Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.
ABSTRACT: BACKGROUND:Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS:Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS:Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS:Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.
Project description:The neuronal connectivity patterns that differentiate consciousness from unconsciousness remain unclear. Previous studies have demonstrated that effective connectivity, as assessed by transcranial magnetic stimulation combined with electroencephalography (TMS-EEG), breaks down during the loss of consciousness. This study investigated changes in EEG connectivity associated with consciousness during non-rapid eye movement (NREM) sleep following parietal TMS. Compared with unconsciousness, conscious experiences during NREM sleep were associated with reduced phase-locking at low frequencies (<4 Hz). Transitivity and clustering coefficient in the delta and theta bands were also significantly lower during consciousness compared to unconsciousness, with differences in the clustering coefficient observed in scalp electrodes over parietal-occipital regions. There were no significant differences in Granger-causality patterns in frontal-to-parietal or parietal-to-frontal connectivity between reported unconsciousness and reported consciousness. Together these results suggest that alterations in spectral and spatial characteristics of network properties in posterior brain areas, in particular decreased local (segregated) connectivity at low frequencies, is a potential indicator of consciousness during sleep.
Project description:Directional connectivity from anterior to posterior brain regions (or "feedback" connectivity) has been shown to be inhibited by propofol and sevoflurane. In this study the authors tested the hypothesis that ketamine would also inhibit cortical feedback connectivity in frontoparietal networks.Surgical patients (n = 30) were recruited for induction of anesthesia with intravenous ketamine (2 mg/kg); electroencephalography of the frontal and parietal regions was acquired. The authors used normalized symbolic transfer entropy, a computational method based on information theory, to measure directional connectivity across frontal and parietal regions. Statistical analysis of transfer entropy measures was performed with the permutation test and the time-shift test to exclude false-positive connectivity. For comparison, the authors used normalized symbolic transfer entropy to reanalyze electroencephalographic data gathered from surgical patients receiving either propofol (n = 9) or sevoflurane (n = 9) for anesthetic induction.Ketamine reduced alpha power and increased gamma power, in contrast to both propofol and sevoflurane. During administration of ketamine, feedback connectivity gradually diminished and was significantly inhibited after loss of consciousness (mean ± SD of baseline and anesthesia: 0.0074 ± 0.003 and 0.0055 ± 0.0027; F(5, 179) = 7.785, P < 0.0001). By contrast, feedforward connectivity was preserved during exposure to ketamine (mean ± SD of baseline and anesthesia: 0.0041 ± 0.0015 and 0.0046 ± 0.0018; F(5, 179) = 2.07; P = 0.072). Like ketamine, propofol and sevoflurane selectively inhibited feedback connectivity after anesthetic induction.Diverse anesthetics disrupt frontal-parietal communication, despite molecular and neurophysiologic differences. Analysis of directional connectivity in frontal-parietal networks could provide a common metric of general anesthesia and insight into the cognitive neuroscience of anesthetic-induced unconsciousness.
Project description:Transcranial magnetic stimulation (TMS) is a noninvasive method to modulate brain activity and behavior in humans. Still, stimulation effects substantially vary across studies and individuals, thereby restricting the large-scale application of TMS in research or clinical settings. We revealed that low-frequency stimulation had opposite impact on the functional connectivity of sensory and cognitive brain regions. Biophysical modeling then identified a neuronal mechanism underlying these region-specific effects. Stimulation of the frontal cortex decreased local inhibition and disrupted feedforward and feedback connections. Conversely, identical stimulation increased local inhibition and enhanced forward signaling in the occipital cortex. Last, we identified functional integration as a macroscale network parameter to predict the region-specific effect of stimulation in individual subjects. In summary, we revealed how TMS modulation critically depends on the connectivity profile of target regions and propose an imaging marker to improve sensitivity of noninvasive brain stimulation for research and clinical applications.
Project description:Attention facilitates the gating of information from the sending brain area to the receiving areas, with this being achieved by dynamical changes in effective connectivity, which refers to the directional influences between cortical areas. To probe the effective connectivity and cortical excitability modulated by covertly shifted attention, transcranial magnetic stimulation (TMS) was used to directly perturb the right retinotopic visual cortex with respect to attended and unattended locations, and the impact of this was tracked from the stimulated area to other areas by concurrent use of electroencephalography (EEG). TMS to the contralateral visual hemisphere led to a stronger evoked potential than stimulation to the ipsilateral hemisphere. Moreover, stronger beta- and gamma-band effective connectivities assessed as time-delayed phase synchronizations between stimulated areas and other areas were observed when TMS was delivered to the contralateral hemisphere. These effects were more enhanced when they preceded more prominent alpha lateralization, which is known to be associated with attentional gating. Our results indicate that attention-regulated cortical feedforward effective connectivity can be probed by TMS-EEG with direct cortical stimulation, thereby bypassing thalamic gating. These results suggest that cortical gating of the feedforward input is achieved by regulating the effective connectivity in the phase dynamics between cortical areas.
Project description:<h4>Background</h4>Cognitive dysfunction is considered a core feature of schizophrenia, and impaired performances in episodic memory (EM) and executive function (EF) tasks are consistently reported in schizophrenia patients. Traditional fMRI and EEG studies have helped identifying brain areas, including the prefrontal cortex (PFC), involved in these tasks. However, it is unclear whether intrinsic defects in prefrontal function per se contribute to poor performance in schizophrenia, given the presence of confounds like reduced motivation and psychotic symptoms. TMS/hd-EEG measurements are obtained without cognitive effort, and can be calculated in any cortical area.<h4>Methods</h4>We performed TMS/hd-EEG recordings in parietal, motor, premotor, and PFC in healthy individuals (N=20) and schizophrenia patients (N=20). Source modeling of TMS-evoked responses was performed, and measures of cortical activity (significant current density, SCD) and connectivity (significant current scattering, SCS) were computed. Patients with schizophrenia also performed Penn Word memory delayed (CPWd) and Penn Conditional Exclusion Test (PCET). CPWd evaluates EM and involves primarily PFC, whereas PCET reflects EF and implicates PFC with other brain regions.<h4>Findings</h4>We found no difference in SCD and SCS after TMS of parietal/motor cortices, whereas those parameters were reduced in premotor/prefrontal areas in schizophrenia patients. In PFC, where these measures were most defective, SCD was negatively correlated with performance in CPWd whereas higher SCS values were associated with more errors in PCET.<h4>Conclusion</h4>These findings indicate that schizophrenia patients have intrinsic defects in both activity and connectivity of PFC, and that these defects are specifically associated with impairments in cognitive abilities.
Project description:Combining resting-state functional magnetic resonance imaging (fMRI) connectivity and behavioral analysis during sedation, we factored out general effects of the anesthetic drug propofol and a specific index of conscious report, participants' level of responsiveness. The factorial analysis shows that increasing concentration of propofol in blood specifically decreases the connectivity strength of fronto-parietal cortical loops. In contrast, loss of responsiveness is indexed by a functional disconnection between the thalamus and the frontal cortex, balanced by an increase in connectivity strength of the thalamus to the occipital and temporal regions of the cortex.
Project description:The brain at rest exhibits a spatio-temporally rich dynamics which adheres to systematic behaviours that persist in task paradigms but appear altered in disease. Despite this hypothesis, many rest state paradigms do not act directly upon the rest state and therefore cannot confirm hypotheses about its mechanisms. To address this challenge, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to study brain's relaxation toward rest following a transient perturbation. Specifically, TMS targeted either the medial prefrontal cortex (MPFC), i.e. part of the Default Mode Network (DMN) or the superior parietal lobule (SPL), involved in the Dorsal Attention Network. TMS was triggered by a given brain state, namely an increase in occipital alpha rhythm power. Following the initial TMS-Evoked Potential, TMS at MPFC enhances the induced occipital alpha rhythm, called Event Related Synchronisation, with a longer transient lifetime than TMS at SPL, and a higher amplitude. Our findings show a strong coupling between MPFC and the occipital alpha power. Although the rest state is organized around a core of resting state networks, the DMN functionally takes a special role among these resting state networks.
Project description:The dose-dependent effects of anesthetics on brain functional connectivity are incompletely understood. Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to assess the functional connectivity in humans and animals. Propofol is an anesthetic agent with desirable characteristics for functional neuroimaging in animals but its dose-dependent effects on rsfMRI functional connectivity have not been determined. Here we tested the hypothesis that brain functional connectivity undergoes specific changes in distinct neural networks at anesthetic depths associated with loss of consciousness. We acquired spontaneous blood oxygen level-dependent (BOLD) signals simultaneously with electroencephalographic (EEG) signals from rats under steady-state, intravenously administered propofol at increasing doses from light sedation to deep anesthesia (20, 40, 60, 80, and 100 mg/kg/h IV). Power spectra and burst suppression ratio were calculated from the EEG to verify anesthetic depth. Functional connectivity was determined from the whole brain correlation of BOLD data in regions of interest followed by a segmentation of the correlation maps into anatomically defined regional connectivity. We found that propofol produced multiphasic, dose dependent changes in functional connectivity of various cortical and subcortical networks. Cluster analysis predicted segregation of connectivity into two cortical and two subcortical clusters. In one cortical cluster (somatosensory and parietal), the early reduction in connectivity was followed by transient reversal; in the other cluster (sensory, motor and cingulate/retrosplenial), this rebound was absent. The connectivity of the subcortical cluster (brainstem, hippocampal and caudate) was strongly reduced, whereas that of another (hypothalamus, medial thalamus and n. basalis) did not. Subcortical connectivity increased again in deep anesthesia associated with EEG burst suppression. Regional correlation analysis confirmed the breakdown of connectivity within and between specific cortical and subcortical networks with deepening propofol anesthesia. Cortical connectivity was suppressed before subcortical connectivity at a critical propofol dose associated with loss of consciousness.
Project description:An event in one sensory modality can phase reset brain oscillations concerning another modality. In principle, this may result in stimulus-locked periodicity in behavioral performance. Here we considered this possible cross-modal impact of a sound for one of the best-characterized rhythms arising from the visual system, namely occipital alpha-oscillations (8-14 Hz). We presented brief sounds and concurrently recorded electroencephalography (EEG) and/or probed visual cortex excitability (phosphene perception) through occipital transcranial magnetic stimulation (TMS). In a first, TMS-only experiment, phosphene perception rate against time postsound showed a periodic pattern cycling at ~10 Hz phase-aligned to the sound. In a second, combined TMS-EEG experiment, TMS-trials reproduced the cyclical phosphene pattern and revealed a ~10 Hz pattern also for EEG-derived measures of occipital cortex reactivity to the TMS pulses. Crucially, EEG-data from intermingled trials without TMS established cross-modal phase-locking of occipitoparietal alpha oscillations. These independently recorded variables, i.e., occipital cortex excitability and reactivity and EEG phase dynamics, were significantly correlated. This shows that cross-modal phase locking of oscillatory visual cortex activity can arise in the human brain to affect perceptual and EEG measures of visual processing in a cyclical manner, consistent with occipital alpha oscillations underlying a rapid cycling of neural excitability in visual areas.
Project description:INTRODUCTION:Autism spectrum disorder (ASD) is a complex and prevalent neurodevelopmental disorder characterized by deficits in social communication and social interaction as well as repetitive behaviors. Alterations in function connectivity are widely recognized in recent electroencephalogram (EEG) studies. However, most studies have not reached consistent conclusions, which could be due to the developmental nature and the heterogeneity of ASD. METHODS:Here, EEG coherence analysis was used in a cohort of children with ASD (n = 13) and matched typically developing controls (TD, n = 15) to examine the functional connectivity characteristics in long-distance and short-distance electrode pairs. Subsequently, we explore the association between the connectivity strength of coherence and symptom severity in children with ASD. RESULTS:Compared with TD group, individuals with ASD showed increased coherence in short-distance electrode pairs in the right temporal-parietal region (delta, alpha, beta bands), left temporal-parietal region (all frequency bands), occipital region (theta, alpha, beta bands), right central-parietal region (delta, alpha, beta bands), and the prefrontal region (only beta band). In the long-distance coherence analysis, the ASD group showed increased coherence in bilateral frontal region, temporal region, parietal region, and frontal-occipital region in alpha and beta bands. The strength of such connections was associated with symptom severity. DISCUSSION:Our study indicates that abnormal connectivity patterns in neuroelectrophysiology may be of critical importance to acknowledge the underlying brain mechanism.