The 5% difference: early sensory processing predicts sarcasm perception in schizophrenia and schizo-affective disorder.

BACKGROUND: Intact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia. METHOD: Auditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory performance. RESULTS: Patients showed large effect-size deficits across auditory measures. Sarcasm deficits correlated significantly with general functioning and impaired pitch processing both across groups and within the patient group alone. Patients also showed reduced sensitivity to alterations in mean pitch and variability. For patients, sarcasm discrimination correlated exclusively with the level of rsFC within primary auditory regions whereas for controls, correlations were observed exclusively within core-mentalizing regions (the right posterior superior temporal gyrus, anterior superior temporal sulcus and insula, and left posterior medial temporal gyrus). CONCLUSIONS: These findings confirm the contribution of auditory deficits to theory of mind (ToM) impairments in schizophrenia, and demonstrate that FC within auditory, but not core-mentalizing, regions is rate limiting with respect to sarcasm detection in schizophrenia.

Amusia and protolanguage impairments in schizophrenia.

BACKGROUND: Both language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed. METHOD: Musical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition. RESULTS: Highly significant deficits were seen between patients and controls across auditory tasks (p < 0.001). Moreover, significant differences were seen in AER between the amusia and intact music-perceiving groups, which remained significant after controlling for group status and education. Correlations with AER were specific to the melody domain, and correlations between protolanguage (melody domain) and language were independent of overall cognition. DISCUSSION: This is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia.

Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern.

BACKGROUND: Brain mechanisms underlying deficits in precision of transient memory storage in schizophrenia were investigated using a combined behavioral and event-related potential approach. Performance was measured simultaneously in 2 tasks: an AX-type visual continuous performance test (AX-CPT), which required subjects to press a button whenever they saw a letter A followed by a letter X, and a mismatch negativity paradigm. The AX-CPT is designed to assess prefrontal function, whereas mismatch negativity assesses functioning of the auditory sensory memory system. METHODS: Subjects were 17 patients with chronic schizophrenia, 13 with recent-onset schizophrenia, and 20 normal comparison subjects. Potentials were recorded from 36 scalp locations in response to cue stimuli in the CPT and to duration- and pitch-deviant stimuli in the mismatch negativity paradigm. Behavioral measures including responses to incorrect cue-target sequences that should have been ignored ("false alarms") were analyzed as a function of cue-target interval. RESULTS: Chronic and recent-onset schizophrenic patients showed significantly decreased mismatch negativity amplitude but normal latency and topography. In the CPT, patients showed significantly higher rates of false alarms following incorrect cues ("BX" errors) and decreased rates of correct detections. Impaired performance correlated with decreased frontocentral event-related potential activation to incorrect cues that was manifest within several hundred milliseconds of cue presentation. All groups performed worse with increasing cue-target intervals. Patients were no more affected by increased cue-target interval than were controls. CONCLUSIONS: Schizophrenic patients are significantly impaired in their ability to form and utilize transient memory traces to guide behavior. These deficits are associated with failures of cortical activation occurring within several hundred milliseconds of stimulus presentation. A similar pattern of deficit is observed across sensory and cognitive systems. Arch Gen Psychiatry. 2000;57:1131-1137.

Auditory sensory dysfunction in schizophrenia: imprecision or distractibility?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.

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 (1) a significant (P<.001) 30%+/-16% reduction in negative symptoms, as measured by the PANSS, and (2) a significant (P<.001) 30%+/-18% improvement in the BPRS total scores. The improvement in negative symptoms was unrelated to alterations in extrapyramidal effects or symptoms of depression. Low pretreatment glycine serum levels significantly predicted (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.

Electrophysiological indices of information processing in methylphenidate responders.

Event-related potential (ERP) studies report that the positive deflection following stimulus evaluation at 300 msec (P3) in hyperactive children is augmented by methylphenidate (MP). This study investigates P3 and preceding ERP components using an auditory oddball task in attention-deficit hyperactivity disorder (ADHD). Mismatch negativity, negativity at 100 and 200 msec, and positivity at 200 msec and 300 msec (P3) were obtained from 14 control and hyperkinetic children. ADHD children who responded to MP were tested on two separate days while receiving either MP or placebo. Controls were tested once. No differences were found between groups for ERP components preceding P3. P3 amplitude was significantly larger under MP than under placebo, but did not differ from controls. Under MP, differences in P3 amplitude unexpectedly occurred when no response was required. A P3 amplitude increase under MP and the unexpected P3 suggest that MP affects attention regulation.

Impaired sensory processing as a basis for object-recognition deficits in schizophrenia.

OBJECTIVE: Individuals are able to recognize common objects even when portions of them are obscured from view, reflecting the operation of neural perceptual closure processes. This study evaluates the integrity of object recognition and perceptual closure as a function of sensory and cognitive manipulations. METHOD: Object recognition was examined in 26 subjects with schizophrenia and 23 nonpsychiatric comparison subjects of similar age with a presentation of fragmented pictures by means of the ascending method of limits. The effects of prior exposure to subsets of stimuli and of word prompting were examined in separate testing phases. Demographic and clinical characteristics were evaluated as covariates. RESULTS: Although they had impairments in perceptual closure, schizophrenic patients showed improvement in performance equivalent to that of nonpatient comparison subjects with prior exposure to the pictures (i.e., repetition priming) and with presentation of valid word prompts. A significant correlation was found between impaired performance and the severity of negative symptoms. CONCLUSIONS: The results support models of widespread dysfunction in information processing in patients with schizophrenia involving both sensory and cognitive regions. Perceptual closure is significantly impaired in schizophrenic patients; however, this deficit in sensory precision is dissociated from the effects of higher-order repetition priming and word prompting. Furthermore, this work suggests that deficits in perceptual closure may contribute to the muted world experience of patients with the persistent negative symptoms of schizophrenia.

Diminished responsiveness of ERPs in schizophrenic subjects to changes in auditory stimulation parameters: implications for theories of cortical dysfunction.

Event-related potentials (ERPs) were recorded from 15 schizophrenic patients and 17 normal controls in an auditory oddball paradigm in order to investigate the effects of stimulus probability and interstimulus interval (ISI) on deficits in mismatch negativity (MMN) generation in schizophrenia. MMN amplitude was reduced for schizophrenics overall, with the degree of deficit increasing as deviant probability decreased. In contrast, schizophrenic subjects were no more affected by alterations in ISI than controls. The experimental design also permitted evaluation of N1 generation as a function of ISI in schizophrenia. Schizophrenic subjects showed decreased N1 amplitude across conditions, with the degree of deficit increasing with increasing ISI. For both MMN and N1, therefore, the degree of deficit increased with increasing component amplitude in normals, implying that the deficit in ERP generation in schizophrenia may reflect a decrease in maximal current flow through underlying neuronal ensembles. The observed pattern of dysfunction is consistent both with observations of impaired precision of processing in schizophrenia, and with predictions of the PCP/NMDA model.

Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia.

Phencyclidine (PCP) induces a psychotic state closely resembling schizophrenia in normal individuals. PCP and related agents induce their unique behavioral effects by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA)-type glutamate receptors, indicating that dysfunction of NMDA receptor-mediated neurotransmission may play a crucial role in the pathophysiology of schizophrenia. NMDA receptors are activated by the amino acids glutamate and glycine, working at independent binding sites. Glutamate cannot be administered exogenously because of excitotoxicity. In contrast, glycine administered exogenously may potentiate NMDA receptor-mediated neurotransmission in vivo following peripheral administration. In rodents, glycine is effective in elevating brain glycine levels and reversing PCP-induced hyperactivity at doses of 0.8 g/kg and above. Three studies have now been completed utilizing moderate to high (0.4-0.8 g/kg/day) doses of glycine, added to neuroleptics, for the treatment of schizophrenia. Across studies, 15 to 30 percent improvement in negative symptoms was observed with no corresponding worsening of positive symptoms. Although preliminary, these studies indicate that dietary supplementation with glycine or treatment with other glycinergic agents may be effective in the treatment of schizophrenia.

Mismatch negativity in hyperactive children: effects of methylphenidate.

This pilot study investigates electrophysiological correlates of methylphenidate (MP) treatment among hyperkinetic children who are clinical responders to therapy. Event-related potentials were obtained from a small sample (6 hyperactive and 5 controls) during an auditory "oddball" task. In the ignore condition, oddball tones elicited a frontocentral "mismatch" negativity (MMN) during the 100- to 200-msec latency range following stimulus presentation. In the attend condition, oddball target tones elicited a centroparietal P3 as well. MP significantly decreased hyperkinetic behaviors. Preliminary analyses of the electrophysiological data indicated a decreased amplitude of the P3 waveform among hyperkinetic children and a trend toward normalization on MP. Waveform abnormalities in the latency range of control MMN suggested either a decrease in MMN amplitude or an increase in MMN latency in hyperactive subjects along with a trend toward normalization by MP. The preliminary data are suggestive of information-processing abnormalities among hyperactive children that may be sensitive to MP therapy.

Adjunctive high-dose glycine in the treatment of schizophrenia.

Glycine is an agonist at brain N-methyl-D-aspartate receptors and crosses the blood-brain barrier following high-dose oral administration. In a previous study, significant improvements in negative and cognitive symptoms were observed in a group of 21 schizophrenic patients receiving high-dose glycine in addition to antipsychotic treatment. This study evaluated the degree to which symptom improvements might be related to alterations in antipsychotic drug levels in an additional group of 12 subjects. Glycine treatment was associated with an 8-fold increase in serum glycine levels, similar to that observed previously. A significant 34% reduction in negative symptoms was observed during glycine treatment. Serum antipsychotic levels were not significantly altered. Significant clinical effects were observed despite the fact that the majority of subjects were receiving atypical antipsychotics (clozapine or olanzapine). As in earlier studies, improvement persisted following glycine discontinuation.