Functional mapping of language-related areas from natural, narrative speech during awake craniotomy surgery.

Accurate localization of brain regions responsible for language and cognitive functions in epilepsy patients is important. Electrocorticography (ECoG)-based real-time functional mapping (RTFM) has been shown to be a safer alternative to electrical cortical stimulation mapping (ESM), which is currently the clinical/gold standard. Conventional methods for analyzing RTFM data mostly account for the ECoG signal in certain frequency bands, especially high gamma. Compared to ESM, they have limited accuracy when assessing channel responses. In the present study, we developed a novel RTFM method based on tensor component analysis (TCA) to address the limitations of current estimation methods. Our approach analyzes the whole frequency spectrum of the ECoG signal during natural continuous speech. We construct third-order tensors that contain multichannel time-frequency information and use TCA to extract low-dimensional temporal, spectral and spatial modes. Temporal modulation scores (correlation values) are then calculated between the time series of voice envelope features and TCA-estimated temporal courses, and significant temporal modulation determines which components' channel weightings are displayed to the neurosurgeon as a guide for follow-up ESM. In our experiments, data from thirteen patients with refractory epilepsy were recorded during preoperative evaluation for their epileptogenic zones (EZs), which were located adjacent to the eloquent cortex. Our results showed higher detection accuracy of our proposed method in a narrative speech task, suggesting that our method complements ESM and is an improvement over the prior RTFM method. To our knowledge, this is the first TCA-based method to pinpoint language-specific brain regions during continuous speech that uses whole-band ECoG.

Clinical application of intraoperative trial-free online-based language mapping for patients with refractory epilepsy.

OBJECTIVE: The objective of the study was to develop and clinically test a trial-free online-based language mapping method for localizing the eloquent cortex easily in epilepsy operation. METHODS: Nine patients with refractory epilepsy were included in this study according to the results of preoperative evaluation for their epileptogenic zones (EZs) located adjacent to the eloquent cortex. When patients were awakened up from general anesthesia during operation, the trial-free online-based language-mapping paradigm was performed. All positive points marked on the cortex in each test were labeled and superimposed together as the result of functional mapping for each patient. The eloquent cortex was mapped according to the results obtained both from the intraoperative trial-free task localization method and the traditional electrical cortical stimulation (ECS). RESULTS: All patients completed this paradigms twice within 10 min. Based on the results of mapping, the EZs were tried to fully resected on the premise of preserving the mapped eloquent cortex as much as possible. The postoperative follow-up showed the outcome of Engel I in six patients and Engel II in three patients, whereas only two patients had aphemia after surgery and recovered within one week and three months, respectively. SIGNIFICANCE: The intraoperative trial-free online-based language mapping method was primarily identified to be safe and effective. This novel method seems to be promising and worthy of improvement.

Evaluating the roles of left middle frontal gyrus in word production using electrocorticography.

To assess the specific roles of left middle frontal gyrus (LMFG) in word production, electrocorticography signals were recorded from an epilepsy patient when he participated in language tasks. We found three sites of LMFG showed high-gamma perturbations with distinct patterns across tasks; and neural activities elicited in the same tasks shared similar patterns, while those elicited by stimuli leading to the same articulations did not. These findings confirmed that the LMFG takes active parts in word production, and suggested that it may serve as a temporal perceptual information storage space, supporting the hierarchical state feedback control model of word production.

Loss of function of FIP200 in human pluripotent stem cell-derived neurons leads to axonal pathology and hyperactivity.

FIP200 plays important roles in homeostatic processes such as autophagy and signaling pathways such as focal adhesion kinase (FAK) signaling. Furthermore, genetic studies suggest an association of FIP200 mutations with psychiatric disorders. However, its potential connections to psychiatric disorders and specific roles in human neurons are not clear. We set out to establish a human-specific model to study the functional consequences of neuronal FIP200 deficiency. To this end, we generated two independent sets of isogenic human pluripotent stem cell lines with homozygous FIP200KO alleles, which were then used for the derivation of glutamatergic neurons via forced expression of NGN2. FIP200KO neurons exhibited pathological axonal swellings, showed autophagy deficiency, and subsequently elevated p62 protein levels. Moreover, monitoring the electrophysiological activity of neuronal cultures on multi-electrode arrays revealed that FIP200KO resulted in a hyperactive network. This hyperactivity could be abolished by glutamatergic receptor antagonist CNQX, suggesting a strengthened glutamatergic synaptic activation in FIP200KO neurons. Furthermore, cell surface proteomic analysis revealed metabolic dysregulation and abnormal cell adhesion-related processes in FIP200KO neurons. Interestingly, an ULK1/2-specific autophagy inhibitor could recapitulate axonal swellings and hyperactivity in wild-type neurons, whereas inhibition of FAK signaling was able to normalize the hyperactivity of FIP200KO neurons. These results suggest that impaired autophagy and presumably also disinhibition of FAK can contribute to the hyperactivity of FIP200KO neuronal networks, whereas pathological axonal swellings are primarily due to autophagy deficiency. Taken together, our study reveals the consequences of FIP200 deficiency in induced human glutamatergic neurons, which might, in the end, help to understand cellular pathomechanisms contributing to neuropsychiatric conditions.

Development of a synchronous recording and photo-stimulating electrode in multiple brain neurons.

The investigation of brain networks and neural circuits involves the crucial aspects of observing and modulating neurophysiological activity. Recently, opto-electrodes have emerged as an efficient tool for electrophysiological recording and optogenetic stimulation, which has greatly facilitated the analysis of neural coding. However, implantation and electrode weight control have posed significant challenges in achieving long-term and multi-regional brain recording and stimulation. To address this issue, we have developed a mold and custom-printed circuit board-based opto-electrode. We report successful opto-electrode placement and high-quality electrophysiological recordings from the default mode network (DMN) of the mouse brain. This novel opto-electrode facilitates synchronous recording and stimulation in multiple brain regions and holds promise for advancing future research on neural circuits and networks.

A defined human-specific platform for modeling neuronal network stimulation in vitro and in silico.

BACKGROUND: Transcription factor-based forward programming enables the efficient generation of forebrain excitatory and inhibitory neurons from human pluripotent stem cells (hPSCs). This provides an opportunity to study stimulation-response patterns in highly defined neuronal networks in a controlled and customizable in vitro environment. NEW METHOD: Cell populations composed of defined ratios of excitatory and inhibitory neurons were generated by forward programming genome-edited human hPSCs carrying the inducible transcription factors NGN2 and ASCL1/DLX2, respectively. These populations were cultured on multi-electrode arrays (MEAs), and population responses elicited by distinct spatial and temporal stimulation patterns were analyzed. In parallel, in silico network models fed with neuronal parameters obtained from the in vitro cultures were developed to explore potential mechanisms underlying experimental observations. RESULTS: Neuronal cultures developed network-level electrophysiological activities with pronounced synchronized network bursts (NBs), which responded to synaptic modulators. Interestingly, local electrical pulse stimulation at frequencies ≤ 0.2 Hz reliably elicited NBs, while frequencies of ≥ 1 Hz yielded no homogeneous responses, but only sporadic NBs. In contrast, multi-site stimulation at the same frequency could elicit NBs robustly. Data from computational models suggest that this phenomenon can be explained by exhaustion and presynaptic functional paralysis of targeted circuits by high-frequency local stimulation. COMPARISON WITH EXISTING METHODS: Compared to hPSC-derived neurons generated solely by small molecule treatment, forward-programmed excitatory and inhibitory neurons enable the composition of highly confectionized networks. In silico simulation of induced biological network responses can be directly used to devise and validate mechanistic hypotheses underlying the recorded network dynamics. CONCLUSIONS: The present study demonstrates the prospect of the iPSC technology for conducting personalized in vitro studies of human neuronal networks and their responses to electric stimuli. It also illustrates how the combined use of biological and in silico neuronal networks can support the development of mechanistic hypotheses underlying network responses to specific stimuli.

µ-Opioid receptor activation modulates CA3-to-CA1 gamma oscillation phase-coupling.

In the intact brain, hippocampal area CA1 alternates between low-frequency gamma oscillations (γ), phase-locked to low-frequency γ in CA3, and high-frequency γ, phase-locked to γ in the medial entorhinal cortex. In hippocampal slices, γ in CA1 is phase-locked to CA3 low-frequency γ. However, when Schaffer collaterals are cut, CA1 can generate its own high-frequency γ. Here we test whether (un)coupling of CA1 γ from CA3 γ can be caused by µ-opioid receptor (MOR) modulation. In CA1 minislices isolated from rat ventral hippocampus slices, MOR activation by DAMGO reduced the dominant frequency of intrinsic fast γ, induced by carbachol. In intact slices, DAMGO strongly reduced the dominant frequency of CA3 slow γ, but did not affect γ power consistently. DAMGO suppressed the phase coupling of CA1 γ to CA3 slow γ and increased the power of CA1 intrinsic fast γ, but not in the presence of the MOR antagonist CTAP. The benzodiazepine zolpidem and local application of DAMGO to CA3 both mimicked the reduction in dominant frequency of CA3 slow γ, but did not reduce the phase coupling. Local application of DAMGO to CA1 reduced phase coupling. These results suggest that MOR-expressing CA1 interneurons, feed-forwardly activated by Schaffer collaterals, are responsible for the phase coupling between CA3 γ and CA1 γ. Modulating their activity may switch the CA1 network between low-frequency γ and high-frequency γ, controlling the information flow between CA1 and CA3 or medial entorhinal cortex respectively.

Continuous behavioral tracing-based online functional brain mapping with intracranial electroencephalography.

Intracranial electroencephalography (iEEG) has proven to be a reliable tool in clinical functional brain mapping. While iEEG signals are believed to be highly informative, making online or real-time functional mapping possible, the utilization of corresponding behavioral information in traditional trial-based paradigms is typically low. This imbalance has limited the efficiency and effectiveness in current iEEG-based functional mapping approaches. OBJECTIVE: In the current study, we were to investigate whether using more dedicate behavioral information can improve iEEG-based functional mapping. APPROACH: We continuously monitored behavioral outputs of patients during iEEG recording, transformed them into regressors, and assessed their correlations with iEEG signals. MAIN RESULTS: Functional cortical sites identified in preliminary test using the proposed method showed considerable consistency with the results from electrical cortical stimulation (ECS) as well as a trial-based method. Continuous behavioral tracing yielded more dependency to neural signals than sole event markers-derived regressor. Based on this, we successfully performed online functional brain mapping during five neurosurgery operations, which yielded satisfactory results. SIGNIFICANCE: In the present study, we showed the utilization of continuous behavioral tracing can improve the efficiency of iEEG-based functional brain mapping. We then demonstrated this approach is adequate for multi-session intraoperative functional assessment within short time span, which is of considerable clinical value.

Using electrocorticography for presurgical language mapping in epilepsy patients.

Of five epilepsy patients with implanted subdural electrodes, electrical cortical stimulation (ECS) on left posterior inferior frontal gyri (LPIFG) of dominant language hemisphere, did not elicit language production related symptoms. These patients were then subjected to six language production tasks with simultaneously electrocorticographic (ECoG) recording. Dada analysis revealed several cortical sites showed event-related cortical high gamma activities. These sites were linked to certain functions, e.g., auditory, visual, and sensorimotor, according to their different activation patterns among tasks. Sites labeled as sensorimotor-related by ECoG showed high accordance with those identified via ECS. Yet ECoG identified few extra crucial sites in LPIFG either. These results demonstrated consistency between ECS and ECoG and reaffirmed the utility of ECoG in preoperative functional cortical mapping.

An Intracranial Electroencephalography (iEEG) Brain Function Mapping Tool with an Application to Epilepsy Surgery Evaluation.

OBJECTS: Before epilepsy surgeries, intracranial electroencephalography (iEEG) is often employed in function mapping and epileptogenic foci localization. Although the implanted electrodes provide crucial information for epileptogenic zone resection, a convenient clinical tool for electrode position registration and Brain Function Mapping (BFM) visualization is still lacking. In this study, we developed a BFM Tool, which facilitates electrode position registration and BFM visualization, with an application to epilepsy surgeries. METHODS: The BFM Tool mainly utilizes electrode location registration and function mapping based on pre-defined brain models from other software. In addition, the electrode node and mapping properties, such as the node size/color, edge color/thickness, mapping method, can be adjusted easily using the setting panel. Moreover, users may manually import/export location and connectivity data to generate figures for further application. The role of this software is demonstrated by a clinical study of language area localization. RESULTS: The BFM Tool helps clinical doctors and researchers visualize implanted electrodes and brain functions in an easy, quick and flexible manner. CONCLUSIONS: Our tool provides convenient electrode registration, easy brain function visualization, and has good performance. It is clinical-oriented and is easy to deploy and use. The BFM tool is suitable for epilepsy and other clinical iEEG applications.