Slow Resting State Fluctuations Enhance Neuronal and Behavioral Responses to Looming Sounds.

We investigate both experimentally and using a computational model how the power of the electroencephalogram (EEG) recorded in human subjects tracks the presentation of sounds with acoustic intensities that increase exponentially (looming) or remain constant (flat). We focus on the link between this EEG tracking response, behavioral reaction times and the time scale of fluctuations in the resting state, which show considerable inter-subject variability. Looming sounds are shown to generally elicit a sustained power increase in the alpha and beta frequency bands. In contrast, flat sounds only elicit a transient upsurge at frequencies ranging from 7 to 45 Hz. Likewise, reaction times (RTs) in an audio-tactile task at different latencies from sound onset also present significant differences between sound types. RTs decrease with increasing looming intensities, i.e. as the sense of urgency increases, but remain constant with stationary flat intensities. We define the reaction time variation or "gain" during looming sound presentation, and show that higher RT gains are associated with stronger correlations between EEG power responses and sound intensity. Higher RT gain further entails higher relative power differences between loom and flat in the alpha and beta bands. The full-width-at-half-maximum of the autocorrelation function of the eyes-closed resting state EEG also increases with RT gain. The effects are topographically located over the central and frontal electrodes. A computational model reveals that the increase in stimulus-response correlation in subjects with slower resting state fluctuations is expected when EEG power fluctuations at each electrode and in a given band are viewed as simple coupled low-pass filtered noise processes jointly driven by the sound intensity. The model assumes that the strength of stimulus-power coupling is proportional to RT gain in different coupling scenarios, suggesting a mechanism by which slower resting state fluctuations enhance EEG response and shorten reaction times.

[Genuine motor phenomena in schizophrenic psychoses : Theoretical background and definition of context]. / Genuine motorische Phänomene bei schizophrenen Psychosen : Theoretischer Hintergrund und Kontextdefinition.

Besides positive and negative symptoms, motor abnormalities have been increasingly recognized as central symptoms of schizophrenia. Recent investigations of antipsychotic-naive first-episode patients with schizophrenia found significantly higher rates of genuine motor abnormalities (GMA) when compared to healthy individuals. The first part of this article introduces the historical and clinical background of GMA in schizophrenia. In the second part the relevance of scientific research and clinical implication of GMA in schizophrenia are discussed. Finally, this article aims at presenting a conceptual framework and a reference system involving both genuine and drug-induced motor abnormalities. The future clinical implications of GMA research are presented and multimodal and transdiagnostic studies are advocated. Future research on GMA will not only essentially enrich the formation of psychiatric theories but also promote progress in clinical neuroscience.

[Genuine motor phenomena in schizophrenia : Neuronal correlates and pathomechanisms]. / Genuine motorische Phänomene bei schizophrenen Psychosen : Neuronale Korrelate und Pathomechanismen.

Despite a growing body of evidence on motor dysfunction in schizophrenia spectrum disorders, the neuronal correlates of genuine motor abnormalities (GMA) are not fully elucidated at present. Moreover, the clinical relevance of a potential "motor intermediate phenotype" remains controversial. This systematic review aims at characterizing a "motor intermediate phenotype" in schizophrenia spectrum disorders. The second goal of this systematic review is to discuss GMA-associated brain alterations as potential biomarkers of psychosis risk syndrome and manifest motor symptoms against the background of current neuroimaging evidence. The detailed clinical assessment of GMA in the context of multimodal imaging could, in the future promote the early recognition of psychotic disorders and the initiation of disorder-oriented and individualized treatment. Taken as a whole the data provide initial evidence that motor dysfunction in schizophrenic spectrum disorders must be considered dimensionally. The predictive value of neurobiological results with respect to the transition to a life-threatening catatonia or the development of chronic dyskinesia, cannot currently be conclusively assessed.

[German version of the Northoff catatonia rating scale (NCRS-dv) : A validated instrument for measuring catatonic symptoms]. / Deutsche Version der Northoff Catatonia Rating Scale (NCRS-dv) : Ein validiertes Messinstrument zur Erfassung katatoner Symptome.

The clinical picture of catatonia includes impressive motor phenomena, such as rigidity, dyskinesia, festination, negativism, posturing, catalepsy, stereotypies and mannerisms, along with affective (e. g. aggression, anxiety, anhedonism or emotional lability) and behavioral symptoms (e.g. mutism, autism, excitement, echolalia or echopraxia). In English speaking countries seven catatonia rating scales have been introduced, which are widely used in clinical and scientific practice. In contrast, only one validated catatonia rating scale is available in Germany so far. In this paper, we introduce the German version of the Northoff catatonia rating scale (NCRS-dv). The original English version of the NCRS consists of 40 items describing motor (13 items), affective (12 items) and behavioral (15 items) catatonic symptoms. The NCRS shows high internal reliability (Crombachs alpha = 0.87), high interrater (r = 0.80-0.96) and high intrarater (r = 0.80-0.95) reliability. Factor analysis of the NCRS revealed four domains: affective, hyperactive or excited, hypoactive or retarded and behavior with individual eigenvalues of 8.98, 3.61, 2.98 and 2.82, respectively, which explained 21.5 %, 9.3 %, 7.6 % and 7.2 % of variance, respectively. In conclusion, the NCRS-dv represents a second validated instrument which can be used by German clinicians and scientists for the assessment of catatonic symptoms.

Abnormal functional-structural cingulum connectivity in mania: combined functional magnetic resonance imaging-diffusion tensor imaging investigation in different phases of bipolar disorder.

OBJECTIVE: The objective of the study was to investigate the relationship between structural connectivity (SC) and functional connectivity (FC) in the cingulum in bipolar disorder (BD) and its various phases. METHOD: We combined resting-state functional magnetic resonance imaging and probabilistic tractographic diffusion tensor imaging to investigate FC and SC of the cingulum and its portions, the SC-FC relationship, and their correlations with clinical and neurocognitive measures on sustained attention in manic (n = 21), depressed (n = 20), and euthymic (n = 20) bipolar patients and healthy controls (HC) (n = 42). RESULTS: First, we found decreased FC between the anterior and posterior parts of the cingulum in manic patients when compared to depressed patients and HC. Second, we observed decreased SC of the cingulum bundle, particularly in its anterior part, in manic patients when compared to HC. Finally, alterations in the cingulum FC (but not SC) correlated with clinical severity scores while changes in the cingulum SC (but not FC) were related with neurocognitive deficits in sustained attention in BD. CONCLUSION: We demonstrate for the first time a reduction in FC and concomitantly in SC of the cingulum in mania, which correlated with psychopathological and neurocognitive parameters, respectively, in BD. This supports the central role of cingulum connectivity specifically in mania.

[Methodological deficits in neuroethics: do we need theoretical neuroethics?]. / Methodische Defizite in der Neuroethik : Benötigen wir eine theoretische Neuroethik?

Current neuroethics can be characterized best as empirical neuroethics: it is strongly empirically oriented in that it not only includes empirical findings from neuroscience but also searches for applications within neuroscience. This, however, neglects the social and political contexts which could be subject to a future social neuroethics. In addition, methodological issues need to be considered as in theoretical neuroethics. The focus in this article is on two such methodological issues: (1) the analysis of the different levels and their inferences among each other which is exemplified by the inference of consciousness from the otherwise purely neuronal data in patients with vegetative state and (2) the problem of linking descriptive and normative concepts in a non-reductive and non-inferential way for which I suggest the mutual contextualization between both concepts. This results in a methodological strategy that can be described as contextual fact-norm iterativity.

Discovering imaging endophenotypes for major depression.

Psychiatry research lacks an in-depth understanding of mood disorders phenotypes, leading to limited success of genetics studies of major depressive disorder (MDD). The dramatic progress in safe and affordable magnetic resonance-based imaging methods has the potential to identify subtle abnormalities of neural structures, connectivity and function in mood disordered subjects. This review paper presents strategies to improve the phenotypic definition of MDD by proposing imaging endophenotypes derived from magnetic resonance spectroscopy measures, such as cortical gamma-amino butyric acid (GABA) and glutamate/glutamine concentrations, and from measures of resting-state activity and functional connectivity. The proposed endophenotypes are discussed regarding specificity, mood state-independence, heritability, familiarity, clinical relevance and possible associations with candidate genes. By improving phenotypic definitions, the discovery of new imaging endophenotypes will increase the power of candidate gene and genome-wide associations studies. It will also help to develop and evaluate novel therapeutic treatments and enable clinicians to apply individually tailored therapeutic approaches. Finally, improvements of the phenotypic definition of MDD based on neuroimaging measures will contribute to a new classification system of mood disorders based on etiology and pathophysiology.

The narcissistic self and its psychological and neural correlates: an exploratory fMRI study.

BACKGROUND: The concept of narcissism has been much researched in psychoanalysis and especially in self psychology. One of the hallmarks of narcissism is altered emotion, including decreased affective resonance (e.g. empathy) with others, the neural underpinnings of which remain unclear. The aim of our exploratory study was to investigate the psychological and neural correlates of empathy in two groups of healthy subjects with high and low narcissistic personality trait. We hypothesized that high narcissistic subjects would show a differential activity pattern in regions such as the anterior insula that are typically associated with empathy. METHOD: A sample of 34 non-clinical subjects was divided into high (n=11) and low (n=11) narcissistic groups according to the 66th and 33rd percentiles of their scores on the Narcissism Inventory (NI). Combining the psychological, behavioral and neuronal [i.e. functional magnetic resonance imaging (fMRI)] measurements of empathy, we compared the high and low narcissistic groups of subjects. RESULTS: High narcissistic subjects showed higher scores on the Symptom Checklist-90 - Revised (SCL-90-R) and the 20-item Toronto Alexithymia Scale (TAS-20) when compared to low narcissistic subjects. High narcissistic subjects also showed significantly decreased deactivation during empathy, especially in the right anterior insula. CONCLUSIONS: Psychological and neuroimaging data indicate respectively higher degrees of alexithymia and lower deactivation during empathy in the insula in high narcissistic subjects. Taken together, our preliminary findings demonstrate, for the first time, psychological and neuronal correlates of narcissism in non-clinical subjects. This might stipulate both novel psychodynamic conceptualization and future psychological-neuronal investigation of narcissism.

The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis.

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.

Intraindividual Characterization of the Sleep Spindle Variability in Healthy Subjects.

Spatial and frequency characterization of sleep spindles have been extensively addressed using M/EEG or fMRI recordings. However, its intraindividual variability across time has not been addressed. Here we propose to assess the intraindividual variability of sleep spindles in a time-resolved way by means of a trial-to-trial-variability (TTV) measure. For that purpose, the EEG of 26 healthy subjects were recorded overnight. After an exhaustive preprocessing pipeline to remove artifacts, spindles were automatically detected using a complex demodulation-based method. Then, the Wavelet Scalogram was estimated to validate it. Spindle TTV of each participant was also computed for all the conventional EEG frequency bands. Root mean square (RMS) of each TTV signal was calculated as a measure of the total variability of each spindle. Results showed significant differences in the variability between frequencies. Specifically, RMS in the beta-1 frequency band showed higher values as compared to all the other frequency bands (p<0.001). TTV curves showed a dichotomic trend, with lower frequencies showing an increase in the variability before the spindle onset, and higher frequencies showing such increase after the onset. The dependence of the spindle variability with the frequency could be explained by the influence of the multiple cortical generators involved.Clinical Relevance- Sleep spindles are similarly affected in different cognitive-related disorders, which supports the relevance of assessing abnormal sleep patterns as a possible cause for such cognitive deficits.

The resting brain and our self: self-relatedness modulates resting state neural activity in cortical midline structures.

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.

Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia.

Schizophrenia is a complex neurodevelopmental disorder where changes in both hippocampus and memory-related cognitive functions are central. However, the exact relationship between neurodevelopmental-genetic factors and hippocampal-cognitive dysfunction remains unclear. The general aim of our study is to link the occurrence of rare damaging mutations involved in susceptibility gene pathways to the structure and function of hippocampus in order to define genetically and phenotypically based subgroups in schizophrenia. In the present study, by analyzing the exome sequencing and magnetic resonance imaging data in 94 first-episode treatment-naive schizophrenia patients and 134 normal controls, we identified that a cluster of rare damaging variants (RDVs) enriched in DNA repair and cell cycle pathways was present only in a subgroup including 39 schizophrenic patients. Furthermore, we found that schizophrenic patients with this RDVs show increased resting-state functional connectivity (rsFC) between left hippocampus (especially for left dentate gyrus) and left inferior parietal cortex, as well as decreased rsFC between left hippocampus and cerebellum. Moreover, abnormal rsFC was related to the deficits of spatial working memory (SWM; that is known to recruit the hippocampus) in patients with the RDVs. Taken together, our data demonstrate for the first time, to our knowledge, that damaging rare variants of genes in DNA repair and cell cycle pathways are associated with aberrant hippocampal rsFC, which was further relative to cognitive deficits in first-episode treatment-naive schizophrenia. Therefore, our data provide some evidence for the occurrence of phenotypic alterations in hippocampal and SWM function in a genetically defined subgroup of schizophrenia.

Plasma homovanillic acid concentrations in catatonia.

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.

Murine interleukin 1 stimulates alpha 2-macroglobulin synthesis in rat hepatocyte primary cultures.

In rat hepatocyte primary cultures recombinant interleukin 1 was found to stimulate alpha 2-macroglobulin synthesis, whereas albumin synthesis was decreased. Although recent experiments gave evidence that a hepatocyte-stimulating factor distinct from interleukin 1 must exist, we conclude that interleukin 1 exerts a direct effect on hepatocytes by inducing acute-phase protein synthesis.

Induction of rat alpha 2-macroglobulin in vivo and in hepatocyte primary cultures: synergistic action of glucocorticoids and a Kupffer cell-derived factor.

Turpentine injection into rats elicits enhanced secretion of acute phase proteins including alpha 2-macroglobulin (alpha 2M). Hypophysectomized rats, however, do not respond in this way unless dexamethasone is given together with turpentine. On the other hand, dexamethasone injection alone did not result in an induction of alpha 2M synthesis. When a medium of Kupffer cell cultures was added to hepatocytes, a dose-dependent stimulation of alpha 2M synthesis of up to 4-fold after 10-12 h was observed. However, the presence of low concentrations (10(-9)M) of dexamethasone was essential for the stimulatory effect. We conclude that the acute phase induction of alpha 2M in hepatocytes requires the synergistic action of glucocorticoids and a non-dialysable factor secreted by Kupffer cells.

Catatonia: short-term response to lorazepam and dopaminergic metabolism.

Therapeutic response to lorazepam and dopaminergic metabolism were investigated in 18 neuroleptically naive acute catatonic patients. They were diagnosed as catatonic according to criteria by Lohr and Rosebush and treated exclusively with lorazepam (2-4 mg) during the first 24 h. Dopaminergic metabolism (plasma HVA, plasma MHPG), anxiety (HAM-A) and parkinsonic/dyskinetic movements (SEPS, AIMS) were measured under standard conditions before initial treatment with lorazepam (day 0) and 24 h after initial treatment (day 1). On day 0 responders to lorazepam treatment (complete remission of catatonic syndrome after 24 h according to Rosebush and Lohr) showed significantly higher (P = 0.004) plasma HVA (130.4 +/- 51.2 pmol/ml; means +/- SD) than non-responders (no remission of catatonic syndrome after 24 h; 73.2 +/- 40.5 pmol/ml; means +/- SD). On day 1 plasma HVA did not differ any more significantly between both groups Clinically, responders showed significantly higher HAM-A (P = 0.025) and AIMS (P = 0.022) scores as well as significantly lower SEPS (P = 0.049) scores than non-responders on day 0. Hence catatonic short-term responders and nonresponders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.

Impairment in visual-spatial function in catatonia: a neuropsychological investigation.

Catatonia is a psychomotor syndrome with motor and behavioral abnormalities which may be due to alterations in fronto-parietal cortical function. We therefore investigated neuropsychological tasks (attention, executive, visual-spatial, working memory) associated with frontal and parietal cortical function. Thirteen catatonic patients, diagnosed as catatonic according to criteria by Rosebush and Bush, were compared with 13 psychiatric non-catatonic controls (matched with regard to underlying psychiatric diagnosis, age, sex, and medication), and 13 age- and sex-matched healthy controls. Catatonics showed significantly poorer performances and different neuropsychological intercorrelation patterns in visual spatial object perception (VOSPobject) than psychiatric and healthy controls. In addition, we found significant correlations between catatonic symptoms, visual-spatial abilities, and attentional measures (i.e., d2, CWI). Catatonia was characterized by specific visual-spatial deficits which are related to attentional abilities and right parietal cortical function. The data suggest attentional-motor and fronto-parietal dysfunction in catatonia, a conclusion which should be considered as preliminary, however, due to the small sample size.

Delayed onset of late movement-related cortical potentials and abnormal response to lorazepam in catatonia.

Catatonia is a psychomotor syndrome with an inability to execute and terminate movements completely, leading consecutively to akinesia and posturing, which both respond almost immediately to benzodiazepines, i.e. gaba-potentiators like lorazepam. However, pathophysiological mechanisms of cortical motor and gaba-ergic dysfunction remain unclear. We therefore investigated movement-related cortical potentials (MRPs) and movement kinematics during a motor task before and after lorazepam. Ten akinetic catatonic patients were compared with 10 psychiatric (similar age, sex, medication, and underlying psychiatric disease but without catatonic syndrome) and 20 healthy controls. MRPs from frontal (F), central (C), and parietal (P) sites were recorded to obtain measures of early and late readiness potential and movement potential. Kinematic measures included parameters for amplitude of movements, peak velocity, average duration of movements, elevation angle, and angle velocity. The motor task consisted in self-initiated extension of the right index finger. All catatonic and psychiatric control patients received intravenous lorazepam (1mg), whereas healthy controls were subjected to a placebo-controlled (10 received lorazepam, 10 received placebo) double-blind study design.Catatonics showed a significantly delayed onset of late readiness and movement potential in central electrodes (Cz, C3) compared with psychiatric and healthy controls. This delayed onset correlated significantly with catatonic motor symptoms and movement duration. Lorazepam led to significantly stronger delays in onset of late readiness potential in left fronto-parietal (F3, C3, P3) electrodes in catatonic patients than in psychiatric and healthy controls. It is concluded that delayed latencies in late MRP components in catatonic patients may reflect their inability to execute and terminate movements completely. Differential and stronger response to lorazepam in catatonia suggests dysfunction in inhibitory control of cortical motor function with increased gaba-ergic sensitivity.

Effects of single-pulse transcranial magnetic stimulation (TMS) on functional brain activity: a combined event-related TMS and evoked potential study.

OBJECTIVE: To further evaluate the potential of slew-rate limiting amplifiers to record electrophysiological signals in spite of concurrent transcranial magnetic stimulation (TMS), and to explore the effects of single-pulse TMS on electroencephalographic (EEG) correlates of functional brain activity. METHODS: Visual-evoked potentials (VEPs) to checkerboards were recorded in 7 right-handed subjects, while single-pulse TMS was applied to the occipital pole either at visual stimulus onset, during the build-up or at the expected peak of the early VEP component P1 (VIS&TMS). Timing of TMS was individually adjusted based on each subject's VEP-latency. A condition of TMS without concurrent visual stimulation (TMS(alone)) served for subtraction purposes (VIS&TMS minus TMS(alone)) to partial out TMS-related contaminations of the EEG signal. RESULTS: When TMS was applied at visual stimulus onset, VEPs (as calculated by subtraction) perfectly matched control VEPs to visual stimulation alone. TMS at around P1, in contrast, modified the targeted (P1) and the subsequent VEP component (N1), independently of whether TMS was given at build-up or peak. CONCLUSIONS: The retrieval of regular VEPs with concomitant TMS at visual stimulus onset suggests that the employed EEG system and subtraction procedure are suited for combined EEG-TMS studies. The VEP changes following TMS at around P1 provide direct clues on the temporal dynamics of TMS pulse effects on functional activity in the human brain. Our data suggest effects of relatively long duration (approximately 100 ms) when TMS is applied while functional neuronal activity evolves.