Timing matters in elaborative processing of positive stimuli: Gamma band reactivity in schizophrenia compared to depression and healthy adults.

Some individuals with schizophrenia report similar feelings of positive affect "in the moment" compared to control participants but report decreased trait positive affect overall. One possible explanation for this disconnection between state and trait positive affect is the extent to which individuals with schizophrenia engage in elaborative processing of positive stimuli. To assess this, we examined evoked gamma band activity in response to positive words over several seconds in a group with schizophrenia, a group with major depressive disorder, and a healthy control group. From a pre-stimulus baseline to 2000 ms after onset of the stimulus (henceforth, "early period"), the schizophrenia group showed a reliable increase in gamma activity compared to both the control and depressed groups, who did not differ from each other. In contrast, the depressed group showed a reliable increase in gamma activity from 2001 to 8000 ms (henceforth, "late period") compared to the other groups, who did not differ from each other. At the same time, the schizophrenia group showed a reliable decrease from the early to late period while the depressed group showed the opposite pattern. In addition, self-reported depression and social anhedonia in the schizophrenia group were related to decreased gamma band activity over the entire processing window. Overall, these results suggest that schizophrenia is associated with increased initial reactivity but decreased sustained elaborative processing over time, which could be related to decreased trait positive affect. The results also highlight the importance of considering depressive symptomology and anhedonia when examining emotional abnormalities in schizophrenia.

Prevalence and Specificity of the Abnormal Niacin Response: A Potential Endophenotype Marker in Schizophrenia.

The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families, appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may prove to be a useful SZ endophenotype. Using a laser Doppler flowmeter, we undertook this study to estimate the prevalence of NRA in SZ (n = 70), bipolar disorder (BP, n = 59), and healthy control (HC, n = 87) groups, and to estimate its specificity for the illness. From the dose-response curves, we calculated the concentration of methylnicotinate required to elicit a half-maximal blood flow (MBF) response (EC50 value) and MBF value for each subject. The median log10EC50 of the SZ was above the third quartile of log10EC50 of either the HC or BP groups, whereas the MBF was significantly lower in the SZ than in the HC or BP groups. With a definition of NRA of having both EC50 above the ninetieth percentile of the control samples and MBF response below the sixtieth percentile for the control range, the NRA predicted SZ with 31% sensitivity and 97% specificity. Moreover, the NRA was not influenced by age, gender, race, and cigarette smoking. In summary, the NRA may define a SZ subtype with a clinically significant phospholipid signaling defect. Understanding its molecular origins may shed light on the pathophysiology of SZ and suggest new tools for its early diagnosis and treatment.

Pharmacological Isolation of Cognitive Components Influencing the Pupillary Light Reflex.

Cognitive operations can be detected by reduction of the pupillary light response. Neurophysiological pathways mediating this reduction have not been distinguished. We utilized selective blockade of pupillary sphincter or dilator muscles to isolate parasympathetic or sympathetic activity during cognition, without modifying central processes. Pupil diameter was measured during the light reaction in 29 normal adults under three processing levels: No Task, during an easy task (Add 1), or a difficult task (Subtract 7). At three separate sessions, the pupil was treated with placebo, tropicamide (blocking the muscarinic sphincter receptor), or dapiprazole (blocking the adrenergic dilator receptor). With placebo, pupil diameter increased with increasing task difficulty. The light reaction was reduced only in the Subtract 7 condition. Dapiprazole (which decreased overall diameter) showed similar task-related changes in diameter and light reflex as for placebo. Following tropicamide (which increased overall diameter), there was a further increase in diameter only in the difficult task. Findings suggest two separate inhibitory components at the parasympathetic oculomotor center. Changes in baseline diameter are likely related to reticular activation. Inhibition of the light reaction in the difficult task is likely associated with cortical afferents. Sustained sympathetic activity also was present during the difficult task.

Associations between purine metabolites and clinical symptoms in schizophrenia.

BACKGROUND: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions. CONCLUSIONS/SIGNIFICANCE: Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.

Cognition, dopamine and bioactive lipids in schizophrenia.

Schizophrenia is a remarkably complex disorder with a multitude of behavioral and biological perturbations. Cognitive deficits are a core feature of this disorder, and involve abnormalities across multiple domains, including memory, attention, and perception. The complexity of this debilitating illness has led to a view that the key to unraveling its pathophysiology lies in deconstructing the clinically-defined syndrome into pathophysiologically distinct intermediate phenotypes. Accumulating evidence suggests that one of these intermediate phenotypes may involve phospholipid signaling abnormalities, particularly in relation to arachidonic acid (AA). Our data show relationships between levels of AA and performance on tests of cognition for schizophrenia patients, with defects in AA signaling associated with deficits in cognition. Moreover, dopamine may moderate these relationships between AA and cognition. Taken together, cognitive deficits, dopaminergic neurotransmission, and bioactive lipids have emerged as related features of schizophrenia. Existing treatment options for cognitive deficits in schizophrenia do not specifically target lipid-derived signaling pathways; understanding these processes could inform efforts to identify novel targets for treatment innovation.

Effects of word frequency on semantic memory in schizophrenia: electrophysiological evidence for a deficit in linguistic access.

BACKGROUND: Abnormal storage and/or access are among the hypothesized causes of semantic memory deficit in schizophrenia. Neuropsychological and connectionist models have emphasized functional systems that serve the processing of word meaning and frequency: semantic storage disturbance is presumed to result from weak representations of word meaning; defective access is assumed to result from compromises to pathways that activate word frequency knowledge. Candidate biological systems include neuromodulatory pathways that normally function to enhance neural signals (e.g., cholinergic system). Electrophysiological responding may be informative regarding the storage-access distinction for schizophrenia. METHODS: Visual event-related potentials were recorded for 14 schizophrenia outpatients receiving atypical antipsychotics, and 14 healthy controls group-matched to patients on age, gender, and demographics. N400 was elicited using an incidental semantic priming paradigm, in which semantic relatedness and word frequency were varied, and a letter probe task. RESULTS: Compared to controls, patients showed reduced N400 (microV) discrimination of semantic relatedness. Groups also showed different patterns of N400 to word frequency. Controls' N400 increased in negativity as words decreased in frequency of occurrence, while patients did not show a linear relationship between N400 and word frequency. Groups also differed for N400 to frequently occurring words. Patients exhibited increased negativity to high and very high frequency words, compared to controls. A subgroup of patients receiving antipsychotics with known affinity binding for muscarinic receptors (clozapine and olanzapine) showed significant albeit limited N400 priming, but their N400 to word frequency remained nonsignificant. CONCLUSIONS: Results suggest a deficit in semantic access for schizophrenia, as well as an influence of neuromodulators on the activation of connections among semantic representations. Cumulative findings indicating only limited N400 priming for patients receiving either typical or atypical antipsychotics support the hypothesis that semantic memory deficit represents a trait marker for schizophrenia.

Sustained gamma-band EEG following negative words in depression and schizophrenia.

INTRODUCTION: Sustained and elaborative emotional information processing in depression and decreased affective elaboration in schizophrenia are considered hallmarks of these disorders but have not been directly measured. Gamma-band (35-45 Hz) EEG has been associated with semantic functions such as feature binding and may index these elaborative processing. This study examined whether there were group differences in baseline and sustained gamma-band EEG following emotional stimuli in healthy adults as well as adults with depression and schizophrenia. METHODS: 24 never-depressed healthy controls, 14 patients with DSM-IV unipolar major depressive disorder, and 15 patients with DSM-IV schizophrenia completed a lexical emotion identification task during EEG assessment. Gamma-band (35-45 Hz) EEG in response to negative words was the primary dependent measure. RESULTS: As predicted, depressed individuals displayed sustained and increased gamma-band EEG throughout the task, and particularly in the seconds following negative words. Individuals with schizophrenia displayed decreased gamma-band activity throughout the task. CONCLUSIONS: These data suggest that gamma-band EEG, measured over several seconds, may serve as a useful index of sustained semantic information processing. Depressed individuals appear to engage in sustained elaboration following emotional stimuli, whereas individuals with schizophrenia are not as prone to this type of elaborative processing.

Semantic memory in schizophrenia: association with cell membrane essential fatty acids.

INTRODUCTION: Semantic memory and language deficits are associated with schizophrenia. Understanding how these systems operate in this disorder will likely require a multi-factorial model that explains their linkages with cognition and modulation by dopamine. A biological factor that may provide causal convergence for these connections is cell membrane composition and dynamics. METHODS: N400 is an electrophysiological measure of semantic memory and language that is sensitive to deficits in schizophrenia. Relationships among N400, cognition, dopamine, and cell membrane polyunsaturated fatty acids (PUFAs) were examined for patients tested under medicated (haloperidol only) and unmedicated (placebo) conditions. Relationships between these factors and clinical symptoms were also evaluated. The sample included 37 male schizophrenia inpatients and 34 male normal controls. The N400 priming effect was measured from visual event-related potentials recorded during a semantic priming-lexical decision task, in which semantic association (related versus unrelated words) and presentation rate (Stimulus Onset Asynchrony/SOAs: 350 and 950 ms) were varied. RESULTS: N400 was associated with cognition (speed, visuoperception, attention) in patients and controls. These relationships were influenced by SOA in both groups, and by pharmacological condition in patients. Levels of total PUFAs and arachidonic acid were associated with N400 in unmedicated patients. Clinical symptoms (paranoia, thought disturbance) were associated with N400, but not with cognition or PUFAs. CONCLUSIONS: Results suggest cell membrane fatty acids are associated with semantic memory and language in schizophrenia. Findings also suggest a series of linkages that are modulated by dopamine: cell membrane fatty acids are associated with N400 semantic priming; N400 semantic priming is associated with clinical symptoms.

Language disorder in schizophrenia as a developmental learning disorder.

Receptive language disorder in schizophrenia is hypothesized to represent a learning disorder that involves a neurodevelopmental etiology. It is argued that a preexisting developmental language disorder may characterize a subset of schizophrenia patients. A primary deficit in the temporal dynamics of brain function is assumed to cause receptive language disorder in schizophrenia. This hypothesized core deficit includes both disturbance in the processing of rapid, sequential information and disruptions to patterns of brain activation and synchronization. These timing deficits may alter the way associative connections are formed and/or accessed in semantic memory. It is suggested that abnormalities in second-messenger pathways of subcortical-cortical circuitry offer an etiological nexus for language dysfunction in schizophrenia and developmental dyslexia.

Sympathetic and parasympathetic innervation of pupillary dilation during sustained processing.

The contributions of separate sympathetic and parasympathetic pathways to pupillary dilation during a sustained processing task were studied through environmental and pharmacological manipulations. In Experiment 1, 22 healthy volunteers (11 female) performed a serial Subtract 7 task while pupil diameter was recorded both during moderate room light and in darkness. In a control for verbalization, subjects performed an easier Add 1 task. In all conditions, pupil diameter increased significantly during the response period as compared to a pre-verbalization baseline period. Pupillary dilation was increased for the difficult task, and further increase in dilation was associated with recording in light. This suggests a major differential contribution to task difficulty mediated through inhibition of the parasympathetic pathway. In Experiment 2, a subgroup of 12 volunteers (seven female) repeated all conditions at three additional sessions in which one eye was instilled with tropicamide (to block the parasympathetic sphincter muscle), dapiprazole (to block the sympathetic dilator muscle) or placebo. All pharmacological conditions resulted in overall dilation during task performance. Differential performance similar to the placebo condition was seen only in the dapiprazole condition, when parasympathetic activation was intact. The findings suggest that sustained performance during a difficult task is modulated by cortical inhibition of the parasympathetic pathway at the oculomotor nucleus. Moreover, modulation of both ambient light intensity and pharmacological blockade of the final pupillary musculature were observed to provide converging approaches for quantifying the activity of identifiable central autonomic pathways.

Automatic activation of the semantic network in schizophrenia: evidence from event-related brain potentials.

BACKGROUND: Language disorder associated with schizophrenia might be due to disturbances in both automatic activation and mechanisms of controlled attention. The contribution of each process to semantic memory dysfunction has not been determined for schizophrenia, and the semantic priming paradigm is well-suited for addressing this question. In the present report, event-related potentials (ERPs) elicited under conditions assumed to reveal automatic activation (short prime-target interval and low proportion of related words) are compared directly with ERPs elicited under conditions associated with controlled processing (long prime-target interval and high proportion of related words). METHODS: Visual ERPs were recorded during a lexical decision task, in which semantic relationship (associated and unassociated words), expectancy (relatedness proportions), and prime-target interval (250- and 850-msec inter-stimulus intervals [ISIs]) were varied. Diagnosis and expectancy were between-subjects factors; semantic relationship and ISI were repeated measures. The N400 priming effect (enhanced negativity to unassociated words) was compared between 34 male normal control subjects tested once and 37 male schizophrenia inpatients evaluated during their participation in a double-blind haloperidol maintenance therapy and placebo replacement protocol. RESULTS: The N400 priming effect for patients was significantly reduced during both pharmacologic phases, compared with controls. During haloperidol treatment, however, patients showed a significant N400 priming effect over the anterior scalp region and additionally under the automatic activation condition. The N400 priming effect was enhanced under the controlled processing condition for control subjects; this effect was not observed for patients. N400 amplitude elicited under the rapid presentation rate (250-msec ISI) differed between medicated patients and controls; groups did not differ for the 850-msec ISI. CONCLUSIONS: Findings suggest that automatic activation and mechanisms of controlled attention are both disrupted during semantic memory access for schizophrenia patients. Pharmacologic agents, such as haloperidol, might enhance automatic activation of the semantic network in this patient population, as indexed by the N400 component of the ERP.

The relationship between membrane pathology and language disorder in schizophrenia.

Receptive language disorder in schizophrenia has been hypothesized to involve a fundamental deficit in the temporal (time-based) dynamics of brain function that includes disruptions to patterns of activation and synchronization. In this paper, candidate mechanisms and pathways that could account for this basic deficit are discussed. Parallels are identified between the patterns of language dysfunction observed for schizophrenia and dyslexia, two separate clinical disorders that may share a common abnormality in cell membrane phospholipids. A heuristic is proposed which details a trajectory involving an interaction of brain fatty acids and second-messenger function that modulates synaptic efficacy, and, in turn, influences language processing in schizophrenia patients. It is additionally hypothesized that a primary deficit of functional excitation originating in the cerebellum, in combination with a compensatory decrease of functional inhibition in the prefrontal cortex, influences receptive language dysfunction in schizophrenia.

The language system in schizophrenia: effects of capacity and linguistic structure.

Dysfunction in receptive language processes has been reliably observed in individuals diagnosed with schizophrenia and their first degree family members. The present study addressed the unresolved issue of whether receptive syntax is intact in schizophrenia. The principal question concerned whether comprehension dysfunction in schizophrenia involves a disturbance in the processing of syntactic structure, a susceptibility to demands placed on temporal auditory processing, or some combination of these two general factors. Comprehension accuracy was compared between 32 males diagnosed with schizophrenia and 22 males with no lifetime diagnosis of psychiatric disorder. Accuracy was examined for responses to Who questions ("Who did X?" and "Who was done X?") about information in the sentential clauses (main vs. relative) of two types of relative sentences (subject-relatives vs. object-relatives) that were presented aurally at conversational and accelerated rates. The relationship between cognitive functions and comprehension accuracy was also tested. Results showed highly significant effects of diagnosis, syntactic structure, and temporal demand. Patients were characterized by reduced overall comprehension accuracy compared to controls. More important, patients and controls differed in their patterns of accuracy across the different types of syntactic structure. Finally, cognitive functions predicted but did not completely account for comprehension accuracy. Findings suggest the hypothesis that receptive syntax is disrupted in schizophrenia, and this dysfunction may not be entirely explained by compromised general cognitive ability.