Jürgen Brinkmeyer

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.

Neuropsychological Profiles in Different At-Risk States of Psychosis: Executive Control Impairment in the Early—and Additional Memory Dysfunction in the Late—Prodromal State

Impairments in neuropsychological functioning have been described in subjects clinically at high risk for psychosis, but the specific cognitive deficits in different clinical high-risk groups remain to be elucidated. The German Research Network on Schizophrenia employs a heuristic 2-stage model: a putatively late prodromal state (LPS), characterized by the onset of attenuated positive or brief psychotic symptoms, and an early prodromal state (EPS), mainly characterized by the presence of basic symptoms, which are predictive for psychosis within the next 10 years. A total of 205 subjects met the criteria for either an EPS or an LPS of psychosis and were assessed with a comprehensive neuropsychological test battery. Neurocognitive profiles of high-risk groups were compared with data of 87 healthy controls comparable with regard to gender, age, and premorbid verbal IQ. Patients in the LPS were impaired in all neurocognitive domains (memory/learning, executive control/processing speed, and working memory) examined, with memory being the worst. Deficits were less pronounced in patients in the EPS, with a specific deficit in the executive control/processing speed domain. Consistent with a progressive neurodevelopmental disorder, some cognitive abilities were already impaired in patients in the EPS, followed by further deterioration in the LPS. Specifically, deficits in executive control functioning were related to the presence of basic symptoms, indicating a vulnerability for psychosis. Memory deficits were associated with the onset of psychotic symptoms indicating further disease progression in the trajectory to psychosis and, thus, may be useful in predicting psychosis and targeting early intervention.

Time course of regional brain activations during facial emotion recognition in humans

Recognition of facial expressions of emotions is very important for communication and social cognition. Neuroimaging studies showed that numerous brain regions participate in this complex function. To study spatiotemporal aspects of the neural representation of facial emotion recognition we recorded neuromagnetic activity in 12 healthy individuals by means of a whole head magnetoencephalography system. Source reconstructions revealed that several cortical and subcortical brain regions produced strong neural activity in response to emotional faces at latencies between 100 and 360 ms that were much stronger than those to neutral as well as to blurred faces. Orbitofrontal cortex and amygdala showed affect-related activity at short latencies already within 180 ms after stimulus onset. Some of the emotion-responsive regions were repeatedly activated during the stimulus presentation period pointing to the assumption that these reactivations represent indicators of a distributed interacting circuitry.

Electrophysiological correlates of emotional and structural face processing in humans.

In order to study brain potentials related to decoding of facial expressions of emotions and those, related to basic perception of faces 16 right-handed subjects performed tasks on facial emotion recognition and perception of blurred faces and objects. Electroencephalograph (EEG) recordings during performance of the tasks revealed similar event-related potentials during the presentation of faces at 120 and 170 ms after stimulus onset in both of the tasks but significant differences in amplitudes between 180 and 300 ms. Whereas faces in the emotion recognition task produced high amplitudes in that latency range, potentials in response to faces in the blurred object condition were virtually absent. These data point to the assumption that decoding of facial expressions starts early in the brain and might be processed separately from basic stages of face perception.

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.

EEG-correlates of facial affect recognition and categorisation of blurred faces in schizophrenic patients and healthy volunteers

The ability to recognise emotional expressions of faces and the ability to categorise blurred and non-blurred faces and complex objects was tested in 16 schizophrenic in-patients and 16 healthy volunteers. EEGs were recorded during performance of the tasks and event-related potentials were compared between groups. Patients performed worse than healthy volunteers in recognition of facial affect but not in categorisation of blurred faces. Furthermore, within a 180-250ms latency range patients showed reduced amplitudes during affect recognition compared with controls but not during categorisation of blurred faces. Amplitudes recorded at frontal electrode sites were associated with performance in facial affect recognition. These results provide a first clue to the neurophysiological basis of the widely reported facial affect recognition deficit in schizophrenic patients.

Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

BACKGROUND Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology. METHODS We conducted a within-subject, randomized, placebo-controlled pharmacoimaging study in twenty-four male volunteers. Subjects were given low-dose S-ketamine (bolus prior to functional imaging: 0.1mg/kg during 5min, thereafter continuous infusion: 0.015625mg/kg/min reduced by 10% every ten minutes) or placebo while performing a visual oddball task during simultaneous functional magnetic resonance imaging (fMRI) with continuous recording of event-related potentials (P300) and electrodermal activity (EDA). Before and after intervention, psychopathological status was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale. RESULTS P300 amplitude and corresponding BOLD responses were diminished in the ketamine condition in cortical regions being involved in sensory processing/selective attention. In both measurement modalities separation of drug conditions was achieved with area under the curve (AUC) values of up to 0.8-0.9. Ketamine effects were also observed in the clinical, behavioral and peripheral physiological domains (Positive and Negative Syndrome Scale, reaction hit and false alarm rate, electrodermal activity and heart rate) which were in part related to the P300/fMRI measures. CONCLUSION The findings from our ketamine experiment are consistent across modalities and directly related to observations in schizophrenia supporting the validity of the model. Our investigation provides the first prototypic example of a pharmacoimaging study using simultaneously acquired fMRI/EEG.

Laser-evoked potential P2 single-trial amplitudes covary with the fMRI BOLD response in the medial pain system and interconnected subcortical structures

Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical representation of pain - the pain matrix - consists of a network of regions including the primary (S1) and secondary (S2) sensory cortex, insula, and anterior cingulate cortex (ACC). These structures interact with brain regions such as the prefrontal cortex and the amygdalae. Simultaneous EEG/fMRI (electroencephalography/functional magnetic resonance imaging) has recently been introduced as a method to study the spatiotemporal characteristics of cognitive processes with high spatial and high temporal resolution at the same time. The present study was conducted to clarify if single trial EEG-informed BOLD modeling supports the definition of functional compartments within the pain matrix and interconnected regions. Twenty healthy subjects received painful laser stimulation while EEG and the fMRI blood oxygen level dependent (BOLD) signal were recorded simultaneously. While the laser-evoked N2 potential provided no additional information for BOLD modeling, the regressor obtained from the single trial laser-evoked P2 potential explained additional variance in a network of cortical and subcortical structures that largely overlapped with the pain matrix. This modeling strategy yielded pronounced activation in the ACC, right amygdala and thalamus. Our results suggest that laser-evoked potential (LEP) informed fMRI can be used to visualize BOLD activation in the pain matrix with an emphasis on functional compartments (as defined by the temporal dynamics of the LEP) such as the medial pain system. Furthermore, our findings suggest a concerted effort of the ACC and the amygdala in the cognitive-emotional evaluation of pain.

Fluctuations in electrodermal activity reveal variations in single trial brain responses to painful laser stimuli--a fMRI/EEG study.

Pain is a complex experience with sensory, emotional and cognitive aspects. It also includes a sympathetic response that can be captured by measuring the electrodermal activity (EDA). The present study was performed to investigate which brain areas are associated with sympathetic activation in experimental pain; an issue that has not been addressed with fMRI (functional magnetic resonance imaging) thus far. Twelve healthy subjects received painful laser stimulation to the left hand. The event-related fMRI BOLD (blood oxygen level dependent) response was measured together with simultaneous EEG (electroencephalography) and EDA recordings. Laser stimuli induced the expected EDA response, evoked EEG potentials and BOLD responses. Single trial EDA amplitudes were used to guide further analysis of fMRI and EEG data. We found significantly higher BOLD responses in trials with high EDA vs. low EDA trials, predominantly in the insula and somatosensory cortex (S1/S2). Likewise, in the EEG we found the N2 laser evoked potentials to have significantly higher amplitudes in trials with high vs. low EDA. Furthermore EDA-informed BOLD modeling explained additional signal variance in sensory areas and yielded higher group level activation. We conclude that the sympathetic response to pain is associated with activation in pain-processing brain regions, predominantly in sensory areas and that single trial (EDA)-information can add to BOLD modeling by taking some of the response variability across trials and subjects into account. Thus, EDA is a useful additional, objective index when pain is studied with fMRI/EEG which might be of particular relevance in the context of genetic- and pharmacoimaging.

Neurophysiological Correlates of Impaired Facial Affect Recognition in Individuals at Risk for Schizophrenia

BACKGROUND Impairments in facial affect recognition are well documented in individuals suffering from schizophrenia. The aim of the present study was to characterize potential impairments in affect recognition and their electrophysiological correlates in at-risk individuals. Such characterization should add to the question whether the neural processes underlying facial affect recognition deficits might be part of a basic neural dysfunction reflecting a vulnerability factor of schizophrenia. METHODS To test facial affect recognition, a digitized series of pictures of facial affect, previously used in related studies, was presented to 37 at-risk individuals and 32 healthy controls. Simultaneously, event-related potentials (ERPs) were recorded to investigate electrophysiological activity during the task. RESULTS At-risk individuals showed significant impairments in facial affect recognition and reduced amplitudes in the ERP components P100, N170, and N250. Furthermore, prodromal signs in these individuals were associated with a poorer task performance and a diminished N250 amplitude. CONCLUSIONS The findings suggest that impairments in facial affect recognition precede the onset of the initial psychotic episode. The impairments are associated with neurophysiological abnormalities similar to those observed in manifest schizophrenia and therefore may serve as indicators of vulnerability for developing schizophrenia.