Summary: Transcorneal electrical stimulation (TES) provided antidepressant effects and reduced stress hormones in mouse models. Additionally, TES induced the expression of genes associated with the development and growth of hippocampal neurons. When tested in models of Alzheimer’s, TES improved memory and reduced amyloid beta deposits in the hippocampus of the animals.
Source: University of Hong Kong
A joint research team from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) and City University of Hong Kong (CityU) has discovered that the electrical stimulation of the eye surface can alleviate depression-like symptoms and improve cognitive function in animal models.
These significant findings were recently published in Brain Stimulation and the Annals of the New York Academy of Sciences.
Major depression is the most common and severe psychiatric disorder across the world. Recently, the World Health Organization reported that the COVID-19 pandemic had triggered a massive increase in the number of people with anxiety and depression. About a quarter of patients do not respond adequately to the treatments available.
Dr. Lim Lee Wei, Assistant Professor in the School of Biomedical Sciences, HKUMed, and a former Lee Kuan Yew Research Fellow in Singapore, reported in 2015 that deep brain stimulation of the prefrontal cortex in the brains of animals could improve memory function and relieve depressive symptoms. These therapeutic effects were attributed to the growth of brain cells in the hippocampus, a region of the brain known to be involved in learning and memory function.
However, this technique, also known as deep brain stimulation, is invasive and requires surgery to implant electrodes in the brain, which may cause side effects such as infections and other post-operative complications.
A team of Hong Kong researchers headed by Dr. Lim Lee Wei; Dr. Leanne Chan Lai-hang, Associate Professor in the Department of Electrical Engineering, CityU; Professor Chan Ying-shing, Dexter H C Man Family Professor in Medical Science, Professor of the School of Biomedical Sciences, Associate Dean (Development and Infrastructure), HKUMed, and Director of the Neuroscience Research Centre, HKU, has been looking for alternative ways to treat neuropsychiatric diseases.
They discovered that the non-invasive stimulation of the corneal surface of the eye (known as transcorneal electrical stimulation, or TES), which activates brain pathways, resulted in remarkable antidepressant-like effects and reduced stress hormones in an animal model for depression.
Furthermore, this technique induced the expression of genes involved in the development and growth of brain cells in the hippocampus.
In related experiments, Yu Wing-shan, a PhD student, and other research members from the School of Biomedical Sciences at HKUMed investigated whether this approach could be used to treat Alzheimer’s disease, a common type of dementia with no definitive cure.
They found that this non-invasive stimulation in mice drastically improved memory performance and reduced beta-amyloid deposits in the hippocampus, which is one of the hallmarks of Alzheimer’s disease.
Dr. Leanne Chan Lai-hang, an expert on the electrical stimulation of visual and non-visual brain targets, said of this research, “Transcorneal electrical stimulation is a non-invasive method initially developed to treat eye diseases, and it would be a major scientific breakthrough if it could be applied to treat neuropsychiatric diseases.”
“These research findings pave the way for new therapeutic opportunities to develop novel treatment for patients suffering from treatment-resistant depression and dementia. Nevertheless, clinical trials must be conducted to validate the efficacy and safety,” remarked Professor Chan Ying-shing.
Antidepressant-like effects of transcorneal electrical stimulation in rat models
Given that visual impairment is bi-directionally associated with depression, we examined whether transcorneal electrical stimulation (TES), a non-invasive treatment for visual disorders, can ameliorate depressive symptoms.
The putative antidepressant-like effects of TES and the underlying mechanisms were investigated in an S334ter-line-3 rat model of retinal degeneration and a rat model of chronic unpredictable stress (CUS).
TES was administered daily for 1 week in S334ter-line-3 and CUS rats. The effects of TES on behavioral parameters, plasma corticosterone levels, and different aspects of neuroplasticity, including neurogenesis, synaptic plasticity, and apoptosis, were examined.
In S334ter-line-3 rats, TES induced anxiolytic and antidepressant-like behaviors in the cylinder, open field, home cage emergence, and forced swim tests. In the CUS rat model, TES induced hedonic-like behavior and decreased behavioral despair, which were accompanied by reduced plasma corticosterone levels and upregulated expression of neurogenesis-related genes. Treatment with the neurogenesis blocker temozolomide only inhibited the hedonic-like effect of TES, suggesting the antidepressant-like effects of TES were mediated through both neurogenesis-dependent and -independent mechanisms. Furthermore, TES was found to normalize the protein expression of synaptic markers and apoptotic Bcl-2-associated X protein in the hippocampus and amygdala in the CUS rat model. The improvements in neuroplasticity may involve protein kinase B (AKT) and protein kinase A (PKA) signaling pathways in the hippocampus and amygdala, respectively, as demonstrated by the altered pAKT/AKT and pPKA/PKA ratios.
The overall findings suggest a possible neuroplasticity mechanism of the antidepressant-like effects of TES.
Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models
Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer’s disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippocampal-dependent learning and memory.
Immunostaining of the hippocampus of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology.
The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism.
Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.