Brian H. Silverstein

P3b, consciousness, and complex unconscious processing.

How can perceptual consciousness be indexed in humans? Recent work with ERPs suggests that P3b, a relatively late component, may be a neural correlate of consciousness (NCC). This proposal dovetails with currently prevailing cognitive theory regarding the nature of conscious versus unconscious processes, which holds that the latter are simple and very brief, whereas consciousness is ostensibly required for more durable, complex cognitive processing. Using a P3b oddball paradigm, we instead show that P3b and even later, related slow wave activity occur under rigorously subliminal conditions. Additional principal component analysis (PCA) further differentiated the presence of both P3a and P3b components, demonstrating that the latter indeed occurred subliminally. Collectively, our results suggest that complex, sustained cognitive processing can occur unconsciously and that P3b is not an NCC after all.

Neural Correlates of Wakefulness, Sleep, and General Anesthesia: An Experimental Study in Rat.

Background:Significant advances have been made in our understanding of subcortical processes related to anesthetic- and sleep-induced unconsciousness, but the associated changes in cortical connectivity and cortical neurochemistry have yet to be fully clarified. Methods:Male Sprague–Dawley rats were instrumented for simultaneous measurement of cortical acetylcholine and electroencephalographic indices of corticocortical connectivity—coherence and symbolic transfer entropy—before, during, and after general anesthesia (propofol, n = 11; sevoflurane, n = 13). In another group of rats (n = 7), these electroencephalographic indices were analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Results:Compared to wakefulness, anesthetic-induced unconsciousness was characterized by a significant decrease in cortical acetylcholine that recovered to preanesthesia levels during recovery wakefulness. Corticocortical coherence and frontal–parietal symbolic transfer entropy in high &ggr; band (85 to 155 Hz) were decreased during anesthetic-induced unconsciousness and returned to preanesthesia levels during recovery wakefulness. Sleep-wake states showed a state-dependent change in coherence and transfer entropy in high &ggr; bandwidth, which correlated with behavioral arousal: high during wakefulness, low during SWS, and lowest during REM sleep. By contrast, frontal–parietal &thgr; connectivity during sleep-wake states was not correlated with behavioral arousal but showed an association with well-established changes in cortical acetylcholine: high during wakefulness and REM sleep and low during SWS. Conclusions:Corticocortical coherence and frontal–parietal connectivity in high &ggr; bandwidth correlates with behavioral arousal and is not mediated by cholinergic mechanisms, while &thgr; connectivity correlates with cortical acetylcholine levels.

Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness

BACKGROUND There is limited understanding of cortical neurochemistry and cortical connectivity during ketamine anaesthesia. We conducted a systematic study to investigate the effects of ketamine on cortical acetylcholine (ACh) and electroencephalographic coherence. METHODS Male Sprague-Dawley rats (n=11) were implanted with electrodes to record electroencephalogram (EEG) from frontal, parietal, and occipital cortices, and with a microdialysis guide cannula for simultaneous measurement of ACh concentrations in prefrontal cortex before, during, and after ketamine anaesthesia. Coherence and power spectral density computed from the EEG, and ACh concentrations, were compared between conscious and unconscious states. Loss of righting reflex was used as a surrogate for unconsciousness. RESULTS Ketamine-induced unconsciousness was associated with a global reduction of power (P=0.02) in higher gamma bandwidths (>65 Hz), a global reduction of coherence (P≤0.01) across a broad frequency range (0.5-250 Hz), and a significant increase in ACh concentrations (P=0.01) in the prefrontal cortex. Compared with the unconscious state, recovery of righting reflex was marked by a further increase in ACh concentrations (P=0.0007), global increases in power in theta (4-10 Hz; P=0.03) and low gamma frequencies (25-55 Hz; P=0.0001), and increase in power (P≤0.01) and coherence (P≤0.002) in higher gamma frequencies (65-250 Hz). Acetylcholine concentrations, coherence, and spectral properties returned to baseline levels after a prolonged recovery period. CONCLUSIONS Ketamine-induced unconsciousness is characterized by suppression of high-frequency gamma activity and a breakdown of cortical coherence, despite increased cholinergic tone in the cortex.

inferring the Dysconnection Syndrome in Schizophrenia: interpretational Considerations on Methods for the Network Analyses of fMRi Data

Schizophrenia has long been considered one of the most intractable psychiatric conditions. Its etiology is likely polygenic, and its symptoms are hypothesized to result from complex aberrations in network-level neuronal activity. While easily identifiable by psychiatrists based on clear behavioral signs, the biological substrate of the disease remains poorly understood. Here, we discuss current trends and key concepts in the theoretical framework surrounding schizophrenia and critically discuss network approaches applied to neuroimaging data that can illuminate the correlates of the illness. We first consider a theoretical framework encompassing basic principles of brain function ranging from neural units toward perspectives of network function. Next, we outline the strengths and limitations of several fMRI-based analytic methodologies for assessing in vivo brain network function, including undirected and directed functional connectivity and effective connectivity. The underlying assumptions of each approach for modeling fMRI data are treated in some quantitative detail, allowing for assessment of the utility of each for generating inferences about brain networks relevant to schizophrenia. fMRI and the analyses of fMRI signals provide a limited, yet vibrant platform from which to test specific hypotheses about brain network dysfunction in schizophrenia. Carefully considered and applied connectivity measures have the power to illuminate loss or change of function at the network level, thus providing insight into the underlying neurobiology which gives rise to the emergent symptoms seen in the altered cognition and behavior of schizophrenia patients.

Diversity of functional connectivity patterns is reduced in propofol-induced unconsciousness

Recent evidence suggests that the conscious brain is characterized by a diverse repertoire of functional connectivity patterns while the anesthetized brain shows stereotyped activity. However, classical time‐averaged methods of connectivity dismiss dynamic and temporal characteristics of functional configurations. Here we demonstrate a new approach which characterizes time‐varying patterns of functional connectivity at the subsecond time scale.

Propofol, Sevoflurane, and Ketamine Induce a Reversible Increase in Delta-Gamma and Theta-Gamma Phase-Amplitude Coupling in Frontal Cortex of Rat

Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling (CFC) between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling (PAC) between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n = 6, sevoflurane: n = 10, and ketamine: n = 8) with distinct molecular mechanisms on changes in PAC in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. PAC was calculated using the modulation index (MI) algorithm between delta (1–4 Hz), theta (4–10 Hz), low gamma (25–55 Hz), and high gamma (65–125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma (p < 0.0001) as well as between theta and low gamma (p < 0.0001) oscillations, which returned to baseline waking levels during the post-anesthetic recovery period. In addition, a reversible reduction in high gamma power (p < 0.0001) was a consistent change during anesthesia induced by all three agents. The changes in delta-high gamma and theta-high gamma PAC as well as power spectral changes in delta, theta, and low gamma bandwidths did not show a uniform response across the three anesthetics. These results encourage the study of alternative PAC patterns as drug-invariant markers of general anesthesia in humans.

Unconscious P3b and complex unconscious processing: Reply to Naccache et al., 2016

We thank Naccache, Marti, Sitt, Trübutschek, and Berkovich (2016) for their thought-provoking commentary on our recent work. While prominent theories of consciousness such as Global Workspace Theory (GWT) and related models argue that the P3b event-related potential is a neural correlate of consciousness (NCC), we suggest instead that it can occur unconsciously (Silverstein, Snodgrass, Shevrin, & Kushwaha, 2015). If so, this would “simply invalidate the P3b” (Naccache et al., 2016, p. 1) as an NCC, and further suggest that unconscious processing can be more complex, sustained, and cortically widespread than generally recognized. Critically, demonstrating an unconscious P3b requires differentiating it from other components e especially the P3a, which reflects relatively simple attentional orienting. Naccache et al. argue that various putative methodological problems render our findings ambiguous, and moreover suggest that our P3b, even if genuine, may actually be triggered by metacognitively-related conscious processes. In reply, we suggest that these concerns are unfounded. Perhaps most notably, Naccache et al. simply ignore our primary (principal components analysis) results and their probative impact.

Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousnessBritish Journal of Anaesthesia, 2015; 114(6): 979–89, DOI 10.1093/bja/aev095

This article was published by mistake in the June issue of BJA due to an administrative error. It was supposed to go into this special issue on Memory and Awareness in Anaesthesia. The article can be accessed free of charge at the following link: http://bja.oxfordjournals.org/lookup/doi/10.1093/bja/aev095 The Publisher apologizes for the error.

T135. Structural connectivity of the human articulatory loop

Introduction Data from electrical stimulation mapping (ESM) have identified areas critical to language function in the left temporal and frontal lobes, and studies of electrocorticography (ECoG) information flow suggest the areas are functionally connected. Yet, the anatomical pathways, especially between the posterior temporal lobe and both the inferior precentral gyrus (iPCG) and the inferior frontal gyrus (IFG), are unclear. We utilized diffusion tensor imaging (DTI) tractography to investigate the white matter tracts connecting ESM-defined language areas. We hypothesized that the posterior middle and superior temporal gyri (pMTG; pSTG) would project directly to the IFG and iPCG, with a bias towards the iPCG, supporting the ECoG findings. Methods 3 Tesla DTI scans were performed on 65 neurosurgical patients (33 males; age: 11.8 ± SD 3.7 y/o). Our group-level ESM probability map was generated via ESM-based determinations of cortical function in vivo from 100 neurosurgical patients with left hemispheric (LH) language dominance. From ESM and anatomy, we generated 8 LH ROIs in 3 domains: Receptive aphasia: pSTG and pMTG; Expressive aphasia: IFG, anterior iPCG (aiPCG), and two middle frontal gyrus (MFG) sites; Speech arrest: posterior iPCG (piPCG) and middle precentral gyrus (mPCG). All ROIs were used as seeds and targets for performing anatomically-constrained probabilistic tractography. The fiber counts between each pair of ROIs were then normalized by ROI volume. Results It was found that the pSTG and pMTG are directly connected with both the IFG and piPCG, with a bias towards the piPCG vs. the IFG ( p p  > .05, r Conclusion Our results demonstrate direct structural connectivity between the pMTG/pSTG and all other ESM-identified language areas. The fiber bundles directly connecting the pSTG with the IFG and piPCG can, in part, support the reciprocal neural interactions which facilitate processing of speech sounds reported in ECoG and fMRI studies of auditory speech perception and articulation. Likewise, the observation of dense interconnecting fibers between 8 ROIs in the frontal and temporal lobes greatly extends a language model beyond the Geschwind model.