Late deviance detection in rats is reduced, while early deviance detection is augmented by the NMDA receptor antagonist MK-801.

One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the amplitude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP amplitudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.

Social cognition dysfunction in adolescents with 22q11.2 deletion syndrome (velo-cardio-facial syndrome): relationship with executive functioning and social competence/functioning.

BACKGROUND: Social difficulties are often noted among people with intellectual disabilities. Children and adults with 22q.11.2 deletion syndrome (22q11DS) often have poorer social competence as well as poorer performance on measures of executive and social-cognitive skills compared with typically developing young people. However, the relationship between social functioning and more basic processes of social cognition and executive functioning are not well understood in 22q11DS. The present study examined the relationship between social-cognitive measures of emotion attribution and theory of mind with executive functioning and their contribution to social competence in 22q11DS. METHOD: The present cross-sectional study measured social cognition and executive performance of 24 adolescents with 22q11DS compared with 27 age-matched typically developing controls. Social cognition was tested using the emotion attribution task (EAT) and a picture sequencing task (PST), which tested mentalising (false-belief), sequencing, cause and effect, and inhibition. Executive functioning was assessed using computerised versions of the Tower of London task and working memory measures of spatial and non-spatial ability. Social competence was also assessed using the parent-reported Strengths and Difficulties Questionnaire. RESULTS: Adolescents with 22q11DS showed impaired false-belief, emotion attribution and executive functioning compared with typically developing control participants. Poorer performance was reported on all story types in the PST, although, patterns of errors and response times across story types were similar in both groups. General sequencing ability was the strongest predictor of false-belief, and performance on the false-belief task predicted emotion attribution accuracy. Intellectual functioning, rather than theory of mind or executive functioning, predicted social competence in 22q11DS. CONCLUSIONS: Performance on social-cognitive tasks of theory of mind indicate evidence of a general underlying dysfunction in 22q11DS that includes executive ability to understand cause and effect, to logically reason about social scenarios and also to inhibit responses to salient, but misleading cues. However, general intellectual ability is closely related to actual social competence suggesting that a generalised intellectual deficit coupled with more specific executive impairments may best explain poor social cognition in 22q11DS.

Gray matter deficits, mismatch negativity, and outcomes in schizophrenia.

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients' levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

Dorsolateral prefrontal cortex activation during automatic auditory duration-mismatch processing in humans: a positron emission tomography study.

This study aimed to identify the neural networks underlying automatic and active auditory deviant detection in six healthy subjects using positron emission tomography. Eight alternating blocks of standard and standard plus duration-deviant tones were presented while subjects performed a visual discrimination task. In an additional four blocks, the subjects then performed an auditory discrimination task on the deviant tones. Actively attending the deviant tones increased regional cerebral blood flow (rCBF) in the superior temporal and inferior frontal gyrus as well as in the superior and medio-frontal gyrus. When performing the visual task and presented with deviant tones, significant increase of rCBF was detected in the caudate nucleus, cerebellum, posterior cingulate, inferior frontal and pre-central gyrus thus indicating automatic extra-pyramidal processing of auditory duration deviants.

Novelty-elicited mismatch negativity in patients with schizophrenia on admission and discharge.

OBJECTIVE: Given recent reports of differences between mismatch negativity (MMN) elicited by always novel sounds (novelty-elicited MMN) and that elicited by repeated rare deviants (conventional MMN), we investigated novelty-elicited MMN and P3a in patients with schizophrenia before and after a nonstandardized inpatient treatment. DESIGN: Electrophysiological and clinical assessment of patients on admission and discharge from hospital. Assessment of control subjects on 2 sessions. SETTING: Inpatient treatment in a psychiatric university hospital. SUBJECTS: 20 patients with schizophrenia and 21 healthy control subjects of similar age and sex. Selection of patients with first- to third-episode schizophrenia. OUTCOME MEASURES: Early and late component MMN amplitudes and latencies, P3a amplitudes and latencies, Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Extrapyramidal Symptom Scale (EPS), Abnormal Involuntary Movement Scale (AIMS) and chlorpromazine equivalents. RESULTS: In patients with schizophrenia, novelty-elicited MMN was unimpaired on admission, and there was a statistically significant reduction of the late MMN component with treatment. Improvements in symptom expression were associated with increased latencies of the early MMN component. CONCLUSION: Results indicate differences in information processing between conventional and novelty-elicited MMN. Some components of the novelty-elicited MMN might be more state dependent than those of the conventional MMN.

Visual lateralization of pattern discrimination in the bottlenose dolphin (Tursiops truncatus).

The aim of the present study was to investigate whether bottlenose dolphins have cerebral asymmetries of visual processing. The monocular performance of the adult dolphin Goliath was tested using a large number of simultaneous multiple pattern discrimination tasks. The experiments revealed a clear right eye advantage in the acquisition and the retention of pattern discriminations as well as asymmetries in the interhemispheric transfer of visual information. As a result of a complete decussation at the optic nerve, this right eye superiority is probably related to a left hemisphere dominance in visual processing.

Pharmacology of sensory gating in the ascending auditory system of the pigeon (Columba livia).

RATIONALE: Whether the underlying neurochemical basis of sensori(motor) gating is exclusively the result of mammalian brain evolution is not known. OBJECTIVE: The effects of ketamine (KET), benztropine (BTP), apomorphine (APO), methylphenidatehydrochloride (AMP) and haloperidol (HAL) on sensorimotor gating of the acoustic startle and gating of auditory input into the telelencephalon was assessed in a within-subject design in pigeons (Columba livia) using the prepulse inhibition (PPI) paradigm. METHODS: The startle blink reflex was recorded using EMG electrodes which were chronically implanted into the adjoining Musculus palpepralis superior et inferior, Musculus elevator palpebralis superior, and Musculus nictitantis. Thalamic gating was recorded using electrodes which were chronically implanted into the nucleus ovoidalis thalami and the neostriatum caudale (field L), respectively. RESULTS: KET, APO and AMP disrupted dose-dependently sensorimotor gating. The effect of APO and AMP was blocked by HAL. PPI disruption following BTP did not reach statistical significance. KET disrupted thalamic gating and increased prepulse-induced inhibition in field L. By contrast, AMP increased thalamic and decreased field L inhibition of field potentials when preceded by a pre-stimulus. Both effects were antagonised by HAL thus providing preliminary evidence for a D2-mediated auditory gating mechanism in the thalamus. However, while the effect of APO at the thalamic level was similar to AMP, prepulse-induced inhibition of field L activity was enhanced. This may be explained by concurrent D1-mediated telencephalic inhibition. CONCLUSION: It is concluded that thalamic gating is modulated by a dopaminergic/glutamatergic mechanism. The findings also confirm the notion of an homologous neurochemical basis of sensorimotor gating in mammals and birds.

Effects of prepulses and d-amphetamine on performance and event-related potential measures on an auditory discrimination task.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia. OBJECTIVE: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs). METHODS: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task. RESULTS: Confirming our previous results, S2 processing is "accentuated" by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets ("prepulse-induced non-target positivity"; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts "S2 accentuation" associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP. CONCLUSIONS: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation.

A topographic event-related potential follow-up study on 'prepulse inhibition' in first and second episode patients with schizophrenia.

Dopamine agonists impair and antagonists normalize prepulse inhibition (PPI) of startle and gating of the P50 event-related potential (ERP), but the within-subject effect of treatment on impaired gating in schizophrenia has not been studied. We report the first results of a longitudinal study using PPI of ERPs as a measure of sensory gating in an auditory Go/NoGo discrimination. After admission and approximately 3 months later, at discharge, 15 patients with schizophrenia performed a discrimination between a 1.4 kHz target tone and an 0.8 kHz non-target tone with no prepulse, or with a prepulse at 100 ms or 500 ms before either tone. ERPs were recorded from 19 sites. Healthy subjects were studied twice, with 3 months between sessions. PPI of the P50 peak in the 100-ms condition was reduced in patients on admission. At discharge, decreased negative symptoms correlated with enhanced P50-PPI at frontocentral sites. After treatment increased N100-PPI at centrotemporal sites correlated with fewer positive symptoms. At frontal sites in the 100-ms condition, the initially small difference of non-target minus target P300 amplitudes increased as negative symptoms decreased. It is concluded that weak auditory prepulses interfere with early auditory stimulus processing (P50), channel selection (N100) and selective attention (P300). Gating of these stages of processing is impaired in psychotic patients and treatment tends to normalize gating in tandem with improvements of different types of symptoms.

Attention-dependent allocation of auditory processing resources as measured by mismatch negativity.

Mismatch negativity (MMN) is a pre-attentive event-related potential measure of echoic memory. However, recent studies suggest attention-related modulation of MMN. This study investigates duration-elicited MMN in healthy subjects (n = 12) who were performing a visual discrimination task and, subsequently, an auditory discrimination task in a series of increasing task difficulty. MMN amplitude was found to be maximal at centro-frontal electrode sites without hemispheric differences. Comparison of both attend conditions (visual vs. auditory), revealed larger MMN amplitudes at Fz in the visual task without differences across task difficulty. However, significantly smaller MMN in the most demanding auditory condition supports the notion of limited processing capacity whose resources are modulated by attention in response to task requirements.

A left temporal lobe impairment of auditory information processing in schizophrenia: an event-related potential study.

A measure of auditory prepulse inhibition (PPI) is the reduction of the scalp-recorded P1 event-related potential (ERP) after a sound that is preceded by 100-300 ms by a click as prepulse. This measure of sensory gating was adapted to study the effect of a prepulse on processing tones that were part of a 'go no-go' discrimination. ERPs were recorded at right and left, frontal and temporal sites in groups of patients with schizophrenia (SCH) or obsessive compulsive disorder (OCD) and healthy controls (CON). A prepulse 100 ms but not 500 ms before either tone reduced the P1 ERP amplitude in healthy and OCD subjects but not SCH patients. At frontal and temporal recording sites the P1 amplitude was similar bilaterally in controls but showed a right temporal shift in the SCH patients. If the tone was the 'no-go' tone, the prepulse reduced the N1 amplitude in both the CON and SCH groups. The N1 was similar, bilaterally in controls but again showed a right temporal shift in the SCH group. These results show a reduction of a PPI-like effect on early processing (P1) that is more marked in the left hemisphere of SCH patients and may affect channel selection for processing information (N1) about task-relevant sounds.

Pain perception of intravenous heroin users on maintenance therapy with levomethadone.

Methadone is a very potent analgesic drug. Accordingly, maintenance therapy of heroin addicts with methadone may conceal pain producing processes. Here we report on the pain perception of 42 patients on a levomethadone maintenance treatment for intravenous heroin users. Pain perception was measured by single-blind, non-invasive pressure stimulation of the nociceptors located in the dorsal extension aponeurosis and the underlying periosteum of the middle phalanx of a digit before and respectively 1,2, and 4 hours after oral routine drug administration. Measures were related to the individual levomethadone plasma levels. Under steady-state conditions, the pain perception of the patients did not differ from a drug-free placebo control group and was not related to individual levomethadone plasma levels, although an analgesic effect in the reabsorption phase was observed. It is concluded that the individual pain perception of maintained patients is adapted to a normal response range and that even prolonged opioid consumption does not diminish dynamic analgesic responsiveness to levomethadone.

Event-related potentials during an auditory discrimination with prepulse inhibition in patients with schizophrenia, obsessive-compulsive disorder and healthy subjects.

Prepulse inhibition (PPI) is a measure of the influence of a stimulus (S1) on the response elicited by a second stimulus (S2) occurring shortly afterwards. Most S1/S2 measures of gating have used behavioural startle and the P50 event-related potential (ERP) amplitudes to detect PPI in a simple paired stimulus paradigm. We report on two behavioural (reaction time, RT, and the electromyographically recorded response of the musculus orbicularis oculi, EMG) and 5 ERP measures of PPI where S2 was the target in an auditory two-tone discrimination. Subjects were 21 healthy controls (CON), 11 obsessive-compulsive (OCD) and 9 schizophrenic patients (SCH). The prepulse 100 ms before S2 induced more omission errors and longer RTs compared to 500ms S1-S2 interval in all subjects. PPI was also evident in EMG, P50, N1, P3 but not P2 or N2 amplitudes of CON subjects. SCH patients showed attenuation of PPI on the same measures. OCD patients were characterized only by their slow RT and a marginal attenuation of PPI of the EMG response. A correlational analysis implied separate relationships of ERP indices of PPI to the cognitive and psychomotor consequences of the prepulse on behavioural and discrimination responses. However, SCH patients showed a general rather than a specific impairment of these indices.

Pharmacokinetic and pharmacodynamic interactions in an outpatient maintenance therapy of intravenous heroin users with levomethadone.

The plasma levels of 42 patients on a levomethadone maintenance treatment programme for intravenous heroin users were measured before and, respectively, 1, 2 or 4 hours after oral routine administration and related to the individual additional drug usage (detected by urine drug screening), liver function, side-effects and withdrawal symptoms. In general, accelerated levomethadone metabolism induced by additional misuse of benzodiazepines, barbiturates and opiates resulted in significantly lower plasma levels of the substitute. In particular, high gamma-glutamyltransferase activity was related to benzodiazepine consumption. On the other hand, an impaired liver function reflected by increased beta-globulins resulted in an insufficient body clearance and drug accumulation. Major side effects, such as sweating, were not related to plasma levels whereas withdrawal symptoms like diarrhoea or "feeling cold" correlate with lower plasma concentrations. It is concluded that polydrug misuse in the methadone maintenance therapy creates a vicious circle of enzyme induction, thus increasing "instrumental drug utilization". However, underestimated maintenance dosage may lead to additional drug consumption resulting, finally, in therapeutic failure.

'Prepulse inhibition' facilitates a liberal response bias in an auditory discrimination task.

This study examined 'prepulse inhibition' in the context of an auditory two-tone discrimination task performed by 15 healthy subjects. In order to distinguish between masking or excitatory information processes, weak acoustic pulses immediately preceded or succeeded a target or non-target tone in the discrimination. Button-press performance was compared with response in a no-pulse condition. Response bias (beta) became more liberal in the 100 ms prepulse and 200 ms postpulse conditions. Beta correlated with P3b amplitude measures of the event-related potential. The weak pulses increased temporarily the cortical excitability, as measured by the decreased amplitude of the P3b component and thus facilitated a more liberal response bias.

The visual forebrain and eating in pigeons (Columba livia).

The contribution of forebrain structures to the control of visually guided eating behaviors was studied using a technique for reversible 'visual decerebration'. The procedure is based upon the fact that structures in the thalamus and telencephalon receive their visual inputs primarily from the contralateral eye. When the eye contralateral to the ablated hemisphere is occluded, the remaining eye has unilateral access to these structures. When the eye ipsilateral to the ablated hemisphere is occluded, the bird is functionally decerebrate; i.e., visual processing by the remaining eye is restricted to structures caudal to the forebrain. The performance of normal and hemispherectomized subjects under binocular and monocular (unilateral, decerebrate) viewing conditions was compared on tests of ingestive efficiency, identification, conditioned peck localization, and grasping. In normal subjects, differences between right and left eye were not significant on any of these tasks. In hemispherectomized subjects, monocular performance on the first three tasks depended critically upon which eye was occluded. In the decerebrate condition (i.e., when the eye opposite the ablated hemisphere was used) performance on the identification, ingestive efficiency and peck localization tasks was significantly degraded, but grasping was unimpaired. We conclude that the brain structures critical for the visuomotor control of grasping lie caudal to the forebrain.