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Science of Gamma Entrainment
Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities
Adaikkan, Chinnakkaruppan et al.
Trends in Neurosciences, Volume 43, Issue 1, 24 - 41
Abstract
Studies have shown that gamma oscillations (30–100 Hz) are relevant for neurocircuit function, behavior, and memory. To examine a possible causal contribution of gamma oscillations to cognitive function, recent studies have employed various types of brain stimulation to induce gamma oscillations. Techniques such as optogenetics or sensory stimulation appear to engage canonical neurocircuits that encompass excitatory and inhibitory interneurons, similarly to those driven by sensory experience, to induce gamma entrainment. Sensory evoked gamma entrainment improves cognitive function in mouse models. Oscillations have traditionally been studied at the neurophysiological level; however, sensory evoked gamma entrainment is able to induce gene expression changes in multiple cell types including neurons and microglia. Furthermore, evidence suggests that chronic gamma entrainment offers neuroprotective effects.
Iaccarino, H., Singer, A., Martorell, A. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).
Abstract
Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology.
Lahijanian, M., Aghajan, H., & Vahabi, Z. (2024). Auditory gamma-band entrainment enhances default mode network connectivity in dementia patients. Scientific reports, 14(1), 13153. https://doi.org/10.1038/s41598-024-63727-z
Abstract
Dementia, and in particular Alzheimer’s disease (AD), can be characterized by disrupted functional connectivity in the brain caused by beta-amyloid deposition in neural links. Non-pharmaceutical treatments for dementia have recently explored interventions involving the stimulation of neuronal populations in the gamma band. These interventions aim to restore brain network functionality by synchronizing rhythmic energy through various stimulation modalities. Entrainment, a newly proposed non-invasive sensory stimulation method, has shown promise in improving cognitive functions in dementia patients. This study investigates the effectiveness of entrainment in terms of promoting neural synchrony and spatial connectivity across the cortex. EEG signals were recorded during a 40 Hz auditory entrainment session conducted with a group of elderly participants with dementia. Phase locking value (PLV) between different intraregional and interregional sites was examined as an attribute of network synchronization, and connectivity of local and distant links were compared during the stimulation and rest trials. Our findings demonstrate enhanced neural synchrony between the frontal and parietal regions, which are key components of the brain’s default mode network (DMN). The DMN operation is known to be impacted by dementia’s progression, leading to reduced functional connectivity across the parieto-frontal pathways. Notably, entrainment alone significantly improves synchrony between these DMN components, suggesting its potential for restoring functional connectivity.
Wang, C., Lin, C., Zhao, Y., Samantzis, M., Sedlak, P., Sah, P., & Balbi, M. (2023). 40-Hz optogenetic stimulation rescues functional synaptic plasticity after stroke. Cell reports, 42(12), 113475. https://doi.org/10.1016/j.celrep.2023.113475
Abstract
Evoked brain oscillations in the gamma range have been shown to assist in stroke recovery. However, the causal relationship between evoked oscillations and neuroprotection is not well understood. We have used optogenetic stimulation to investigate how evoked gamma oscillations modulate cortical dynamics in the acute phase after stroke. Our results reveal that stimulation at 40 Hz drives activity in interneurons at the stimulation frequency and phase-locked activity in principal neurons at a lower frequency, leading to increased cross-frequency coupling. In addition, 40-Hz stimulation after stroke enhances interregional communication. These effects are observed up to 24 h after stimulation. Our stimulation protocol also rescues functional synaptic plasticity 24 h after stroke and leads to an upregulation of plasticity genes and a downregulation of cell death genes. Together these results suggest that restoration of cortical dynamics may confer neuroprotection after stroke.
Fu, W., Yu, X., Lai, M., Li, Y., Yang, Y., Qin, Y., ... & Wang, C. (2024). Gamma oscillations induced by 40-Hz visual-auditory stimulation for the treatment of acute-phase limb motor rehabilitation after stroke: study protocol for a prospective randomized controlled trial. Trials, 25(1), 284.
Abstract
Background
The incidence of hemiparetic limb dysfunction reaches 85% in stroke patients, emerging as a critical factor influencing their daily lives. However, the effectiveness of current rehabilitation treatments is considerably limited, particularly in patients with upper extremity impairment. This study aims to conduct a prospective clinical trial to validate the safety and effectiveness of gamma oscillations induced by 40-Hz visual-auditory stimulation in treating post-stroke upper limb dysfunction and to explore the relevant mechanisms.
Methods
This trial is a prospective, randomized controlled, double-blind study. All enrolled patients were randomly assigned to two groups. The experimental group received intervention through 40-Hz visual-auditory stimulation, while the control group underwent intervention with randomly matched visual-auditory stimulation frequencies. The primary efficacy endpoint is the change in motor function. Secondary efficacy endpoints include motor-evoked potentials, cerebral hemodynamic changes, neural network connectivity, and alterations in synaptic-related genes. Safety evaluation included major adverse events, all-cause mortality, and photosensitive epilepsy. Assessments will be conducted at baseline, after a 14-day treatment period, and during subsequent follow-up visits (at 3 and 6 months) post-treatment. The differences between the two groups will be compared.
Yang, X., Li, X., Yuan, Y., Sun, T., Yang, J., Deng, B., Yu, H., Gao, A., & Guan, J. (2022). 40 Hz Blue LED Relieves the Gamma Oscillations Changes Caused by Traumatic Brain Injury in Rat. Frontiers in neurology, 13, 882991. https://doi.org/10.3389/fneur.2022.882991
Abstract
Background
Photobiomodulation (PBM) using low-level light-emitting diodes (LEDs) can be rapidly applied to various neurological disorders safely and non-invasively.
Materials and Methods
Forty-eight rats were involved in this study. The traumatic brain injury (TBI) model of rat was set up by a controlled cortical impact (CCI) injury. An 8-channel cortex electrode EEG was fixed to two hemispheres, and gamma oscillations were extracted according to each electrode. A 40 hz blue LED stimulation was set at four points of the frontal and parietal regions for 60 s each, six times per day for 1 week. Modified Neurologic Severity Scores (mNSS) were used to evaluate the level of neurological function.
Results
In the right-side TBI model, the gamma oscillation decreased in electrodes Fp2, T4, C4, and O2; but significantly increased after 1 week of 40 hz Blue LED intervention. In the left-side TBI model, the gamma oscillation decreased in electrodes Fp1, T3, C3, and O1; and similarly increased after 1 week of 40 hz Blue LED intervention. Both left and right side TBI rats performed significantly better in mNSS after 40 hz Blue LED intervention.
Conclusion
TBI causes the decrease of gamma oscillations on the injured side of the brain of rats. The 40 hz Blue LED therapy could relieve the gamma oscillation changes caused by TBI and improve the prognosis of TBI.
Liu Y, Liu H, Lu Y, et al. Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice. Exp Neurol. 2023;364:114396. doi:10.1016/j.expneurol.2023.114396
Abstract
Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein (α-Syn) aggregates, but lacks effective treatments for the disease progression and non-motor symptoms. Recently, combined 40 Hz auditory and visual stimulation is emerging as a promising non-invasive method to decrease amyloid and improve cognition in Alzheimer's disease (AD), but whether this treatment can modify α-Syn-induced PD pathology remains unclear. Here we evaluated the effects of chronic exposure to 40 Hz and 80 Hz auditory and visual stimulation on α-Syn accumulation and the functional effects of 40 Hz stimulation on motor, cognitive and mood dysfunctions in PD mice. We found that 40 Hz and 80 Hz auditory and visual stimulation activated multiple cortical regions, entrained gamma oscillations and markedly attenuated p-α-Syn deposition in neurons, but not astrocytes, microglial cells in the primary and secondary motor cortex (M1, M2), medial prefrontal cortex (mPFC) and the striatum. Moreover, 40 Hz stimulation significantly reduced cell apoptosis in M1, increased the neuromuscular strength selectively in PD mice, which correlated with p-α-Syn reduction in the motor cortex. In addition, 40 Hz stimulation improved spatial working memory and decreased depressive-like behaviors specifically in PD mice, which correlated with p-α-Syn reduction in mPFC, but promoted anxiety-like behaviors and increased stress-related adreno-cortico-tropic-hormone (ACTH), corticosterone levels in the plasma of normal mice. Collectively, we demonstrated that chronic multisensory gamma stimulation (40 Hz and 80 Hz) significantly attenuates α-Syn deposition in neurons of the interconnected cortex and 40 Hz stimulation improved neuromuscular strength, spatial working memory, and reduced depressive behaviors, which support its non-invasive therapeutic potential for modifying PD progression and treating non-motor symptoms.
Suk, H. J., Buie, N., Xu, G., Banerjee, A., Boyden, E. S., & Tsai, L. H. (2023). Vibrotactile stimulation at gamma frequency mitigates pathology related to neurodegeneration and improves motor function. Frontiers in Aging Neuroscience, 15, 1129510.
Abstract
The risk for neurodegenerative diseases increases with aging, with various pathological conditions and functional deficits accompanying these diseases. We have previously demonstrated that non-invasive visual stimulation using 40 Hz light flicker ameliorated pathology and modified cognitive function in mouse models of neurodegeneration, but whether 40 Hz stimulation using another sensory modality can impact neurodegeneration and motor function has not been studied. Here, we show that whole-body vibrotactile stimulation at 40 Hz leads to increased neural activity in the primary somatosensory cortex (SSp) and primary motor cortex (MOp). In two different mouse models of neurodegeneration, Tau P301S and CK-p25 mice, daily exposure to 40 Hz vibrotactile stimulation across multiple weeks also led to decreased brain pathology in SSp and MOp. Furthermore, both Tau P301S and CK-p25 mice showed improved motor performance after multiple weeks of daily 40 Hz vibrotactile stimulation. Vibrotactile stimulation at 40 Hz may thus be considered as a promising therapeutic strategy for neurodegenerative diseases with motor deficits.
Barzegar Behrooz, A., Aghanoori, MR., Nazari, M. et al. 40 Hz light preserves synaptic plasticity and mitochondrial function in Alzheimer’s disease model. Sci Rep 14, 26949 (2024). https://doi.org/10.1038/s41598-024-78528-7
Abstract
Alzheimer’s disease (AD) is the most prevalent type of dementia. Its causes are not fully understood, but it is now known that factors like mitochondrial dysfunction, oxidative stress, and compromised ion channels contribute to its onset and progression. Flickering light therapy has shown promise in AD treatment, though its mechanisms remain unclear. In this study, we used a rat model of streptozotocin (STZ)-induced AD to evaluate the effects of 40 Hz flickering light therapy. Rats received intracerebroventricular (ICV) STZ injections, and 7 days after, they were exposed to 40 Hz flickering light for 15 min daily over seven days. Cognitive and memory functions were assessed using Morris water maze, novel object recognition, and passive avoidance tests. STZ-induced AD rats exhibited cognitive decline, elevated reactive oxygen species, amyloid beta accumulation, decreased serotonin and dopamine levels, and impaired mitochondrial function. However, light therapy prevented these effects, preserving cognitive function and synaptic plasticity. Additionally, flickering light restored mitochondrial metabolites and normalized ATP-insensitive mitochondrial calcium-sensitive potassium (mitoBKCa) channel activity, which was otherwise downregulated in AD rats. Our findings suggest that 40 Hz flickering light therapy could be a promising treatment for neurodegenerative disorders like AD by preserving synaptic and mitochondrial function.
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