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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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).

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.

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.

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.