsing at 40 Hz.
The idea is that the flickering sensory stimuli will “entrain” nerves deep within the brain to fire at the same
frequency, which may, over time, restore their lost connectivity.
In murine models of Alzheimer’s, the researchers found that sensory entrainment at gamma
frequenciesTrusted Source leads to immune changes that clear beta-amyloid, a toxic protein associated
with the disease.
However, the effects of this type of sensory flicker on the brains of people with Alzheimer’s are unknown.
The question also remained whether humans would tolerate the treatment and stick with the
necessary daily regimen of sensory stimulation.
To test its safety and tolerability, Dr. Singer’s lab enrolled 10 participants with MCI associated with early
Alzheimer’s.
They selected people with mild disease to ensure that they would be able to describe how well they
tolerated the treatment.
In addition, they excluded anyone with a history of migraine, tinnitus, or seizures from the study because
flickering sensory stimuli can exacerbate these conditions.
The researchers randomly assigned the volunteers to either 8 weeks of 1 hour of flicker treatment per day
or 4 weeks without treatment followed by 4 weeks of treatment.
This study design allowed them to account for any effects related to the progression of the disease and
the measurements that they carried out as part of the experiment.
During the treatment, the participants wore an experimental visor and headphones that delivered flashes
of light and sound at 40 Hz.
Promising results
The researchers report that no severe adverse events occurred in relation to these flickering stimuli.
Among the mild adverse events that the treatment may or may not have caused were dizziness,
tinnitus, headache, and worsened hearing loss.
Electroencephalography (EEG) recordings revealed that the participants’ brain activity synchronized with
the 40-Hz stimulation.
In addition, MRI brain scans after 8 weeks of daily flicker suggested a strengthening of
connectivity between two nodes of the brain’s default mode network, which is involved in self-
referential thought processes.
Connectivity between these particular nodes is known to weaken as Alzheimer’s disease progresses.
After 8 weeks of treatment, there was also evidence from immune signaling molecules in the participants’
cerebrospinal fluid that the 40-Hz brain stimulation was modifying their immune system.
The results appear in the journal Translational Research & Clinical InterventionsTrusted Source.
Deep brain structures
Medical News Today asked Dr. Singer why the team chose flickering sound and light to entrain people’s
brain waves rather than transcranial electricalTrusted Source or magnetic stimulation.
“We think other forms of 40-Hz stimulation could work because we know that has been the case in animal
studies,” she said. “But a key challenge is reaching deep brain structures involved in Alzheimer’s disease,
especially in humans with large brains.”
She said that it remained unclear whether existing forms of magnetic or electrical stimulation
would be able to drive 40-Hz neural activity in these deep brain structures.
Further trials of flicker treatment over longer periods will show how the effects that occurred in this
preliminary study change over time.
“In animal studies, some of the beneficial effects of gamma sensory stimulation wear off a week or more
after stimulation stops,” said Dr. Singer. “That’s one of the reasons we have participants perform
stimulation every day.”
“That said, we won’t know how long the effects last in humans without further study,” she added.
“So far, this is very preliminary, and we’re nowhere close to drawing conclusions about the clinical benefit
of this treatment,” says Dr. James J. Lah, Ph.D., a neurologist at Emory University and a co-author of the
paper.
“But we now have some very good arguments for a larger, longer study with more people,” he
concludes.
Limitations of the research
The authors acknowledge that the small number of participants and short duration of their study were
limitations.
The trial also lacked a “sham stimulation” control condition for comparison because the team’s research in
mice showed that random sensory flicker actually increased levels of beta-amyloid in the animals’ brains.
“It is unclear what stimulus patterns might be used as an appropriate placebo control for audiovisual
flicker,” they write.
It is also worth noting that Dr. Singer owns shares in Cognito Therapeutics — a company that partially
funded the study and aims to develop gamma stimulation-related products.
Revista mexicana de neurociencia

versión On-line ISSN 2604-6180versión impresa ISSN 1665-5044
Rev. mex. neurocienc. vol.22 no.6 Ciudad de México nov./dic. 2021 Epub 28-Feb-2022
https://doi.org/10.24875/rmn.20000100
REVIEW ARTICLES
Effects of binaural beats and isochronic tones on brain wave modulation: Literature review
Efectos de los tonos binaurales y isocrónicos en la modulación cerebral: Revisión de la literatura
Sandro Aparecido-Kanzler1 *
Francisco J. Cidral-Filho2
Rui D. Prediger1 3
1
Department of Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina
(UFSC), Florianopolis
Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina (UNISUL),
2
Palhoça, Santa Catarina

3
Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina
(UFSC), Florianopolis. Brazil
ABSTRACT
This systematic review is dedicated to deepening the study of two phenomena: binaural beats and
isochronic tones. Data from the scientific literature suggest the existence of a promising therapeutic
potential in neurology and psychophysiology due to their influence on specific frequencies of brain waves
and their implications for mental health and homeostasis of brain neurotransmitters. Prolonged audio
stimuli in repetitive and synchronized manner may induce changes in brain waves patterns and,
consequently, modulating neurophysiological, and behavioral responses. The literature review was
conducted using PUBMED, MEDLINE, LILLACS, and SCIENCE DIRECT online platforms using the
search words: “audio brain entrainment,” “auditory beat stimulation, “ “binaural beats,” “brainwave
entrainment (BWE),” and “isochronic tones.” The search yielded 674 studies, of which 49 were in
duplicate, and 592 were out of the scope of this review, and, therefore, were excluded from the study. The
remaining studies were analyzed according to the Cochrane Handbook for Systematic Reviews, resulting
in 33 randomized, controlled clinical trials that were then evaluated by the Jadad scale. From that, 17
studies obtained a score of three points or more on the Jadad scale. These studies were fully read and
critically analyzed. Binaural beats were used in 15 studies (88.25%), whereas isochronic tones were used
only in two studies (11.76%). Although most of the studies reviewed here indicated audio BWE
effectiveness, some positive outcomes may require further investigation, with more refined and
appropriate evaluation tools, better suited for each specific type of intervention and/or therapeutic target.
Considering these limitations, the performance of additional studies with more adequate experimental
design and data analysis is recommended, particularly focusing on the neurophysiological and behavioral
effects of brain wave entrainment on mental states.
Key words Audio brain entrainment; Binaural beats; Brainwave entrainment; Isochronic tones
RESUMEN
Esta revisión sistemática está dedicada a profundizar en el estudio de dos fenómenos: latidos binaurales
y tonos isocrónicos. Los datos de la literatura científica sugieren la existencia de un potencial terapéutico
prometedor en neurología y psicofisiología debido a su influencia en frecuencias específicas de ondas
cerebrales y sus implicaciones para la salud mental y la homeostasis de los neurotransmisores
cerebrales; los estímulos de audio repetitivos y sincronizados pueden inducir cambios en los patrones de
ondas cerebrales y modular las respuestas neurofisiológicas. La revisión de la literatura se realizó con
plataformas en línea PUBMED, MEDLINE, LILLACS y SCIENCE DIRECT, con las palabras de búsqueda:
“arrastre cerebral de audio”, “estimulación del ritmo auditivo”, “ritmos binaurales”, “arrastre de ondas
cerebrales” y “tonos isocrónicos”. La búsqueda produjo 674 estudios, de los cuales 49 estaban
duplicados y 592 estaban fuera del alcance de esta revisión y fueron excluidos. Los estudios restantes se
analizaron de acuerdo con el Manual Cochrane de Revisiones Sistemáticas, que tuvo como resultado 33
ensayos clínicos controlados aleatorios que fueron evaluados por la escala de Jadad. A partir de esto, 17
estudios obtuvieron una puntuación igual o superior a tres puntos y fueron leídos íntegramente y
analizados críticamente. Los tonos binaurales se utilizaron en 15 estudios (88. 25%) y los tonos
isocrónicos sólo en 2 estudios (11. 76%). Aunque la mayoría de los estudios revisados demuestran la
eficacia del arrastre de ondas cerebrales, algunos resultados pueden requerir más investigación con
herramientas más refinadas y apropiadas, para cada intervención y/u objetivo terapéutico. Teniendo en
cuenta estas limitaciones, se recomienda que se lleve a cabo un diseño experimental y análisis de datos
más adecuados, centrándose en los efectos neurofisiológicos del arrastre de ondas cerebrales y los
estados mentales.
Palabras clave Estimulación cerebral con audio; Tonos binaurales; Arrastre de ondas cerebrales; Tonos
isocrónicos
INTRODUCTION
Brain waves consist of rhythmic patterns of neuronal activity or synchronized electrochemical pulses from
groups of neurons in the central nervous system (CNS)1. There are several well-established brainwave
range patterns: gamma (30-70 Hz), beta (13-30 Hz), alpha (8-13 Hz), theta (4-8 Hz), and delta (1-4 Hz) 2.
Each one of these frequency bands has been correlated with different states of consciousness, such as
awake, relaxed, rapid eye movement (REM) sleep, as well as non-REM sleep stages3.
According to Gruzelier4, prolonged audio stimuli in repetitive and synchronized manner may induce
changes in brain waves patterns and, consequently, may modulate neurophysiological and behavioral
responses. More specifically, repetitive external or environmental stimuli may temporarily affect the
predominance of specific brain wave frequencies, a phenomenon namely brainwave entrainment (BWE)5-
7
. Therefore, BWE can be defined as rhythmic synchronization of brainwave oscillation with an external
repetitive stimulus.
BWE is a recurrent phenomenon in nature and biologically present in living beings8. The principle of
entrainment or harmonization was discovered around 1665, by the Dutch scientist Christian Huygens9.
The synchronization obtained through the entrainment principle is the result of the harmonization
principle, a physical phenomenon that occurs systematically in nature, and that is dependent on
environmental stimuli, for example, visual, auditory, or tactile. These stimuli may be used to elicit
synchronized brainwave patterns to match that of different mental states and/or levels of consciousness,
as seen with data acquisition techniques, such as the electroencephalography (EEG). In this context,
Oster10 stated the possibility to improve, amplify or modulate brain wave patterns to conditioned events in
the cerebral cortex3,11. The proposed therapeutic benefits have a wide scope, including the improvement
of cerebral blood flow, neuroplasticity stimulation, and neurophysiological compensations between the
cerebral hemispheres3.
In this review, we focused on the most common forms of auditory BWE, that is, binaural beats and
isochronic tones. Acoustic waves are characterized in Hertz (number of cycles per second). The audible
sound spectrum for humans comprises frequencies between 20 Hz and 20,000 Hz, regardless of its
complexity, and as long as it has an amplitude greater than 0 dB (decibel)12,13.
Isochronic tones consist of distinct and repetitive regular beats of a single tone. The number of peaks per
second in the signal amplitude is the isochronic frequency heard at regular and standardized time
intervals. On the other hand, binaural beats represent the auditory experience that occurs when two
sounds of close frequencies are presented separately to each ear with headphones or stereo speakers.
The brain integrates the two signals, producing a third “phantom sound” representing the difference
between the two auditory stimuli. For example, if a frequency of 114 Hz is presented to the right ear, and
another of 124 Hz to left ear, a binaural beat of 10 Hz is created by the brain as a result of these stimuli. In
this case, brain waves tend to match the binaural beat frequency, in this example 10 Hz, which
corresponds to alpha brainwave pattern. Binaural beats are created in the superior olivary nucleus of the
brain stem, the local of contralateral integration of auditory input14 (Fig. 1).
Figure 1 Binaural beats generated by the brain.
The beat is neurologically transported to the reticular formation, which uses neurotransmitters to trigger
changes in brain wave activity10 that synchronizes with that of the stimulus generated. The mental
features associated with each brain wave pattern can be elicited based on the scientific principle of
harmonization, also known as “brain wave entrainment.”
Most of studies with binaural beats and isochronic tones provides positive outcomes, indicating that audio
brain entrainment may yield different benefits, both physically and mentally15,16. More specifically, brain
entrainment can be applied to induce mental states and as adjunctive treatment to several brain disorders
in a safe and non-invasive manner, such as for the treatment of depression and anxiety disorders17. For
instance, it was demonstrated that a group of individuals exposed to 6 Hz sounds for 10 min presented a
significant increase on theta wave (4-8 Hz) cortical activity in comparison to control group that did not
receive the stimulus. These findings indicate a facilitatory effect on induction of a meditative state and
altered states of consciousness18. In this context, the aim of this study was to review the scientific
evidence on the therapeutic use of binaural beats and isochronic tones for the modulation of brain wave
patterns and mood states.
Development
Methodology
The central question of the current study was: what are the therapeutic and/or neuroplastic and behavioral
effects of binaural beats and isochronic tones on brain wave patterns and mood state modulation?
The following electronic databases were used for the studies search: PUBMED, MEDLINE, LILLACS, and
SCIENCE DIRECT, and the following search words (key words) were used: “audio brain entrainment,”
“auditory beat stimulation,” “binaural beats,” “BWE,” and “isochronic tones.”
The bibliographic search was conducted independently by the authors from October to December 2019,
and blindly to the results obtained by the other authors. The studies that met inclusion criteria (see below)
were later compared and compiled. The Cochrane Handbook for Systematic Reviews19 recommendations
were followed to assess the risk of bias; and the Jadad scale20 to evaluate methodological quality. The
Jadad scale consists of five criteria items, ranging from 0 to 5 points. A score below 3 indicates low
methodological quality and a score of 3 points or more indicates superior methodological quality. The
scale consists of the following questions:
1. Was the study randomized?
2. Was the randomization method appropriate?
3. Was the study blinded? Double blinded?
4. Was the blinding method appropriate?
5. Were drop-offs properly reported?
For questions 1, 3, and 5, a single point for yes, or zero for no, is assigned. For questions 2 and 4, a
single point for the use of the appropriate method, zero points for no description of the method, or a single
negative point for the inappropriate use of the method is assigned.
Inclusion criteria
The following criteria were included in the study:
1. Publication date: studies published from 2009 to 2019
2. Study design: clinical studies, such as case report, case series, case-control study, non-
randomized controlled clinical trial, and randomized clinical trial
3. Population: without limitation
4. Intervention: stimulation with binaural beats or isochronic tones
5. Comparison: without limitation
6. Result: qualitative and quantitative.
RESULTS
The search yielded a total of 674 studies (PUBMED: 74; MEDLINE: 396; LILLACS: 138; and SCIENCE
DIRECT: 66). As illustrated in figure 2, from the total of studies, 49 studies were in duplicate, and 592
studies addressed other themes beyond the scope of this review, and, therefore, were excluded from the
study.
Figure 2 Randomization algorithm and study selection.

The selected studies were analyzed according to the Cochrane Handbook for Systematic Reviews19,
resulting in 33 randomized, controlled clinical trials that were then evaluated by the Jadad scale20 (Fig. 3).
Only 17 studies obtained a score of three points or more on the Jadad scale20, and them were fully read
and critically analyzed; studies are summarized in Table 1. Binaural beats were used in 15 studies
(88.25%) whereas isochronic tones were used in only two studies (11.76%) (Fig. 3). In 82.35% of these
publications monaural and/or binaural audio stimulation were more effective in comparison to control
group.
Figure 3 Summary of the selected studies - handbook for systematic reviews.
Table 1 Summary of the main findings of the 17 selected studies according to the therapeutic use of
binaural beats and isochronic tones auditory brainwave entrainment
Method and Sample size Number of interventions and

Study Population/Type/Special? Outcomes
(N) frequency
3 weeks with three

Male and female children and interventions
adolescents per week with
Kennel et al., 2010
R+DB+PC; 20. Improved focus and attention
with Attention-deficit/hyperactivity
binauraldisorder
beta-16 Hz- beats 10
min
Acute intervention (single):

Vernon et al., 2014
R, 22 Healthy male and female young
10 Hzadults
(Alpha) Induced brainwave entrainment
20 Hz (Beta)
Single post-workoutIncreased parasympathetic

McConnell et al.,
R+DB+PC,
2014 21Young adults post-exercise intervention of 4-7activation,
Hz theta increased
waves sympathetic withdrawal, and
increased self-reported
(N) frequency
relaxation after exercise
Acute pre-surgical intervention,

the duration of the main
Increased intracranial flow
experiment varied between 15
Becher et al., 2015
R+PC, 10 Patients with temporal lobe epilepsy modulation in patients with
and 40 min, and the total
temporal lobe epilepsy
number of auditory stimuli
varied between 87 and 214 Hz
Applications of binaural
Measurement and control of
frequencies of gamma
attentional blink (AB), EBR
Reedjik et al., 2015
R+PC, 24. Healthy male and female young
frequency
adults(40 Hz) and alpha
method (predictor of dopamine
(10 Hz), for 3 min before and
levels and mood states)
during a global-local task
Intermittent intervention of 3
min with 1 min ofPromoted
intertrial brainwave
Tirdad et al., 2015
R+PC, 15 Healthy male and female young adults
interval, 7 Hz applications
entrainment
of
binaural tones during 9 min
Single 40 Hz gamma binaural

Colzato et al., 2016
R+PC+DB, 40Healthy male and female adults Improved selective attention
beat intervention
Sequential intervention for 14

Zampi, 201616 R+PC, 36 Chronic pain patients Attenuated severity of pain
days with Theta 6 Hz
Acute intervention (single) with

six acoustic stimulation
Improved visuospatial working
Beaucheneet al.,
R+PC,
2016 28 Healthy male and female young
conditions:
adults None,memory
Pure Tone,
performance and
Classical Music, 5cortical
Hz, 10connectivity
Hz
and 15 Hz binaural beats
Acute intervention (single) with

six acoustic stimulation
Improved working memory
Beauchene et al.,
R+PC,
201734 Healthy male and female young
conditions:
adults None, Pure Tone,
performance
Classical Music, 5 Hz, 10 Hz
and 15 Hz binaural beats
Acute intervention (single)

applications of binaural
frequencies of gamma
High frequency binaural beats
Colzato et al., 2017
R+PC+DB, 36Healthy male and female young adults
frequency (40 Hz),improved
for 3 minthe attention
before and during a global-local
task
Lopez-CaballeroR+PC,
and Escera,
40. Healthy male and female young
Beatsadults
of 5 different
Promoted
frequencies
brainwave
(N) frequency
(4.53 Hz - theta -, 8.97 Hz -

alpha-, 17.93 Hz -beta-, 34.49
Hz -gamma -or 57.3 Hz-super-
gamma) binaurally and
201758 entrainment
acoustically for 3 min, preceded
and followed. For periods of
white noise of 90 s (baseline
and post values, respectively)
Applications binaural beats of

Improved working memory
Nantawachara gamma frequency (40 Hz), for
R+PC, 40 Healthy male and female young adults function assessed by the word
Jirakittayakorn, 2017 20 min before and after global-
list retrieval task
local task
6 interventions
Epilepsy in pre-surgical situation
1 time per week, Improved
5 Hz thetalong-term memory in
Chaieb et al., 2015
R + PC; 15
Male and female adults. binaural tones, 6 epileptic
min with patients
3.5 s
and 5 s intervals.
Single progressive intervention

with isochronic tones
Reduced
6 HZ anxiety levels
Chaieb et al., 2017
R+PC; 25 Male and female young adults
theta, 10 HZ alpha,
(modulation
and 40 HZof mental states)
gamma
2 randomized and
counterbalanced Improved
sessions ofmotor and non-motor
sound stimulationsymptoms
(14 Hz including anxiety
Gálvez et al., 2017
R+DB+PC,14 Parkinson’s disease patients
binaural beats) for
symptoms
10 min and cognitive
separated by a minimum
deficits of 7
days of interval
Single intervention of 5 Hz
Improved long-term memory
Garcia-Argibay R+PC,
et al.,2017
32 Healthy male and female adults
theta waves and another group
and attention
with 20 Hz Beta
R: randomized study; DB: double-blinded study; PC: placebo-controlled study.

After the evaluation made by the Jadad scale, the 17 selected studies were classified according to the
methodological criteria adopted in each experiment (Randomized Study (R); Double Blind Study (BD),
Controlled Study with Placebo (PC), type of sample and number of individuals in the study and results
obtained by each researcher. The summary of therapeutic targets and forms of intervention and
approaches of these selected studies are described in Table 2.
Table 2 Summary of therapeutic applications of different brain waves patterns
Type of intervention Method Time Wave frequency range
Acute Theta, alpha, beta, gamma, and super

Isochronic tones 5,10,40 and 80 Hz 15 to 40 min
Single sequential gamma
Acute
Isochronic tones 6,10 and 40 Hz 5 min Alpha, beta, and gamma
Single sequential
Acute
Binaural 5,10 and 15 Hz 5 min Theta, alpha and beta
Single sequential
Acute
Binaural 40 Hz 20 min Gamma
Single sequential
Acute
Binaural 5 and 20 Hz 15 min Theta and beta
Single sequential
Acute
Binaural 10 and 20 Hz 1 min Alpha and beta
Single alternate
Acute
Binaural 7 Hz 9 min Theta
>Single
Acute
Binaural 10 and 40 Hz 3 min Alpha and gamma
Single alternate
Acute
Binaural 40 Hz 10 min Gamma
Single
Acute Theta, alpha, beta, gamma, and super

Binaural 5,10,40 and 80 Hz 15-40 min
Single sequential gamma
Acute
Binaural 4 a 7 Hz 20 min Theta
Single sequential
Chronic
3 repetitions per week for 6 weeks
Chronic
2 daily repetitions for 14 days
Chronic
Binaural 14 Hz 10 min Beta
2 repetitions a day for 7 days
Chronic
Binaural beta - performance range 10 min Beta
3 repetitions per week for 3 weeks
Main findings of the studies addressing the effects of brain waves on mental states
In this section is presented a description of the different brainwaves, their effects, and the discussion of
the main findings obtained in the studies reviewed here. The study performed by Washington and
collaborators21 indicated that each brain wave frequency produces particular neurophysiological and
cognitive effects, been associated with a specific state of consciousness.
Delta waves (< 4 Hertz): the slowest waves are associated with the deepest state of sleep and
unconscious. These waves represent the ideal for sleep, physical and mental recovery, and deep
meditation. Delta waves lead to a state of mental happiness and empathy where the person feels more
connected with her/himself. This state improves intuition and memory. Delta waves are associated with
the release of growth hormone22, which is beneficial for cell regeneration, as well as the production of
endogenous opioids23. None of the selected studies review here used delta waves.
Theta waves (4-8 Hz): this frequency pattern is related to the processes of creativity, enhanced intuition,
more intense emotional connections that elevate sensitivity, and a sense of tranquility and reduced
anxiety. Theta waves also contribute to the improvement of problem-solving skills and retention of much
larger amounts of information in shorter period of time. This pattern is associated with decreased levels of
serum cortisol and with the modulation of serotonin and melatonin. Theta waves generate a relaxed state
of consciousness24,25.
Eight of the studies reviewed here were conducted with Theta waves, with binaural beats as well as
isochronic tones interventions. Major targets were cognitive and/or pathological states. Increased long-
term memory performance was observed in patients with epilepsy who underwent 6-min 5 Hz brain
entrainment sessions, once a week for 6 weeks with binaural and isochronic tones26. On the other hand,
in non-epileptic adult subjects, 15-min 5 Hz brain entrainment sessions did not induce significant effects27.
Visuospatial working memory and cortical connectivity were not altered following a single intervention of 5
min with 5 Hz therapy28. Another study using binaural beats also describes absence of significant effects
in the working memory of healthy young adults29. Interestingly, 20-min 6 Hz binaural beat entrainment
twice a week for 14 days effectively reduced the perception of pain severity16.
In addition, in patients with temporal lobe epilepsy who underwent brain implants with EEG signal control,
acute therapy of temporolateral (5 Hz for 5 min) increased memory acuity with EEG synchronization17.
Moreover, in young adult’s post-physical training, binaural beat entrainment (4-7 Hz for 20 min) increased
parasympathetic activation and self-reported relaxation30. Finally, a single intervention with isochronic
tones at 6, 10 and 40 Hz during 5 min reduced anxiety and improved well-being reports of healthy
individuals31.
Alpha waves (8-13 Hz): this frequency pattern is related to mental relaxation32, visualization, and creative
processes; therapeutically uses include memory optimization, and modulation of pain perception
threshold. The use of this wave pattern in the elderly population has been shown an excellent therapeutic
potential to treat memory disorders33.
Alpha waves were used with a therapeutic and/or neurocognitive focus in six studies reviewed here.
Vernon et al.34 reported that 10 Hz alpha pattern for 1 or 5 min did not elicit significant EEG alteration.
However, isochronic stimulation with 7 Hz for 9 min with 3 min intervals induced temporal and parietal
lobe activation with the potential to alter brain networks in adult’s healthy young individuals35. Alpha
binaural beats for 3 min in healthy young adults did not affect attentional blink (AB) control with the EBR
method (predictor of mood states associated with dopamine levels)36. Moreover, patients with temporal
lobe epilepsy who underwent brain implants, the acute exposure to 10 Hz isochronic tones for 5 min
increased significantly medio temporal synchronization17,30.
Beta waves (13-39 Hz): this frequency pattern is related to attention, focus, concentration, and cognition.
Beta BWE was shown to be effective in improving fatigue and some symptoms of attention deficit
hyperactive disorder (ADHD), including learning and attention deficits. Additional studies showed
improvement in visual acuity, coordination, potential for the dyslexia treatment and low of concentration,
as well as, to promote IQ gain in the range of 8-10 points37. Beta wave entrainment influenced self-
confidence and socialization and makes people more optimistic and energetic38-41. Finally, it helps learning
as well as sports-related abilities3,42.
Five independent studies reviewed here used beta waves. Beauchene et al.28 demonstrated that 15 Hz
beta pattern for 5 min increased short-term visuospatial working memory and cortical connectivity in
healthy young subjects. A single 15-min session of 20 Hz significantly increased long-term memory,
improving the codification of new information without previous memories24. Interestingly, Vernon et
al.34 demonstrated that two daily sessions (14 Hz, during 10 min) increased motor and non-motor
symptoms in Parkinson’s disease (PD) patients. In addition, Gálvez et al.43 showed a decrease of
functional connectivity and optimization of working memory, with no changes in gait or anxiety levels in PD
patients in comparison to control group. Kennel et al.44 submitted a group of children and adolescents with
diagnosis of ADHD to brain entrainment sessions (duration of 10 min, 3 days per week for 3 weeks).
Results were not totally conclusive, although parents reported improvement in the performance of
homework tasks after the interventions.
Gamma Waves (> 40 Hz): this frequency pattern is involved in blinking and processing of information from
all parts of the brain. High gamma wave activity in the brain is associated with intelligence, compassion,
self-control, and feelings of happiness45-48. In addition, gamma brainwaves have been associated with
improved memory and a greater ability of reality perception49,50. Gamma brainwave activity has been
shown to be increased in monks during meditation51.
Six studies were conducted with gamma BWE. It was demonstrated that 40 Hz gamma stimulation for 20
min improved working memory performance and mnemonic function in healthy subjects52. AB control,
using the EBR method (predictor of mood states associated with dopamine levels), was significantly
affected by 3-min binaural gamma stimulation in healthy young adults, before and during a global-local
task36. These benefits were observed only in individuals with low rates of spontaneous blinking, which
indicates low levels of dopamine in the striatum. Colzato et al.53 reported that 3-min 40 Hz binaural beats
stimulation improved focus and attention in healthy young adults. Moreover, a study using 10-min 40 Hz
stimulation in healthy adults54 demonstrated that BWE acts by modeling specific brain oscillations, in
cognitive processes sustained in the gamma wave frequency range, such as mental processes related to
intelligence, self-control, and well-being. In epileptic patients subjected to brain implants, acute isochronic
tones and binaural beats exposure, in the range of 40-80 Hz for 5 min significantly decreased
synchronization in medio-temporal sites, demonstrating their potential as a non-invasive therapy for
modulating intracranial flow in synchronization of the EEG signals17. A single intervention with isochronic
tones 6, 10, and 40 Hz over 5 min reduced anxiety and, consequently, increased the subjects’ well-being,
however, without marked effects on cognition55.
As illustrated in figure 3, in 82.35% of the reviewed studies, monaural, and/or binaural audio stimulation
were more effective in comparison to control group. As previously mentioned, binaural beats were used as
therapeutic modality in 15 studies (88.25%), and isochronic tones were only used in two studies (11.76%).
DISCUSSION
The data reviewed in the present study indicates that binaural beats are more commonly used than
isochronic tones, at least in research (as seen in Fig. 3). Unfortunately, in our view, there is no standard in
the choice of therapy parameters, such as brainwave range (in Hz), treatment duration, frequency, and
regimen, neither for the treatment of specific conditions or disorders, nor for simple increase of executive
brain functions and stimulation of inherent mental processes, and neurocognitive performance. A relevant
observation is the absence of properly controlled double-blinded studies, which compromises the validity
of the results available in the literature. Nevertheless, the results reviewed here suggest that auditory
BWE, although still scarcely explored in behavioral and neurophysiological therapy, may represent an
effective and inexpensive therapeutic approach, with minimal side effects. It is well known that all brain
activity occurs through the bioelectric activity of neural networks and that the brain wave phenomenon is
produced as a result of the sum of bioelectric interactions of the billions of neurons and their trillions of
synaptic connections56. Changes in states of consciousness (concentration, excitement, relaxation, sleep,
dreams, etc.) are closed related to changes in the frequency of the vibratory pattern of brain waves, which
varies according to the intensity of these bioelectric activities.
According to this system and considering that our state of consciousness is influenced by brain wave
patterns, it is plausible to conclude that BWE can modulate many aspects of behavior, from states of
consciousness to perception, learning, and cognition57.
The adaptation to daily activities requires the brain ability to modulate brain wave activity, in consonance
to external stimuli and signals, as well as when faced with challenges and/or problems to be solved. Each
type of brain wave can modulate different neurotransmitter systems, inducing particular synaptic and
neurochemical readjustments12,56.
CONCLUSIONS
Based on the data reviewed in this study, binaural beats and isochronic tones BWE may effectively
modulate mood states, improving attention, and memory processes. Promising results were also obtained
in subjects suffering from different CNS disorders, including ADHD, PD, epilepsy, chronic pain, and
anxiety disorders.
Despite the audio BWE effectiveness described in many studies reviewed here, it is important to
emphasize that some positive outcomes may require further investigation, with more refined and
appropriate evaluation tools, better suited for each specific type of intervention, and/or therapeutic target.
Considering these limitations, the performance of additional studies with more adequate experimental
design and data analysis is recommended, particularly focusing on the neurophysiological and behavioral
effects of brain wave entrainment on mental states.
ACKNOWLEDGMENTS
The authors would like to thank the Experimental Laboratory of Neurodegenerative Diseases - LEXDON,
Federal University of Santa Catarina – UFSC.
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Gamma Waves therapy

Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role

Artemis Traikapi* and Nikos Konstantinou

HASTA AQUÍ 22-03-2023

Can flickering light and sound treat Alzheimer’s?

Revista mexicana de neurociencia

Palhoça, Santa Catarina

Figure 2 Randomization algorithm and study selection.

Method and Sample size Number of interventions and

3 weeks with three

Acute intervention (single):

Single post-workoutIncreased parasympathetic

relaxation after exercise

Acute pre-surgical intervention,

Single 40 Hz gamma binaural

Sequential intervention for 14

Acute intervention (single) with

Acute intervention (single) with

Acute intervention (single)

(4.53 Hz - theta -, 8.97 Hz -

Applications binaural beats of

Single progressive intervention

R: randomized study; DB: double-blinded study; PC: placebo-controlled study.

Acute Theta, alpha, beta, gamma, and super

Acute Theta, alpha, beta, gamma, and super

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