Gail Silipo

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.

High dose D-serine in the treatment of schizophrenia

BACKGROUND D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). METHODS 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated. RESULTS Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. DISCUSSION These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

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.

Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging.

Sensory processing deficits in schizophrenia have been documented for several decades, but their underlying neurophysiological substrates are still poorly understood. In the visual system, the pattern of pathophysiology reported in several studies is suggestive of dysfunction within the magnocellular visual pathway beginning in early sensory cortex or even subcortically. The present study used functional magnetic resonance imaging to investigate further the neurophysiological bases of visual processing deficits in schizophrenia and in particular the potential role of magnocellular stream dysfunction. Sinusoidal gratings systematically varying in spatial frequency content were presented to subjects at low and high levels of contrast to differentially bias activity in magnocellular and parvocellular pathways based on well established differences in neuronal response profiles. Hemodynamic responses elicited by different spatial frequencies were mapped over the occipital lobe and then over the entire brain. Retinotopic mapping was used to localize the occipital activations with respect to the boundaries of visual areas V1 and V2, which were demarcated in each subject. Relative to control subjects, schizophrenia patients showed markedly reduced activations to low, but not high, spatial frequencies in multiple regions of the occipital, parietal, and temporal lobes. These findings support the hypothesis that schizophrenia is associated with impaired functioning of the magnocellular visual pathway and further suggest that these sensory processing deficits may contribute to higher-order cognitive deficits in working memory, executive functioning, and attention.

Magnocellular and parvocellular contributions to backward masking dysfunction in schizophrenia

Patients with schizophrenia have repeatedly shown deficits in visual processing. These deficits have been well documented using visual backward masking (VBM). The VBM deficit in schizophrenia is thought to be due to aberrant interactions between magnocellular (M) and parvocellular (P) visual pathways. To date, no study has studied these claims with rigorous stimuli isolating M and P pathway responses. This study examined the function of each pathway and their interactions by creating M- and P-biased targets based on their known physiological properties. The M system responds to very low luminance contrast whereas the P system does not, and the P system responds to color contrast whereas the M system generally does not. Thus, to activate the P system, target letters and masks utilized color contrast, and to activate the M system, target letters and masks utilized very low luminance contrast. Four conditions were presented such that M- and P-biased targets were paired with both M- and P-biased masks. A significant Group x Mask Condition interaction was found when a P target was used in combination with an M or P mask, but not when an M target was used. In particular, schizophrenia patients needed significantly longer interstimulus intervals (ISIs) than controls to escape from masking in the P target/M mask condition, but not in any of the other three conditions. In addition, the critical stimulus durations (CSDs) for unmasked stimuli were significantly increased for both M and P targets in patients relative to controls. These findings demonstrate a significant impairment in M, but not P pathway, function in patients with schizophrenia. Furthermore, deficits of letter identification, including those of P targets, may also reflect impairment of the M pathway given the priming function of the dorsal stream.

Neurocognitive and symptom correlates of daily problem-solving skills in schizophrenia

Functional outcome for individuals with schizophrenia has been associated with cognitive impairment. Deficits in attention, memory, speed of information processing and problem-solving skills affect independent functioning, vocational performance, and interpersonal functioning. This study investigated the relationship between neurocognitive functioning, clinical symptoms and daily problem-solving skills in seriously and persistently ill persons. Thirty-eight inpatients and outpatients were administered a neurocognitive battery for attention, working memory, processing speed, perceptual organization, and executive functioning; and semi-structured clinical interviews using the BPRS and SANS. Estimates of daily problem-solving skills were obtained using the relevant factor subscale from the Independent Living Scales (ILS-PB). Daily problem-solving skills were significantly correlated with negative symptoms, processing speed, verbal memory, and working memory scores. A regression model using an enter method suggests that working memory and negative symptoms are significant predictors of daily problem-solving skills and account for 73.2% of the variance. Further analyses demonstrate that daily problem-solving skills and negative symptoms were significantly different for inpatients and outpatients and significantly correlated with community status. The findings suggest the ILS-PB has utility as a proxy measure for assessing real-world functioning in schizophrenia.

Sensory Deficits and Distributed Hierarchical Dysfunction in Schizophrenia

OBJECTIVE Schizophrenia is characterized by widespread cognitive deficits that reflect distributed dysfunction across multiple cortical regions. Here the authors examined the relationship between lower- and higher-level dysfunction within the auditory domain using the event-related brain potentials mismatch negativity (MMN) and P300. METHOD Event-related brain potentials were obtained from 50 schizophrenia patients and 21 healthy subjects in two conditions: a standard condition employing fixed differences between standard tones and pitch deviants and a novel individualized condition employing tones matched to each individuals tone-discrimination threshold. The relationship among measures was assessed by multiple regression analysis and structural equation modeling. RESULTS In the standard fixed-deviance condition, schizophrenia patients showed deficits of large effect size in generation of MMN (d>1.26) and P300 (d=1.08) relative to comparison subjects. Assessment of deviance-detection thresholds showed that patients required significantly elevated tone-matching thresholds relative to comparison subjects (d=0.97). When tone differences were individually adjusted to equate tone-matching performance across groups, the groups no longer differed significantly in MMN amplitude during deviant pitch tones, and the degree of deficit in P300 generation was significantly reduced. In both multiple regression analysis and structural equation modeling, MMN and diagnostic group were significant independent predictors of reduced P300 amplitude. MMN generation was well explained (>90% variance) by dipoles seeded within the bilateral auditory cortex. CONCLUSIONS These findings confirm and extend previous reports of impaired basic sensory processing in schizophrenia and demonstrate significant contributions of early sensory processing dysfunction to higher-order cognitive impairments. Overall, the findings support distributed, hierarchical models of cognitive impairment in schizophrenia, consistent with glutamatergic and other widespread neurochemical models of the disorder.

In support of Bleuler: Objective evidence for increased affective ambivalence in schizophrenia based upon evocative testing

BACKGROUND Ambivalence and anhedonia have long been identified as schizophrenic symptoms. However, ambivalence has rarely been studied, and in most evocative studies, schizophrenia participants are not anhedonic. Affective neurosciences posit two evaluative systems (one for Positivity and one for Negativity), the coactivation of which produces ambivalence, and point to two asymmetries in affective processing: Positivity Offset (which measures our capacity to explore the environment) and Negativity Bias (a measure of reactivity to intense threat). These characteristics have not received much attention in schizophrenia research. METHODS Sixty-four individuals with schizophrenia and 32 non-patient control participants completed an evocative emotional task with pictures, sounds and words of various valences and intensities. Following each presentation, participants rated the level of pleasantness, unpleasantness, and arousal elicited by the stimulus. Finally, participants completed questionnaires on anhedonia, and practical life skills were assessed. RESULTS Schizophrenia participants showed higher levels of ambivalence, greater arousal, greater Positivity Offset, and non-significantly different hedonic capacities and Negativity Bias. Ambivalence to positive stimuli significantly correlated with duration of illness, current level of psychopathology, anhedonia questionnaires and practical life skills. Schizophrenia patients with negative symptoms did not differ from patients without negative symptoms on computer tasks. CONCLUSIONS Ambivalence is greater in schizophrenia, and can be understood as a de-differentiation of the activation of the two evaluative systems. Ambivalence to positive stimuli, which may reflect early-stage affective processing is associated with impairments in higher-level emotional processes and in everyday functioning. Future studies should clarify the status of anhedonia in schizophrenia.

Auditory Emotion Recognition Impairments in Schizophrenia: Relationship to Acoustic Features and Cognition

OBJECTIVE Schizophrenia is associated with deficits in the ability to perceive emotion based on tone of voice. The basis for this deficit remains unclear, however, and relevant assessment batteries remain limited. The authors evaluated performance in schizophrenia on a novel voice emotion recognition battery with well-characterized physical features, relative to impairments in more general emotional and cognitive functioning. METHOD The authors studied a primary sample of 92 patients and 73 comparison subjects. Stimuli were characterized according to both intended emotion and acoustic features (e.g., pitch, intensity) that contributed to the emotional percept. Parallel measures of visual emotion recognition, pitch perception, general cognition, and overall outcome were obtained. More limited measures were obtained in an independent replication sample of 36 patients, 31 age-matched comparison subjects, and 188 general comparison subjects. RESULTS Patients showed statistically significant large-effect-size deficits in voice emotion recognition (d=1.1) and were preferentially impaired in recognition of emotion based on pitch features but not intensity features. Emotion recognition deficits were significantly correlated with pitch perception impairments both across (r=0.56) and within (r=0.47) groups. Path analysis showed both sensory-specific and general cognitive contributions to auditory emotion recognition deficits in schizophrenia. Similar patterns of results were observed in the replication sample. CONCLUSIONS The results demonstrate that patients with schizophrenia show a significant deficit in the ability to recognize emotion based on tone of voice and that this deficit is related to impairment in detecting the underlying acoustic features, such as change in pitch, required for auditory emotion recognition. This study provides tools for, and highlights the need for, greater attention to physical features of stimuli used in studying social cognition in neuropsychiatric disorders.

Seeing the World Dimly: The Impact of Early Visual Deficits on Visual Experience in Schizophrenia

Deficits in early visual processing are well documented in schizophrenia, using methods such as contrast sensitivity. Higher, integrative stages of functioning, such as susceptibility to visual illusions, have been evaluated less extensively. For example, patients show increased susceptibility to (ie, are more easily affected by) the Muller-Lyer illusion but decreased susceptibility (ie, are less easily affected by) to stereopsis based upon binocular disparity. The basis for pattern of illusion response and interaction between sensory and integrative stages of processing, however, is unclear. We tested a group of 38 patients and 28 control subjects in contrast sensitivity, the Muller-Lyer and Poggendorff illusions, as well as a subgroup in stereopsis and the Ponzo illusion, Sander parallelogram, and Hermann grid illusions. We predicted that patients would be more susceptible to tests that become more apparent with increased contrast (Muller-Lyer illusion), less susceptible to tests that become less apparent with increased contrast (stereopsis, Ponzo illusion, Hermann grid), and equally susceptible to contrast-insensitive tests (Poggendorff illusion). Additionally, the Hermann grid was tested at varying levels of contrast. Patients demonstrated significant deficits in contrast sensitivity, especially to brief, low spatial frequency stimuli, and the predicted differential response to the tested illusions. Additionally, poor performance on stereopsis and the Hermann grid significantly correlated with decreased contrast sensitivity (all Ps <.01). Muller-Lyer illusion and stereopsis performance were also inversely related (P < .01). This study replicates and expands upon previous findings with visual illusions. Our results offer a unifying explanation for disparate studies and suggest that deficits in early sensory gain affect subsequent integrative processes.