Preattentional and attentional cognitive deficits as targets for treating schizophrenia

Abstract

Background and rationale: Pharmacotherapy of schizophrenia has traditionally targeted positive psychotic symptoms. An emerging view is that developing medications that improve cognition in schizophrenia patients is a major step forward in achieving better functional outcome. The cognitive deficits that are often observed in schizophrenia can be assessed using (1) neuropsychological tests; and (2) neurophysiological tests, the topic of this article. These neurophysiological measures cover a spectrum from automatic preattentional to attention-dependent processes. Objectives: This article focuses on cognitive deficits that appear to be promising targets for a new "third generation" of medications that may be used to treat schizophrenia and other patients with specific deficits in cognition and functioning. We discuss the possible use of the following six measures of preattentional and attention-dependent cognitive deficits: mismatch negativity, P50 event-related potential suppression, prepulse inhibition of the startle response, P300 event-related potential, continuous performance task performance, and oculomotor antisaccade performance. Conclusions: The use of preattentional and attention-dependent measures offer unique opportunities to improve our armamentarium of pharmacologic strategies for the treatment of cognitive deficits in schizophrenia patients. This review illustrates the usefulness of these measures as targets for existing and new antipsychotic medications that will potentially (1) characterize the cognitive deficits that occur in schizophrenia patients and (2) assess medication-related improvement on these measures and the potential associated improvement in functional outcome.

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

“…A similar mechanism could govern the regulation of PPI by the LC-NE system, with hyperactivation of LC resulting in the stimulation of a1 receptors via enhanced NE release in terminal regions. Importantly, disruption of PPI and working memory are two of the cardinal features observed in schizophrenia patients, and are thought to provide operational measures for the information-processing deficits that are hypothesized to contribute to the pathophysiology of this illness (Arnsten, 2004;Braff and Light, 2004). The present results thus further strengthen the notion that central a1 receptors may regulate cognitive processes that are deficient in psychiatric illnesses such as schizophrenia.…”

“…PPI refers to the normal diminution of the startle response when the startling stimulus is preceded immediately by a weak intensity prepulse, and is deficient in a number of psychiatric illnesses that involve disturbed sensorimotor gating, including schizophrenia (Braff et al, 1978;Hoffman and Ison, 1980;Ison and Hoffman, 1983). Sensorimotor gating, as indexed by PPI, represents an important form of preattentional information processing that is critical for the maintenance of selective attention and normal cognitive functioning (Braff and Light, 2004). A breakdown in PPI can thus have devastating effects, contributing to the sensory inundation and cognitive fragmentation that are often seen in disorders such as schizophrenia McGhie and Chapman, 1961).…”

Mismatch negativity is a breakthrough biomarker for understanding and treating psychotic disorders

“…The collection of findings indicate that MMN-a low-cost, fast, and well-tolerated EEG-based translational biomarker-offers great promise for contributing to the continued development of pharmacologic and nonpharmacologic therapeutics (32). Moreover, MMN biomarker-informed prediction and treatment algorithms have the potential to pave the way for a next generation of "precision medicine" and perhaps even preemptive treatment approaches (1, 2).…”

Toward a Neuro-Cognitive Animal Model of the Cognitive Symptoms of Schizophrenia: Disruption of Cortical Cholinergic Neurotransmission Following Repeated Amphetamine Exposure in Attentional Task-Performing, but Not Non-Performing, Rats

“…Based on the fundamental role of attentional processes for learning and general cognitive control, attentional dysfunctions have been considered a central and even essential characteristic of schizophrenia (Braff, 1993;Braff and Light, 2004;Braver et al, 1999;Keefe et al, 2006;McGhie and Chapman, 1961;Nuechterlein et al, 1994;Venables, 1964).…”