In your eyes only: deficits in executive functioning after frontal TMS reflect in eye movements

This study investigated the roles of the right and left dorsolateral prefrontal (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functioning using a theta burst transcranial magnetic stimulation (TMS) approach. Healthy subjects solved two visual search tasks: a number search task with low cognitive demands, and a number and letter search task with high cognitive demands. To observe how subjects solved the tasks, we assessed their behavior with and without TMS using eye movements when subjects were confronted with specific executive demands. To observe executive functions, we were particularly interested in TMS-induced changes in visual exploration strategies found to be associated with good or bad performance in a control condition without TMS stimulation. TMS left processing time unchanged in both tasks. Inhibition of the rDLPFC resulted in a decrease in anticipatory fixations in the number search task, i.e., a decrease in a good strategy in this low demand task. This was paired with a decrease in stimulus fixations. Together, these results point to a role of the rDLPFC in planning and response selection. Inhibition of the lDLPFC and the MFC resulted in an increase in anticipatory fixations in the number and letter search task, i.e., an increase in the application of a good strategy in this task. We interpret these results as a compensatory strategy to account for TMS-induced deficits in attentional switching when faced with high switching demands. After inhibition of the lDLPFC, an increase in regressive fixations was found in the number and letter search task. In the context of high working memory demands, this strategy appears to support TMS-induced working memory deficits. Combining an experimental TMS approach with the recording of eye movements proved sensitive to discrete decrements of executive functions and allows pinpointing the functional organization of the frontal lobes.

The emotional power of music: How music enhances the feeling of affective pictures

Music is an intriguing stimulus widely used in movies to increase the emotional experience. However, no brain imaging study has to date examined this enhancement effect using emotional pictures (the modality mostly used in emotion research) and musical excerpts. Therefore, we designed this functional magnetic resonance imaging study to explore how musical stimuli enhance the feeling of affective pictures. In a classical block design carefully controlling for habituation and order effects, we presented fearful and sad pictures (mostly taken from the IAPS) either alone or combined with congruent emotional musical excerpts (classical pieces). Subjective ratings clearly indicated that the emotional experience was markedly increased in the combined relative to the picture condition. Furthermore, using a second-level analysis and regions of interest approach, we observed a clear functional and structural dissociation between the combined and the picture condition. Besides increased activation in brain areas known to be involved in auditory as well as in neutral and emotional visual-auditory integration processes, the combined condition showed increased activation in many structures known to be involved in emotion processing (including for example amygdala, hippocampus, parahippocampus, insula, striatum, medial ventral frontal cortex, cerebellum, fusiform gyrus). In contrast, the picture condition only showed an activation increase in the cognitive part of the prefrontal cortex, mainly in the right dorsolateral prefrontal cortex. Based on these findings, we suggest that emotional pictures evoke a more cognitive mode of emotion perception, whereas congruent presentations of emotional visual and musical stimuli rather automatically evoke strong emotional feelings and experiences.

Chronometric features of processing unpleasant stimuli: a functional MRI-based transcranial magnetic stimulation study.

The quick identification of potentially threatening events is a crucial cognitive capacity to survive in a changing environment. Previous functional MRI data revealed the right dorsolateral prefrontal cortex and the region of the left intraparietal sulcus (IPS) to be involved in the perception of emotionally negative stimuli. For assessing chronometric aspects of emotion processing, we applied transcranial magnetic stimulation above these areas at different times after negative and neutral picture presentation. An interference with emotion processing was found with transcranial magnetic stimulation above the dorsolateral prefrontal cortex 200-300 ms and above the left intraparietal sulcus 240/260 ms after negative stimuli. The data suggest a parallel and conjoint involvement of prefrontal and parietal areas for the identification of emotionally negative stimuli.

Modulation of anticipatory emotion and perception processing by cognitive control.

Strategies of cognitive control are helpful in reducing anxiety experienced during anticipation of unpleasant or potentially unpleasant events. We investigated the associated cerebral information processing underlying the use of a specific cognitive control strategy during the anticipation of affect-laden events. Using functional magnetic resonance imaging, we examined differential brain activity during anticipation of events of unknown and negative emotional valence in a group of eighteen healthy subjects that used a cognitive control strategy, similar to "reality checking" as used in psychotherapy, compared with a group of sixteen subjects that did not exert cognitive control. While expecting unpleasant stimuli, the "cognitive control" group showed higher activity in left medial and dorsolateral prefrontal cortex areas but reduced activity in the left extended amygdala, pulvinar/lateral geniculate nucleus and fusiform gyrus. Cognitive control during the "unknown" expectation was associated with reduced amygdalar activity as well and further with reduced insular and thalamic activity. The amygdala activations associated with cognitive control correlated negatively with the reappraisal scores of an emotion regulation questionnaire. The results indicate that cognitive control of particularly unpleasant emotions is associated with elevated prefrontal cortex activity that may serve to attenuate emotion processing in for instance amygdala, and, notably, in perception related brain areas.

Disturbed cortico–amygdalar functional connectivity as pathophysiological correlate of working memory deficits in bipolar affective disorder

Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric “cognitive–emotional” interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients.

From Similes to Allegory: The Deconstruction of Chariot Imagery in Early Buddhist Texts, Analyzed with Cognitive Metaphor Theory

The presentation will start by unfolding the various layers of chariot imagery in early Indian sources, namely, chariots as vehicles of gods such as the sun (sūrya), i.e. as symbol of cosmic stability; chariots as symbols of royal power and social prestige e.g. of Brahmins; and, finally, chariots as metaphors for the “person”, the “mind” and the “way to liberation” (e.g., Kaṭ.-Up. III.3; Maitr.-Up. II. 6). In Buddhist and non-Buddhist sources, chariots are in certain aspects used as a metaphor for the (old) human body (e.g., Caraka-S., Vi.3.37-38; D II.100; D II.107); apart from that, there is, of course, mention of the “real” use of chariots in sports, cults, journey, and combat. The most prominent example of the Buddhist use of chariot imagery is its application as a model for the person (S I.134 f.; Milindapañha, ed. Trenckner, 26), i.e., for highlighting the “non-substantial self”. There are, however, other significant examples of the usage of chariot imagery in early Buddhist texts. Of special interest are those cases in which chariot metaphors were applied in order to explain how the ‘self’ may proceed on the way to salvation – with ‘mindfulness’ or the ‘self’ as charioteer, with ‘wisdom’ and ‘confidence’ as horses etc. (e.g. S I. 33; S V.7; Dhp 94; or the Nārada-Jātaka, No. 545, verses 181-190). One might be tempted to say that these instances reaffirm the traditional soteriology of a substantial “progressing soul”. Taking conceptual metaphor analysis as a tool, I will, in contrast, argue that there is a special Buddhist use of this metaphor. Indeed, at first sight, it seems to presuppose a non-Buddhist understanding (the “self” as charioteer; the chariot as vehicle to liberation, etc.). Yet, it will be argued that in these cases the chariot imagery is no longer fully “functional”. The Buddhist usage may, therefore, best be described as a final allegorical phase of the chariot-imagery, which results in a thorough deconstruction of the “chariot” itself.

Individual group efficacy beliefs and performance motivation: A mediational approach

Introduction: According to the theoretical model of Cranach, Ochsenbein, and Valach (1986) understanding group actions needs consideration of aspects at both the group level and the level of individual members. For example individual action units constituting group actions are motivated at the individual level while potentially being affected by characteristics of the group. Theoretically, group efficacy beliefs could be a part of this motivational process as they are an individual’s cognitive contents about group-level abilities to perform well in a specific task. Positive relations between group level efficacy-beliefs and group performance have been reported and Bandura and Locke (2003) argue that this relationship is being mediated by motivational processes and goal setting. The aims of this study were a) to examine the effects of group characteristics on individual performance motivation and b) to test if those are mediated by individual group efficacy beliefs. Methods: Forty-seven students (M=22.83 years, SD=2.83, 34% women) of the university of Berne participated in this scenario based experiment. Data were collected on two collection points. Subjects were provided information about fictive team members with whom they had to perform a group triathlon. Three values (low, medium, high) of the other team members’ abilities to perform in their parts of the triathlon (swimming and biking respectively) were combined in a 3x3 full factorial design (Anderson, 1982) yielding nine groups. Subjects were asked how confident they were that the teams would perform well in the task (individual group efficacy beliefs), and to provide information about their motivation to perform at their best in the respective group contexts (performance motivation). Multilevel modeling (Mplus) was used to estimate the effects of the factors swim and bike, and the context-varying covariate individual group efficacy beliefs on performance motivation. Further analyses were undertaken to test if the effects of group contexts on performance motivation are mediated by individual group efficacy beliefs. Results: Significant effects were reported for both the group characteristics (βswim = 7.86; βbike = 8.57; both p < .001) and the individual group efficacy beliefs (βigeb; .40, p < .001) on performance motivation. The subsequent mediation model indicated that the effects of group characteristics on performance motivation were partly mediated by the individual group efficacy beliefs of the subjects with significant mediation effects for both factors swim and bike. Discussion/Conclusion: The results of the study provide further support for the motivational character of efficacy beliefs and point out a mechanism by which team characteristics influence performance relevant factors at the level of individual team members. The study indicates that high team abilities lead to augmented performance motivation, adding a psychological advantage to teams already high on task relevant abilities. Future investigations will be aiming at possibilities to keep individual performance motivation high in groups with low task relevant abilities. One possibility could be the formulation of individual task goals. References: Anderson, N. H. (1982). Methods of information integration theory. New York: Academic Press. Bandura, A. & Locke, E. A. (2003). Negative self-efficacy and goal effects revisited. Journal of Applied Psychology, 88, 87-99. Cranach, M. von, Ochsenbein, G. & Valach, L. (1986). The group as a self-active system: Outline of a theory of group action. European Journal of Social Psychology, 16, 193-229.

Prediction and prevention of psychosis: current progress and future tasks

Prevention of psychoses has been intensively investigated within the past two decades, and particularly, prediction has been much advanced. Depending on the applied risk indicators, current criteria are associated with average, yet significantly heterogeneous transition rates of ≥30 % within 3 years, further increasing with longer follow-up periods. Risk stratification offers a promising approach to advance current prediction as it can help to reduce heterogeneity of transition rates and to identify subgroups with specific needs and response patterns, enabling a targeted intervention. It may also be suitable to improve risk enrichment. Current results suggest the future implementation of multi-step risk algorithms combining sensitive risk detection by cognitive basic symptoms (COGDIS) and ultra-high-risk (UHR) criteria with additional individual risk estimation by a prognostic index that relies on further predictors such as additional clinical indicators, functional impairment, neurocognitive deficits, and EEG and structural MRI abnormalities, but also considers resilience factors. Simply combining COGDIS and UHR criteria in a second step of risk stratification produced already a 4-year hazard rate of 0.66. With regard to prevention, two recent meta-analyses demonstrated that preventive measures enable a reduction in 12-month transition rates by 54-56 % with most favorable numbers needed to treat of 9-10. Unfortunately, psychosocial functioning, another important target of preventive efforts, did not improve. However, these results are based on a relatively small number of trials; and more methodologically sound studies and a stronger consideration of individual profiles of clinical needs by modular intervention programs are required

Early adolescent cognitive gains are marked by increased sleep EEG coherence

Although the increases in cognitive capacities of adolescent humans are concurrent with significant cortical restructuring, functional associations between these phenomena are unclear. We examined the association between cortical development, as measured by the sleep EEG, and cognitive performance in a sample of 9/10 year olds followed up 1 to 3 years later. Our cognitive measures included a response inhibition task (Stroop), an executive control task (Trail Making), and a verbal fluency task (FAS). We correlated sleep EEG measures of power and intra-hemispheric coherence at the initial assessment with performance at that assessment. In addition we correlated the rate of change across assessments in sleep EEG measures with the rate of change in performance. We found no correlation between sleep EEG power and performance on cognitive tasks for the initial assessment. In contrast, we found a significant correlation of the rate of change in intra-hemispheric coherence for the sigma band (11 to 16 Hz) with rate of change in performance on the Stroop (r = 0.61; p<0.02) and Trail Making (r =  -0.51; p<0.02) but no association for the FAS. Thus, plastic changes in connectivity (i.e., sleep EEG coherence) were associated with improvement in complex cognitive function.

White matter matters: a multimodal approach to investigate white matter microstructure and metabolism

White matter connects different brain areas and applies electrical insulation to the neuron’s axons with myelin sheaths in order to enable quick signal transmission. Due to its modulatory properties in signal conduction, white matter plays an essential role in learning, cognition and psychiatric disorders (Fields, 2008a). In respect thereof, the non-invasive investigation of white matter anatomy and function in vivo provides the unique opportunity to explore the most complex organ of our body. Thus, the present thesis aimed to apply a multimodal neuroimaging approach to investigate different white matter properties in psychiatric and healthy populations. On the one hand, white matter microstructural properties were investigated in a psychiatric population; on the other hand, white matter metabolic properties were assessed in healthy adults providing basic information about the brain’s wiring entity. As a result, three research papers are presented here. The first paper assessed the microstructural properties of white matter in relation to a frequent epidemiologic finding in schizophrenia. As a result, reduced white matter integrity was observed in patients born in summer and autumn compared to patients born in winter and spring. Despite the large genetic basis of schizophrenia, accumulating evidence indicates that environmental exposures may be implicated in the development of schizophrenia (A. S. Brown, 2011). Notably, epidemiologic studies have shown a 5–8% excess of births during winter and spring for patients with schizophrenia on the Northern Hemisphere at higher latitudes (Torrey, Miller, Rawlings, & Yolken, 1997). Although the underlying mechanisms are unclear, the seasonal birth effect may indicate fluctuating environmental risk factors for schizophrenia. Thus, exposure to harmful factors during foetal development may result in the activation of pathologic neural circuits during adolescence or young adulthood, increasing the risk of schizophrenia (Fatemi & Folsom, 2009). While white matter development starts during the foetal period and continues until adulthood, its major development is accomplished by the age of two years (Brody, Kinney, Kloman, & Gilles, 1987; Huang et al., 2009). This indicates a vulnerability period of white matter that may coincide with the fluctuating environmental risk factors for schizophrenia. Since microstructural alterations of white matter in schizophrenia are frequently observed, the current study provided evidence for the neurodevelopmental hypothesis of schizophrenia. In the second research paper, the perfusion of white matter showed a positive correlation between white matter microstructure and its perfusion with blood across healthy adults. This finding was in line with clinical studies indicating a tight coupling between cerebral perfusion and WM health across subjects (Amann et al., 2012; Chen, Rosas, & Salat, 2013; Kitagawa et al., 2009). Although relatively little is known about the metabolic properties of white matter, different microstructural properties, such as axon diameter and myelination, might be coupled with the metabolic demand of white matter. Furthermore, the ability to detect perfusion signal in white matter was in accordance with a recent study showing that technical improvements, such as pseudo-continuous arterial spin labeling, enabled the reliable detection of white matter perfusion signal (van Osch et al., 2009). The third paper involved a collaboration within the same department to assess the interrelation between functional connectivity networks and their underlying structural connectivity.

Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease

OBJECTIVE The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.

Time-course of "off-line" prefrontal rTMS effects--a PET study.

Low-frequency "off-line" repetitive transcranial magnetic stimulation (rTMS) over the course of several minutes has attained considerable attention as a research tool in cognitive neuroscience due to its ability to induce functional disruptions of brain areas. This disruptive rTMS effect is highly valuable for revealing a causal relationship between brain and behavior. However, its influence on remote interconnected areas and, more importantly, the duration of the induced neurophysiological effects, remain unknown. These aspects are critical for a study design in the context of cognitive neuroscience. In order to investigate these issues, 12 healthy male subjects underwent 8 H(2)(15)O positron emission tomography (PET) scans after application of long-train low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC). Immediately after the stimulation train, regional cerebral blood flow (rCBF) increases were present under the stimulation site as well as in other prefrontal cortical areas, including the ventrolateral prefrontal cortex (VLPFC) ipsilateral to the stimulation site. The mean increases in rCBF returned to baseline within 9 min. The duration of this unilateral prefrontal rTMS effect on rCBF is of particular interest to those who aim to influence behavior in cognitive paradigms that use an "off-line" approach.

Effectiveness of integrated cognitive remediartion therapy for schizophrenia outpatients: Early versus long-term course of illness – results from an international RCT

Background Nowadays there is extensive evidence available showing the efficacy of cognitive remediation therapies. Integrative approaches seem superior regarding the maintenance of proximal outcome at follow-up as well as generalization to other areas of functioning. To date, only limited evidence about the efficacy of CRT is available concerning elder schizophrenia patients. The Integrated Neurocognitive Therapy (INT) represents a new developed cognitive remediation approach. It is a manualized group therapy approach targeting all 11 NIMH-MATRICS dimensions within one therapy concept. In this study we compared the effects of INT on an early course group (duration of disease<5 years) to a long-term group of schizophrenia outpatients (duration of disease>15 years). Methods An international multicenter study carried out in Germany, Switzerland and Austria with a total of 90 outpatients diagnosed with Schizophrenia (DSM-IV-TR) were randomly assigned either to an INT-Therapy or to Treatment-As-Usual (TAU). 50 of the 90 Patients were an Early-Course (EC) group, suffering from schizophrenia for less than 5 years (Mean age=29 years, Mean duration of illness=3.3 years). The other 40 were a Long-term Course (LC) group, suffering from schizophrenia longer than 15 years (Mean age= 45 years, Mean duration of illness=22 years). Treatment comprised of 15 biweekly sessions. An extensive assessment battery was conducted before and after treatment and at follow up (1 year). Multivariate General Linear Models (GLM) (duration of illness x treatment x time) examined our hypothesis, if an EC group of schizophrenia outpatients differ in proximal and distal outcome from a LC group. Results Irrespective of the duration of illness, both groups (EC & LC) were able to benefit from the INT. INT was superior compared to TAU in most of the assessed domains. Dropout rate of EC group was much higher (21.4%) than LC group (8%) during therapy phase. However, interaction effects show that the LC group revealed significantly higher effects in the neurocognitive domains of speed of processing (F>3.6) and vigilance (F>2.4). In social cognition the EC group showed significantly higher effects in social schema (F>2.5) and social attribution (blame; F>6.0) compared to the LC group. Regarding more distal outcome, patients treated with INT obtained reduced general symptoms unaffected by the duration of illness during therapy phase and at follow-up (F>4.3). Discussion Results suggest that INT is a valid goal-oriented treatment to improve cognitive functions in schizophrenia outpatients. Irrespective of the duration of illness significant treatment, effects were evident. Against common expectations, long-term, more chronic patients showed higher effects in basal cognitive functions compared to younger patients and patients without any active therapy (TAU). Consequently, more integrated therapy offers are also recommended for long-term course schizophrenia patients.

Significance of social cognitive remediation therapy within a comprehensive treatment concept

Objectives: The final goal in the successful treatment of schizophrenia patients is defined in improved functional recovery. Thus the integration of social cognitive tasks within a comprehensive treatment concept should offer significant advantages in generalization and transfer of therapy effects. Recent therapy outcome research supports these advantages. Empirical modeling identified social cognition as a mediating factor between neurocognition and functional recovery. Regarding this, we first developed the Integrated Psychological Therapy Program (IPT). It consists of 5 subprograms and combines interventions on neurocognition, social cognition, and social competence. As a further development of the cognitive part of IPT we developed the Integrated Neurocognitive Therapy (INT), which focuses on all social and neurocognitive domains defined by MATRICS. Methods: The aim was to investigate whether the application of the complete IPT is superior in comparison to the use of single IPT subprograms. Data were based on 37 independent IPT studies including a total sample of 1692 schizophrenia patients. Additionally, the proximal outcome in cognitive domains as well as in more distal outcome areas was investigated in an international RCT on INT including 169 schizophrenia outpatients. Results: All IPT subprogram variations obtained significant effects in proximal outcome. Each subprogram domain reached the largest effects in the targeted area. With regard to distal outcomes, combinations of subprograms showed a significant reduction of negative symptoms and an improvement in not targeted areas of functioning. This strongly supports vertical generalization effects to other functional domains. Regarding INT, results support efficacy compared to TAU in various cognitive domains, in psychosocial functioning and symptoms after therapy and at 1-year-follow-up. Conclusion: Results support evidence for the efficacy of longer lasting integrated therapy. The success of these treatment concepts is strongly based on successful therapy of social cognitive functions.

Functional connectivity in BOLD and CBF data: similarity and reliability of resting brain networks

Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain's intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2×2×2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test-retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905±0.033 between-sessions; 0.885±0.052 between-scanners) than ASL (0.545±0.048; 0.575±0.059). Nevertheless, ASL provided highly reproducible (0.955±0.021; 0.970±0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners.