AimsAlcohol consumption could lead to a series of health problems and social issues. In the current study, we investigated the resting-state functional brain networks of healthy volunteers before and after drinking through graph-theory analysis, aiming to ascertain the effects of acute alcohol intake on topology and information processing mode of the functional brain networks.Materials and methodsThirty-three healthy volunteers were enrolled in this experiment. Each volunteer accepted alcohol breathalyzer tests followed by resting-state magnetic resonance imaging at three time points: before drinking, (...) 0.5 h after drinking, and 1 h after drinking. The data obtained were grouped based on scanning time into control group, 0.5-h group and 1-h group, and post-drinking data were regrouped according to breath alcohol concentration (BrAC) into relative low BrAC group (A group; 0.5-h data, n = 17; 1-h data, n = 16) and relative high BrAC group (B group; 0.5-h data, n = 16; 1-h data, n = 17). The graph-theory approach was adopted to construct whole-brain functional networks and identify the differences of network topological properties among all the groups.ResultsThe network topology of most groups was altered after drinking, with the B group presenting the most alterations. For global network measures, B group exhibited increased global efficiency, Synchronization, and decreased local efficiency, clustering coefficient, normalized clustering coefficient, characteristic path length, normalized characteristic path length, as compared to control group. Regarding nodal network measures, nodal clustering coefficient and nodal local efficiency of some nodes were lower in B group than control group. These changes suggested that the network integration ability and synchrony improved, while the segregation ability diminished.ConclusionThis study revealed the effects of acute alcohol intake on the topology and information processing mode of resting-state functional brain networks, providing new perceptions and insights into the effects of alcohol on the brain. (shrink)

Phillips & Silverstein's focus on schizophrenia as a failure of “cognitive coordination” is welcome. They note that a simple hypothesis of reduced Gamma synchronisation subserving impaired coordination does not fully account for recent observations. We suggest that schizophrenia reflects a dynamic compensation to a core deficit of coordination, expressed either as hyper- or hyposynchronisation, with neurotransmitter systems and arousal as modulatory mechanisms.

Phillips & Silverstein offer an exciting synthesis of ongoing efforts to link the clinical and cognitive manifestations of schizophrenia with cellular accounts of its pathophysiology. We applaud their efforts but wonder whether the highly inclusive notion of “context” adequately captures some important details regarding schizophrenia and NMDA/glutamate function that are suggested by work on language processing and cognitive electrophysiology.

Phillips & Silverstein's ambitious link between receptor abnormalities and the symptoms of schizophrenia involves a certain amount of fuzziness: No detailed mechanism is suggested through which the proposed abnormality would lead to psychological traits. We propose that detailed simulation of brain regions, using model neural networks, can aid in understanding the relation between biological abnormality and psychological dysfunction in schizophrenia.

Although interesting, the hypotheses proposed by Phillips & Silverstein lack unifying structure both in specific mechanisms and in cited evidence. They provide little to support the notion that low-level sensory processing and high-level cognitive coordination share dynamic grouping by synchrony as a common processing mechanism. We suggest that more realistic large-scale modeling at multiple levels is needed to address these issues.

In chronic schizophrenic patients with both positive and negative symptoms (see Table 1), interhemispheric connections at the high frequency beta2-rhythm are absent during cognitive tasks, in contrast to normal controls, who have many interhemispheric connections at this frequency in the same situation. Connectivity is a fundamental brain feature, evidently greatly promoted by the NMDA system. It is a more reliable measure of brain function than the spectral power of this rhythm.

Many kinds of complex systems exhibit characteristic patterns of temporal correlations that emerge as the result of functional interactions within a structured network. One such complex system is the brain, composed of numerous neuronal units linked by synaptic connections. The activity of these neuronal units gives rise to dynamic states that are characterized by specific patterns of neuronal activation and co-activation. These patterns, called functional connectivity, are possible neural correlates of perceptual and cognitive processes. Which functional connectivity patterns arise depends (...) on the anatomical structure of the underlying network, which in turn is modified by a broad range of activity-dependent processes. Given this intricate relationship between structure and function, the question of how patterns of anatomical connectivity constrain or determine dynamical patterns is of considerable theoretical importance. The present study develops computational tools to analyze networks in terms of their structure and dynamics. We identify different classes of network, including networks that are characterized by high complexity. These highly complex networks have distinct structural characteristics such as clustered connectivity and short wiring length similar to those of large-scale networks of the cerebral cortex. (shrink)

Neural Darwinism (ND) is a large scale selectionist theory of brain development and function that has been hypothesized to relate to consciousness. According to ND, consciousness is entailed by reentrant interactions among neuronal populations in the thalamocortical system (the ‘dynamic core’). These interactions, which permit high-order discriminations among possible core states, confer selective advantages on organisms possessing them by linking current perceptual events to a past history of value-dependent learning. Here, we assess the consistency of ND with 16 widely recognized (...) properties of consciousness, both physiological (for example, consciousness is associated with widespread, relatively fast, low amplitude interactions in the thalamocortical system), and phenomenal (for example, consciousness involves the existence of a private flow of events available only to the experiencing subject). While no theory accounts fully for all of these properties at present, we find that ND and its recent extensions fare well. (shrink)

The standard behavioral index for human consciousness is the ability to report events with accuracy. While this method is routinely used for scientific and medical applications in humans, it is not easy to generalize to other species. Brain evidence may lend itself more easily to comparative testing. Human consciousness involves widespread, relatively fast low-amplitude interactions in the thalamocortical core of the brain, driven by current tasks and conditions. These features have also been found in other mammals, which suggests that consciousness (...) is a major biological adaptation in mammals. We suggest more than a dozen additional properties of human consciousness that may be used to test comparative predictions. Such homologies are necessarily more remote in non-mammals, which do not share the thalamocortical complex. However, as we learn more we may be able to make “deeper” predictions that apply to some birds, reptiles, large-brained invertebrates, and perhaps other species. (shrink)

Impairments in cognitive coordination in schizophrenia are supported by phenomenological data that suggest deficits in the processing of visual context. Although the target article is sympathetic to such a phenomenological perspective, we argue that the relevance of phenomenological data for a wider understanding of consciousness in schizophrenia is not sufficiently addressed by the authors.

Numerous searches have failed to identify a single co-occurrence of total blindness and schizophrenia. Evidence that blindness causes loss of certain NMDA-receptor functions is balanced by reports of compensatory gains. Connections between visual and anterior cingulate NMDA-receptor systems may help to explain how blindness could protect against schizophrenia.

Phillips & Silverstein argue that schizophrenia is a result of a deficit of the contextual coordination of neuronal responses. The authors propose that NMDA-receptors control these modulatory effects. However, hallucinations, which are among the principle symptoms of schizophrenia, imply a flaw in the interactions between neurons that is more fundamental than just a general weakness of contextual modulation.

Phillips & Silverstein emphasize the gain-control properties of NMDA synapses in cognitive coordination. We endorse their view and suggest that NMDA synapses play a crucial role in biased attentional competition and (visual) working memory. Our simulations show that NMDA synapses can control the storage rate of visual objects. We discuss specific predictions of our model about cognitive effects of NMDA-antagonists and schizophrenia.

The concept of locally specialized functions dominates research on higher brain function and its disorders. Locally specialized functions must be complemented by processes that coordinate those functions, however, and impairment of coordinating processes may be central to some psychotic conditions. Evidence for processes that coordinate activity is provided by neurobiological and psychological studies of contextual disambiguation and dynamic grouping. Mechanisms by which this important class of cognitive functions could be achieved include those long-range connections within and between cortical regions that (...) activate synaptic channels via NMDA-receptors, and which control gain through their voltage-dependent mode of operation. An impairment of these mechanisms is central to PCP-psychosis, and the cognitive capabilities that they could provide are impaired in some forms of schizophrenia. We conclude that impaired cognitive coordination due to reduced ion flow through NMDA-channels is involved in schizophrenia, and we suggest that it may also be involved in other disorders. This perspective suggests several ways in which further research could enhance our understanding of cognitive coordination, its neural basis, and its relevance to psychopathology. Key Words: attention; cerebral cortex; cognitive coordination; cognitive neuropsychiatry; cognitive neuropsychology; context disorganization; Gamma rhythms; Gestalt theory; glutamate; grouping; memory; NMDA-receptors; PCP-psychosis; perceptual organization; schizophrenia. (shrink)

This commentary highlights methods for using scalp EEG to make inferences about contextual field interactions, which, in view of the target article, may be specially relevant to the study of schizophrenia. Although scalp EEG has limited spatial resolution, prior knowledge combined with experimental manipulations may be used to strengthen inferences about underlying brain processes. Both spatial and temporal context are discussed within the framework of nonlinear interactions. Finally, results from a visual contour integration EEG pilot study are summarized in view (...) of a hypothesis that relates receptive field and contextual field processing to evoked and induced activity, respectively. (shrink)

Although context-processing deficits may be core features of schizophrenia, context remains a poorly defined concept. To test Phillips & Silverstein's model, we need to operationalize context more precisely. We offer several useful ways of framing context and discuss enhancing or facilitating schizophrenic patients' performance under different contextual situations. Furthermore, creativity may be a byproduct of cognitive uncoordination.

Context, connection, and coordination (CCC) describe well where the problems that apply to thought-disordered patients with schizophrenia lie. But they may be part of the experience of those with other symptom constellations. Switching is an important mechanism to allow context to be applied appropriately to changing circumstances. In some cases, NMDA-voltage modulations may be central, but gain and shift are also functions that monoaminergic systems express in CCC.

This commentary challenges the authors to use their computational modeling techniques to support one of their central claims: that schizophrenic deficits in bottom-up (Gestalt-type tasks) and top-down (cognitive control tasks) context processing tasks arise from the same dysfunction. Further clarification about the limits of cognitive coordination would also strengthen the hypothesis.

Schizophrenics exhibit a deficit in theory of mind (ToM), but an intact theory of biology (ToB). One explanation is that ToM relies on an independent module that is selectively damaged. Phillips & Silverstein's analyses suggest an alternative: ToM requires the type of coordination that is impaired in schizophrenia, whereas ToB is spared because this type of coordination is not involved.

Neurophysiological investigations of the past two decades have consistently demonstrated a deficit in sensory gating associated with schizophrenia. Phillips & Silverstein interpret this impairment as being consistent with cognitive coordination dysfunction. However, the physiological mechanisms that underlie sensory gating have not been shown to involve gamma-band oscillations or NMDA-receptors, both of which are critical neural elements in the cognitive coordination model.

Degeneracy is ubiquitous across biological systems where structurally different elements can yield a similar outcome. Degeneracy is of particular interest in neuroscience too. On the one hand, degeneracy confers robustness to the nervous system and facilitates evolvability: Different elements provide a backup plan for the system in response to any perturbation or disturbance. On the other, a difficulty in the treatment of some neurological disorders such as chronic pain is explained in light of different elements all of which contribute to (...) the pathological behavior of the system. Under these circumstances, targeting a specific element is ineffective because other elements can compensate for this modulation. Understanding degeneracy in the physiological context explains its beneficial role in the robustness of neural circuits. Likewise, understanding degeneracy in the pathological context opens new avenues of discovery to find more effective therapies. (shrink)

N-methyl-d-aspartate receptor (NMDAR) dysfunction plays a crucial role in schizophrenia, leading to impairments in cognitive coordination. NMDAR agonists (e.g., glycine) ameliorate negative and cognitive symptoms, consistent with NMDAR models. However, not all types of cognitive coordination use NMDAR. Further, not all aspects of cognitive coordination are impaired in schizophrenia, suggesting the need for specificity in applying the cognitive coordination construct.

We propose that the primary cause of schizophrenia is a pathological extension of synaptic pruning involving local connectivity that unfolds ordinarily during adolescence. Computer simulations suggest that this pathology provides reasonable accounts of a range of symptoms in schizophrenia, and is consistent with recent postmortem and genetic studies. NMDA-receptors play a regulatory role in maintaining and/or eliminating cortical synapses, and therefore may play a pathophysiological role.

This commentary addresses: (a) the problems of definition which have been prominent in the use of the term context in schizophrenia research; (b) potentially useful distinctions and links with other theories of schizophrenic cognition; and (c) possible pathways to schizophrenic symptoms. It is suggested that at least two major aspects of the operation of context may be distinguished and that both may be impaired in schizophrenia.

To understand schizophrenia, a linking hypothesis is needed that shows how brain mechanisms lead to behavioral functions in normals, and also how breakdowns in these mechanisms lead to behavioral symptoms of schizophrenia. Such a linking hypothesis is now available that complements the discussion offered by Phillips & Silverstein (P&S).

Reductionist explanations in biology generally assume that biological mechanisms are highly deterministic and basically similar between individuals. A contrasting view has emerged recently that takes into account the degeneracy of biological processes—the ability to arrive at a given endpoint by a variety of available paths, even within the same individual. This perspective casts significant doubt on the prospects for the ability to predict behavior accurately based on brain imaging or genotyping, and on the ability of neuroscience to stipulate ethics.

The Phillips & Silverstein model of NMDA-mediated coordination deficits provides a useful heuristic for the study of schizophrenic cognition. However, the model does not specifically account for the development of schizophrenia-spectrum disorders. The P&S model is compared to Meehl's seminal model of schizotaxia, schizotypy, and schizophrenia, as well as the model of schizophrenic cognitive dysfunction posited by McCarley and colleagues.

In approaching the question of whether groups of people can have cognitive capacities that are fundamentally different than the cognitive capacities of the individuals within the group, we lay out a Multiple, Interactive Levels of Cognitive Systems (MILCS) framework. The goal of MILCS is to explain the kinds of cognitive processes typically studied by cognitive scientists, such as perception, attention, memory, categorization, decision making, problem solving, and judgment. Rather than focusing on high-level constructs such as modules in an information processing (...) flow diagram or internal representations, MILCS focuses on mechanisms that allow systems to engage in flexible, adaptive behavior. Examples of these mechanisms are network structure-process pairs that: combine data from perception with top-down theories, achieve consistency and consensus through information exchange, selectively attend to information globally assessed as relevant, and develop specialized units from originally homogeneous networks through competition among the units. Two such systems are considered in some detail -- lateral inhibition within a network for selecting from a candidate set the option that is most attractive, and a diffusion process for accumulating evidence to reach a generally rapid and accurate decision. These system descriptions are aptly applied at multiple levels, including within and across people. These systems provide accounts that unify cognitive processes across multiple levels, can be expressed in a common vocabulary provided by network science, are inductively powerful yet appropriately constrained, and are applicable to a large number of superficially diverse cognitive systems. Given that people are typically highly motivated to participate in strong groups, cognitively resourceful people will tend to form groups that effectively employ cognitive systems at higher levels than the individuals. The impressive cognitive capacities of individual people do not eliminate the need to talk about group cognition. Instead, smart people generally form smart groups. (shrink)

The claim that the disorganized subtype of schizophrenia results from glutamate hypofunction is enhanced by consideration of current subtypology of schizophrenia, symptom definition, interdependence of neurotransmitters, and the nature of the data needed to support the hypothesis. Careful specification clarifies the clinical reality of disorganization as a feature of schizophrenia and increases the utility of the subtype.

This paper describes how Tononi’s information integration theory of consciousness was used to make detailed predictions about the distribution of phenomenal states in a spiking neural network. This network had approximately 18,000 neurons and 700,000 connections and it used models of emotion and imagination to control the eye movements of a virtual robot and avoid ‘negative’ stimuli. The first stage in the analysis was the development of a formal definition of Tononi’s theory of consciousness. The network was then analysed for (...) information integration and detailed predictions were made about the distribution of consciousness for each time step of recorded activity. This work demonstrates how an artificial system can be analysed for consciousness using a particular theory and in the future this approach could be used to make predictions about the phenomenal states associated with biological systems. (shrink)

Mechanisms that contribute to perceptual processing dysfunction in schizophrenia were examined by Phillips & Silverstein, and formulated as involving disruptions in both local and higher-level coordination of signals. We agree that dysfunction in the coordination of cognitive functions (disconnection) is also indicated for many of the linguistic processing deficits documented for schizophrenia. We suggest, however, that it may be necessary to add a timing mechanism to the theoretical account.

Evidence for a dysfunction in cognitive coordination in schizophrenia is emerging, but it is not specific enough to prove (or disprove) this long-standing hypothesis. Many aspects of the external world are spatially mapped in the brain. A comprehensive internal representation relies on integration of information across space. Focus on spatial integration in the perceptual and cognitive processes will generate empirical data that shed light on the pathophysiology of schizophrenia.

It is proposed that cortical activity is normally coordinated across synaptically connected areas and that this coordination supports cognitive coherence relations. This view is consistent with the NMDA- hypoactivity hypothesis of the target article in regarding disorganization symptoms in schizophrenia as arising from disruption of normal interareal coordination. This disruption may produce abnormal contextual effects in the cortex that lead to anomalous cognitive coherence relations.

Phillips & Silverstein argue that a range of cognitive disturbances in schizophrenia result from a deficit in cognitive coordination attributable to NMDA receptor dysfunction. We suggest that the viability of this hypothesis would be further supported by explicit implementation in a computational framework that can produce quantitative estimates of the behavior of both healthy individuals and individuals with schizophrenia.

The target article presents a model for schizophrenia extending four levels of abstraction: molecules, cells, cognition, and syndrome. An important notion in the model is that of coordination, applicable to both the level of cells and of cognition. The molecular level provides an “implementation” of the coordination at the cellular level, which in turn underlies the coordination at the cognitive level, giving rise to the clinical symptoms.

This commentary compares clinical aspects of ketamine with the amphetamine model of schizophrenia. Hallucinations and loss of insight, associated with amphetamine, seem more schizophrenia-like. Flat affect encountered with ketamine is closer to the clinical presentation in schizophrenia. We argue that flat affect is not a sign of schizophrenia, but rather, a risk factor for chronic schizophrenia.

Resting state networks comprise several brain regions that exhibit complex patterns of interaction. Switching from eyes closed (EC) to eyes open (EO) during the resting state modifies these patterns of connectivity, but precisely how these change remains unclear. Here we use functional magnetic resonance imaging to scan healthy participants in two resting conditions (viz., EC and EO). Seven resting state networks were chosen for this study: salience network (SN), default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), (...) visual network (VN), motor network (MN) and auditory network (AN). We performed functional connectivity (FC) analysis for each network, comparing the FC maps for both EC and EO. Our results show increased connectivity between most networks during EC relative to EO, thereby suggesting enhanced integration during EC and greater modularity or specialization during EO. Among these networks, SN is distinctive: during the transition from EO to EC it evinces increased connectivity with DMN and decreased connectivity with VN. This change might imply that SN functions in a manner analogous to a circuit switch, modulating resting state relations with DMN and VN, when transitioning between EO and EC. (shrink)

Arguably the most remarkable property of the human brain is its ability to construct the world that appears to consciousness. The brain is capable of building worlds during waking life, but also in the complete absence of extrinsic sensory data, entirely from intrinsic thalamocortical activity, as during dreaming. DMT, an extraordinary psychedelic, perturbs brain activity such that indescribably bizarre and apparently alien worlds are built. This property of DMT continues to defy explanation. However, by regarding this unique molecule as equivalent (...) to serotonin, an endogenous neuromodulator with a long-standing relationship with the brain, DMT's effects may be explained. Serotonin has evolved to hold the brain's thalamocortical system in a state in which the consensus world is built. When serotonin is replaced by DMT, the thalamocortical system shifts into an equivalent state, but one in which an apparently alien world is built. This suggests that DMT may be an ancestral neuromodulator, at one time secreted endogenously in psychedelic concentrations-a function apparently now lost. However, DMT maintains a number of unique pharmacological characteristics and a peculiar affinity with the human brain that supports this model. Thus, the modern practice of ingesting exogenous DMT may be the reconstitution of an ancestral function. (shrink)

This article provides a retrospective, current and prospective overview on developments in brain research and neuroscience. Both theoretical and empirical studies are considered, with emphasis in the concept of multivariability and metastability in the brain. In this new view on the human brain, the potential multivariability of the neuronal networks appears to be far from continuous in time, but confined by the dynamics of short-term local and global metastable brain states. The article closes by suggesting some of the implications of (...) this view in future multidisciplinary brain research. (shrink)