Anke Brockhaus-Dumke

Neurocognitive indicators for a conversion to psychosis: Comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis

The study aims to identify potential neurocognitive indicators of an enhanced risk for developing psychosis. N=44 patients meeting clinical inclusion criteria for initial prodromal states (IPS) who developed psychosis within a median interval of 10 months were compared to N=39 IPS patients not developing psychosis within a minimum interval of 1 year (median 36 months), and to N=44 healthy controls on a comprehensive neuropsychological test battery (pattern recognition, divided and sustained attention, spatial and verbal working memory, verbal/visual memory, speed of processing, executive and intellectual functions). IPS patients who converted to psychosis performed worse than healthy controls on all broad neurocognitive domains. They were more impaired than IPS patients not developing psychosis on the Subject Ordered Pointing Task (SOPT; working memory), verbal memory functions, verbal executive, verbal IQ and speed of processing tests. After a Bonferroni-Holms adjustment for multiple testing differences on SOPT, Digit-Symbol Test, and verbal IQ remained significant (effect sizes d=0.54-0.88). Neurocognitive predictors had a sensitivity of 0.75 and a specificity of 0.79. Results support several cognitive domains as indicators of vulnerability to psychosis, and additionally suggest that subtle deficits in verbal abilities (working and long-term memory, executive and intellectual functions) and decreased speed of processing may help to predict conversion to psychosis in a clinically defined IPS group.

Prediction of psychosis by mismatch negativity.

BACKGROUND To develop risk-adapted prevention of psychosis, an accurate estimation of the individual risk of psychosis at a given time is needed. Inclusion of biological parameters into multilevel prediction models is thought to improve predictive accuracy of models on the basis of clinical variables. To this aim, mismatch negativity (MMN) was investigated in a sample clinically at high risk, comparing individuals with and without subsequent conversion to psychosis. METHODS At baseline, an auditory oddball paradigm was used in 62 subjects meeting criteria of a late risk at-state who remained antipsychotic-naive throughout the study. Median follow-up period was 32 months (minimum of 24 months in nonconverters, n = 37). Repeated-measures analysis of covariance was employed to analyze the MMN recorded at frontocentral electrodes; additional comparisons with healthy controls (HC, n = 67) and first-episode schizophrenia patients (FES, n = 33) were performed. Predictive value was evaluated by a Cox regression model. RESULTS Compared with nonconverters, duration MMN in converters (n = 25) showed significantly reduced amplitudes across the six frontocentral electrodes; the same applied in comparison with HC, but not FES, whereas the duration MMN in in nonconverters was comparable to HC and larger than in FES. A prognostic score was calculated based on a Cox regression model and stratified into two risk classes, which showed significantly different survival curves. CONCLUSIONS Our findings demonstrate the duration MMN is significantly reduced in at-risk subjects converting to first-episode psychosis compared with nonconverters and may contribute not only to the prediction of conversion but also to a more individualized risk estimation and thus risk-adapted prevention.

Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients.

BACKGROUND Abnormal sensory gating in schizophrenia has frequently been reported; however, only limited data on unmedicated patients and patients at risk to develop a psychosis have, as yet, been available. METHODS P50 and N100 suppression were assessed with an auditory double-click paradigm in five groups: 18 at-risk subjects who did not develop a full psychosis within the follow-up period of 2 years, 21 truly prodromal subjects who developed frank psychosis within the follow-up period, 46 antipsychotic-naïve subjects with first-episode schizophrenia, 20 antipsychotic-free subjects with chronic schizophrenia, and 46 healthy control subjects. RESULTS P50 and N100 suppression indices differed significantly between groups and were lowest in chronic schizophrenia patients. Compared with healthy control subjects, P50 suppression was significantly impaired in at-risk subjects, truly prodromal and first-episode patients (stimulus 2 [S2]/stimulus 1 [S1] P50 amplitude ratio), and chronic schizophrenia patients (difference and ratio), and N100 suppression was significantly reduced in truly prodromal and first-episode patients (S1-S2 difference) and in chronic schizophrenia patients (difference and ratio) but not at-risk subjects. At-risk subjects with and without conversion to psychosis did not significantly differ on any test parameter. CONCLUSIONS Sensory gating is already impaired in early stages of schizophrenia, though this is most prominent in chronic stages. Future studies will have to clarify the type and impact of variables modifying sensory gating disturbances, such as illness progression and genetic load. Furthermore, the meaning and nature of differences between P50 and N100 suppression need further elucidation.

Preventing progression to first-episode psychosis in early initial prodromal states.

BACKGROUND Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred. AIMS To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive-behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS. METHOD A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up. RESULTS A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019). CONCLUSIONS Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.

Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia.

Evidence from neurobiological studies suggests that schizophrenia arises from an early abnormality in brain development and possibly further progressive developmental mechanisms. Despite a delay between the acquisition of neuropathology and the triggering of psychosis, neurobiological susceptibility is likely to be expressed subclinically by biobehavioral markers in the premorbid stage. The exploratory study aims at identifying potential neurocognitive risk factors and investigating the unfolding of the illness within a cross-sectional design by comparing neurocognitive profiles in 179 healthy controls, 38 clinically identified subjects in an early initial prodromal state (EIPS) for psychosis, 90 subjects in a late initial prodromal state (LIPS), 86 first-episode patients with schizophrenia, and 88 multiple-episode patients. Subjects at risk were substantially impaired in verbal executive and verbal memory functions. Compared to EIPS subjects, LIPS subjects demonstrated additional attentional deficits. Both EIPS and LIPS subjects were superior to first-episode patients who presented a generalized neuropsychological deficit profile, and to multiple-episode patients who showed evidence for further decline. Although results were influenced by general intellectual abilities and demographic and clinical characteristics, they could not account for total group differences. Results support a neurodevelopmental model of psychosis with further progressive mechanisms and are consistent with a primary involvement of left frontotemporal networks in the prodromal phase.

Sensory gating revisited: Relation between brain oscillations and auditory evoked potentials in schizophrenia

Disturbances of auditory information processing have repeatedly been shown in schizophrenia. To contribute to a better understanding of the neurophysiological underpinnings of habituation in auditory processing and its disturbance in schizophrenia we used three different approaches to analyze auditory evoked responses, namely phase-locking (PL) analyses, single trial amplitudes, and averaged event-related potentials (P50 and N100). Given that brain oscillations reflect the neuronal correlates of information processing we hypothesized that PL and amplitudes reflect even more essential parts of auditory processing than the averaged ERP responses. In 32 schizophrenia patients and 32 matched controls EEG was continuously recorded using an auditory paired click paradigm. PL of the lower frequency bands (alpha and theta) was significantly reduced in patients whereas no significant differences were present in higher frequencies (gamma and beta). Alpha and theta PL and amplitudes showed a marked increase after the first click and to a minor degree after the second one. This habituation was more prominent in controls whereas in schizophrenia patients the response to both clicks differed only slightly. N100 suppression was significantly reduced in schizophrenia patients whereas no group differences were present with respect to the P50. This corresponded to the finding that gamma mostly contributed to the prediction of the P50 response and theta mostly to the N100 response. Our data showed that analyzing phase and amplitude in single trials provides more information on auditory information processing and reflects differences between schizophrenia patients and controls better than analyzing the averaged ERP responses.

Dimensions of working memory dysfunction in schizophrenia

The aim of this study was to investigate the underlying structure of eight working memory tests used to assess prefrontal dysfunction in schizophrenia research [Letter-Number Span (LNS), Digit-Symbol Test (DST), Trail-Making Test B (TMT-B), Delayed Response Task (DRT) for spatial working memory, Subject Ordered Pointing Task (SOPT), Dual Tasking (DUAL), Continuous Performance Test (CPT)-Identical Pairs, Wisconsin Card Sorting Test (WCST)]. Sixty-six patients with schizophrenia showed significant working memory performance deficits in all tests when compared with 45 healthy controls. Performance was not systematically related to psychopathology. When differences in IQ were controlled, working memory deficits remained stable except in the WCST. Principal components analyses yielded three components for healthy controls: a comparator function of the central executive defined by a comparison of working memory content with information from the environment, an allocation of attentional resources function, and a maximum storage capacity function. The comparator and maximum storage functions could be replicated in the schizophrenia sample. However, the allocation function did not emerge as an independent component and was replaced by a component defined by the WCST. These findings suggest that working memory is not a unitary concept but rather should be conceptually differentiated as functions of transient storage/active rehearsal capacity and central executive manipulation supporting a previous suggestion proposed by Perry et al. [Schizophr. Bull. 27 (2001) 157].

Auditory P300 in individuals clinically at risk for psychosis

BACKGROUND Alterations of the auditory evoked P300 potential are among the most reliable biological markers of schizophrenia. The aim of this study was to assess the amplitude, latency, and topography of the P300 in individuals at clinical high risk for psychosis. METHODS P300 event-related potentials were acquired with an auditory oddball paradigm from 100 patients putatively in an early initial prodromal state (EIPS) for psychosis or in a late initial prodromal state (LIPS), according to the criteria of the German Research Network on Schizophrenia, and from 40 healthy controls comparable with respect to age, gender, and estimated verbal IQ. RESULTS In the LIPS group, P300 amplitude was significantly smaller at midline and left hemispheric electrodes in comparison with controls. In the EIPS group, P300 amplitude was significantly reduced at a left temporoparietal site (TP7). A family history of schizophrenia was associated with smaller posterior P300 amplitudes in high-risk individuals. Midline P300 amplitudes were smaller in LIPS who had experienced already brief limited intermittent psychotic symptoms. CONCLUSION Smaller P300 amplitudes are present prior to a putative onset of psychosis in high-risk individuals. Selective left temporoparietal amplitude deficits may indicate a trait-like abnormality whereas deficits at sagittal midline electrodes may be partly determined by the changes that underlie the appearance of psychotic symptoms. P300 amplitude may be associated with left superior temporal lobe maturation abnormalities followed by further functional impairments later in life. Our follow-up study will reveal whether P300 amplitude alterations predict psychosis and help to targeting early intervention.

Sensory-gating deficit of the N100 mid-latency auditory evoked potential in medicated schizophrenia patients

The clinical and neuro-cognitive correlates of the P50 and N100 auditory evoked responses gating deficits in schizophrenia have thus far eluded identification. Based on our prior results, we hypothesized that, in addition to the P50, gating of the N100 is significantly decreased in schizophrenia and that this deficit correlates with the negative symptoms dimension of schizophrenia. Amplitudes and gating measures of the P50 and N100 were compared between stable out-patients (N=45) (mainly on atypical antipsychotics) with chronic schizophrenia and age- and gender-matched healthy controls (N=49) and the clinical correlates examined. All subjects underwent the paired-stimulus paradigm in 3 or 4 different days. Data from day one and the mean of all days (MOAD) were examined. P50 and N100 amplitudes and gating measures were correlated with PANSS and Wisconsin Card Sorting Test data. Utilizing day one data, no amplitude or gating measures were significantly different between the groups. Utilizing MOAD data, both P50 and N100 gating were significantly decreased in schizophrenia patients. The N100 gating deficit correlated with the negative-symptoms cluster and measures of frontal lobe dysfunction. The data suggest a correlation between N100 gating deficit and the negative-cognitive deficits dimensions of schizophrenia. Data also suggest that improving the signal to noise ratio (MOAD data) increases the sensitivity for detecting gating abnormalities and assessing their clinical correlates.

Basic symptoms in early psychotic and depressive disorders.

BACKGROUND Depression is a frequent condition in early psychosis. Therefore, early detection instruments should distinguish depression from beginning psychosis. AIMS To examine whether basic symptoms, i.e. subtle subjective deficits, differ between participants suffering from a potential prodrome (n=146), first-episode schizophrenia (n=153) and non-psychotic depression (n=115). METHOD Basic symptoms were assessed with the Schizophrenia Proneness Instrument. RESULTS The prodrome and schizophrenia groups did not differ in level of basic symptoms but both had higher levels than the depression group. DSM-IV depression was frequent in those suffering from a potential prodrome (38%) and first-episode schizophrenia (21%). In both groups, participants with and without depression did not differ in basic symptoms. In multivariate analyses, consideration of current depression generally facilitated correct group classification, except for participants suffering from both a potential prodrome and depression. CONCLUSIONS Cognitive basic symptoms distinguished well between all three groups. However, identification of persons suffering from a potential prodrome might be enhanced by considering current affective status.