Ulrich Schall

Risk factors for transition to first episode psychosis among individuals with 'at-risk mental states'

Recently developed criteria have been successful at identifying individuals at imminent risk of developing a psychotic disorder, but these criteria lead to 50-60% false positives. This study investigated whether measures of family history, peri-natal complications, premorbid social functioning, premorbid personality, recent life events and current symptoms would be able to improve predictions of psychosis in a group of young, help-seeking individuals who had been identified as being at risk. Individuals (N=74) were followed up at least 1 year after initial assessment. Half the sample went on to develop a psychotic disorder. The most reliable scale-based predictor was the degree of presence of schizotypal personality characteristics. However, individual items assessing odd beliefs/magical thinking, marked impairment in role functioning, blunted or inappropriate affect, anhedonia/asociality and auditory hallucinations were also highly predictive of transition, yielding good sensitivity (84%) and specificity (86%). These predictors are consistent with a picture of poor premorbid functioning that further declines in the period up to transition.

Deviant Matters: Duration, Frequency, and Intensity Deviants Reveal Different Patterns of Mismatch Negativity Reduction in Early and Late Schizophrenia

BACKGROUND A reduction in the size of the auditory event-related potential component known as mismatch negativity (MMN) is a consistent finding in schizophrenia. This study was designed to test the hypothesis that sound intensity and duration might be more sensitive to MMN reduction early in the development of schizophrenia because of the computational complexity in extracting these two sound dimensions. METHODS The MMN elicited to sounds deviating in duration, frequency, or intensity was measured in participants with a short (n = 14, mean 2.6 years) and longer length of illness (n = 29, mean 18.9 years) relative to healthy age-matched control subjects. RESULTS For participants early in the illness, a clear reduction was evident in MMN to duration and intensity but not frequency deviants. A different pattern was observed in patients with a longer length of illness--that is, a reduction in frequency and in duration to a lesser degree but not intensity MMN. CONCLUSIONS The results indicate a pronounced age-related decline in duration and intensity MMN in control subjects that might reduce the sensitivity of these indices in schizophrenia when measured later in the course of the illness. The MMN elicited to changes in different sound properties provides potentially complementary information on the onset and progression of neuropathological changes that underlie the reduction in MMN in schizophrenia.

Duration mismatch negativity and P3a in first-episode psychosis and individuals at ultra-high risk of psychosis.

BACKGROUND Reduction in a pre-attentive measure of auditory change detection, mismatch negativity (MMN), is one of the most consistent findings in schizophrenia. Recently, our group showed a reduction in MMN to changes in the duration and intensity of background sounds in those within 5 years of illness onset, whereas reduced MMNs to changes in sound frequency were only seen in patients with longer illness duration. In this report, we examine whether reduced MMN, as well as P3a, another index of auditory deviance detection, to duration changes is evident even earlier in the illness, that is, in individuals in the first episode of a psychosis (FEP) and individuals identified as being at ultra-high risk of developing schizophrenia (UHR). METHODS Mismatch negativity and P3a were measured in 30 UHR individuals, 10 FEP individuals, and 20 healthy control subjects to both long (100 msec) and short (50 msec) duration deviant sounds. RESULTS Mismatch negativity was reduced to both duration deviants not only in the FEP group but also in the UHR group. P3a amplitude was also reduced in the UHR group but at trend level only in FEP. However, MMN and P3a reductions were unrelated in both UHR and FEP groups, suggesting that they reflect distinct deficits. CONCLUSIONS These results suggest that MMN, as well as P3a, to duration deviants are reduced in very early stages of a psychotic illness including those in an at-risk mental state. Both should be considered as potential markers of the prodrome.

Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia.

Schizophrenia is a heterogenous disorder that is phenomenologically characterised by a combination of negative, positive, and cognitive symptoms with variable expression in the course of illness. Here, we investigated differential gene expression in relation to age to address the heterogeneity of this disorder We used 6000 gene cDNA microarrays to generate gene expression profiles from peripheral blood lymphocytes from 14 individuals with schizophrenia and 14 non-psychiatric controls. Genes showing altered expression were identified and 18 genes with brain-related functions were altered, 4 of which, endothelial differentiation gene 2 (Edg-2), ezrin-radixin-moesin phosphoprotein 50 (EBP50), Myc-associated zinc finger protein (MAZ) and Tumor Necrosis Factor Receptor 2 (TNFR2), were confirmed by relative real-time PCR. Dendrograms were constructed using genes that showed significantly different expression (p<0.05) between groups based on median split of age dividing the matched pairs into distinct subclasses. Our findings suggest that distinct gene expression profiles in peripheral blood lymphocytes associated with schizophrenia phenotypes may provide a first step towards the biological classification of schizophrenia subtypes. The validity of this approach may lead to better methods of defining this enigmatic disease.

Functional brain maps of Tower of London performance: a positron emission tomography and functional magnetic resonance imaging study

Regional cerebral blood flow (rCBF) and blood oxygenation level-dependent (BOLD) contrasts represent different physiological measures of brain activation. The present study aimed to compare two functional brain imaging techniques (functional magnetic resonance imaging versus [(15)O] positron emission tomography) when using Tower of London (TOL) problems as the activation task. A categorical analysis (task versus baseline) revealed a significant BOLD increase bilaterally for the dorsolateral prefrontal and inferior parietal cortex and for the cerebellum. A parametric haemodynamic response model (or regression analysis) confirmed a task-difficulty-dependent increase of BOLD and rCBF for the cerebellum and the left dorsolateral prefrontal cortex. In line with previous studies, a task-difficulty-dependent increase of left-hemispheric rCBF was also detected for the premotor cortex, cingulate, precuneus, and globus pallidus. These results imply consistency across the two neuroimaging modalities, particularly for the assessment of prefrontal brain function when using a parametric TOL adaptation.

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.

Australian schizophrenia research bank: a database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia

Objective: This article describes the establishment of the Australian Schizophrenia Research Bank (ASRB), which operates to collect, store and distribute linked clinical, cognitive, neuroimaging and genetic data from a large sample of people with schizophrenia and healthy controls. Method: Recruitment sources for the schizophrenia sample include a multi-media national advertising campaign, inpatient and community treatment services and non-government support agencies. Healthy controls have been recruited primarily through multi-media advertisements. All participants undergo an extensive diagnostic and family history assessment, neuropsychological evaluation, and blood sample donation for genetic studies. Selected individuals also complete structural MRI scans. Results: Preliminary analyses of 493 schizophrenia cases and 293 healthy controls are reported. Mean age was 39.54 years (SD = 11.1) for the schizophrenia participants and 37.38 years (SD = 13.12) for healthy controls. Compared to the controls, features of the schizophrenia sample included a higher proportion of males (cases 65.9%; controls 46.8%), fewer living in married or de facto relationships (cases 16.1%; controls 53.6%) and fewer years of education (cases 13.05, SD = 2.84; controls 15.14, SD = 3.13), as well as lower current IQ (cases 102.68, SD = 15.51; controls 118.28, SD = 10.18). These and other sample characteristics are compared to those reported in another large Australian sample (i.e. the Low Prevalence Disorders Study), revealing some differences that reflect the different sampling methods of these two studies. Conclusion: The ASRB is a valuable and accessible schizophrenia research facility for use by approved scientific investigators. As recruitment continues, the approach to sampling for both cases and controls will need to be modified to ensure that the ASRB samples are as broadly representative as possible of all cases of schizophrenia and healthy controls.

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.

Mismatch Negativity: Translating the Potential

The mismatch negativity (MMN) component of the auditory event-related potential has become a valuable tool in cognitive neuroscience. Its reduced size in persons with schizophrenia is of unknown origin but theories proposed include links to problems in experience-dependent plasticity reliant on N-methyl-d-aspartate glutamate receptors. In this review we address the utility of this tool in revealing the nature and time course of problems in perceptual inference in this illness together with its potential for use in translational research testing animal models of schizophrenia-related phenotypes. Specifically, we review the reasons for interest in MMN in schizophrenia, issues pertaining to the measurement of MMN, its use as a vulnerability index for the development of schizophrenia, the pharmacological sensitivity of MMN and the progress in developing animal models of MMN. Within this process we highlight the challenges posed by knowledge gaps pertaining to the tool and the pharmacology of the underlying system.

Epidural Auditory Event-Related Potentials in the Rat to Frequency and duration Deviants: Evidence of Mismatch Negativity?

The capacity of the human brain to detect deviance in the acoustic environment pre-attentively is reflected in a brain event-related potential (ERP), mismatch negativity (MMN). MMN is observed in response to the presentation of rare oddball sounds that deviate from an otherwise regular pattern of frequent background standard sounds. While the primate and cat auditory cortex (AC) exhibit MMN-like activity, it is unclear whether the rodent AC produces a deviant response that reflects deviance detection in a background of regularities evident in recent auditory stimulus history or differential adaptation of neuronal responses due to rarity of the deviant sound. We examined whether MMN-like activity occurs in epidural AC potentials in awake and anesthetized rats to high and low frequency and long and short duration deviant sounds. ERPs to deviants were compared with ERPs to common standards and also with ERPs to deviants when interspersed with many different standards to control for background regularity effects. High frequency (HF) and long duration deviant ERPs in the awake rat showed evidence of deviance detection, consisting of negative displacements of the deviant ERP relative to ERPs to both common standards and deviants with many standards. The HF deviant MMN-like response was also sensitive to the extent of regularity in recent acoustic stimulation. Anesthesia in contrast resulted in positive displacements of deviant ERPs. Our results suggest that epidural MMN-like potentials to HF sounds in awake rats encode deviance in an analogous manner to the human MMN, laying the foundation for animal models of disorders characterized by disrupted MMN generation, such as schizophrenia.