Dynamics of the immediate behavioral response to partial social exclusion.

Social rejection and exclusion (ostracism) represent main stressors in daily life and even threaten mental and physical health. Abundant data from subjective measures in social exclusion paradigms are available, but the dynamic behavioral response is largely unexplored. Here, we applied modified variants of the Cyberball paradigm in two consecutive experiments to investigate the adaptive behavioral and emotional reactions to partial social exclusion. In experiment 1, 68 healthy participants (females, mean age 24.76 ± 4.05 years) played 2 min inclusion, 5 min partial exclusion and 2 min total exclusion. In experiment 2, 94 healthy participants (48 females, mean age 34.50 ± 12.08 years) underwent an experimental condition (2 min inclusion, 10 min partial exclusion) and a control condition (12 min inclusion only) in randomized order. In experiment 1, behavioral responses to partial exclusion showed two characteristics: (1) an immediate increase in ball passes to the excluding player followed (2) by a later return of participants' behavior to baseline. This finding was replicated for both genders and in comparison to a control condition in experiment 2. The dynamic behavioral response observed here may point to overlapping principles of cooperation in this ball tossing paradigm and serves as a novel experimental proxy.

Emotional experience in patients with clinically isolated syndrome and early multiple sclerosis.

BACKGROUND AND PURPOSE: Evidence suggests that there are changes in the processing of emotional information (EP) in people with multiple sclerosis (MS). It is unclear which functional domains of EP are affected, whether these changes are secondary to other MS-related neuropsychological or psychiatric symptoms and if EP changes are present in early MS. The aim of the study was to investigate EP in patients with early MS (clinically isolated syndrome and early relapsing/remitting MS) and healthy controls (HCs). METHODS: A total of 29 patients without neuropsychological or psychiatric deficits and 29 matched HCs were presented with pictures from the International Affective Picture System with negative, positive or neutral content. Participants rated the induced emotion regarding valence and arousal using nine-level Likert scales. A speeded recognition test assessed memory for the emotional stimuli and for the emotional modulation of response time. A subgroup of participants was tested during a magnetic resonance imaging (MRI) session. RESULTS: Patients in the MRI subgroup rated the experience induced by pictures with positive or negative emotional content significantly more weakly than HCs. Further, these patients were significantly less aroused when watching the pictures from the International Affective Picture System. There were no effects in the non-MRI subgroup or effects on emotional memory or response times. CONCLUSIONS: Emotional processing changes may be present in early MS in the form of flattened emotional experience on both the valence and arousal dimensions. These changes do not appear to be secondary to neuropsychological or psychiatric deficits. The fact that emotional flattening was only found in the MRI setting suggests that EP changes may be unmasked within stressful environments and points to the potential yet underestimated impact of the MRI setting on behavioral outcomes.

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the 'missing heritability' of complex phenotypes.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Modelling and analysis of time-variant directed interrelations between brain regions based on BOLD-signals.

Time-variant Granger Causality Index (tvGCI) was applied to simulated and measured BOLD signals to investigate the reliability of time-variant analysis approaches for the identification of directed interrelations between brain areas on the basis of fMRI data. Single-shot fMRI data of a single image slice with short repetition times (200 ms, 16000 frames/subject, 64x64 voxels) were acquired from 5 healthy subjects during an externally-driven, self-paced finger-tapping paradigm (57-59 single taps for each subject). BOLD signals were derived from the pre-supplementary motor area (preSMA), the supplementary motor area (SMA), and the primary motor cortex (M1). The simulations were carried out by means of a Dynamic Causal Modelling (DCM) approach. The tvGCI as well as time-variant Partial Directed Coherence (tvPDC) were used to identify the modelled connectivity network (connectivity structure - CS - of the DCM). Different CSs were applied by using dynamic systems (Generalized Dynamic Neural Network - GDNN) and trivariate autoregressive (AR) processes. The influence of the low-pass characteristics of the simulated hemodynamic response (Balloon model) and of the measuring noise was tested. Additionally, our modelling strategy considered "spontaneous" BOLD fluctuations before, during, and after the appearance of the event-related BOLD component. Couplings which were extracted from the simulated signals were statistically evaluated (tvGCI for shuffled data, confidence tubes for tvGCI courses). We demonstrate that connections of our CS models can be correctly identified during the event-related BOLD component and with signal-to-noise-ratios corresponding to those of the measured data. The results based on simulations can be used to examine the reliability of connectivity identification based on BOLD signals by means of time-variant as well as time-invariant connectivity measures and enable a better interpretation of the analysis results using fMRI data. A readiness-BOLD response was only detected in one subject. However, in two subjects a strong time-variant connection (tvGCI) from preSMA to SMA was observed 3 s before the tapping was executed. This connection was accompanied by a weaker rise of the tvGCI from preSMA to M1. These preceding interrelations were confirmed in the other subjects by the dynamics of tvGCI courses. Based on the results of tvGCI analysis, the time-evolution of an individual connectivity network is shown for each subject.

Signal informatics as an advanced integrative concept in the framework of medical informatics. New trends demonstrated by examples derived from neuroscience.

OBJECTIVES: The main objective is to show current topics and future trends in the field of medical signal processing which are derived from current research concepts. Signal processing as an integrative concept within the scope of medical informatics is demonstrated. METHODS: For all examples time-variant multivariate autoregressive models were used. Based on this modeling, the concept of Granger causality in terms of the time-variant Granger causality index and the time-variant partial directed coherence was realized to investigate directed information transfer between different brain regions. RESULTS: Signal informatics encompasses several diverse domains including: processing steps, methodologies, levels and subject fields, and applications. Five trends can be recognized and in order to illustrate these trends, three analysis strategies derived from current neuroscientific studies are presented. These examples comprise high-dimensional fMRI and EEG data. In the first example, the quantification of time-variant-directed information transfer between activated brain regions on the basis of fast-fMRI data is introduced and discussed. The second example deals with the investigation of differences in word processing between dyslexic and normal reading children. Different dynamic neural networks of the directed information transfer are identified on the basis of event-related potentials. The third example shows time-variant cortical connectivity networks derived from a source model. CONCLUSIONS: These examples strongly emphasize the integrative nature of signal informatics, encompassing processing steps, methodologies, levels and subject fields, and applications.

Neurological soft signs and brain morphology in first-episode schizophrenia.

BACKGROUND: Although minor motor and sensory deficits, or neurological soft signs (NSS), are a well-established finding in schizophrenia, the cerebral changes underlying these signs are only partly understood. We therefore investigated the cerebral correlates of NSS by using magnetic resonance imaging (MRI) in patients with schizophrenia and healthy controls. METHOD: Forty-two patients, all receiving atypical neuroleptics, with first-episode schizophrenia or schizophreniform disorder and 22 healthy controls matched for age and gender were included. NSS were examined on the Heidelberg Scale after remission of the acute symptoms before discharge and correlated to density values by using optimized voxel-based morphometry (VBM). RESULTS: NSS scores were significantly higher in patients than healthy controls. Within the patient group NSS were significantly associated with reduced grey or white-matter densities in the pre- and post-central gyrus, pre-motor area, middle and inferior frontal gyri, cerebellum, caudate nucleus and thalamus. These associations did not apply for the control group, in whom only the associations between NSS and reduced frontal gyri densities could be confirmed. CONCLUSIONS: The pattern of cerebral changes associated with NSS clearly supports the model of 'cognitive dysmetria' with a disrupted cortico-cerebellar-thalamic-cortical circuit in schizophrenia. The variety of sites may correspond with the clinical diversity of NSS, which comprises both motor and sensory signs, and with the putative heterogeneity of the pathogenetic changes involved. That the respective associations did not apply for the healthy control group indicates that NSS in patients and controls refer to different pathogenetic factors.

Time-variant analysis of fast-fMRI and dynamic contrast agent MRI sequences as examples of 4-dimensional image analysis.

OBJECTIVES: Image sequences with time-varying information content need appropriate analysis strategies. The exploration of directed information transfer (interactions) between neuronal assemblies is one of the most important aims of current functional MRI (fMRI) analysis. Additionally, we examined perfusion maps in dynamic contrast agent MRI sequences of stroke patients. In this investigation, the focus centers on distinguishing between brain areas with normal and reduced perfusion on the basis of the dynamics of contrast agent inflow and washout. METHODS: Fast fMRI sequences were analyzed with time-variant Granger causality (tvGC). The tvGC is based on a time-variant autoregressive model and is used for the quantification of the directed information transfer between activated brain areas. Generalized Dynamic Neural Networks (GDNN) with time-variant weights were applied on dynamic contrast agent MRI sequences as a nonlinear operator in order to enhance differences in the signal courses of pixels of normal and injured tissues. RESULTS: A simple motor task (self-paced finger tapping) is used in an fMRI design to investigate directed interactions between defined brain areas. A significant information transfer can be determined for the direction primary motor cortex to supplementary motor area during a short time period of about five seconds after stimulus. The analysis of dynamic contrast agent MRI sequences demonstrates that the trained GDNN enables a reliable tissue classification. Three classes are of interest: normal tissue, tissue at risk for death, and dead tissue. CONCLUSIONS: The time-variant multivariate analysis of directed information transfer derived from fMRI sequences and the computation of perfusion maps by GDNN demonstrate that dynamic analysis methods are essential tools for 4D image analysis.

[MR-based methods of the functional imaging of the central nervous system]. / MR-basierte Methoden der funktionellen Bildgebung des zentralen Nervensystems.

This review presents the basic principles of functional imaging of the central nervous system utilizing magnetic resonance imaging. The focus is set on visualization of different functional aspects of the brain and related pathologies. Additionally, clinical cases are presented to illustrate the applications of functional imaging techniques in the clinical setting. The relevant physics and physiology of contrast-enhanced and non-contrast-enhanced methods are discussed. The two main functional MR techniques requiring contrast-enhancement are dynamic T1- and T2*-MRI to image perfusion. Based on different pharmacokinetic models of contrast enhancement diagnostic applications for neurology and radio-oncology are discussed. The functional non-contrast enhanced imaging techniques are based on "blood oxygenation level dependent (BOLD)-fMRI and arterial spin labeling (ASL) technique. They have gained clinical impact particularly in the fields of psychiatry and neurosurgery.

[Methodological principles for optimising functional MR experiments]. / Methodische Grundlagen der Optimierung funktioneller MR-Experimente.

Functional magnetic resonance imaging (fMRI) is one of the most common methods for localising neuronal activity in the brain. Even though the sensitivity of fMRI is comparatively low, the optimisation of certain experimental parameters allows obtaining reliable results. In this article, approaches for optimising the experimental design, imaging parameters and analytic strategies will be discussed. Clinical neuroscientists and interested physicians will receive practical rules of thumb for improving the efficiency of brain imaging experiments.

Asymmetry of cortical activation during maximum and convenient tapping speed.

An effect of finger tapping rate on the hemodynamic response in primary motor cortex and the cerebellum has been well established over the last years (the rate effect). The present study compares the magnitude of this effect when either the dominant or subdominant hand is used by right and left handers. In contrast to previous studies maximum and convenient tapping rate for both hands are used as tapping tasks. The results confirm "rate effects" for the primary motor cortex and the cerebellum. In addition, a "rate effect" was found for the cingulate motor area. A novel finding is that the cortical and cerebellar "rate effects" are similar for the subdominant and for the dominant hand even though tapping rates are lower for the subdominant hand. This result demonstrates that the subdominant motor cortex and neurally connected cerebellar areas operate at suboptimal control levels although maximum neurophysiological activation has been reached during the maximum tapping task.

Evidence for rapid auditory perception as the foundation of speech processing: a sparse temporal sampling fMRI study.

We examined the processing of verbal and nonverbal auditory stimuli using an event-related functional magnetic resonance imaging (fMRI) study to reveal the neural underpinnings of rapid temporal information processing and it's relevance during speech perception. In the context of a clustered sparse-temporal fMRI data collection eight right-handed native German speakers performed: (i) an auditory gap detection task; and (ii) a CV syllable discrimination task. A tone perception task served as a nontemporal control condition. Here we aimed to research to what extent the left hemisphere preferentially processes linguistically relevant temporal information available in speech and nonspeech stimuli. Furthermore, we sought to find out as to whether a left hemisphere's preference for linguistically relevant temporal information is specifically constrained to verbal utterances or if nonlinguistic temporal information may also activate these areas. We collected haemodynamic responses from three time points of acquisition (TPA) with varying temporal distance from stimulus onset to gain an insight on the time course of auditory processing. Results show exclusively left-sided activations of primary and secondary auditory cortex associated with the perception of rapid temporal information. Furthermore, the data shows an overlap of activations evoked by nonspeech sounds and speech stimuli within primary and secondary auditory cortex of the left hemisphere. The present data clearly support the assumption of a shared neural network for rapid temporal information processing within the auditory domain for both speech and nonspeech signals situated in left superior temporal areas.

[Physiological and technical limitations of functional magnetic resonance imaging (fMRI)--consequences for clinical use]. / Physiologische und technische Grenzen der funktionellen Magnetresonanztomographie und die damit verbundenen Konsequenzen für die klinische Anwendung.

Functional magnetic resonance imaging (fMRI) is the most common noninvasive technique in functional neuroanatomy. The capabilities and limitations of the method will be discussed based on a short review of the current knowledge about the neurovascular relationship. The focus of this article is on current methodical and technical problems regarding fMRI-based detection and localization of neuronal activity. Main error sources and their influence on the reliability and validity of fMRI-methods are presented. Appropriate solution strategies will be proposed and evaluated. Finally, the clinical relevance of MR-based diagnostic methods are discussed.

[Functional magnetic resonance imaging and dementia]. / Funktionelle Magnetresonanztomographie und Demenz.

Currently, different cerebral neuroimaging methods are being applied to varying questions in the diagnosis of dementia. In patients with manifest Alzheimer's disease a reduction of cortical perfusion and metabolism in temporal and temporoparietal regions has been demonstrated when compared to healthy controls on a diversity of memory tasks. Since differing levels of performance and varying degrees of cortical atrophy may influence functional results considerably, an understanding of the processes associated with normal ageing is perceived as prerequisite for studies applying functional neuroimaging. The integration of knowledge concerning neuropsychological and neurobiological alterations associated with healthy ageing allows hypotheses for the differentiation of pathological ageing processes to be phrased. In this connection non-invasive methods such as fMRI and ASL are of increasing importance.

Calibrated LCD/TFT stimulus presentation for visual psychophysics in fMRI.

Standard projection techniques using liquid crystal (LCD) or thin-film transistor (TFT) technology show drastic distortions in luminance and contrast characteristics across the screen and across grey levels. Common luminance measurement and calibration techniques are not applicable in the vicinity of MRI scanners. With the aid of a fibre optic, we measured screen luminances for the full space of screen position and image grey values and on that basis developed a compensation technique that involves both luminance homogenisation and position-dependent gamma correction. By the technique described, images displayed to a subject in functional MRI can be specified with high precision by a matrix of desired luminance values rather than by local grey value.

Asymmetric hemodynamic responses of the human auditory cortex to monaural and binaural stimulation.

Applying whole-head functional magnetic resonance imaging (fMRI) in 11 neurologically intact subjects, hemodynamic responses to mon- or binaurally presented auditory stimuli were measured. To expand on previous studies in this research area, we used tones and consonant-vowel (CV) syllables. In one group of subjects (n=6) the perceived loudness of the monaurally presented stimuli were adjusted so that they matched the loudness of the binaurally presented stimuli. In a second group (n=5) no loudness adjustment was performed, thus the monaural stimuli were perceived less loud ( approximately 10 dB) than the binaural stimuli. These extensions allowed us to test whether CV syllables and tones produce different contralaterality effects (stronger hemodynamic responses in the auditory cortex contralateral to the stimulated ear) and whether binaural stimulation results in stronger activations in the auditory areas than during both monaural stimulation conditions (binaural summation) independent of loudness influences. In summary, we obtained the following findings: (1) strong contralaterality effects during monaural acoustic stimulation in the posterior superior temporal gyrus (STG) comprising the planum temporale and the dorsal bank of the superior temporal sulcus to CV syllables and tones; (2) the hemodynamic responses to contralaterally presented stimuli (during the monaural conditions) were mostly stronger than those to binaurally presented CV syllables; (3) there was no interaction between stimulus type and the size of the contralaterality effect; (4) there was no indication of binaural summation, rather we found stronger hemodynamic responses to the sum of both monaural stimulations (right and left ear) than to binaural stimulation in all auditory areas; (5) there were generally stronger hemodynamic responses to CV syllables than to tones in the posterior STG, while the hemodynamic responses to tones were stronger in the anterior part of the STG (temporal pole); and finally (6) there was no general difference in terms of hemodynamic response in the auditory cortex between the two groups when receiving either loudness-matched or non-loudness-matched monaural stimulation. These findings are discussed in the context of the underlying neurophysiological mechanisms, the peculiarities of functional fMRI, and the direct access and callosal relay models of hemispheric lateralization.

Phonetic perception and the temporal cortex.

Recent functional neuroimaging studies have emphasized the role of the different areas within the left superior temporal sulcus (STS) for the perception of various speech stimuli. We report here the results of three independent studies additionally demonstrating hemodynamic responses in the vicinity of the planum temporale (PT). In these studies we used consonant-vowel (CV) syllables, tones, white noise, and vowels as acoustic stimuli in the context of whole-head functional magnetic resonance imaging, applying a long TR to attenuate possible masking effects by the scanner noise. To summarize, we obtained the following results for the contrasts comparing hemodynamic responses obtained during the perception of CV syllables compared to tones or white noise: (i) stronger activation in the vicinity of the left PT with two distinct foci of activation, one in a lateral position and the other more medial in the vicinity of Heschl's sulcus; (ii) stronger activation in the vicinity of the right PT; and (iii) stronger bilateral activation within the mid-STS. Further contrasts revealed the following findings: (iv) stronger bilateral activation to CV syllables than to vowels in the medial PT, (v) stronger left-sided activation to CV syllables than to vowels in the mid-STS, and (vi) stronger activation to CV syllables with voiceless initial consonants than to CV syllables with voiced initial consonants in the left medial PT. The results are compatible with the hypothesis that the STS contains neurons specialized for speech perception. However, these results also emphasize the role of the PT in the analysis of phonetic features, namely the voice-onset-time. Yet this does not mean that the PT is solely specialized for phonetic analysis. We hypothesize rather that the PT contains neurons specialized for the analysis of rapidly changing cues as was suggested by P. Tallal et al. (1993, Ann. N. Y. Acad. Sci. 682: 27-47).

Short-term functional plasticity in the human auditory cortex: an fMRI study.

Applying functional magnetic resonance imaging (fMRI) techniques, hemodynamic responses elicited by sequences of pure tones of 950 Hz (standard) and deviant tones of 952, 954, and 958 Hz were measured before and 1 week after subjects had been trained at frequency discrimination for five sessions (over 1 week) using an oddball procedure. The task of the subject was to detect deviants differing from the standard stimulus. Frequency discrimination improved during the training session for three subjects (performance gain: T+) but not for three other subjects (no performance gain: T-). Hemodynamic responses in the auditory cortex comprising the planum temporale, planum polare and sulcus temporalis superior significantly decreased during training only for the T+ group. These activation changes were strongest for those stimuli accompanied by the strongest performance gain (958 and 954 Hz). There was no difference with respect to the hemodynamic responses in the auditory cortex for the T- group and the control group (CO) who did not received any pitch discrimination training. The results suggest a plastic reorganization of the cortical representation for the trained frequencies which can be best explained on the basis of 'fast learning' theories.