Precise timing of audiovisual stimulation conquers chemobrain

Abstract

In a recent study, Kim et al. employed Gamma entrainment using sensory stimuli (GENUS) to rescue cognitive impairment and glial dysregulation associated with cisplatin and methotrexate chemotherapy, specifically when applied both throughout and after chemotherapy administration. GENUS provides a time-dependent, noninvasive method for treating chemobrain with broader implications for resolving neurodegenerative neuroinflammation.

Advancements in cancer immunotherapies have transformed the landscape of cancer research, yet chemotherapy remains a cornerstone of cancer treatment. A majority of cancer survivors experience chemotherapy-related cognitive impairment (CRCI), a neurological disorder encompassing deficits in memory, executive function, attention, information processing, and multitasking that diminishes quality of life for cancer survivors [1]. There is an urgent need for consensus on treatment strategies for CRCI, yet preclinical research has focused on a multitude of pharmacological interventions. In contrast, nonpharmacological approaches are limited to cognitive training techniques to navigate daily life and physical activity, whose mechanisms of combatting neurological dysfunction remain incompletely understood [2].

GENUS is a novel, noninvasive brain stimulation technique harnessing natural rhythmic oscillations in central nervous system (CNS) electrical activity, specifically those with a frequency of 30-100 Hertz (Hz), known as gamma oscillations. GENUS synchronizes gamma oscillations through application of auditory and/or visual light stimuli at a frequency in the gamma range [3]. Entrainment of gamma oscillations in preclinical models can not only enhance neuronal circuit and cognitive function, but also alter activity in astrocytes (glial regulators of synapses), microglia (brain-resident glial macrophages), and vascular cells in the CNS [4]. In clinical trials, GENUS is well-tolerated and feasible in healthy individuals and patients with Alzheimer’s disease [5]. Given that CRCI and neurodegenerative disorders share neuroinflammation as a common etiology [6], GENUS represents a compelling candidate for treating CRCI.

In their recent publication in Science Translational Medicine, Kim et al. sought to determine whether GENUS could alleviate CRCI cellular and cognitive dysfunction in animal models treated with cisplatin and methotrexate [7]. Authors simultaneously administered chemotherapy and daily 40-Hz GENUS for 1-hour to entrain gamma oscillations; they then continued GENUS post-chemotherapy before assessing short-term, acute CRCI and long-term, chronic CRCI.

Following cisplatin treatment, mice demonstrated decrements in behavioral measures of attention, short-term memory, and executive function, validating the cisplatin-induced CRCI model. Cisplatin-treated animals acutely exhibited CNS structural damage and dysregulation of neuronal and glial cell populations in a brain region-specific manner. Cellular dysregulation was predominantly observed in the hippocampus, a brain structure vital for memory consolidation, and the corpus callosum (CC), a structure connecting the left and right brain hemispheres. The CC has a high density of lipid-rich myelin, which is produced by mature oligodendrocytes that wrap around neuronal axons to promote proper neurotransmission. Structurally, cisplatin treated animals presented with expansion of lateral ventricles and thinner myelin in the CC. At the cellular level, while neurons and neural stem cells (NSCs) displayed DNA damage and dysregulation in the hippocampus, it is neuroinflammatory glia (microglia and astrocytes) and myelin-forming oligodendroglial lineage cells that were most severely impacted by cisplatin (Figure 1).

Figure 1. Gamma entrainment using sensory stimuli (GENUS) rescues cognitive dysfunction and acute cellular dysregulation caused by cisplatin chemotherapy.

Cisplatin impairs short-term memory, attention, and executive function behaviors in mice. With respect to cellular mechanism, cisplatin alters microglia and astrocyte dynamics and induces neuroinflammation. Simultaneously, cisplatin causes DNA damage in and depletes neural stem cells (NSCs) and neurons. Cisplatin also potently disrupts myelin-forming oligodendroglial lineage cells, which includes both oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes that produce the myelin that ensheathes neuronal axons. The dysregulation of oligodendroglial lineage cell dynamics ultimately results in impaired myelination, which can affect proper neurotransmission. Administration of 40-Hz audiovisual stimuli with GENUS during and after chemotherapy normalizes cognitive function in mice and the majority of brain cellular deficits. Figure created using BioRender.com.

Specifically, cisplatin acutely increased microglia and astrocyte number and reactivity in the hippocampus, and this neuroinflammatory microglial response was recapitulated in the CC. Oligodendroglial lineage cells of the CC exposed to cisplatin also had significantly more cell death (Figure 1). Notably, the transcriptome of hippocampal myelin-forming mature oligodendrocytes was the most significantly dysregulated by cisplatin treatment. Collectively, this work reinforces the critical link between chemobrain neurodegenerative pathology and myelin-forming cells.

Remarkably, GENUS administered during and after cisplatin restored myelination, alleviated hippocampal neuronal DNA damage, normalized NSCs, decreased oligodendroglial cell death, and quelled microglial and astrocytic reactivity (Figure 1). GENUS also modulated oligodendrocyte gene expression by upregulating DNA damage repair and anti-inflammatory genes, while downregulating pro-apoptotic genes. Unsurprisingly given its dramatic rescue of broad CNS cellular dysfunction, GENUS also improved attention, short-term memory, and executive function.

A hallmark of CRCI in human cancer survivors is that it can persist months to years after chemotherapy has ended. Authors next asked whether GENUS applied during and after cisplatin chemotherapy could treat chronic CRCI. GENUS successfully rescued persistent microglial dysregulation in the hippocampus and myelin basic protein deficits in the prefrontal cortex that remained months after completion of chemotherapy administration. Long-term impairment of attention, short-term memory, and executive function by cisplatin treatment were again recuperated by GENUS administration, suggesting that GENUS limits the progression of CRCI. Intriguingly, when GENUS was administered only after the completion of cisplatin treatment, it could halt chronic microglial reactivity and rescue executive function but was no longer able to normalize glial cell counts or impaired short-term memory and attention, implicating the importance of GENUS treatment timing.

Finally, Kim and colleagues investigated if GENUS could ameliorate CRCI caused by chemotherapies with different mechanisms of action. To test this, authors applied GENUS treatment during and after the administration of commonly used antimetabolite, methotrexate. As with cisplatin, GENUS could normalize myelin thickness, oligodendrocyte loss, microglial dynamics, and cognition in the acute setting. Moreover, GENUS could also rescue chronic hippocampal microglia and astrocyte reactivity, thereby revealing that the cellular and cognitive benefits of GENUS may be broadly applicable to CRCI.

This elegant work calls to light the challenge of identifying the ideal therapeutic window for GENUS treatment. It remains to be seen whether pre-treatment with GENUS prior to chemotherapy could confer a protective effect against CRCI. As it stands, further studies will be necessary to refine GENUS dosing paradigms.

This work successfully demonstrates that GENUS holds promise for treating CRCI induced by different classes of chemotherapies. Yet, a pivotal remaining question is how GENUS may impact tumor growth, CNS metastases, and the anti-cancer efficacy of chemotherapy given that GENUS is most potent when administered concurrently with cancer treatment. Indeed, neuronal activity has been shown to actively promote glioma growth [8] as well as the progression of small cell lung cancer brain metastases [9], thus limiting the application of GENUS to non-CNS tumors and peripheral tumors without brain tropism. As such, more preclinical studies in animal tumor models will be necessary before GENUS clinical trials can commence in cancer patients.

Nonetheless, the body of work presented by Kim et al. ensconces GENUS as a promising strategy to noninvasively treat CRCI as well as other neuroinflammatory and neurodegenerative disorders. The ability of GENUS to rescue oligodendroglial lineage cell dynamics and myelin thickness suggests that it may effectively treat diseases with pronounced myelin pathologies such as multiple sclerosis. Furthermore, since GENUS can be administered to resolve neuroinflammation, it is an attractive option for treating cognitive impairment with diverse causes such as COVID-19 [10].