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OBJECTIVE: Laser interstitial thermal therapy (LITT) is a minimally invasive surgery for mesial temporal lobe epilepsy (mTLE), but the effects of individual patient anatomy and location of ablation volumes affect seizure outcomes. The purpose of this study is to see if features of individual patient structural connectomes predict surgical outcomes after LITT for mTLE. METHODS: This is a retrospective analysis of seizure outcomes of LITT for mTLE in 24 patients. We use preoperative diffusion tensor imaging (DTI) to simulate changes in structural connectivity after laser ablation. A two-step machine-learning algorithm is applied to predict seizure outcomes from the change in connectomic features after surgery. RESULTS: Although node-based network features such as clustering coefficient and betweenness centrality have some predictive value, changes in connection strength between mesial temporal regions predict seizure outcomes significantly better. Changes in connection strength between the entorhinal cortex (EC), and the insula, hippocampus, and amygdala, as well as between the temporal pole and hippocampus, predict Engel Class I outcomes with an accuracy of 88%. Analysis of the ablation location, as well as simulated, alternative ablations, reveals that a more medial, anterior, and inferior ablation volume is associated with a greater effect on these connections, and potentially on seizure outcomes. SIGNIFICANCE: Our results indicate (1) that seizure outcomes can be retrospectively predicted with excellent accuracy using changes in structural connectivity, and (2) that favorable connectomic changes are associated with an ablation volume involving relatively mesial, anterior, and inferior locations. These results may provide a framework whereby individual pre-operative structural connectomes can be used to optimize ablation volumes and improve outcomes in LITT for mTLE.
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Conectoma , Epilepsia do Lobo Temporal , Terapia a Laser , Imagem de Tensor de Difusão , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/cirurgia , Liberdade , Hipocampo/cirurgia , Humanos , Terapia a Laser/métodos , Lasers , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Convulsões/cirurgia , Resultado do TratamentoRESUMO
Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.
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Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Conformação MolecularRESUMO
BACKGROUND: Converging literatures suggest that deep brain stimulation (DBS) in Parkinson's disease affects multiple circuit mechanisms. One proposed mechanism is the normalization of primary motor cortex (M1) pathophysiology via effects on the hyperdirect pathway. OBJECTIVES: We hypothesized that DBS would reduce the current intensity necessary to modulate motor-evoked potentials from focally applied direct cortical stimulation (DCS). METHODS: Intraoperative subthalamic DBS, DCS, and preoperative diffusion tensor imaging data were acquired in 8 patients with Parkinson's disease. RESULTS: In 7 of 8 patients, DBS significantly reduced the M1 DCS current intensity required to elicit motor-evoked potentials. This neuromodulation was specific to select DBS bipolar configurations. In addition, the volume of activated tissue models of these configurations were significantly associated with overlap of the hyperdirect pathway. CONCLUSIONS: DBS reduces the current necessary to elicit a motor-evoked potential using DCS. This supports a circuit mechanism of DBS effectiveness, potentially involving the hyperdirect pathway that speculatively may underlie reductions in hypokinetic abnormalities in Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.
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Estimulação Encefálica Profunda , Córtex Motor , Doença de Parkinson , Núcleo Subtalâmico , Imagem de Tensor de Difusão , Humanos , Doença de Parkinson/terapiaRESUMO
Over the past decade, numerous neuroimaging studies based on hemodynamic markers of brain activity have examined the feeling of body ownership using perceptual body-illusions in humans. However, the direct electrophysiological correlates of body ownership at the cortical level remain unexplored. To address this, we studied the rubber hand illusion in 5 patients (3 males and 2 females) implanted with intracranial electrodes measuring cortical surface potentials. Increased high-γ (70-200 Hz) activity, an index of neuronal firing rate, in premotor and intraparietal cortices reflected the feeling of ownership. In both areas, high-γ increases were intimately coupled with the subjective illusion onset and sustained both during and in-between touches. However, intraparietal activity was modulated by tactile stimulation to a higher degree than the premotor cortex through effective connectivity with the hand-somatosensory cortex, which suggests different functional roles. These findings constitute the first intracranial electrophysiological characterization of the rubber hand illusion and extend our understanding of the dynamic mechanisms of body ownership.
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Imagem Corporal , Córtex Cerebral/fisiologia , Neurônios/fisiologia , Adolescente , Adulto , Feminino , Ritmo Gama , Mãos/fisiologia , Humanos , Ilusões , Masculino , Córtex Motor/fisiologia , Lobo Parietal/fisiologia , Estimulação Física , Córtex Somatossensorial/fisiologia , Percepção do Tato/fisiologia , Adulto JovemRESUMO
Functional imaging investigations into the brain's resting state interactions have yielded a wealth of insight into the intrinsic and dynamic neural architecture supporting cognition and behavior. Electrophysiological studies however have highlighted the fact that synchrony across large-scale cortical systems is composed of spontaneous interactions occurring at timescales beyond the traditional resolution of fMRI, a feature that limits the capacity of fMRI to draw inference on the true directional relationship between network nodes. To approach the question of directionality in resting state signals, we recorded resting state functional MRI (rsfMRI) and electrocorticography (ECoG) from four human subjects undergoing invasive epilepsy monitoring. Using a seed-point based approach, we employed phase-amplitude coupling (PAC) and biPhase Locking Values (bPLV), two measures of cross-frequency coupling (CFC) to explore both outgoing and incoming connections between the seed and all non-seed, site electrodes. We observed robust PAC between a wide range of low-frequency phase and high frequency amplitude estimates. However, significant bPLV, a CFC measure of phase-phase synchrony, was only observed at specific narrow low and high frequency bandwidths. Furthermore, the spatial patterns of outgoing PAC connectivity were most closely associated with the rsfMRI connectivity maps. Our results support the hypothesis that PAC is relatively ubiquitous phenomenon serving as a mechanism for coordinating high-frequency amplitudes across distant neuronal assemblies even in absence of overt task structure. Additionally, we demonstrate that the spatial distribution of a seed-point rsfMRI sensorimotor network is strikingly similar to specific patterns of directional PAC. Specifically, the high frequency activities of distal patches of cortex owning membership in a rsfMRI sensorimotor network were most likely to be entrained to the phase of a low frequency rhythm engendered from the neural populations at the seed-point, suggestive of greater directional coupling from the seed out to the site electrodes.
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Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Vias Neurais/fisiologia , Descanso/fisiologia , Transmissão Sináptica/fisiologia , Adolescente , Adulto , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocorticografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
The majority of subjects who attempt to learn control of a brain-computer interface (BCI) can do so with adequate training. Much like when one learns to type or ride a bicycle, BCI users report transitioning from a deliberate, cognitively focused mindset to near automatic control as training progresses. What are the neural correlates of this process of BCI skill acquisition? Seven subjects were implanted with electrocorticography (ECoG) electrodes and had multiple opportunities to practice a 1D BCI task. As subjects became proficient, strong initial task-related activation was followed by lessening of activation in prefrontal cortex, premotor cortex, and posterior parietal cortex, areas that have previously been implicated in the cognitive phase of motor sequence learning and abstract task learning. These results demonstrate that, although the use of a BCI only requires modulation of a local population of neurons, a distributed network of cortical areas is involved in the acquisition of BCI proficiency.
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Interfaces Cérebro-Computador/psicologia , Córtex Cerebral/fisiologia , Aprendizagem/fisiologia , Adaptação Fisiológica , Adolescente , Adulto , Córtex Cerebral/anatomia & histologia , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Rede Nervosa/anatomia & histologia , Rede Nervosa/fisiologia , Adulto JovemRESUMO
The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy ((1)H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous (1)H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two (1)H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized (1)H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N-acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches.
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Núcleo Caudado/patologia , Doença de Huntington/metabolismo , Atividade Motora/fisiologia , Adulto , Idoso , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Atrofia , Núcleo Caudado/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Adulto JovemRESUMO
BACKGROUND: Electroencephalography (EEG) and electrocorticography (ECoG) recordings have been used to decode finger movements by analyzing brain activity. Traditional methods focused on single bandpass power changes for movement decoding, utilizing machine learning models requiring manual feature extraction. NEW METHOD: This study introduces a 3D convolutional neural network (3D-CNN) model to decode finger movements using ECoG data. The model employs adaptive, explainable AI (xAI) techniques to interpret the physiological relevance of brain signals. ECoG signals from epilepsy patients during awake craniotomy were processed to extract power spectral density across multiple frequency bands. These data formed a 3D matrix used to train the 3D-CNN to predict finger trajectories. RESULTS: The 3D-CNN model showed significant accuracy in predicting finger movements, with root-mean-square error (RMSE) values of 0.26-0.38 for single finger movements and 0.20-0.24 for combined movements. Explainable AI techniques, Grad-CAM and SHAP, identified the high gamma (HG) band as crucial for movement prediction, showing specific cortical regions involved in different finger movements. These findings highlighted the physiological significance of the HG band in motor control. COMPARISON WITH EXISTING METHODS: The 3D-CNN model outperformed traditional machine learning approaches by effectively capturing spatial and temporal patterns in ECoG data. The use of xAI techniques provided clearer insights into the model's decision-making process, unlike the "black box" nature of standard deep learning models. CONCLUSIONS: The proposed 3D-CNN model, combined with xAI methods, enhances the decoding accuracy of finger movements from ECoG data. This approach offers a more efficient and interpretable solution for brain-computer interface (BCI) applications, emphasizing the HG band's role in motor control.
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Neuroimaging-based investigations in humans have established the existence of brain regions that are selectively metabolically active while resting. We report a population-scale neurophysiological measurement of activity in regions of this "default network," by recording high-frequency power (76-200 Hz) electrical potentials directly from these regions in three human subjects. A selective increase observed during only resting, when compared with activity, firmly establishes a neuronal origin for default network phenomena.
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Fenômenos Eletrofisiológicos/fisiologia , Rede Nervosa/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Eletrodos , Eletroencefalografia , Feminino , Humanos , MasculinoRESUMO
[This corrects the article DOI: 10.3389/fnins.2021.769872.].
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Response inhibition refers to the ability to suppress inappropriate actions that interfere with goal-driven behavior. The inferior frontal gyrus (IFG) is known to be associated with inhibition of a motor response by assuming executive control over motor cortex outputs. This study aimed to evaluate the pediatric development of response inhibition through subdural electrocorticography (ECoG) recording. Subdural ECoG recorded neural activities simultaneously during a Go/No-Go task, which was optimized for children. Different frequency power [theta: 4-8 Hz; beta: 12-40 Hz; high-gamma (HG): 70-200 Hz] was estimated within the IFG and motor cortex. Age-related analysis was computed by each bandpass power ratio between Go and No-Go conditions, and phase-amplitude coupling (PAC) over IFG by using the modulating index metric in two conditions. For all the eight pediatric patients, HG power was more activated in No-Go trials than in Go trials, in either right- or left-side IFG when available. In the IFG region, the power over theta and HG in No-Go conditions was higher than those in Go conditions, with significance over the right side (p < 0.05). The age-related lateralization from both sides to the right side was observed from the ratio of HG power and PAC value between the No-Go and Go trials. In the pediatric population, the role of motor inhibition was observed in both IFG, with age-related lateralization to the right side, which was proved in the previous functional magnetic resonance imaging studies. In this study, the evidence correlation of age and response inhibition was observed directly by the evidence of cortical recordings.
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Recent evidence suggests that a rapid, automatic face detection system is supported by subcortical structures including the amygdala, pulvinar, and superior colliculus. Early-emerging abnormalities in these structures may be related to reduced social orienting in children with autism, and subsequently, to aberrant development of cortical circuits involved in face processing. Our objective was to determine whether functional abnormalities in the subcortical face processing system are present in adults with autism spectrum disorders (ASD) during supraliminal fearful face processing. Participants included twenty-eight individuals with ASD and 25 controls group-matched on age, IQ, and behavioral performance. The ASD group met diagnostic criteria on the ADI-R, ADOS-G, and DSM-IV. Both the ASD and control groups showed significant activation in bilateral fusiform gyri. The control group exhibited additional significant responses in the right amygdala, right pulvinar, and bilateral superior colliculi. In the direct group comparison, the controls showed significantly greater activation in the left amygdala, bilateral fusiform gyrus, right pulvinar, and bilateral superior colliculi. No brain region showed significantly greater activation in the ASD group compared to the controls. Thus, basic rapid face identification mechanisms appear to be functional in ASD. However, individuals with ASD failed to engage the subcortical brain regions involved in face detection and automatic emotional face processing, suggesting a core mechanism for impaired socioemotional processing in ASD. Neural abnormalities in this system may contribute to early-emerging deficits in social orienting and attention, the putative precursors to abnormalities in social cognition and cortical face processing specialization.
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Face , Imageamento por Ressonância Magnética/métodos , Reconhecimento Visual de Modelos/fisiologia , Adolescente , Adulto , Tonsila do Cerebelo/fisiopatologia , Criança , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Emoções , Expressão Facial , Medo , Giro do Cíngulo/fisiopatologia , Humanos , Inteligência , MáscarasRESUMO
Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story-Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.
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Mapeamento Encefálico/métodos , Lobo Temporal/fisiologia , Adolescente , Adulto , Compreensão/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Idioma , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10(-6) s(-1) and a dissociative half-life (t(1/2)) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t(1/2), at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.
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DNA Viral/metabolismo , Inibidores de Integrase de HIV/metabolismo , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/metabolismo , Pirrolidinonas/metabolismo , Quinolonas/metabolismo , Substituição de Aminoácidos , DNA Complementar , Farmacorresistência Viral , Genótipo , Integrase de HIV/genética , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Mutação , Oxazinas , Piperazinas , Piridonas , Pirrolidinonas/farmacologia , Quinolonas/farmacologia , Raltegravir PotássicoRESUMO
Accurate anatomical localization of intracranial electrodes is important for identifying the seizure foci in patients with epilepsy and for interpreting effects from cognitive studies employing intracranial electroencephalography. Localization is typically performed by coregistering postimplant computed tomography (CT) with preoperative magnetic resonance imaging (MRI). Electrodes are then detected in the CT, and the corresponding brain region is identified using the MRI. Many existing software packages for electrode localization chain together separate preexisting programs or rely on command line instructions to perform the various localization steps, making them difficult to install and operate for a typical user. Further, many packages provide solutions for some, but not all, of the steps needed for confident localization. We have developed software, Locate electrodes Graphical User Interface (LeGUI), that consists of a single interface to perform all steps needed to localize both surface and depth/penetrating intracranial electrodes, including coregistration of the CT to MRI, normalization of the MRI to the Montreal Neurological Institute template, automated electrode detection for multiple types of electrodes, electrode spacing correction and projection to the brain surface, electrode labeling, and anatomical targeting. The software is written in MATLAB, core image processing is performed using the Statistical Parametric Mapping toolbox, and standalone executable binaries are available for Windows, Mac, and Linux platforms. LeGUI was tested and validated on 51 datasets from two universities. The total user and computational time required to process a single dataset was approximately 1 h. Automatic electrode detection correctly identified 4362 of 4695 surface and depth electrodes with only 71 false positives. Anatomical targeting was verified by comparing electrode locations from LeGUI to locations that were assigned by an experienced neuroanatomist. LeGUI showed a 94% match with the 482 neuroanatomist-assigned locations. LeGUI combines all the features needed for fast and accurate anatomical localization of intracranial electrodes into a single interface, making it a valuable tool for intracranial electrophysiology research.
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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective tool for treating medically refractory Parkinson's disease (PD), but its neural mechanisms remain debated. Previous work has demonstrated that STN DBS results in evoked potentials (EPs) in the primary motor cortex (M1), suggesting that modulation of cortical physiology may be involved in its therapeutic effects. Due to technical challenges presented by high-amplitude DBS artifacts, these EPs are often measured in response to low-frequency stimulation, which is generally ineffective at PD symptom management. This study aims to characterize STN-to-cortex EPs seen during clinically relevant high-frequency STN DBS for PD. Intraoperatively, we applied STN DBS to 6 PD patients while recording electrocorticography (ECoG) from an electrode strip over the ipsilateral central sulcus. Using recently published techniques, we removed large stimulation artifacts to enable quantification of STN-to-cortex EPs. Two cortical EPs were observed - one synchronized with DBS onset and persisting during ongoing stimulation, and one immediately following DBS offset, here termed the "start" and the "end" EPs respectively. The start EP is, to our knowledge, the first long-latency cortical EP reported during ongoing high-frequency DBS. The start and end EPs differ in magnitude (p < 0.05) and latency (p < 0.001), and the end, but not the start, EP magnitude has a significant relationship (p < 0.001, adjusted for random effects of subject) to ongoing high gamma (80-150 Hz) power during the EP. These contrasts may suggest mechanistic or circuit differences in EP production during the two time periods. This represents a potential framework for relating DBS clinical efficacy to the effects of a variety of stimulation parameters on EPs.
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Studying the neural correlates of sleep can lead to revelations in our understanding of sleep and its interplay with different neurological disorders. Sleep research relies on manual annotation of sleep stages based on rules developed for healthy adults. Automating sleep stage annotation can expedite sleep research and enable us to better understand atypical sleep patterns. Our goal was to create a fully unsupervised approach to label sleep and wake states in human electro-corticography (ECoG) data from epilepsy patients. Here, we demonstrate that with continuous data from a single ECoG electrode, hidden semi-Markov models (HSMM) perform best in classifying sleep/wake states without excessive transitions, with a mean accuracy (n=4) of 85.2% compared to using K-means clustering (72.2%) and hidden Markov models (81.5%). Our results confirm that HSMMs produce meaningful labels for ECoG data and establish the groundwork to apply this model to cluster sleep stages and potentially other behavioral states.
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Eletrocorticografia , Vigília , Adulto , Humanos , Polissonografia , Sono , Fases do SonoRESUMO
Two-metal binding HIV-1 integrase inhibitors (INIs) are potent inhibitors of HIV-1 in vitro and in patients. We report here for the first time the kinetics of inhibition of integrase-catalyzed strand transfer. First, the IC(50) values for each of six structurally distinct INIs decreased when a preincubation was included: S-1360 (1.3 microM vs 0.12 microM), L-731,988 (130 nM vs 9 nM), L-870,810 (130 nM vs 4 nM), raltegravir (300 nM vs 9 nM), elvitegravir (90 nM vs 6 nM), and GSK364735 (90 nM vs 6 nM). When reactions with these INIs were initiated with integrase, progress curve analyses indicated time-dependent inhibition, which could be fitted to a two-step mechanism of binding. Overall fitted K(i) values matched the IC(50) values measured with a preincubation: S-1360 (0.17 microM), L-731,988 (34 nM), L-870,810 (2.4 nM), raltegravir (10 nM), elvitegravir (4.0 nM), and GSK364735 (2.5 nM). To begin to understand the mechanism for this slow onset of inhibition and its possible impact on drug resistance, studies of resistance mutations were initiated. T66I/M154I exhibited little if any time-dependent inhibition by any of the six INIs, as measured by differences in potency upon preincubation or by progress curve analysis. These data demonstrate that slow binding is a signature of two-metal binding INIs, and that the second slow step is required for full potency. We discuss a possible structural explanation of the second slow step of inhibition and also the relationship between loss of time-dependent inhibition and drug resistance of this important new class of HIV-1 antiretroviral drugs.
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Farmacorresistência Viral/genética , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Mutação , Sequência de Bases , Primers do DNA , HIV-1/genética , CinéticaRESUMO
Prior studies using functional magnetic resonance imaging, electroencephalography, and magnetoencephalography have observed both structured patterns in resting-state functional connectivity and spontaneous longitudinal variation in connectivity patterns independent of a task. In this first study using electrocorticography (ECoG), we characterized spontaneous, intersession variation in resting-state functional connectivity not linked to a task. We evaluated pairwise connectivity between electrodes using three measures (phase locking value [PLV], amplitude correlation, and coherence) for six canonical frequency bands, capturing different characteristics of time-evolving signals. We grouped electrodes into 10 functional regions and used intraclass correlation (ICC) to estimate pairwise longitudinal stability. We found that stronger PLV (PLV ≥0.4) in theta through gamma bands and strong correlation in all bands (R2's ≥0.6) are linked to substantial stability (ICC ≥0.6), but that stability does not imply strong phase locking or amplitude correlation. There was no notable link between strong coherence and high ICC. All within-region PLVs are markedly stable across frequencies. In addition, we highlight interaction patterns across several regions: parahippocampal/entorhinal cortex is characterized by stable, weak functional connectivity except self-connections. Dorsolateral prefrontal cortex connectivity is weak and unstable, except self-connections. Inferior parietal lobule has little stability despite narrow connectivity bounds. We confirm prior studies linking functional connectivity strength and intersession variability, extending into higher frequencies than other modalities, with greater spatial specificity than scalp electrophysiology. We suggest further studies quantitatively compare ECoG to other modalities and/or use these findings as a baseline to capture functional connectivity and dynamics linked to perturbations with a task or disease state.
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Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Adulto , Ondas Encefálicas/fisiologia , Conectoma/métodos , Eletrocorticografia/métodos , Eletroencefalografia/métodos , Epilepsia/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Magnetoencefalografia/métodos , Masculino , Lobo Parietal/fisiologia , Córtex Pré-Frontal/fisiologia , Reprodutibilidade dos Testes , DescansoRESUMO
Brain-computer interfaces (BCIs) benefit greatly from performance feedback, but current systems lack automatic, task-independent feedback. Cortical responses elicited from user error have the potential to serve as state-based feedback to BCI decoders. To gain a better understanding of local error potentials, we investigate responsive cortical power underlying error-related potentials (ErrPs) from the human cortex during a one-dimensional center-out BCI task, tracking the topography of high-gamma (70-100 Hz) band power (HBP) specific to BCI error. We measured electrocorticography (ECoG) in three human subjects during dynamic, continuous control over BCI cursor velocity. Subjects used motor imagery and rest to move the cursor toward and subsequently dwell within a target region. We then identified and labeled epochs where the BCI decoder incorrectly moved the cursor in the direction opposite of the subject's expectations (i.e., BCI error). We found increased HBP in various cortical areas 100-500 ms following BCI error with respect to epochs of correct, intended control. Significant responses were noted in primary somatosensory, motor, premotor, and parietal areas and generally regardless of whether the subject was using motor imagery or rest to move the cursor toward the target. Parts of somatosensory, temporal, and parietal areas exclusively had increased HBP when subjects were using motor imagery. In contrast, only part of the parietal cortex near the angular gyrus exclusively had an increase in HBP during rest. This investigation is, to our knowledge, the first to explore cortical fields changes in the context of continuous control in ECoG BCI. We present topographical changes in HBP characteristic specific to the generation of error. By focusing on continuous control, instead of on discrete control for simple selection, we investigate a more naturalistic setting and provide high ecological validity for characterizing error potentials. Such potentials could be considered as design elements for co-adaptive BCIs in the future as task-independent feedback to the decoder, allowing for more robust and individualized BCIs.