The Time Course of Dorsal and Rostral-Ventral Anterior Cingulate Cortex Activity in the Emotional Stroop Experiment Reveals Valence and Arousal Aberrant Modulation in Patients with Schizophrenia.

This paper aims to investigate the temporal dynamics within the dorsal anterior cingulate cortex (dACC) and the rostral-ventral (rv) ACC during the interaction of emotional valence and arousal with cognitive control in patients with Schizophrenia (SZ). Although cognitive deficits in SZ are highly relevant and emotional disturbances are common, the temporal relationship of brain regions involved in the interaction of emotional and cognitive processing in SZ is yet to be determined. To address this issue, the reaction time (RT), event-related potential (ERP) and temporal dynamics of the dACC and rvACC activity were compared between SZ subjects and healthy controls (HC), using a modified emotional Stroop experiment (with factors namely congruence, arousal and valence). EEG was recorded with 64 channels and source localisation was performed using the sLORETA software package. We observed slower initial increase and lower peaks of time course activity within the dACC and rvACC in the SZ group. In this particular group, the dACC activity during late negativity was negatively correlated with a significantly higher RT in the high arousal conflict condition. In contrast to HC subjects, at the N450 window, there was no significant valence (ERP and rvACC ROI) modulation effect in the SZ subjects. Using high density EEG and source localisation, it was possible to distinguish various disturbances within the dACC and rvACC in patients with SZ, during emotion-cognition processing.

Theta and high-beta networks for feedback processing: a simultaneous EEG-fMRI study in healthy male subjects.

The reward system is important in assessing outcomes to guide behavior. To achieve these purposes, its core components interact with several brain areas involved in cognitive and emotional processing. A key mechanism suggested to subserve these interactions is oscillatory activity, with a prominent role of theta and high-beta oscillations. The present study used single-trial coupling of simultaneously recorded electroencephalography and functional magnetic resonance imaging data to investigate networks associated with oscillatory responses to feedback during a two-choice gambling task in healthy male participants (n=19). Differential associations of theta and high-beta oscillations with non-overlapping brain networks were observed: Increase of high-beta power in response to positive feedback was associated with activations in a largely subcortical network encompassing core areas of the reward network. In contrast, theta-band power increase upon loss was associated with activations in a frontoparietal network that included the anterior cingulate cortex. Trait impulsivity correlated significantly with activations in areas of the theta-associated network. Our results suggest that positive and negative feedback is processed by separate brain networks associated with different cognitive functions. Communication within these networks is mediated by oscillations of different frequency, possibly reflecting different modes of dopaminergic signaling.

[Significance of clinical electroencephalogram in psychiatry]. / Stellenwert des Elektroenzephalogramms in der Psychiatrie.

The generation of an electroencephalogram (EEG) provides a sensitive, non-invasive and inexpensive method for the investigation of brain function. This article critically reviews the significance of EEG examinations in clinical psychiatric practice and describes relevant applications and limitations. A summary of the basic principles of the production and interpretation of an EEG is followed by a survey of typical EEG patterns in healthy subjects and pathological alterations of EEG patterns. The importance of the EEG for the clinical diagnostics of Alzheimer's disease and acute delirium as well as the differentiation between psychiatric syndromes and non-convulsive status epilepticus is reviewed. Moreover, the usefulness of the EEG is highlighted with respect to the diagnostics and monitoring of the course of lithium intoxication. Finally, this article gives a brief insight into promising research approaches that are currently being followed in modern psychiatry using an EEG.

Age effects on the P300 potential and the corresponding fMRI BOLD-signal.

Age has been reported to influence amplitude and latency of the P300 potential. Nevertheless, it is not yet fully understood which brain regions are responsible for these effects. The aim of this study was to investigate age-effects on the P300 potential and the simultaneously acquired BOLD signal of functional MRI. 32 healthy male subjects were investigated using an auditory oddball paradigm. The functional MRI data were acquired in temporal synchrony to the task. The evoked potential data were recorded during the intervals in between MR image acquisitions in order to reduce the influence of the scanner noise on the presentation of the tones and to reduce gradient artifacts. The age-effects were calculated by means of regression analyses. In addition, brain regions modulated by the task-induced amplitude variation of the P300 were identified (single trial analysis). The results indicated an age effect on the P300 amplitude. Younger subjects demonstrated increased parietal P300 amplitudes and increased BOLD responses in a network of brain regions including the anterior and posterior cingulate cortex, the insula, the temporo-parietal junction, the superior temporal gyrus, the caudate body, the amygdala and the parahippocampal gyrus. Single trial coupling of EEG and fMRI indicated that P300 amplitudes were predominantly associated with neural responses in the anterior cingulate cortex, the putamen and temporal brain areas. Taken together, the results indicate diminished neural responses in older compared to younger subjects especially in frontal, temporo-parietal and subcortical brain regions.

Subjective well-being of patients with schizophrenia as a target of drug treatment.

An important development within the last decades is the consideration of the patient's perspective and the acknowledgement that the majority of patients are able to judge their state of well-being. Several self-report scales such as the "The Subjective Well-being under Neuroleptics Scale" (SWN) have been established. Additionally to their beneficial impact, current antipsychotics have considerable limitations. Antipsychotic-related side effects, such as extrapyramidalmotor symptoms, weight gain and obesity, apathy and anhedonia have an important influence on the patient's wellbeing. Evidence suggests that the so-called neuroleptic-induced deficit syndrome under antipsychotics might be caused by the inhibition of the dopaminergic reward system. A reduced activation of the ventral striatum, including the nucleus accumbens is associated with negative symptom severity. Second-generation antipsychotics (henceforth SGA) block striatal D2 receptors less and show a weaker binding to D2 receptors, have interactions with several other neurotransmitters and inhibit to a lesser degree the reward functions compared to first-generation antipsychotics (henceforth FGA). This may support the reduction of negative symptoms, contributes to a higher subjective well-being, a better medication adherence and thereby an improved therapeutic outcome. The involvement of the patient and the consideration of his/her subjective wellbeing will be a major aspect in the development of new treatment strategies in schizophrenia and has a significant impact on the adherence and the long-term prognosis.

Long-range synchrony of γ oscillations and auditory hallucination symptoms in schizophrenia.

Phase locking in the gamma-band range has been shown to be diminished in patients with schizophrenia. Moreover, there have been reports of positive correlations between phase locking in the gamma-band range and positive symptoms, especially hallucinations. The aim of the present study was to use a new methodological approach in order to investigate gamma-band phase synchronization between the left and right auditory cortex in patients with schizophrenia and its relationship to auditory hallucinations. Subjects were 18 patients with chronic schizophrenia (SZ) and 16 healthy control (HC) subjects. Auditory hallucination symptom scores were obtained using the Scale for the Assessment of Positive Symptoms. Stimuli were 40-Hz binaural click trains. The generators of the 40Hz-ASSR were localized using eLORETA and based on the computed intracranial signals lagged interhemispheric phase locking between primary and secondary auditory cortices was analyzed. Current source density of the 40 ASSR response was significantly diminished in SZ in comparison to HC in the right superior and middle temporal gyrus (p<0.05). Interhemispheric phase locking was reduced in SZ in comparison to HC for the primary auditory cortices (p<0.05) but not in the secondary auditory cortices. A significant positive correlation was found between auditory hallucination symptom scores and phase synchronization between the primary auditory cortices (p<0.05, corrected for multiple testing) but not for the secondary auditory cortices. These results suggest that long-range synchrony of gamma oscillations is disturbed in schizophrenia and that this deficit is related to clinical symptoms such as auditory hallucinations.

Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study.

Prefrontal transcranial direct current stimulation (tDCS) with the anode placed on the left dorsolateral prefrontal cortex (DLPFC) has been reported to enhance working memory in healthy subjects and to improve mood in major depression. However, its putative antidepressant, cognitive and behavior action is not well understood. Here, we evaluated the distribution of neuronal electrical activity changes after anodal tDCS of the left DLPFC and cathodal tDCS of the right supraorbital region using spectral power analysis and standardized low resolution tomography (sLORETA). Ten healthy subjects underwent real and sham tDCS on separate days in a double-blind, placebo-controlled cross-over trial. Anodal tDCS was applied for 20 min at 2 mA intensity over the left DLPFC, while the cathode was positioned over the contralateral supraorbital region. After tDCS, EEG was recorded during an eyes-closed resting state followed by a working memory (n-back) task. Statistical non-parametric mapping showed reduced left frontal delta activity in the real tDCS condition. Specifically, a significant reduction of mean current densities (sLORETA) for the delta band was detected in the left subgenual PFC, the anterior cingulate and in the left medial frontal gyrus. Moreover, the effect was strongest for the first 5 min (p<0.01). The following n-back task revealed a positive impact of prefrontal tDCS on error rate, accuracy and reaction time. This was accompanied by increased P2- and P3- event-related potentials (ERP) component-amplitudes for the 2-back condition at the electrode Fz. A source localization using sLORETA for the time window 250-450 ms showed enhanced activity in the left parahippocampal gyrus for the 2-back condition. These results suggest that anodal tDCS of the left DLPFC and/or cathodal tDCS of the contralateral supraorbital region may modulate regional electrical activity in the prefrontal and anterior cingulate cortex in addition to improving working memory performance.

Single-trial coupling of the gamma-band response and the corresponding BOLD signal.

Oscillations in the gamma-band frequency range have been described to be more closely connected to hemodynamic changes as assessed with functional magnetic resonance imaging (fMRI) than other aspects of neuronal activity. In addition, gamma-band oscillations have attracted much interest during the last few years since they are thought to play a crucial role in many aspects of brain function related to perception and cognition. It was the aim of the present simultaneous EEG-fMRI study to identify brain regions specifically involved in the generation of the auditory gamma-band response (GBR) using single-trial coupling of EEG and fMRI. Ten healthy subjects participated in this study. Three different runs of an auditory choice reaction task with increasing difficulty were performed. Brain activity was recorded simultaneously with high density EEG (61 channels) and fMRI (1.5 T). BOLD correlates of the GBR have been predicted using the single-trial amplitude of the GBR. Reaction times (p<0.001), error rates (p<0.05) and self-ratings of task difficulty and effort demands (p<0.001) were related to the level of difficulty in the task. In addition, we found a significant influence of task difficulty on the amplitude of the GBR at Cz (p<0.05). Using single-trial coupling of EEG and fMRI GBR-specific activations were found only in the auditory cortex, the thalamus and the anterior cingulate cortex (ACC) in the most difficult run. Single-trial coupling might be a useful method in order to increase our knowledge about the functional neuroanatomy of "neural ensembles" coupled by 40 Hz oscillations.

Independent component analysis applied to pharmacological magnetic resonance imaging (phMRI): new insights into the functional networks underlying panic attacks as induced by CCK-4.

Pharmacological magnetic resonance imaging (phMRI) is a method to study effects of psychopharmacological agents on neural activation. Changes of the blood oxygen level dependent (BOLD), the basis of functional MRI (fMRI), are typically obtained at relatively high sampling frequencies. This has more recently been exploited in the field of fMRI by applying independent component analysis (ICA), an explorative data analysis method decomposing activation into distinct neural networks. While already successfully used to investigate resting network and task-induced activity, its use in phMRI is new. Further extension of this method to tensorial probabilistic ICA (tensor PICA) allows to group similar brain activation across the anatomical, temporal, subject or session domain. This approach is useful for pharmacological experiments when no pharmacokinetic model exists. We exemplify this method using data from a placebo-controlled cholecystokinine-4 (CCK-4) injection experiment performed on 16 neuropsychiatrically and medically healthy males (age 25.6 +/- 4.2 years). Tensor PICA identified strong increases in activity in 12 networks. Comparison with results gained from the standard approach (voxelwise regression analysis) revealed good reproduction of areas previously associated with CCK-4 action, such as the anterior cingulate, orbitofrontal cortex, cerebellum, temporolateral, left parietal and insular areas, striatum, and precuneus. Several other components such as the dorsal anterior cingulate and medial prefrontal cortex were identified, suggesting higher sensitivity of the method. Exploration of the time courses of each activated network revealed differences, that might be lost when a fixed time course is modeled, e. g. neuronal responses to an acoustic warning signal prior to injection. Comparison of placebo and CCK-4 runs further showed that a proportion of networks are newly elicited by CCK-4 whereas other components are significantly active in the placebo conditions but further enhanced by CCK-4. In conclusion, group ICA is a promising tool for phMRI studies that allows quantifying and visualizing the modulation of neural networks by pharmacological interventions.

Prolonged confusional state following electroconvulsive therapy--diagnostic clues from serial electroencephalography.

INTRODUCTION: Cognitive impairment occasionally occurs after electroconvulsive therapy (ECT) and usually resolves within a few days. Any prolonged cognitive alterations or confusional states may have additional causes and require extensive diagnostic effort. Since cognitive dysfunction can also be caused by ictal states, electroencephalography (EEG) is an essential tool for these conditions. METHODS: We report on a female patient with pharmacotherapy resistant major depression who had been treated by a series of ECT and subsequently developed severe confusion and fluctuating amnesia. RESULTS: Laboratory and neuroimaging examinations were normal, however, EEG revealed a severe intermittent slowing with rhythmic high amplitude delta-/theta-activity and sporadic bitemporal sharp waves. Oral application of 1 mg lorazepam led to a sudden improvement of EEG abnormalities. Consequently, non-convulsive status epilepticus (NCSE) was suspected and the patient was regularly treated with lorazepam, accordingly. Clinically the confusional and amnesic symptoms declined, whereas serial EEG recordings showed a further improvement and normalization of brain electric activity. CONCLUSION: Routine EEG is an indispensable tool in patients with sudden deterioration of cognitive functions and unclear neuropsychiatric symptomatology. A testing dose of lorazepam can help to classify EEG abnormalities in terms of ictal EEG patterns.

The neural basis of the P300 potential. Focus on the time-course of the underlying cortical generators.

The locations and time-courses of the neural generators of the event-related P300 potential have been well described using intracranial recordings. However, this invasive method is not adequate for usage in healthy volunteers or psychiatric patients and not all brain regions can be covered well with this approach. With functional MRI, a non-invasive method with high spatial resolution, most of these locations could be found again. However, the time-course of these activations can only be roughly determined with this method, even if an event-related fMRI design has been chosen. Therefore, we have now tried to analyse the time-course of the activations using EEG data providing a better time resolution. We have used Low Resolution Electromagnetic Tomography (LORETA) in the analysis of P300 data (27 electrodes) of healthy volunteers (n = 50) in the time frame 230-480 ms and found mainly the same activations that have been described using intracranial recordings or fMRI, i. e. the inferior parietal lobe/temporo-parietal junction (TPJ), the supplementary motor cortex (SMA) and the anterior cingulate cortex (ACC), the superior temporal gyrus (STG), the insula and the dorsolateral prefrontal cortex. In these selected regions, an analysis of the activation time-courses has been performed.

Comparison between the analysis of the loudness dependency of the auditory N1/P2 component with LORETA and dipole source analysis in the prediction of treatment response to the selective serotonin reuptake inhibitor citalopram in major depression.

OBJECTIVES: The loudness dependency of the auditory evoked potentials (LDAEP) is used as an indicator of the central serotonergic system and predicts clinical response to serotonin agonists. So far, LDAEP has been typically investigated with dipole source analysis, because with this method the primary and secondary auditory cortex (with a high versus low serotonergic innervation) can be separated at least in parts. METHODS: We have developed a new analysis procedure that uses an MRI probabilistic map of the primary auditory cortex in Talairach space and analyzed the current density in this region of interest with low resolution electromagnetic tomography (LORETA). LORETA is a tomographic localization method that calculates the current density distribution in Talairach space. RESULTS: In a group of patients with major depression (n=15), this new method can predict the response to an selective serotonin reuptake inhibitor (citalopram) at least to the same degree than the traditional dipole source analysis method (P=0.019 vs. P=0.028). The correlation of the improvement in the Hamilton Scale is significant with the LORETA-LDAEP-values (0.56; P=0.031) but not with the dipole source analysis LDAEP-values (0.43; P=0.11). CONCLUSIONS: The new tomographic LDAEP analysis is a promising tool in the analysis of the central serotonergic system.

Simultaneous ERP and event-related fMRI: focus on the time course of brain activity in target detection.

The event-related P300 potential has been widely used in neurophysiological research. It is usually evoked with an oddball paradigm. One main reason for its broad application in neurophysiological research is the fact that in several brain/mental diseases, such as Alzheimer's disease or schizophrenia, attenuations of the P300 amplitude and latency have been described. However, a precise correlation of the scalp data to the underlying brain regions was not possible, as the correct localization of the generators of scalp-measured electroencephalogram (EEG) data was limited, due to the low spatial resolution of EEG-data. With the availability of modern imaging technologies, functional Magnetic Resonance Imaging (fMRI) in particular, the underlying brain activations could be detected using an oddball task. Although the spatial resolution of fMRI is excellent, the time resolution is restricted. For a comprehensive understanding of the brain activity underlying the P300 paradigm, we have used a combination of EEG and fMRI to get a precise localization and a high-time resolution of the underlying brain activity.

P300 and LORETA: comparison of normal subjects and schizophrenic patients.

It was the aim of the present study 1) to investigate how many cortical activity maxima of scalp-recorded P300 are detected by Low Resolution Electromagentic Tomography (LORETA) when analyses are performed with high time-resolution, 2) to see if the resulting LORETA-solution is in accordance with intracortical recordings as reported by others and 3) to compare the given pattern of cortical activation maxima in the P300-timeframe between schizophrenic patients and normal controls. Current density analysis was performed in 3-D Talairach space with high time resolution i.e. in 6 ms steps. This was done during an auditory choice reaction paradigm separately for normal subjects and schizophrenic patients with subsequent group comparisons. In normal subjects, a sequence of at least seven cortical activation maxima was found between 240-420ms poststimulus: the prefrontal cortex, anterior or medial cingulum, posterior cingulum, parietal cortex, temporal lobe, prefrontal cortex, medial or anterior cingulum. Within the given limits of spatial resolution, this sequential maxima distribution largely met the expectations from reports on intracranial recordings and functional neuroimaging studies. However, localization accuracy was higher near the central midline than at lateral aspects of the brain. Schizophrenic patients less activated their cortex in a widespread area mainly in the left hemisphere including the prefrontal cortex, posterior cingulum and the temporal lobe. From these analyses and comparsions with intracranial recordings as reported by others, it is concluded that LORETA correctly localizes P300-related cortical activity maxima on the basis of 19 electrodes except for lateral cortical aspects which is most likely an edge-phenomenon. The data further suggest that the P300-deficit in schizophrenics involves an extended cortical network of the left hemisphere at several steps in time during the information processing stream.

Reduced event-related current density in the anterior cingulate cortex in schizophrenia.

There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90-100 ms) and a later N1 peak (120-130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100-140 ms poststimulus).

Frontal dysfunction in schizophrenia--a new electrophysiological classifier for research and clinical applications.

We determined whether schizophrenic patients can be reliably classified with electrophysiological tools. We developed a fully computerized classifier based on 5 minutes of EEG recording during an acoustical choice reaction time task (AMDP-module IV). We included factorized variables from the frequency domain and evoked potentials (N100/P200-complex) from central and frontal electrodes, which were preprocessed in a sample of 150 normal subjects prior to classification. We applied discriminant analyses to the electrophysiological data from depressive, schizophrenic and schizotypal subjects, most of them being unmedicated or drug-naive. The classifier was developed on a training set (33 schizophrenics, 49 normals) and tested on an independent sample (32 schizophrenics, 49 normals). A simple three-variable classifier was found to classify schizophrenics and normals in 77% of those tested correctly. Diagnostic specificity of the classifier proved to be low as the inclusion of depressive patients (n= 60) significantly decreased classification power. It was demonstrated that atypical but not typical neuroleptic drugs may influence the classification results. Correctly classified schizophrenics showed significantly more negative symptoms and slower reaction times than those schizophrenics who were misclassified as normals. In contrast, these misclassified schizophrenics showed a non-significant trend for more positive symptoms and shorter reaction times. As the correctly classified schizophrenics showed increased frontally pronounced delta-activity and decreased signal power of the N100/P200 amplitude, it was concluded that these schizophrenics show dysfunction of the frontal lobe. It is proposed that this new classifier can be useful for clinical and research applications when subtyping of schizophrenics with detection of frontal dysfunction as the aim.

Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing.

OBJECTIVE: This study was performed in order to clarify the mechanisms which underlie the reduced signal-to-noise of event-related potentials in schizophrenic patients. Specifically, we wanted to find out, whether it is reduced activation and/or synchronization (phase-locking) in specific frequency bands of the ongoing EEG which is related to the decreased signal amplitude and signal-to-noise ratio in schizophrenics. METHODS: We investigated 41 unmedicated schizophrenics (10 of them drug-naïve) and compared them with healthy control subjects (n = 233) as well as unmedicated subjects with schizotypal personality (n = 21), who were considered to be high-risk subjects for schizophrenia, and unmedicated depressive patients (n = 71). We measured event-related activity during an acoustical choice reaction paradigm and calculated the signal-to-noise ratio, signal power and noise for a time interval of 50-200 ms after stimulus presentation. Signal-to-noise ratio was calculated from the power of the averaged trials (signal power) divided by the mean power of the single trials minus the power of the average (noise power). Also, we performed a frequency analysis of the pre- and poststimulus EEG based on a factor analytical approach. Group comparisons were performed with ANCOVA. RESULTS: As expected, a decreased signal-to-noise ratio of evoked activity was found in the schizophrenic and a non-significant trend in the schizotypal subjects and the depressive patients. We were able to show that the observed decrease is due to a reduced signal power and an increase of absolute noise power. Frequency analysis of the evoked activity revealed that normals, schizophrenics schizotypal subjects and depressive patients increased theta/delta activity between pre- and poststimulus interval to a similar extend. However, this theta/delta-augmentation does not correlate with signal power in schizophrenics. Also, normals and depressive subjects augment coherence between both temporal lobes during information processing, which is not found in schizophrenics and schizotypal subjects. In contrast, these two groups augment frontal lobe coherence, which goes along with an increase of noise. CONCLUSIONS: Reduced stimulus-induced phase-locking and bitemporal coherence of cortically evoked activity but not a failure to activate the cortex may be responsible for the observed low signal-to-noise ratio during information processing in schizophrenics. Accordingly, schizophrenics increase noise after stimulus presentation instead of building up a signal. This is discussed in the framework of the theory of stochastic resonance.