Search

We are all intuitively aware that when we are under stress, we think differently and often less well than when we are calmer. The study by Chiapelli et al1 in this issue of the journal addresses some of the critical links underlying the effects of stress on cognition. In particular, their study highlights the effects of stress on circulating kynurenic acid (KYNA) levels in patients with schizophrenia, as measured in saliva, and the interaction of KYNA with persistence during cognitive testing. The main findings of the study1 are (1) that schizophrenic patients as a group showed increased KYNA levels when performing stress-inducing cognitive tasks and (2) that the higher levels of KYNA were associated with an increased likelihood of terminating the tasks early, an effect termed distress intolerance. Kynurenic acid is one of the primary metabolites of the amino acid tryptophan. At the center of the study by Chiapelli et al1 is the basic observation, made more than 50 years ago, that stress of many kinds modulates the expression of one of the main enzymes, tryptophan 2,3-dioxygenase, that converts tryptophan to kynurenine in the liver.2–4 Kynurenine is then actively transported into the brain and metabolized in astrocytes to KYNA. Many others factors, including inflammation, also affect kynurenine pathway metabolism, so elevations of kynurenine and KYNA are observed in a great many inflammatory and neoplastic disorders, as well as in conditions (such as stress) that modulate kynurenine pathway metabolism via the glucocorticoid system. Interestingly, as discussed in the study by Chiapelli et al,1 despite deriving from a metabolic pathway totally separate from that involved in either acetylcholine or glutamate metabolism, KYNA in the brain inhibits with both α7 nicotinic and N-methyl-D-aspartate–type glutamate receptors to influence brain function.3,4 As expected, therefore, when elevated, KYNA impairs sensory gating and various types of cognitive functions. Over the years, many different types of stress have been used to induce KYNA metabolism, including physical manipulations, such as cold stressors,2 and difficult mental manipulations, such as cognitive testing, as in the study by Chiapelli et al.1 A central question to this line of research is why evolution has selected for kynurenine metabolism to be sensitive to circulating glucocorticoid levels. One possibility is that the primary consequence of kynurenine pathway upregulation is the shunting of tryptophan metabolism away from serotonin synthesis, which could potentially lead to depressive behaviors. Darwin argued that depressive responses to stress may act to conserve resources when resource expenditure would not be beneficial. However, the fact that KYNA affects cognition directly argues that stress effects on KYNA metabolism may also be evolutionarily beneficial. One effect of KYNA, for example, is to decrease cognitive flexibility.3,4 While reduced cognitive flexibility is usually considered a negative, when one is being exposed to an aversive stimulus such as a cold pressor, it could be that the time for deep thinking has passed and the time for immediate action has arrived. The fact that there is a glucocorticoid-sensitive element built into the promotor for tryptophan 2,3-dioxygenase may be testament to the fact that, in many situations, individuals who thought less and acted were more likely to live to think (and reproduce) another day. The effect of stress on cognition is also not limited to psychiatric conditions. For example, it has recently been reported that stockbrokers exposed to higher market volatility show elevations in glucocorticoids and that, when induced experimentally, such elevations correlate with an increase in “risk aversion” during trading.5 Moreover, the effects of stress on brain function are not mediated solely through the kynurenine pathway system. For example, glucocorticoids have direct effects on glutamate transmission at both presynaptic and postsynaptic sites,6 providing an alternative pathway by which stress could lead to alterations in cognition. Finally, it has been suggested that stress responses, in general, may be divided into those that are “hawklike,” which involve fight-flight decisions mediated primarily by the sympathetic nervous system, and those that are “dovelike,” which involve freeze-hide behaviors mediated by glucocorticoid effects.7 To the extent that distress intolerance may be viewed as an example of freeze-hide behavior, the present findings suggest that elevations in KYNA may play a role in alterations in brain function involved in glucocorticoid-induced behavioral response patterns. As noted previously by these authors and others, both schizophrenia and bipolar disorder are associated with increased cerebrospinal fluid and postmortem KYNA levels that are associated with polymorphisms of kynurenine 3-monooxygenase, the enzyme that converts kynurenine to 3-hydroxykynurenine and away from KYNA.8,9 In the study by Chiapelli et al,1 no differences in salivary KYNA were observed between groups at reset. Therefore, the relationship between stress-induced changes in salivary KYNA levels, as measured in this study,1 and more tonic alterations in cerebrospinal fluid KYNA levels may require further clarification. Nevertheless, there are several important take-home messages. First, the study1 highlights that patients may be more stressed than controls, even by simple tasks such as mental arithmetic or mirror drawing. This must be taken into account when asking patients to participate in other mentally demanding activities, such as cognitive remediation or supported employment. Patients, in general, may have difficulty reporting their emotions, including subjective feelings of stress. Monitoring salivary KYNA levels, potentially along with glucocorticoid levels, may provide additional information as to the subjective stress experienced by an individual and might help identify individuals who would benefit from additional supportive therapy. Second, many of the enzymes involved in kynurenine metabolism are inherently “druggable.” These include not only tryptophan 2,3-dioxygenase and kynurenine 3-monooxygenase, but also kynurenine aminotransferase,10 the enzyme that converts kynurenine to KYNA. Given the complexity of these systems, it is difficult to know whether or not the net effects of such interventions would be beneficial. Nevertheless, a naive expectation is that acute alterations of behavior by stress systems may be evolutionarily advantageous but that chronic activations are unlikely to be so advantageous. Thus, for individuals with chronic KYNA elevations, whether due to genetic variation or simply to circumstance, pharmacological manipulation of the kynurenine pathway may be therapeutically beneficial.

Context: The AX version of the visual continuous performance task (AX-CPT) is widely used for investigating visual working memory dysfunction in schizophrenia. Event-related potentials (ERP) provide an objective index of brain function and can be used to evaluate brain substrates underlying impaired cognition in schizophrenia. Objective: To assess the mechanisms that underlie visual working memory dysfunction in schizophrenia relative to impairment of early visual processing. Design: Case-control study. Setting: Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. Participants: A total of 30 individuals with schizophrenia and 17 healthy comparison subjects. Interventions: Three versions of the AX-CPT, with parametric variations in the proportions of trial types, were used to test performance and underlying neural activity during differential challenge situations. Contrast sensitivity measures were obtained from most subjects. Main Outcome Measures: Behavioral performance was assessed using d context scores. Integrity of stimulusand task-related cortical activation to both cue and probe stimuli was assessed using sensory (C1, P1, N1) and cognitive (N2, contingent negative variation [CNV]) ERP components. Early magnocellular/parvocellular function was assessed using contrast sensitivity. Linear regression and path analyses were used to assess relations between physiological and behavioral parameters. Results: Patients showed reduced amplitude of both early sensory (P1, N1) and later cognitive (N2, CNV) ERP components. Deficits in sensory (N1) and cognitive (N2) component activation to cue stimuli contributed independently to impaired behavioral performance. In addition, sensory deficits predicted impaired cognitive ERP generation. Finally, deficits in performance correlated with impairments in contrast sensitivity to low, but not high, spatial frequency stimuli. Conclusions: Working memory deficits in schizophrenia have increasingly been attributed to impairments in stimulus encoding rather than to failures in memory retention. This study provides objective physiological support for encoding hypotheses. Further, deficits in sensory processing contribute significantly to impaired working memory performance, consistent with generalized neurochemical models of schizophrenia.

Context: The imperative to establish so-called endophenotypes—quantifiable measures of risk for neurological dysfunction—is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests. Objective: Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability. Design, Setting, and Participants: Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV– diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent’s Psychiatric Hospital in Fairview, Dublin, Ireland. Results: Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives. Conclusions: Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal. Arch Gen Psychiatry. 2006;63:1180-1188

Patients with schizophrenia show deficits in early-stage visual processing, potentially reflecting dysfunction of the magnocellular visual pathway. The magnocellular system operates normally in a nonlinear amplification mode mediated by glutamatergic (N-methyl-D-aspartate) receptors. Investigating magnocellular dysfunction in schizophrenia therefore permits evaluation of underlying etiologic hypotheses.To evaluate magnocellular dysfunction in schizophrenia, relative to known neurochemical and neuroanatomical substrates, and to examine relationships between electrophysiological and behavioral measures of visual pathway dysfunction and relationships with higher cognitive deficits.Between-group study at an inpatient state psychiatric hospital and outpatient county psychiatric facilities. Thirty-three patients met DSM-IV criteria for schizophrenia or schizoaffective disorder, and 21 nonpsychiatric volunteers of similar ages composed the control group.(1) Magnocellular and parvocellular evoked potentials, analyzed using nonlinear (Michaelis-Menten) and linear contrast gain approaches; (2) behavioral contrast sensitivity measures; (3) white matter integrity; (4) visual and nonvisual neuropsychological measures, and (5) clinical symptom and community functioning measures.Patients generated evoked potentials that were significantly reduced in response to magnocellular-biased, but not parvocellular-biased, stimuli (P = .001). Michaelis-Menten analyses demonstrated reduced contrast gain of the magnocellular system (P = .001). Patients showed decreased contrast sensitivity to magnocellular-biased stimuli (P.001). Evoked potential deficits were significantly related to decreased white matter integrity in the optic radiations (P.03). Evoked potential deficits predicted impaired contrast sensitivity (P = .002), which was in turn related to deficits in complex visual processing (Por =.04). Both evoked potential (Por =.04) and contrast sensitivity (P = .01) measures significantly predicted community functioning.These findings confirm the existence of early-stage visual processing dysfunction in schizophrenia and provide the first evidence that such deficits are due to decreased nonlinear signal amplification, consistent with glutamatergic theories. Neuroimaging studies support the hypothesis of dysfunction within low-level visual pathways involving thalamocortical radiations. Deficits in early-stage visual processing significantly predict higher cognitive deficits.

Background Schizophrenia is associated with well-documented deficits in high-order cognitive processes such as attention and executive functioning. The integrity of sensory-level processing, however, has been evaluated only to a limited degree. Our study evaluated the ability of patients with schizophrenia to recognize complete objects based on fragmentary information, a process termed perceptual closure. Perceptual closure processes are indexed by closure negativity (N cl ), a recently defined event-related potential(ERP) component that is generated within the visual association cortex. This study assessed the neural integrity of perceptual closure processes in schizophrenia by examining N cl generation. Generation of the preceding positive(P1) and negative (N1) ERP components was also examined. Methods We evaluated 16 patients with chronic schizophrenia and 16 healthy comparison subjects. Successively less fragmented images were presented during high-density ERP recording, which permitted the monitoring of brain activity during perceptual closure processes prior to object recognition. Analyses were performed at parieto-occipital and occipitotemporal sites consistent with dorsal and ventral stream generators of P1, N1, and N cl . Results Patients with schizophrenia showed significant impairment in the ability to recognize fragmented objects, along with impaired generation of N cl . The amplitude of visual P1 was significantly reduced, particularly over dorsal stream sites. In contrast, the generation of visual N1 was intact. Conclusions Patients with schizophrenia are profoundly impaired in perceptual closure as indicated by both impaired performance and impaired N cl generation. The selective impairment in dorsal stream P1 is consistent with prior reports of impaired magnocellular processing in schizophrenia. By contrast, intact ventral N1 generation suggests that the initial stages of ventral stream processing are relatively preserved and that impaired magnocellular dorsal stream functioning in schizophrenia may lead to secondary dysregulation of ventral stream object recognition processing.

Schizophrenia is associated with large effect-size deficits in auditory sensory processing, as reflected in impaired delayed-tone matching performance. The deficit may reflect either impaired sensory precision, which would be indicative of neural dysfunction within auditory sensory (temporal) regions, or of increased distractibility, which would be indicative of impaired prefrontal function. The present study evaluates susceptibility of schizophrenic subjects to same-modality distraction to determine whether patients fit a "bitemporal" or "prefrontal" model of sensory dysfunction.Tone-matching ability was evaluated in 15 first-episode patients, 18 outpatients with chronic illness, and 21 patients in long-term residential care, relative to 32 nonpsychiatric controls of a similar age. A staircase procedure determined individual thresholds for attaining criterion level correct performance.Tone-matching thresholds in the absence of distractors were significantly elevated in patients in long-term residential care relative to all other groups (P.001). The effect size (d) of the difference relative to controls was extremely large (SD, 1.95). Schizophrenic patients, even those with elevated tone-matching thresholds, showed no increased susceptibility to auditory distraction (P =.42). Deficits in tone-matching performance in subjects with chronic illness could not be attributed to medication status or level of symptoms.These findings suggest that sensory processing dysfunction in schizophrenia is particularly severe in a subgroup of patients who can be considered poor-outcome based on their need for long-term residential treatment. Furthermore, the absence of increased auditory distractibility argues against prefrontal dysfunction as an origin for auditory sensory imprecision in schizophrenia. Arch Gen Psychiatry. 2000;57:1149-1155.

Background Disturbances of N -methyl-D-aspartate (NMDA) receptor–mediated glutamatergic neurotransmission may play an important role in the pathophysiology of negative symptoms of schizophrenia. Glycine, a small nonessential amino acid, functions as an obligatory coagonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor–mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia. Methods Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication. Clinical assessments, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Simpson-Angus Scale for Extrapyramidal Symptoms, and the Abnormal Involuntary Movement Scale, were performed biweekly throughout the study. Clinical laboratory values and amino acid serum levels were monitored. Results Glycine treatment was well tolerated and induced increased glycine ( P =.001) and serine ( P =.001) serum levels. Glycine administration resulted in (l) a significant ( P P r =0.80) clinical response. Conclusion These findings support hypoglutamatergic hypotheses of schizophrenia and suggest a novel approach for the pharmacotherapy of negative symptoms associated with this illness.