Reconstruction of time-shifted hemodynamic response.

Regression of voxel time course onto expected response is a standard procedure in functional magnetic resonance imaging that relies on exact onset time and shape of superimposed hemodynamic response functions. Elegant capture of time deviation by time derivative regressors appears complicated by shape distortion and limited to ±1 s, and is usually not exploited for reconstructing the true time-shifted response function together with its magnitude. This analysis of the time-derivative approach provides closed-form functional relations between time shift and regression coefficients that allow for hemodynamic shifts of ±5 s and can explain shape distortion and reconstruction behavior. Reliable absolute latencies were no smaller than 0.6 s in a best-case experiment. Confusions of latency are a previously undiscussed shortcoming where current limitation strategy may eliminate correct latencies and protect incorrect ones.

The neural signature of social norm compliance.

All known human societies establish social order by punishing violators of social norms. However, little is known about how the brain processes the punishment threat associated with norm violations. We use fMRI to study the neural circuitry behind social norm compliance by comparing a treatment in which norm violations can be punished with a control treatment in which punishment is impossible. Individuals' increase in norm compliance when punishment is possible exhibits a strong positive correlation with activations in the lateral orbitofrontal cortex and right dorsolateral prefrontal cortex. Moreover, lateral orbitofrontal cortex activity is strongly correlated with Machiavellian personality characteristics. These findings indicate a neural network involved in social norm compliance that might constitute an important basis for human sociality. Different activations of this network reveal individual differences in the behavioral response to the punishment threat and might thus provide a deeper understanding of the neurobiological sources of pathologies such as antisocial personality disorder.

Neuroplasticity of semantic representations for musical instruments in professional musicians.

Professional musicians constitute a model par excellence for understanding experience-dependent plasticity in the human brain, particularly in the auditory domain. Their intensive sensorimotor experience with musical instruments has been shown to entail plastic brain alterations in cortical perceptual and motor maps. It remains an important question whether this neuroplasticity might extend beyond basic perceptual and motor functions and even shape higher-level conceptualizations by which we conceive our physical and social world. Here we show using functional magnetic resonance imaging (fMRI) that conceptual processing of visually presented musical instruments activates auditory association cortex encompassing right posterior superior temporal gyrus, as well as adjacent areas in the superior temporal sulcus and the upper part of middle temporal gyrus (pSTG/MTG) only in musicians, but not in musical laypersons. These areas in and adjacent to auditory association cortex were not only recruited by conceptual processing of musical instruments during visual object recognition, but also by auditory perception of real sounds. Hence, the unique intensive experience of musicians with musical instruments establishes a link between auditory perceptual and conceptual brain systems. Experience-driven neuroplasticity in musicians is thus not confined to alterations of perceptual and motor maps, but even leads to the establishment of higher-level semantic representations for musical instruments in and adjacent to auditory association cortex. These findings highlight the eminent importance of sensory and motor experience for acquiring rich concepts.

Neural signatures of bullying experience and social rejection in teenagers.

Relational bullying in schools is one of the most frequent forms of violence and can have severe negative health impact, e.g. depression. Social exclusion is the most prominent form of relational bullying that can be operationalized experimentally. The present study used MR-based perfusion imaging (pCASL) to investigate the neural signatures of social exclusion and its relationship with individually different extent of previous bullying experience. Twenty-four teenagers reporting bullying experience at different extent were scanned during a virtual ball-tossing (Cyberball game). Our findings showed that social exclusion (relative to social inclusion) activated frontal brain areas: sub- and perigenual anterior cingulate cortex (sg/pgACC), left inferior frontal cortex (IFG), and dorsolateral prefrontal cortex. Positive relationship between exclusion-specific signal increase and individually different extents of prior bullying experience was for the first time observed in left IFG and sgACC. This suggests that more frequent prior experience has conditioned greater mentalizing and/or rumination, in order to cope with the situation. While this interpretation remains speculative, the present data show that the experience of being bullied partly sensitizes the neural substrate relevant for the processing of social exclusion.

Xenon-induced changes in CNS sensitization to pain.

Electrophysiological investigations of the spinal cord in animals have shown that pain sensitizes the central nervous system via glutamate receptor dependent long-term potentiation (LTP) related to an enhancement of pain perception. To expand these findings, we used functional magnetic resonance (fMRI), blood oxygen level dependent (BOLD) and perfusion imaging in combination with repeated electrical stimulation in humans. Specifically we monitored modulation of somatosensory processing during inhibition of excitatory transmission by ocular application of the glutamate receptor antagonist xenon. BOLD responses upon secondary stimulation increased in mid insular and in primary/secondary sensory cortices under placebo and decreased under xenon treatments. Xenon-induced decreases in regional perfusion were confined to stimulation responsive brain regions and correlated with time courses of xenon concentrations in the cranial blood. Moreover, effects of xenon on behavioral, fMRI and perfusion data scaled with stimulus intensity. The dependence of pain sensitization on sufficient pre-activation reflects a multistage process which is characteristic for glutamate receptor related processes of LTP. This study demonstrates how LTP related processes known from the cellular level can be investigated at the brain systems level.

The sound of concepts: four markers for a link between auditory and conceptual brain systems.

Traditionally, concepts are conceived as abstract mental entities distinct from perceptual or motor brain systems. However, recent results let assume modality-specific representations of concepts. The ultimate test for grounding concepts in perception requires the fulfillment of the following four markers: conceptual processing during (1) an implicit task should activate (2) a perceptual region (3) rapidly and (4) selectively. Here, we show using functional magnetic resonance imaging and recordings of event-related potentials, that acoustic conceptual features recruit auditory brain areas even when implicitly presented through visual words. Fulfilling the four markers, the findings of our study unequivocally link the auditory and conceptual brain systems: recognition of words denoting objects, for which acoustic features are highly relevant (e.g.,"telephone"), ignited cell assemblies in posterior superior and middle temporal gyri (pSTG/MTG) within 150 ms that were also activated by sound perception. Importantly, activity within a cluster of pSTG/MTG increased selectively as a function of acoustic, but not of visual and action-related feature relevance. The implicitness of the conceptual task, the selective modulation of left pSTG/MTG activity by acoustic feature relevance, the early onset of this activity at 150 ms and its anatomical overlap with perceptual sound processing are four markers for a modality-specific representation of auditory conceptual features in left pSTG/MTG. Our results therefore provide the first direct evidence for a link between perceptual and conceptual acoustic processing. They demonstrate that access to concepts involves a partial reinstatement of brain activity during the perception of objects.

From uncertainty to reward: BOLD characteristics differentiate signaling pathways.

BACKGROUND: Reward value and uncertainty are represented by dopamine neurons in monkeys by distinct phasic and tonic firing rates. Knowledge about the underlying differential dopaminergic pathways is crucial for a better understanding of dopamine-related processes. Using functional magnetic resonance blood-oxygen level dependent (BOLD) imaging we analyzed brain activation in 15 healthy, male subjects performing a gambling task, upon expectation of potential monetary rewards at different reward values and levels of uncertainty. RESULTS: Consistent with previous studies, ventral striatal activation was related to both reward magnitudes and values. Activation in medial and lateral orbitofrontal brain areas was best predicted by reward uncertainty. Moreover, late BOLD responses relative to trial onset were due to expectation of different reward values and likely to represent phasic dopaminergic signaling. Early BOLD responses were due to different levels of reward uncertainty and likely to represent tonic dopaminergic signals. CONCLUSIONS: We conclude that differential dopaminergic signaling as revealed in animal studies is not only represented locally by involvement of distinct brain regions but also by distinct BOLD signal characteristics.

Continuous theta-burst stimulation over the dorsal premotor cortex interferes with associative learning during object lifting.

When lifting objects of different mass, humans scale grip force according to the expected mass. In this context, humans are able to associate a sensory cue, such as a colour, to a particular mass of an object and link this association to the grip forces necessary for lifting. Here, we study the role of the dorsal premotor cortex (PMd) in setting-up an association between a colour cue and a particular mass to be lifted. Healthy right-handed subjects used a precision grip between the index finger and thumb to lift two different masses. Colour cues provided information about which of the two masses subjects would have to lift. Subjects first performed a series of lifts with the right hand to establish a stable association between a colour cue and a mass, followed by 20sec of continuous high frequency repetitive trancranial magnetic stimulation using a recently developed protocol (continuous theta-burst stimulation, cTBS) over (i) the left primary motor cortex, (ii) the left PMd and (iii) the left occipital cortex to be commenced by another series of lifts with either the right or left hand. cTBS over the PMd, but not over the primary motor cortex or O1, disrupted the predictive scaling of isometric finger forces based on colour cues, irrespective of whether the right or left hand performed the lifts after the stimulation. Our data highlight the role of the PMd to generalize and maintain associative memory processes relevant for predictive control of grip forces during object manipulation.

Regional gray matter volume and structural network strength in somatic vs. non-somatic delusional disorders.

BACKGROUND: Monothematic delusional disorders are characterized by a single tenacious belief. They provide a great opportunity to study underlying brain structures in the absence of confounding symptoms that accompany delusions in schizophrenia. Delusional beliefs include persecution, jealousy or somatic delusions including infestation. It is unclear whether specific delusional content is associated with distinct neural substrates. METHODS: We used magnetic resonance imaging in patients presenting with somatic vs. non-somatic delusional disorders. Patients with delusional infestation (DI, n=18), and individuals with non-somatic delusional disorders (n=19) were included, together with healthy volunteers (n=20). Uni- and multivariate techniques for structural data analysis were applied to provide a comprehensive characterization of abnormal brain volume at both the regional and neural network level. RESULTS: Patients with DI showed lower gray matter volume in thalamic, striatal (putamen), insular and medial prefrontal brain regions in contrast to non-somatic delusional disorders and healthy controls. Importantly, these differences were consistently detected at regional and network level. Compared to healthy controls, patients with delusional disorders other than DI showed lower gray matter volume in temporal cortical regions. CONCLUSION: The data support the notion that dysfunctional somatosensory and peripersonal networks could mediate somatic delusions in patients with DI in contrast to delusional disorders without somatic content. The data also suggest putative content-specific neural signatures in delusional disorders and in delusion formation per se.

Error processing in major depressive disorder: evidence from event-related potentials.

In a previous study we showed that errors following errors activate a strategic (prefrontal) mechanism. In an error trial (trial n) following an erroneous previous trial (trial n - 1) healthy control subjects were found to have enlarged (more negative) amplitudes of the error related negativity (ERN)/error negativity (Ne), an electrophysiological correlate of response monitoring, in response to a negative feedback signal. Contrary to that, patients with major depressive disorder showed smaller (less negative) ERN/Ne amplitudes. It has been discussed controversially whether errors of choice (e.g., pressing an incorrect response button in an Eriksen flanker task) and errors of commission (e.g., pressing a button when one is not supposed to in a Go/Nogo task) are related to different ERN/Ne mechanisms. In the present study, we examined whether our previous result only holds for errors of choice in an Eriksen flankers task or extends to errors of commission in a Go/Nogo task, as well. Ten patients with DSM-IV major depressive disorder and 10 matched controls participated in a Go/Nogo task with performance feedback which signaled monetary reward. Patients with major depressive disorder again showed a less negative ERN/Ne amplitude in error trials following error trials. This result might reflect impaired response monitoring processes in major depressive disorder resulting from an impaired activation of a central reward pathway and/or a deficit in strategic reasoning.

Dissociating the representation of action- and sound-related concepts in middle temporal cortex.

Modality-specific models of conceptual memory propose close links between concepts and the sensory-motor systems. Neuroimaging studies found, in different subject groups, that action-related and sound-related concepts activated different parts of posterior middle temporal gyrus (pMTG), suggesting a modality-specific representation of conceptual features. However, as these different parts of pMTG are close to each other, it is possible that the observed anatomical difference is merely related to interindividual variability. In the present functional magnetic resonance imaging study, we now investigated within the same participant group a possible conceptual feature-specific organization in pMTG. Participants performed lexical decisions on sound-related (e.g., telephone) and action-related (hammer) words. Sound words elicited higher activity in anterior pMTG adjacent to auditory association cortex, but action-related words did so in posterior pMTG close to motion sensitive areas. These results confirm distinct conceptual representations of sound and action in pMTG, just adjacent to the respective modality-specific cortices.

Mechanisms underlying flexible adaptation of cognitive control: behavioral and neuroimaging evidence in a flanker task.

Cognitive control can be adapted flexibly according to the conflict level in a given situation. In the Eriksen flanker task, interference evoked by flankers is larger in conditions with a higher, rather than a lower proportion of compatible trials. Such compatibility ratio effects also occur for stimuli presented at two spatial locations suggesting that different cognitive control settings can be simultaneously maintained. However, the conditions and the neural correlates of this flexible adaptation of cognitive control are only poorly understood. In the present study, we further elucidated the mechanisms underlying the simultaneous maintenance of two cognitive control settings. In behavioral experiments, stimuli were presented centrally above and below fixation and hence processed by both hemispheres or lateralized to stimulate hemispheres differentially. The different compatibility ratio at two stimulus locations had a differential influence on the flanker effect in both experiments. In an fMRI experiment, blocks with an identical compatibility ratio at two central spatial locations elicited stronger activity in a network of prefrontal and parietal brain areas, which are known to be involved in conflict resolution and cognitive control, as compared with blocks with a different compatibility ratio at the same spatial locations. This demonstrates that the simultaneous maintenance of two conflicting control settings vs. one single setting does not recruit additional neural circuits suggesting the involvement of one single cognitive control system. Instead a crosstalk between multiple control settings renders adaptation of cognitive control more efficient when only one uniform rather than two different control settings has to be simultaneously maintained.

Speaking in multiple languages: neural correlates of language proficiency in multilingual word production.

The human brain has the fascinating ability to represent and to process several languages. Although the first and further languages activate partially different brain networks, the linguistic factors underlying these differences in language processing have to be further specified. We investigated the neural correlates of language proficiency in a homogeneous sample of multilingual native Ladin speakers from a mountain valley in South Tyrol, Italy, who speak Italian as second language at a high level, and English at an intermediate level. In a constrained word production task under functional magnetic resonance imaging (fMRI), participants had to name pictures of objects in Ladin, Italian and English in separate blocks. Overall, multilingual word production activated a common set of brain areas dedicated to known subcomponents of picture naming. In comparison to English, the fluently spoken languages Ladin and Italian were associated with enhanced right prefrontal activity. In addition, the MR signal in right prefrontal cortex correlated with naming accuracy as a measure of language proficiency. Our results demonstrate the significance of right prefrontal areas for language proficiency. Based on the role of these areas for cognitive control, our findings suggest that right prefrontal cortex supports language proficiency by effectively supervising word retrieval.

A neural signature of anorexia nervosa in the ventral striatal reward system.

OBJECTIVE: Animal studies assessing mechanisms of self-starvation under conditions of stress and diet suggest a pivotal role for the mesolimbic reward system in the maintenance of core symptoms in anorexia nervosa, which is corroborated by initial empirical evidence in human studies. The authors examined activity in the ventral striatal system in response to disease-specific stimuli in women with acute anorexia nervosa. METHOD: Participants were 14 women with acute anorexia nervosa and 14 matched healthy comparison women who underwent functional magnetic resonance imaging (fMRI) during evaluation of visual stimuli depicting a female body with underweight, normal weight, and overweight canonical whole-body features according to standardized body mass indices. Participants were required to process each stimulus in a self-referring way. Ratings for each weight category were used as the control task. RESULTS: Behaviorally, women with anorexia nervosa provided significantly higher positive ratings in response to underweight stimuli than in response to normal-weight stimuli, while healthy comparison women showed greater preference for normal-weight stimuli relative to underweight stimuli. Functionally, ventral striatal activity demonstrated a highly significant group-by-stimulus interaction for underweight and normal-weight stimuli. In women with anorexia nervosa, activation was higher during processing of underweight stimuli compared with normal-weight stimuli. The reverse pattern was observed in healthy comparison women. CONCLUSIONS: These findings are consistent with predictions in animal studies of the pivotal role of the human reward system in anorexia nervosa and thus support theories of starvation dependence in maintenance of the disorder.

Conceptual flexibility in the human brain: dynamic recruitment of semantic maps from visual, motor, and motion-related areas.

Traditionally, concepts are assumed to be situational invariant mental knowledge entities (conceptual stability), which are represented in a unitary brain system distinct from sensory and motor areas (amodality). However, accumulating evidence suggests that concepts are embodied in perception and action in that their conceptual features are stored within modality-specific semantic maps in the sensory and motor cortex. Nonetheless, the first traditional assumption of conceptual stability largely remains unquestioned. Here, we tested the notion of flexible concepts using functional magnetic resonance imaging and event-related potentials (ERPs) during the verification of two attribute types (visual, action-related) for words denoting artifactual and natural objects. Functional imaging predominantly revealed crossover interactions between category and attribute type in visual, motor, and motion-related brain areas, indicating that access to conceptual knowledge is strongly modulated by attribute type: Activity in these areas was highest when nondominant conceptual attributes had to be verified. ERPs indicated that these category-attribute interactions emerged as early as 116 msec after stimulus onset, suggesting that they reflect rapid access to conceptual features rather than postconceptual processing. Our results suggest that concepts are situational-dependent mental entities. They are composed of semantic features which are flexibly recruited from distributed, yet localized, semantic maps in modality-specific brain regions depending on contextual constraints.

Anisotropy in the visual cortex investigated by neuronavigated transcranial magnetic stimulation.

Responses to transcranial magnetic stimulation (TMS) of the motor cortex depend on the direction of the induced current with an optimum perpendicular to the orientation of the precentral gyrus. Little is known about anisotropy in other cortical regions. We measured phosphene thresholds in the visual cortex using a frameless neuronavigation system. Comparing horizontal and vertical current orientation as well as monophasic and biphasic pulses in 7 subjects, we found lower thresholds with biphasic pulses and a tendency for lower thresholds with horizontal currents. When varying current directions in steps of 45 degrees centered on a hot spot over the occipital cortex, in 10 out of 12 measurements optimal current orientation ran perpendicular to the underlying gyrus (mean deviation 14.6 degrees). Optimal current orientation was determined as the orientation of the second eigenvector from the covariance matrix of the stimulation sites that had been shifted along the respective current direction by the amount of the measured threshold. Individual cortical architecture was obtained by segmentation of a 3d anatomical MR scan, with large interindividual differences among the orientations of the stimulated gyrus. As with the motor system, the optimum threshold with biphasic pulses was flipped about 180 degrees compared to the optimum with monophasic pulses (p<.02) throughout subjects, suggesting both similar anisotropic properties of networks in the visual and motor cortices and the existence of anisotropic behaviour in any cortical region. As a consequence, optimal TMS application should always take into account the individual orientation of the gyrus to be stimulated.

Basic maps in the auditory midbrain.

Topologic maps at consecutive levels of sensory pathways indicate behaviorally relevant features of stimuli at increasing degrees of complexity. In the auditory system, except for tonotopic maps, the nature of represented features is unknown. In a model analogous to visual map formation we show that in the auditory midbrain, layers of neurons with preference to the same frequency (isofrequency planes) may hold maps of two basic, mutually orthogonal parameters--instantaneous amplitude and phase--of basilar membrane displacement at the cochlear location responding to that frequency. The proposed neural tuning to frequency, amplitude, and phase implies that sound is transformed into specific temporal trajectories of neural activation, with consequences for experimental design and interpretation of neural response behavior.

The effect of erroneous responses on response monitoring in patients with major depressive disorder: a study with event-related potentials.

Perceived failure is reported to have detrimental effects on subsequent performance in patients with major depressive disorder. We investigated the error-related negativity (ERN)/error negativity (Ne), an electrophysiological correlate of response monitoring, using a 64-channel EEG. Sixteen patients with DSM-IV major depressive disorder and 16 matched controls participated in an Eriksen flanker task with continuous performance feedback that signaled monetary reward. Compared to controls, patients with major depressive disorder showed a less negative ERN/Ne in error trials following error trials. This result might reflect impaired response monitoring processes in major depressive disorder resulting from an underactivity in a central reward pathway and/or a deficit in strategic reasoning.