Gamma Sensory Flicker for Parkinson's Disease
(Flicker w FOG Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Emory University
Must be taking: Levodopa
Disqualifiers: Atypical parkinsonism, Dementia, Major depression, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study aims to answer the question: to assess the safety, and tolerability of gamma light in Parkinson's disease (PD) patients with freezing of gait (FOG).
Parkinson's disease (PD) patients often experience a complex gait disorder known as Freezing of Gait (FOG). FOG is characterized by brief arrests of stepping when initiating gait, turning, and walking straight and patients describe it as their feet being "glued" to the floor. FOG in Parkinson's disease (PD) is a considerable public health burden worldwide. It is a poorly understood gait symptom that has potentially grave consequences as FOG is intermittent and unpredictable, a leading cause of falls with injury, and results in loss of independence. FOG is generally found to be associated with cognitive decline, particularly executive dysfunction which, in turn, has been associated with higher spinal fluid amyloid (Aβ42) levels in PD.
There is data linking amyloid to FOG. A previous study showed that the gamma light helped reduce some amyloid. The research team is studying if gamma light exposure for 1 hour daily is well tolerated. Also, does it have any effect on freezing of gait severity?
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it requires participants to manage 12 hours without dopaminergic medication. This suggests you may need to adjust your medication schedule during the study.
What data supports the effectiveness of the Gamma Sensory Flicker treatment for Parkinson's Disease?
Research shows that 40 Hz sensory stimulation, similar to Gamma Sensory Flicker, has been effective in reducing symptoms in Parkinson's disease mice and improving sleep and daily activities in Alzheimer's patients. This suggests potential benefits for Parkinson's patients as well.
12345Is 40 Hz sensory stimulation safe for humans?
Research shows that 40 Hz sensory stimulation, used in studies for Alzheimer's and Parkinson's diseases, is generally safe for humans. In Alzheimer's patients, it was well tolerated over six months, and in Parkinson's disease models, it showed potential benefits without significant adverse effects.
34678How is the Gamma Sensory Flicker treatment different from other treatments for Parkinson's disease?
Gamma Sensory Flicker is unique because it uses non-invasive light and sound at a specific frequency (40 Hz) to potentially reduce harmful protein buildup in the brain and improve symptoms in Parkinson's disease, unlike traditional treatments that often focus on medication to manage symptoms.
346910Eligibility Criteria
This trial is for Parkinson's disease patients who experience freezing of gait (FOG), a condition where they feel their feet are 'glued' to the floor. Participants should have cognitive function good enough to follow study procedures and provide consent.Inclusion Criteria
My Parkinson's responds to levodopa treatment.
I can go 12 hours without my Parkinson's medication.
PD Diagnosis by UK Brain Bank Criteria
+5 more
Exclusion Criteria
Dementia precluding completing study protocol including those meeting criteria for dementia with Lewy bodies
I have been diagnosed with major depression.
I do not have migraines, tinnitus, or seizures that could worsen with sensory stimuli.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive gamma light exposure for 1 hour daily to assess safety and tolerability
7 months
Monthly check-ins every 2 weeks (virtual or in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Open-label extension (optional)
Participants may opt into a one-year extension of the study with additional visits at month 12 and month 18
12 months
2 visits (in-person)
Participant Groups
The study tests special eyewear and earphones that emit gamma flicker stimuli, used for one hour daily. It aims to see if this non-drug approach can reduce FOG by affecting amyloid levels in spinal fluid, which are high in such patients.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Flicker Exposure (Treatment Group)Experimental Treatment1 Intervention
Participants will be instructed to take home the stimulation equipment. Participants and their study partners (if applicable) will be trained on how to use the device before leaving the facility. Each device case also includes an instruction document. Participants and/or study partners (if applicable) will keep a manual log of daily operation, including the time of day used, whether the participant felt drowsy or, was able to complete the entire session, or if the participant was unable to complete the therapy that day. Finally, study staff will contact participants monthly every 2 weeks to ensure compliance, assess adverse events, and log concomitant medications.
Group II: Control GroupPlacebo Group1 Intervention
Participants will receive sham stimulation. Participants and/or study partners (if applicable) will keep a manual log of daily operation, including the time of day used, whether the participant felt drowsy or, was able to complete the entire session, or if the participant was unable to complete the therapy that day. Finally, study staff will contact participants monthly every 2 weeks to ensure compliance, assess adverse events, and log concomitant medications.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Emory Movement Disorders CenterAtlanta, GA
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Who Is Running the Clinical Trial?
Emory UniversityLead Sponsor
Parkinson's FoundationCollaborator
References
Clinical outcome of deep brain stimulation for Parkinson's disease. [2022]Deep brain stimulation is one of the most effective treatments of Parkinson's disease (PD). This report summarizes the state of the art as at January 2013. Stimulation of the subthalamic nucleus is the most commonly used approach. It improves the core motor symptoms better than medication in patients with advanced disease. It also improves the majority of nonmotor symptoms, such as mood, impulse control disorders, sleep, and some autonomic dysfunctions. Quality of life (QoL) is improved significantly more than with medication. Long-term data show that the treatment is effective for up to 10 years, but the late appearance of l-dopa-resistant symptoms is seemingly not influenced. Internal globus pallidus (GPi) stimulation is less well studied but seems to have similar short-term efficacy. Importantly l-dopa use cannot be reduced with GPi DBS, which is a major disadvantage for patients suffering from medication side-effects, although gait may be influenced more positively. Although short-term QoL improvement seems to be similar to that for subthalamic nucleus (STN) DBS - gait and speech may be better improved - long-term data are rare for GPi DBS. Thalamic stimulation in the ventral intermediate nucleus (VIM) is applied only in tremor-dominant elderly patients. The treatment improves the dopa-sensitive symptoms and effectively reduces fluctuations leading to an overall QoL improvement. Although most of the controlled studies have been on advanced PD, the recently published EARLYSTIM study suggests that even patients with a very short duration of their fluctuations and dyskinesia are doing significantly better with neurostimulation in terms of QoL and all major motor outcome parameters.
A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson's disease. [2022]For the past 40 years the primary purpose of therapeutics for Parkinson's disease (PD) has been to replace deficient dopamine (DA) in the nigrostriatal dopamine (NSD) system. Even in the presence of limited efficacy, abundant side effects and impoverished quality of life, the involvement of other systems in the aetiology and treatment of this disorder has been sorely neglected and the excessive use of DA replacement therapy (DART) continues on a global basis. Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. After a thorough review of historical evidence supporting this contention, a retrospective, open-label study on 129 PD patients, whereby they were monitored for a period extending for a few months to eight years, was carried out. Primary motor and non-motor symptoms were monitored using an objectified global rating scale and timed motor tests that were assessed at regular intervals for the duration of the study. Thirty-one patients with other neurological disorders (OND) served as controls to determine whether any therapeutic effects seen with light were generalizable across other conditions. Patients were classified as compliant (COM), semi-compliant (SCOM), or early quit (EQUIT; prematurely discontinued treatment). EQUIT patients showed deterioration, while the COM group improved on most parameters. The SCOM patients were not as good as the COM group. The OND group showed significant improvement in depression and insomnia, but exposure to light did not improve motor function. The total drug burden of PD patients maintained on light was less with fewer side effects than SCOM or EQUIT groups. These results confirm the value of the strategic application of light therapy with controlled doses of DART in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD.
Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice. [2023]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.
Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients. [2021]Pathological proteins contributing to Alzheimer's disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT03556280.
Light Modulation of Brain and Development of Relevant Equipment. [2021]Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used to dissect neural circuits in animal models of Alzheimer's disease, Parkinson's disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future.
40 Hz Light Flicker Alters Human Brain Electroencephalography Microstates and Complexity Implicated in Brain Diseases. [2021]Previous studies showed that entrainment of light flicker at low gamma frequencies provided neuroprotection in mouse models of Alzheimer's disease (AD) and stroke. The current study was set to explore the feasibility of using 40 Hz light flicker for human brain stimulation for future development as a tool for brain disease treatment. The effect of 40 Hz low gamma frequency light on a cohort of healthy human brains was examined using 64 channel electroencephalography (EEG), followed by microstate analyses. A random frequency light flicker was used as a negative control treatment. Light flicker at 40 Hz significantly increased the corresponding band power in the O1, Oz, and O3 electrodes covering the occipital areas of both sides of the brain, indicating potent entrainment with 40 Hz light flicker in the visual cortex area. Importantly, the 40 Hz light flicker significantly altered microstate coverage, transition duration, and the Lempel-Ziv complexity (LZC) compared to the rest state. Microstate metrics are known to change in the brains of Alzheimer's disease, schizophrenia, and stroke patients. The current study laid the foundation for the future development of 40 Hz light flicker as therapeutics for brain diseases.
Optimal flickering light stimulation for entraining gamma rhythms in older adults. [2022]With aging, optimal parameters of flickering light stimulation (FLS) for gamma entrainment may change in the eyes and brain. We investigated the optimal FLS parameters for gamma entrainment in 35 cognitively normal old adults by comparing event-related synchronization (ERS) and spectral Granger causality (sGC) of entrained gamma rhythms between different luminance intensities, colors, and flickering frequencies of FLSs. ERS entrained by 700 cd/m2 FLS and 32 Hz or 34 Hz FLSs was stronger than that entrained by 400 cd/m2 at Pz (p < 0.01) and 38 Hz or 40 Hz FLSs, respectively, at both Pz (p < 0.05) and Fz (p < 0.01). Parieto-occipital-to-frontotemporal connectivities of gamma rhythm entrained by 700 cd/m2 FLS and 32 Hz or 34 Hz FLSs were also stronger than those entrained by 400 cd/m2 at Pz (p < 0.01) and 38 Hz or 40 Hz FLSs, respectively (p < 0.001). ERS and parieto-occipital-to-frontotemporal connectivities of entrained gamma rhythms did not show significant difference between white and red lights. Adverse effects were comparable between different parameters. In older adults, 700 cd/m2 FLS at 32 Hz or 34 Hz can entrain a strong gamma rhythm in the whole brain with tolerable adverse effects.
Bright light therapy with a head-mounted device for anxiety, depression, sleepiness and fatigue in patients with Parkinson's disease. [2020]The beneficial effects of bright light therapy (BLT) on the disabling non-motor symptoms of Parkinson's disease (PD) remain uncertain. The objective of this study was to investigate if daily BLT, with a head-mounted device (Luminette®), has a beneficial effect on depression, anxiety, daytime sleepiness and fatigue in patients with PD. In this double-blind, placebo-controlled study, 16 patients with PD were randomized to receive either 1 month of BLT or 1 month of placebo therapy, separated by a 2-week washout period, in a crossover fashion. Patients completed questionnaires for the Hospital Anxiety and Depression Scale (HADS), the Epworth Sleepiness Scale (ESS) and the Fatigue Impact Scale (FIS) before and after each treatment period. The primary outcome measures were changed from baseline in scores between treatment groups. No significant changes were observed in the HADS anxiety scores and FIS scores after BLT and after placebo. The ESS scores decreased non-significantly only after BLT. A post hoc analysis of patients who had baseline ESS scores > 11 revealed a significantly greater decrease in ESS scores after BLT than after placebo. Future studies investigating the effect of BLT on sleepiness could focus specifically on patients with high ESS scores.
'Gamma' band oscillatory response to chromatic stimuli in volunteers and patients with idiopathic Parkinson's disease. [2021]The signal structure of the responses to equiluminant chromatic and achromatic (contrast) stimuli was studied in normal volunteers and patients with mild to moderate idiopathic Parkinson's disease. Visual stimuli were full-field (14 x 16 deg) achromatic or equiluminant (red-green or blue-yellow) sinusoidal gratings at 2c/deg and 90% contrast presented in onset-offset mode. The signal was processed offline by DFT and factor analysis was performed in the frequency domain. The conventional VEPs to chromatic onset stimuli showed a monophasic negative wave, while the response to offset stimuli was comparable in shape to the on-/offset achromatic responses; latencies were longer and amplitudes higher than those of responses to contrast stimulation. In patients, latencies were longer than in controls after achromatic and (to a lesser extent) red-green stimulations, but not after blue-yellow stimulation; amplitudes were comparable in all stimulus conditions. In healthy subjects, two non-overlapping factors accounted for the approximately 2-30.0 Hz and approximately 25.0-50.0 Hz signal components (representative of the low-frequency VEP and gamma oscillatory responses, respectively); the frequency of the approximately 25.0-50.0 Hz factor was lower after color than after contrast stimulation. The same factor structure was identified in patients, but the peak frequency of the factor on gamma activity was higher than in controls and did not vary with color-opponent stimulation. These observations indicate that stimulus-related gamma activity originates in cortex irrespective of the activated (magno-, parvo-, or konio-cellular) visual pathway, consistent with the suggested role in the phase coding of neuronal activities. Some dopaminergic modulation of gamma activity is conceivable.
Phase-adaptive brain stimulation of striatal D1 medium spiny neurons in dopamine-depleted mice. [2023]Brain rhythms are strongly linked with behavior, and abnormal rhythms can signify pathophysiology. For instance, the basal ganglia exhibit a wide range of low-frequency oscillations during movement, but pathological "beta" rhythms at ~ 20 Hz have been observed in Parkinson's disease (PD) and in PD animal models. All brain rhythms have a frequency, which describes how often they oscillate, and a phase, which describes the precise time that peaks and troughs of brain rhythms occur. Although frequency has been extensively studied, the relevance of phase is unknown, in part because it is difficult to causally manipulate the instantaneous phase of ongoing brain rhythms. Here, we developed a phase-adaptive, real-time, closed-loop algorithm to deliver optogenetic stimulation at a specific phase with millisecond latency. We combined this Phase-Adaptive Brain STimulation (PABST) approach with cell-type-specific optogenetic methods to stimulate basal ganglia networks in dopamine-depleted mice that model motor aspects of human PD. We focused on striatal medium spiny neurons expressing D1-type dopamine receptors because these neurons can facilitate movement. We report three main results. First, we found that our approach delivered PABST within system latencies of 13 ms. Second, we report that closed-loop stimulation powerfully influenced the spike-field coherence of local brain rhythms within the dorsal striatum. Finally, we found that both 4 Hz PABST and 20 Hz PABST improved movement speed, but we found differences between phase only with 4 Hz PABST. These data provide causal evidence that phase is relevant for brain stimulation, which will allow for more precise, targeted, and individualized brain stimulation. Our findings are applicable to a broad range of preclinical brain stimulation approaches and could also inform circuit-specific neuromodulation treatments for human brain disease.