Kucewicz, Michał T.

Ultrafast oscillations (UFOs) are brief bursts of high-frequency (2–8 kHz) activity recorded using depth electrodes in epileptic brain tissue. While reliably detected at small scales using microelectrodes, UFOs have thus far likely not been observed at larger scales using macroelectrodes. Here we show that faint echoes of these bursting patterns can be detected in macroelectrode signals using a model of cross-scale propagation. To model this cross-scale effect, we extend the classical damped wave equation to include an explicit scale coordinate governed by the dilation operator. We then use Green's functions to obtain an expression for the spectral echo expected at the macroelectrode scale. This echo takes the form of a carrier envelope modulated by the temporal structure of the original microscale bursting event. We test the predicted signature echo pattern in human intracranial recordings from eleven epilepsy patients implanted with both micro- and macroelectrodes. Statistically significant echoes are confirmed in two out of eleven patients, appearing in 2% of all tested micro-macro pairs.

Abstract Objective The upper frequency limit of human brain activity remains unknown. Using ultrahigh sampling rate (≥20 kHz) intracranial microelectroencephalography, this study aimed to systematically explore and quantitatively characterize brain field oscillations beyond the established high‐frequency oscillation range (>2 kHz), and to determine their relationship to epileptogenic tissue. Methods We analyzed intracranial electroencephalographic recordings from 15 patients with drug‐resistant epilepsy, comprising 466 microcontacts and 434 macrocontacts implanted in mesiotemporal structures across four international epilepsy centers. A custom spectrogram‐based detector optimized for ultrahigh frequencies was developed to identify ultrafast oscillations (UFOs; >2 kHz). UFO rates were assessed in epileptic (successfully resected) and nonepileptic hippocampi and compared with established electrophysiological biomarkers, including interictal epileptiform discharges, ripples, and fast ripples. Statistical comparisons were performed using mixed‐effects models to account for intersubject and interelectrode variability. Results We identified a previously undescribed class of short‐duration oscillatory events spanning 2–8 kHz. UFOs occurred at significantly higher rates in epileptic compared with nonepileptic mesiotemporal regions, with the strongest differentiation observed in the 2–3‐kHz band. Two distinct UFO phenotypes were consistently observed: (1) spindlelike, narrow‐band oscillations and (2) sharp‐onset, rapidly decaying bursts. Both forms were prevalent within epileptic hippocampi but were exceedingly rare in nonepileptic structures. UFOs exhibited pronounced temporal intermittency and spatial focality and frequently arose independently of ripples, fast ripples, and very high‐frequency oscillations, indicating that they represent a distinct electrophysiological phenomenon. Macrocontacts detected UFOs only exceptionally, highlighting the necessity of microelectrode recordings to capture activity in this ultrahigh‐frequency regime. Significance These findings substantially extend the known frequency range of human brain field activity and identify ultrafast oscillations as a novel biomarker of neuronal hyperexcitability. UFOs likely reflect pathological microcircuit dynamics inaccessible to conventional clinical recordings and provide new insights into the organization and pathophysiology of epileptogenic networks.

Abstract Objective Memory impairments are common in neurological disorders, especially drug‐resistant epilepsy, where cognitive deficits such as accelerated long‐term forgetting may occur before surgery due to interictal/ictal discharges, antiseizure medications, and disease progression. Postsurgical memory decline affects 40%–60% of patients. Understanding the neural mechanisms of memory encoding is essential for identifying critical network hubs and guiding surgical interventions that preserve cognitive function. Methods We analyzed intracranial electroencephalographic recordings from epilepsy patients ( n = 15) performing a verbal memory encoding task to identify key structures involved in successful memory formation. Functional connectivity was computed using multiple features across several frequency bands. Temporal dynamics of connectivity were examined to characterize pre‐encoding and encoding phases. Results The middle temporal gyrus (MTG) consistently emerged as a verbal memory hub across features and frequency bands. The inferior frontal gyrus (IFG) was identified as a beta‐band‐specific hub via phase synchrony. Temporal analyses revealed that MTG exhibited stable and widespread connectivity differences across all encoding phases, suggesting a role in pre‐encoding network priming. In contrast, IFG displayed a transient decrease in connectivity and spatial extent during early encoding, indicating a more focal and dynamic contribution. Significance These findings suggest that successful memory encoding relies on widespread, frequency‐specific connectivity patterns centered on MTG, complemented by transient, localized IFG activity. Identifying such hubs may inform surgical planning by highlighting regions critical for cognitive outcomes, ultimately supporting strategies to preserve memory in epilepsy surgery.

Background: The external environment continuously shapes human perception, often without conscious awareness. This influence can be objectively studied using non-invasive recordings of brain activity in controlled virtual reality (VR) settings. We hypothesized that brief presentations of natural features would elicit distinct neural oscillatory patterns detectable through changes in the spectral power of resting-state electroencephalogram (EEG) activity in specific brain regions. Methods: To test this, participants passively viewed three minimalist VR environments—with and without biophilic elements—while their EEG was recorded. Results: Our results revealed consistent changes in spectral power, particularly suppression in the alpha band and an increase in the theta band in the occipital cortex. Conclusions: These findings support the use of resting-state EEGs in immersive VR as a promising and objective method for evaluating how specific design elements influence neural activity, offering valuable insights into the field of neuro-architecture.

Abstract Oscillations in the high gamma and ripple frequency ranges are known to coordinate local hippocampal and neocortical neuronal assemblies during memory encoding and recall. Here, we explored spatiotemporal dynamics and the role of global coordination of these fast oscillatory discharges across the sensory and associational cortical areas in distinct phases of memory processing. Individual bursts of high frequency oscillations were detected in intracranial recordings from epilepsy patients remembering word lists for immediate free recall. We found constant coincident bursting across visual and higher order processing areas, peaking before recall and elevated during encoding of words. This global co-bursting was modulated by memory processing, engaged approximately half of the recorded electrode sites, and clustered into a sequence of multiple consecutive bursting discharges. Our results suggest a general role of global coincident high frequency oscillations in organizing large-scale information processing across the brain necessary especially, but not exclusively, for memory functions.

Abstract Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.

The dorsolateral prefrontal cortex (dlPFC) is increasingly targeted by various noninvasive transcranial magnetic stimulation or transcranial current stimulation protocols in a range of neuropsychiatric and other brain disorders. The rationale for this therapeutic modulation remains elusive. A model is proposed, and up-to-date evidence is discussed, suggesting that the dlPFC is a high-level cortical centre where uncertainty management, movement facilitation, and cardiovascular control processes are intertwined and integrated to deliver optimal behavioural responses in particular environmental or emotional contexts. A summary of the state-of-the-art in the field is provided to accelerate the development of emerging neuromodulation technologies for brain stimulation and recording for patients with mood, sleep, and cognitive disorders in our ageing population.

AbstractObjectiveCognitive 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.MethodsWe 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.ResultsThe 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).SignificanceTheta EEG power in the anterior prefrontal cortex provides 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.

Abstract Despite advances in understanding the cellular and molecular processes underlying memory and cognition, and recent successful modulation of cognitive performance in brain disorders, the neurophysiological mechanisms remain underexplored. High frequency oscillations beyond the classic electroencephalogram spectrum have emerged as a potential neural correlate of fundamental cognitive processes. High frequency oscillations are detected in the human mesial temporal lobe and neocortical intracranial recordings spanning gamma/epsilon (60–150 Hz), ripple (80–250 Hz) and higher frequency ranges. Separate from other non-oscillatory activities, these brief electrophysiological oscillations of distinct duration, frequency and amplitude are thought to be generated by coordinated spiking of neuronal ensembles within volumes as small as a single cortical column. Although the exact origins, mechanisms and physiological roles in health and disease remain elusive, they have been associated with human memory consolidation and cognitive processing. Recent studies suggest their involvement in encoding and recall of episodic memory with a possible role in the formation and reactivation of memory traces. High frequency oscillations are detected during encoding, throughout maintenance, and right before recall of remembered items, meeting a basic definition for an engram activity. The temporal coordination of high frequency oscillations reactivated across cortical and subcortical neural networks is ideally suited for integrating multimodal memory representations, which can be replayed and consolidated during states of wakefulness and sleep. High frequency oscillations have been shown to reflect coordinated bursts of neuronal assembly firing and offer a promising substrate for tracking and modulation of the hypothetical electrophysiological engram.

Low frequency brain rhythms facilitate communication across large spatial regions in the brain and high frequency rhythms are thought to signify local processing among nearby assemblies. A heavily investigated mode by which these low frequency and high frequency phenomenon interact is phase-amplitude coupling (PAC). This phenomenon has recently shown promise as a novel electrophysiologic biomarker, in a number of neurologic diseases including human epilepsy. In 17 medically refractory epilepsy patients undergoing phase-2 monitoring for the evaluation of surgical resection and in whom temporal depth electrodes were implanted, we investigated the electrophysiologic relationships of PAC in epileptogenic (seizure onset zone or SOZ) and non-epileptogenic tissue (non-SOZ). That this biomarker can differentiate seizure onset zone from non-seizure onset zone has been established with ictal and pre-ictal data, but less so with interictal data. Here we show that this biomarker can differentiate SOZ from non-SOZ interictally and is also a function of interictal epileptiform discharges. We also show a differential level of PAC in slow-wave-sleep relative to NREM1-2 and awake states. Lastly, we show AUROC evaluation of the localization of SOZ is optimal when utilizing beta or alpha phase onto high-gamma or ripple band. The results suggest an elevated PAC may reflect an electrophysiology-based biomarker for abnormal/epileptogenic brain regions.