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.

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.

[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.

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.

[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.

Resting network is composed of more than one neural pattern: an fMRI study.

In resting state, the dynamics of blood oxygen level-dependent signals recorded by functional magnetic resonance imaging (fMRI) showed reliable modular structures. To explore the network property, previous research used to construct an adjacency matrix by Pearson's correlation and prune it using stringent statistical threshold. However, traditional analyses may lose useful information at middle to moderate high correlation level. This resting fMRI study adopted full connection as a criterion to partition the adjacency matrix into composite sub-matrices (neural patterns) and investigated the associated community organization and network features. Modular consistency across subjects was assessed using scaled inclusivity index. Our results disclosed two neural patterns with reliable modular structures. Concordant with the results of traditional intervention, community detection analysis showed that neural pattern 1, the sub-matrix at highest correlation level, was composed of sensory-motor, visual associative, default mode/midline, temporal limbic and basal ganglia structures. The neural pattern 2 was situated at middle to moderate high correlation level and comprised two larger modules, possibly associated with mental processing of outer world (such as visuo-associative, auditory and sensory-motor networks) and inner homeostasis (such as default-mode, midline and limbic systems). Graph theoretical analyses further demonstrated that the network feature of neural pattern 1 was more local and segregate, whereas that of neural pattern 2 was more global and integrative. Our results suggest that future resting fMRI research may take the neural pattern at middle to moderate high correlation range into consideration, which has long been ignored in extant literature. The variation of neural pattern 2 could be relevant to individual characteristics of self-regulatory functions, and the disruption in its topology may underlie the pathology of several neuropsychiatric illnesses.

[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.

Grey matter density and GABAA binding potential show a positive linear relationship across cortical regions.

Voxel based morphometry (VBM) is a widely used technique for studying the structure of the brain. Direct comparisons between the results obtained using VBM and the underlying histology are limited, however. To circumvent the problems inherent in comparing VBM data in vivo with tissue samples that must generally be obtained post-mortem, we chose to consider GABAA receptors, measured using (18)F-flumazenil PET (18F-FMZ-PET), as non-invasive neural markers to be compared with VBM data. Consistent with previous cortical thickness findings, GABAA receptor binding potential (BPND) was found to correlate positively across regions with grey matter (GM) density. These findings confirm that there is a general positive relationship between MRI-based GM density measures and GABAA receptor BPND on a region-by-region basis (i.e., regions with more GM tend to also have higher BPND).

Glutamate modulates resting state activity in the perigenual anterior cingulate cortex - a combined fMRI-MRS study.

The perigenual anterior cingulate cortex (PACC) shows high resting state activity and is considered part of the default-mode network (DMN). However, the biochemical underpinnings of the PACC's high resting state activity remain unclear. While animal-based evidence points toward a role for the glutamatergic system, the modulation of the resting state activity level by itself as distinguished from stimulus-induced activity remains to be shown in humans. Using combined fMRI-MRS in healthy subjects, we here demonstrate that the PACC resting state concentration of glutamate is directly related to the level of resting state activity in the same region. In contrast, no such relationship could be detected during the anticipation of reward and punishment, nor in an independent control region (the left anterior insula). Taken together, our findings demonstrate for the first time the modulation of the PACC resting state activity level by the concentration of glutamate in the same regions. This contributes to a better understanding of the biochemical basis for the brain's resting state activity as well as providing some clues regarding its apparent pathological upregulation in psychiatric disorders like the major depressive disorder.

Neural correlates of a single-session massage treatment.

The current study investigated the immediate neurophysiological effects of different types of massage in healthy adults using functional magnetic resonance imaging (fMRI). Much attention has been given to the default mode network, a set of brain regions showing greater activity in the resting state. These regions (i.e. insula, posterior and anterior cingulate, inferior parietal and medial prefrontal cortices) have been postulated to be involved in the neural correlates of consciousness, specifically in arousal and awareness. We posit that massage would modulate these same regions given the benefits and pleasant affective properties of touch. To this end, healthy participants were randomly assigned to one of four conditions: 1. Swedish massage, 2. reflexology, 3. massage with an object or 4. a resting control condition. The right foot was massaged while each participant performed a cognitive association task in the scanner. We found that the Swedish massage treatment activated the subgenual anterior and retrosplenial/posterior cingulate cortices. This increased blood oxygen level dependent (BOLD) signal was maintained only in the former brain region during performance of the cognitive task. Interestingly, the reflexology massage condition selectively affected the retrosplenial/posterior cingulate in the resting state, whereas massage with the object augmented the BOLD response in this region during the cognitive task performance. These findings should have implications for better understanding how alternative treatments might affect resting state neural activity and could ultimately be important for devising new targets in the management of mood disorders.

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 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.

Is our self based on reward? Self-relatedness recruits neural activity in the reward system.

Every organism has to evaluate incoming stimuli according to their current and future significance. The immediate value of stimuli is coded by the reward system, but the processing of their long-term relevance implements a valuation system that implicates self-relatedness. The neuronal relationship between reward and self-relatedness remains unclear though. Using event-related functional MRI, we investigated whether self-relatedness induces neural activity in the reward system. Self-relatedness induced signal changes in the same regions that were recruited during reward including the bilateral nucleus accumbens (NACC), ventral tegmental area (VTA) and ventromedial prefrontal cortex (VMPFC). The fMRI signal time courses revealed no differences in early BOLD signals between reward and self-relatedness. In contrast, both conditions differed in late BOLD signals with self-relatedness showing higher signal intensity. In sum, our findings indicate sustained recruitment of the reward system during self-relatedness. These findings may contribute to a better understanding of the reward-based nature of our self.

[Neurobiological basis of depressive disorders]. / Neurobiologische Grundlagen depressiver Syndrome.

Depressive disorders belong to the most frequent diseases worldwide showing a lifetime prevalence of up to 20%. Moreover they are one of the leading causes for the amount of years lived with disability. Increasing knowledge about the pathological mechanisms underlying depressive syndromes is obtained by using modern neurobiological research-techniques. Thereby some older theories that have been the basis of emotion-research for decades--like the monoamine hypothesis--have been strengthened. In addition new aspects of the pathological processes underlying depressive disturbances have been unraveled. In this review established models and recent findings will be discussed, to bridge various research-fields, ranging from genetics, epigenetics and morphological changes to the functional consequences of depression. Finally therapeutic implications that could be derived from these results will be presented, showing up putative possibilities for diagnosis and treatment of depressive syndromes.

[Subjective experience and neuronal integration in the brain: do we need a first-person neuroscience?]. / Subjektives Erleben und neuronale Integration im Gehirn: Benötigen wir eine Erste-Person-Neurowissenschaft?

Unlike other medical disciplines psychiatry can be characterized by the special importance of subjective experience. Since subjective experience is tied to First-Person-Perspective and investigation of the brain is possible only in Third-Person-Perspective, the question how subjective experience can be linked to neuronal processes is raised in psychiatry. We suggest a novel methodological approach, First-Person-Neuroscience where subjective experience can be linked directly and systematically to neuronal processes. Due to complexity of the structures and contents of subjective experience, localization in specific brain regions seems inappropriate. Instead, the interplay and coordination of neuronal activity across several brain regions, so-called neuronal integration, should be considered in First-Person-Neuroscience. This is illustrated by two principles of neuronal integration, top-down modulation and reciprocal modulation, whose abnormal function can be related to subjective experience of patients with catatonia and depression. It is concluded that First-Person-Neuroscience can contribute to reveal abnormal brain function in psychiatric disorders and ultimately to development of diagnostic and therapeutic markers.

[Neuroethics--a future discipline?]. / Was ist "Neuroethik"--eine Disziplin der Zukunft?

Progress in neuroscience leads not only to novel therapeutic opportunities but also raises several ethical problems. These problems are often subsumed under the term "neuroethics," of which the definition and purpose often remain unclear. We discuss the problems of informed consent, free will, sense of self, and personality in light of recent neuroscientific progress. Due to distinct categories and frames of reference, these philosophical-ethical terms cannot be limited only to the brain; the development of systematic relations is suggested. This accounts for the "special ethical position of the brain." It is concluded that only this sense can neuroethics account for the ethical complexity in neuropsychiatric disorders.