An EEG in Time Saves Nine: Predicting Cognitive Decline in Epilepsy

Abstract

Anterior Prefrontal EEG Theta Activities Indicate Memory and Executive Functions in Patients With Epilepsy

Hamedi N, García-Salinas JS, Berry BM, Worrell GA, Kucewicz MT. Epilepsia. 2025 Jan 6. doi: 10.1111/epi.18246. Epub ahead of print. PMID: 39760669.

Objective: Cognitive deficits are one of the most debilitating comorbidities in epilepsy and other neurodegenerative, neuropsychiatric, and neurodevelopmental brain disorders. Current diagnostic and therapeutic options are limited and lack objective measures of the underlying neural activities. In this study, electrophysiological biomarkers that reflect cognitive functions in clinically validated batteries were determined to aid diagnosis and treatment in specific brain regions. Methods: We employed the Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks to probe memory and executive functions in 86 patients with epilepsy undergoing clinical electroencephalography (EEG) monitoring. EEG electrode signals during performance of particular battery tasks were decomposed to identify specific frequency bands and cortical areas that differentiated patients with impaired, normal, and good standardized performance according to their age and gender. Results: The anterior prefrontal cortical EEG power in the theta frequency band was consistently lower in patients with impaired memory and executive function performance (z-score < −1). This effect was evident in all four behavioral measures of executive, visual, spatial, and working memory functions and was confined to the cortical area of all four frontal pole electrodes (Nz, Fpz, Fp1, and Fp2). Significance: Theta EEG power in the anterior prefrontal cortex provides a simple, accessible, and objective electrophysiological measure of memory and executive functions in epilepsy. Our results suggest a feasible clinical biomarker for diagnosis, monitoring, and treatment of cognitive deficits with emerging targeted neuromodulation approaches.

Commentary

Cognitive deficits, particularly in memory and executive function, are among the most prevalent comorbidities in persons with epilepsy (PWE).^1,2 Despite their pervasive impact, identifying reliable biomarkers to assess and mitigate these impairments remains a formidable challenge. Cognitive dysfunction in PWE substantially diminishes the quality of life, ¹ yet standard clinical assessments often fail to provide objective and scalable measures of neural activity associated with these deficits. The study by Hamedi et al ³ endeavors to bridge this gap by investigating the electrophysiological biomarkers of cognition in PWE, with the overarching aim of refining diagnostic and therapeutic strategies for cognitive impairment.

A pivotal strength of the study lies in its methodological rigor. The authors employed the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess memory and executive functions in 86 PWE undergoing electroencephalography (EEG) monitoring. Participants were classified as good, normal, or poor performers based on their cognitive performance. Strikingly, one-third exhibited memory impairment, while one-fifth demonstrated deficits in executive function. By converting EEG signals into frequency bands, the researchers uncovered a robust correlation between diminished anterior prefrontal theta power and poorer cognitive performance. These findings resonate with prior research underscoring the crucial role of theta oscillations in working memory and executive function. ⁴ Notably, while previous studies have alluded to theta activity as a diagnostic marker of cognitive decline in PWE, they often lacked the rigor of clinically validated cognitive battery testing. ⁵ The inclusion of standardized neuropsychological assessments in the present study enhances the translational relevance of its findings, providing a robust framework for future clinical applications.

One of the most compelling revelations of this study was the consistent reduction in theta power among patients with impaired cognition, a trend observed across all four behavioral measures: visual memory, spatial memory, working memory, and executive function. ³ Intriguingly, this effect was confined to the anterior prefrontal cortex, particularly the frontal pole, ³ reinforcing its putative role as a hub for cognitive processing. This discovery fuels fascinating inquiries: Are these oscillations merely reflective of cognitive dysfunction, or do they constitute a modifiable target for intervention? If prefrontal theta activity is indeed a reliable diagnostic marker of cognitive function, could interventions aimed at enhancing theta power ameliorate cognitive decline in epilepsy?

This latter proportion is particularly tantalizing in light of emerging evidence that neurofeedback, direct brain stimulation, and transcranial magnetic stimulation can bolster theta activity and improve cognitive function.^6,7 These interventions harbor immense potential for preserving or even restoring cognitive function in PWE. Future clinical trials exploring the efficacy of such modalities could pave the way for novel therapeutic strategies targeting cognitive impairment in PWE.

Further reinforcing the study's significance, correlation analysis revealed a strong correlation between various memory and executive function tasks. These findings suggest that while distinct brain regions contribute to specific cognitive processes, these processes are likely intertwined within a broader neural network. This aligns with the existing literature positing that cognition is not confined to isolated regions but rather emerges from an intricate web of neural connections. ⁸ Identifying a central hub orchestrating these functions could hold profound therapeutic implications. Based on the study's findings, the frontal pole emerged as a pivotal region, likely coordinating cognitive tasks across domains. While different networks underpin various cognitive abilities, an overarching system may coordinate and harmonize these processes, with prefrontal theta oscillations likely playing a crucial role. Consequently, prefrontal theta may not only serve as a diagnostic biomarker but also as a viable target for neuromodulation.

Another key strength of the study is its nuanced distinction between spectral power alterations across different frequency bands and cortical regions. While prior research has implicated both theta and gamma oscillations in memory and executive function, ⁹ Hamedi et al ³ provided gripping evidence that anterior prefrontal theta activity exhibited the most consistent association with cognitive performance. Additionally, the study underscored the significance of occipital gamma activity in visual processing, with elevated gamma power correlating with better performance in visual memory-related tasks. This dual finding highlights the necessity of analyzing spectral power across multiple frequency bands and cortical regions, fostering a richer understanding of how neural oscillations underpin cognitive function.

The implications of these findings likely extend well beyond epilepsy. Theta oscillations have been implicated in a spectrum of neurocognitive disorders, including Alzheimer's disease and attention-deficit/hyperactivity disorder,^10,11 suggesting that similar neural mechanisms might underlie cognitive deficits across these conditions. This raises an enthralling query: Could theta activity serve as a transdiagnostic biomarker for cognitive dysfunction across neurological and psychiatric disorders? If so, EEG-based assessments could dramatically expand in their clinical utility, offering a noninvasive and scalable tool for diagnosing and tracking cognitive impairments.

An equally captivating avenue for future research is the potential application of EEG-based biomarkers in epilepsy surgery. Patient selection and outcome prediction remain critical challenges in surgical decision-making. If the preoperative assessment of theta power can prognosticate postoperative cognitive outcomes, it could refine patient selection criteria and improve clinical outcomes. Validating these findings in larger cohorts could usher in a personalized, data-driven approach to epilepsy surgery.

Despite its strengths, the study is not without limitations. The cross-sectional design precludes conclusions about causality. ³ Moreover, key aspects of memory, such as encoding and recall, were not explicitly examined. EEG recordings were conducted in a controlled clinical environment, which may not fully encapsulate the natural variability in cognitive performance. ³ Additionally, since the study focused exclusively on PWE, the potential influence of epilepsy-related factors—such as epileptic activity, medication use, and comorbidities—on theta power remains uncertain. The heterogeneity of the epilepsy cohort further complicates interpretation, as differences in epilepsy etiology may introduce variability in neural oscillatory patterns. A more granular analysis in the future examining how these factors interact with neural oscillatory patterns could provide deeper mechanistic insights. Future studies incorporating longitudinal designs, real-world EEG assessments, and expanded cognitive and memory testing could clarify the temporal dynamics of theta power and strengthen its case as a predictive biomarker.

In essence, Hamedi et al ³ provide compelling evidence that anterior prefrontal theta activity may serve as a robust and promising electrophysiological biomarker of cognitive function in epilepsy. Their findings highlight the promise of theta oscillations as a clinically viable biomarker for diagnosis, monitoring, and therapeutic interventions. While further research is warranted to establish causality and clinical utility, this study lays a strong foundation for future explorations into the role of neural oscillations in epilepsy and beyond. The prospect of leveraging theta activity for cognitive enhancement via neuromodulation heralds an exciting frontier in translational neuroscience—one that could have profound implications for improving cognitive outcomes in epilepsy and other neurocognitive disorders.