Non-literal understanding and psychosis: Metaphor comprehension in individuals with a diagnosis of schizophrenia.

Previous studies suggest that understanding of non-literal expressions, and in particular metaphors, can be impaired in people with schizophrenia; although it is not clear why. We explored metaphor comprehension capacity using a novel picture selection paradigm; we compared task performance between people with schizophrenia and healthy comparator subjects and we further examined the relationships between the ability to interpret figurative expressions non-literally and performance on a number of other cognitive tasks. Eye-tracking was used to examine task strategy. We showed that even when IQ, years of education, and capacities for theory of mind and associative learning are factored in as covariates, patients are significantly more likely to interpret metaphorical expressions literally, despite eye-tracking findings suggesting that patients are following the same interpretation strategy as healthy controls. Inhibitory control deficits are likely to be one of multiple factors contributing to the poorer performance of our schizophrenia group on the metaphor trials of the picture selection task.

Associations between childhood maltreatment and inflammatory markers.

BACKGROUND: Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.AimsTo determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis. METHOD: We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum. RESULTS: Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD. CONCLUSIONS: Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.Declaration of interestD.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck.

Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction.

OBJECTIVES: To explore cognitive performance in chronic fatigue syndrome (CFS) examining two cohorts. To establish findings associated with CFS and those related to co-morbid depression or autonomic dysfunction. METHODS: Identification and recruitment of participants was identical in both phases, all CFS patients fulfilled Fukuda criteria. In Phase 1 (n = 48) we explored cognitive function in a heterogeneous cohort of CFS patients, investigating links with depressive symptoms (HADS). In phase 2 (n = 51 CFS & n = 20 controls) participants with co-morbid major depression were excluded (SCID). Furthermore, we investigated relationships between cognitive performance and heart rate variability (HRV). RESULTS: Cognitive performance in unselected CFS patients is in average range on most measures. However, 0-23% of the CFS sample fell below the 5th percentile. Negative correlations occurred between depressive symptoms (HAD-S) with Digit-Symbol-Coding (r = -.507, p = .006) and TMT-A (r = -.382, p = .049). In CFS without depression, impairments of cognitive performance remained with significant differences in indices of psychomotor speed (TMT-A: p = 0.027; digit-symbol substitution: p = 0.004; digit-symbol copy: p = 0.007; scanning: p = .034) Stroop test suggested differences due to processing speed rather than inhibition. Both cohorts confirmed relationships between cognitive performance and HRV (digit-symbol copy (r = .330, p = .018), digit-symbol substitution (r = .313, p = .025), colour-naming trials Stroop task (r = .279, p = .050). CONCLUSION: Cognitive difficulties in CFS may not be as broad as suggested and may be restricted to slowing in basic processing speed. While depressive symptoms can be associated with impairments, co-morbidity with major depression is not itself responsible for reductions in cognitive performance. Impaired autonomic control of heart-rate associates with reductions in basic processing speed.

Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome.

Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n = 48), primary Sjögren's syndrome (a disease group control) (n = 27), and sedentary healthy controls (HCs) (n = 20), and to investigate its relationship with clinical measures. In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFα, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined. CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score. The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross-sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression.

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome.

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

The intraparietal sulcus governs multisensory integration of audiovisual information based on task difficulty.

Object recognition benefits maximally from multimodal sensory input when stimulus presentation is noisy, or degraded. Whether this advantage can be attributed specifically to the extent of overlap in object-related information, or rather, to object-unspecific enhancement due to the mere presence of additional sensory stimulation, remains unclear. Further, the cortical processing differences driving increased multisensory integration (MSI) for degraded compared with clear information remain poorly understood. Here, two consecutive studies first compared behavioral benefits of audio-visual overlap of object-related information, relative to conditions where one channel carried information and the other carried noise. A hierarchical drift diffusion model indicated performance enhancement when auditory and visual object-related information was simultaneously present for degraded stimuli. A subsequent fMRI study revealed visual dominance on a behavioral and neural level for clear stimuli, while degraded stimulus processing was mainly characterized by activation of a frontoparietal multisensory network, including IPS. Connectivity analyses indicated that integration of degraded object-related information relied on IPS input, whereas clear stimuli were integrated through direct information exchange between visual and auditory sensory cortices. These results indicate that the inverse effectiveness observed for identification of degraded relative to clear objects in behavior and brain activation might be facilitated by selective recruitment of an executive cortical network which uses IPS as a relay mediating crossmodal sensory information exchange.

Grey and white matter differences in Chronic Fatigue Syndrome - A voxel-based morphometry study.

OBJECTIVE: Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. METHODS: Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments. RESULTS: Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe. CONCLUSION: Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.

Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes?

IMPORTANCE: Chronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ). OBJECTIVE: To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ. DESIGN: Case control study. SETTING: Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK. PARTICIPANTS: 49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression. MAIN OUTCOMES AND MEASURES: Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS) and Cognitive Failures Questionnaire (COGFAIL) respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment. RESULTS: Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups. CONCLUSIONS AND RELEVANCE: The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS subgroups suggest subjects have a different disease burden on subjective and objective measures of function, autonomic parameters and cognitive impairment when categorised using the DSQ. Different CFS criteria may at best be diagnosing a spectrum of disease severities and at worst different CFS phenotypes or even different diseases. This complicates research and disease management and may contribute to the significant stigma associated with the condition.

Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study.

Objectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS). Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls. Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning. Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments. Trail registration number: Registered with NIHR Portfolio CLRN ID 97805.

Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study.

OBJECTIVES: To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements. METHODS: Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin. RESULTS: The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r(2)=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r(2)=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities. CONCLUSIONS: This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

The Impact of Target Frequency on Intra-Individual Variability in Euthymic Bipolar Disorder: A Comparison of Two Sustained Attention Tasks.

Greater intra-individual variability (IIV) in reaction time (RT) on a sustained attention task has been reported in patients with bipolar disorder (BD) compared with healthy controls. However, it is unclear whether IIV is task specific, or whether it represents general cross-task impairment in BD. This study aimed to investigate whether IIV occurs in sustained attention tasks with different parameters. Twenty-two patients with BD (currently euthymic) and 17 controls completed two sustained attention tasks on different occasions: a low target frequency (~20%) Vigil continuous performance test (CPT) and a high target frequency (~70%) CPT version A-X (CPT-AX). Variability measures (individual standard deviation and coefficient of variation) were calculated per participant, and ex-Gaussian modeling was also applied. This was supplemented by Vincentile analysis to characterize RT distributions. Results indicated that participants (patients and controls) were generally slower and more variable when completing the Vigil CPT compared with CPT-AX. Significant group differences were also observed in the Vigil CPT, with euthymic BD patients being more variable than controls. This result suggests that IIV in BD demonstrates some degree of task specificity. Further research should incorporate analysis of additional RT distributional models (drift diffusion and fast Fourier transform) to fully characterize the pattern of IIV in BD, as well as its relationship to cognitive processes.

Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. METHODS: This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. FINDINGS: Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2-24·4] in the metyrapone group vs 22·6 points [20·1-24·8] in the placebo group; adjusted mean difference of -0·51 points [95% CI -3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. INTERPRETATION: Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities. FUNDING: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Empathy in individuals clinically at risk for psychosis: brain and behaviour.

BACKGROUND: Empathy is a basic human ability, and patients with schizophrenia show dysfunctional empathic abilities on the behavioural and neural level. AIMS: These dysfunctions may precede the onset of illness; thus, it seems mandatory to examine the empathic abilities in individuals at clinical high risk for psychosis. METHOD: Using functional magnetic resonance imaging, we measured 15 individuals at clinical high risk of psychosis (CHR group) and compared their empathy performance with 15 healthy volunteers and 15 patients with schizophrenia. RESULTS: Behavioural data analysis indicated no significant deficit in the CHR group. Functional data analysis revealed hyperactivation in a frontotemporoparietal network including the amygdala in the CHR group compared with the other two groups. CONCLUSIONS: Despite normal behavioural performance, the CHR group activated the neural empathy network differently and specifically showed hyperactivation in regions critical for emotion processing. This could suggest a compensatory mechanism reflecting emotional hypersensitivity or dysfunctional emotion regulation. Further investigations should clarify the role of these neural alterations for development and exacerbation of psychosis.

On utilizing uncertainty information in template-based EEG-fMRI ballistocardiogram artifact removal.

The correction of ballistocardiogram artifacts in simultaneous EEG-fMRI often yields unsatisfactory results. To improve the signal-to-noise ratio (SNR) of results, we inferred EEG signal uncertainty from postcorrection artifact residuals and computed the uncertainty-weighted mean of ERPs. Using an uncertainty-weighted mean significantly and consistently reduced both inter- and intrasubject SEM in the analysis of auditory evoked responses (AER, indicated by the N1-P2 complex) and in the effects of an auditory oddball paradigm (N1-P3 complex, standard-deviant difference). SNR increased by 3% on average for the AER amplitude (intrasubject) and 17% on average for the auditory oddball ERP (intersubject). This demonstrates that weighting by uncertainty complements existing artifact correction algorithms to increase SNR in ERPs. More specifically, it is an efficient method to utilize seemingly corrupt (difficult-to-correct) EEG data that might otherwise be discarded.

Negative BOLD response in the hippocampus during short-term spatial memory retrieval.

A parieto-medial temporal pathway is thought to underlie spatial navigation in humans. fMRI was used to assess the role of this pathway, including the hippocampus, in the cognitive processes likely to underlie navigation based on environmental cues. Participants completed a short-term spatial memory task in virtual space, which required no navigation but involved the recognition of a target location from a foil location based on environmental landmarks. The results showed that spatial memory retrieval based on environmental landmarks was indeed associated with increased signal in regions of the parieto-medial temporal pathway, including the superior parietal cortex, the retrosplenial cortex, and the lingual gyrus. However, the hippocampus demonstrated a signal decrease below the fixation baseline during landmark-based retrieval, whereas there was no signal change from baseline during retrieval based on viewer position. In a discussion of the origins of such negative BOLD response in the hippocampus, we consider both a suppression of default activity and an increase in activity without a corresponding boost in CBF as possible mechanisms.

The neural correlates of positive self-evaluation and self-related memory.

Humans tend to have a positive self-evaluation (PSE). To what extent positive self-perception is interacting with valenced self-related memories is debated. The underlying neural substrates are not adequately explained yet. To explore the cerebral correlates of PSE and its influence on memory, 24 healthy subjects were asked during fMRI to decide in two conditions whether presented positive and negative personality traits characterized their own selves (self-evaluation) or an intimate other (other-evaluation). A lexical condition served as control task. In a subsequent unannounced recognition task, trait adjectives had to be classified as old or new. Activation during positive self- vs positive other-evaluation was found in the medial ventral and dorsolateral prefrontal gyri, the parahippocampus and the supplementary motor area. Memory increased for positive personality traits and traits that had been referred to oneself or the other. In contrast to adjectives of the other-evaluation or lexical condition, recollection of negative vs positive traits of the self-evaluation condition specifically induced increased activation in the hippocampus and several prefrontal and temporal areas. Our data imply a specific network for PSE (although intimate others are perceived similarly). Moreover, memory for traits contradicting PSE resulted in activation increases indicating greater cognitive effort and emotional involvement.

Auditory processing under cross-modal visual load investigated with simultaneous EEG-fMRI.

Cognitive task demands in one sensory modality (T1) can have beneficial effects on a secondary task (T2) in a different modality, due to reduced top-down control needed to inhibit the secondary task, as well as crossmodal spread of attention. This contrasts findings of cognitive load compromising a secondary modality's processing. We manipulated cognitive load within one modality (visual) and studied the consequences of cognitive demands on secondary (auditory) processing. 15 healthy participants underwent a simultaneous EEG-fMRI experiment. Data from 8 participants were obtained outside the scanner for validation purposes. The primary task (T1) was to respond to a visual working memory (WM) task with four conditions, while the secondary task (T2) consisted of an auditory oddball stream, which participants were asked to ignore. The fMRI results revealed fronto-parietal WM network activations in response to T1 task manipulation. This was accompanied by significantly higher reaction times and lower hit rates with increasing task difficulty which confirmed successful manipulation of WM load. Amplitudes of auditory evoked potentials, representing fundamental auditory processing showed a continuous augmentation which demonstrated a systematic relation to cross-modal cognitive load. With increasing WM load, primary auditory cortices were increasingly deactivated while psychophysiological interaction results suggested the emergence of auditory cortices connectivity with visual WM regions. These results suggest differential effects of crossmodal attention on fundamental auditory processing. We suggest a continuous allocation of resources to brain regions processing primary tasks when challenging the central executive under high cognitive load.

Effective connectivity of the human cerebellum during visual attention.

Insights from both lesion and neuroimaging studies increasingly substantiate the view that the human cerebellum not only serves motor control but also supports various cognitive processes. Higher cognitive functions like working memory or executive control have been associated with the phylogenetically younger parts of the cerebellum, crus I and crus II. Functional connectivity studies corroborate this notion as activation of the cerebellum correlates with activity in numerous areas of the cerebral cortex. Moreover, these cerebrocerebellar loops were shown to be topographically organized. We used an attention-to-motion paradigm to elaborate on the effective connectivity of cerebellar crus I during visual attention. Psychophysiological interaction analyses demonstrated enhanced connectivity of the cerebellum--during attention--with dorsal visual stream regions including posterior parietal cortex (PPC) and left secondary visual cortex (V5). Dynamic causal modeling revealed a modulation of the connections from V5 to PPC and from crus I to V5 by attention. Remarkably, the influence which V5 exerted on PPC was reduced during attention, resulting in a suppression of the sensitivity of PPC to bottom-up information. Moreover, the sensitivity of V5 populations to inputs from crus I was increased under attention. This might underscore the presumed role of the cerebellum as a state estimator that provides hierarchically lower regions (V5) with top-down predictions, which in turn might be based on endogenous inputs from PPC to the cerebellum. These results are in line with formulations of attention in predictive coding, where attention increases the precision or sensitivity of hierarchically lower neuronal populations that may encode prediction error.

Empathic behavioral and physiological responses to dynamic stimuli in depression.

Major depressive disorder (MDD) is strongly linked to social withdrawal and interpersonal problems which characterize the disorder and further aggravate symptoms. Investigating the nature of impaired emotional-social functioning as a basis of interpersonal functioning in MDD has been widely restricted to static stimuli and behavioral emotion recognition accuracy. The present study aimed at examining higher order emotional processes, namely empathic responses and its components, emotion recognition accuracy and affective responses in 28 MDD patients and 28 healthy control participants. The dynamic stimulus material included 96 short video clips depicting actors expressing basic emotions by face, voice prosody, and sentence content. Galvanic skin conductance measurements revealed implicit processes in the multimethod assessment of empathy. Overall, patients displayed lower empathy, emotion accuracy, and affective response rates than controls. Autonomous arousal was higher in patients. A generalized emotion processing deficit is in line with the "emotional context insensitivity" (ECI) theory which proposes decreased overall responsiveness to emotional stimuli. The dissociation between hypo-reactivity in explicit and hyper-reactivity in implicit measures of emotion processing can be related to the "limbic-cortical dysregulation" model of depression. Our findings support the dissociation of autonomic and subjective emotional responses which may account for interpersonal as well as emotional deficits in depression.