Context-sensitivity has been studied in paradigms that are many and various. But do these paradigms reflect any common underlying processes? This issue can be studied by looking for basic physiological mechanisms that could implement various forms of context-sensitivity, and by studying the consequences of their malfunction. Companion papers by Javitt et al. [1] and Umbricht et al. [2] use this strategy to make major advances towards solving these problems. In doing so they could also lay foundations for a better understanding of some common psychiatric disorders.

Context-sensitivity was studied concurrently in post-attentive visual processing and in pre-attentive auditory processing, in both healthy subjects (in Umbricht et al.) and schizophrenic patients (Javitt et al.). Letters were presented at a rate of 1/s on a computer monitor and subjects were asked to press a button whenever they saw an X, but only if it followed an A (the "AX-Continuous Performance Task" or AX-CPT). Each letter thus formed a context that modulated the response to the next letter.

Irrelevant auditory tones were also presented while subjects performed the AX-CPT. Most were of a standard pitch and duration, but some deviated in either pitch or duration. Event-related potentials (ERP) were recorded by an array of 36 scalp electrodes. Such recordings usually show that deviant tones produce larger negative potentials in auditory sensory cortex than standards. This is called mismatch negativity (MMN). Prior tones thus form a context that automatically reduces cortical sensory responses to standards and increases responses to deviants.

Many human and animal studies provide evidence that contextual modulation involves NMDA-receptors for glutamate, which is the major excitatory neurotransmitter. In their paper, Umbricht et al. examined this possibility by giving healthy volunteers sub-anaesthetic doses of ketamine, which impairs NMDA function. Their placebo-controlled study showed that ketamine caused more errors to BX sequences than to AY sequences in the AX-CPT; that is, letters other than A failed to inhibit the well-rehearsed button-press response to Xs. This shows that ketamine produces a selective deficit of the form of context-sensitivity involved in the AX-CPT. Two different inter-stimulus intervals were used, but the effects of this variable did not interact with drug treatment, showing that the ketamine effect was not the result of more rapid forgetting. ERP measures showed that, as predicted, ketamine also decreased the amplitude of the MMN, but did not affect the context-independent components of the ERP response. Thus, ketamine also produced a selective deficit in the form of context-sensitivity underlying MMN.

Javitt et al. used the same combined AX-CPT and MMN paradigm with schizophrenia patients, because there is a rapidly growing body of evidence suggesting that they have impairments in both context-sensitivity and NMDA-mediated neurotransmission. Even though they were not given ketamine, essentially the same results were obtained with the schizophrenic patients as in the healthy subjects who had been given the drug.

These findings have important implications. A single pharmacological treatment produced selective impairments of context-sensitivity in both post-attentive visual processing and pre-attentive auditory processing. The results indicate that different forms of context-sensitivity are implemented by common physiological mechanisms that include NMDA-receptors, and they suggest that both these mechanisms and the functions that they could provide are impaired in schizophrenia. Furthermore, some of the cognitive deficits that are associated with schizophrenia can be produced within minutes in healthy volunteers by a temporary and reversible disturbance of neurochemistry. In both the pre- and the post-attentive tests, the relevant contextual information in these studies was provided by preceding stimuli. There are good reasons to suppose that concurrent stimuli can also act as a context, however, so one important task for the future is to study both pre- and post-attentive effects of concurrent context using the general approach pioneered by these researchers.