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There is a general consensus that schizophrenia (SZ) is characterized by major changes in the sense of self. Phenomenological studies suggest that these changes in the sense of self stem from a basic disturbance, hence the term 'basic self-disturbance'. While imaging studies demonstrate changes in various regions during self-focused tasks, the exact neural correlates of such basic self-disturbances remain unclear. If the self-disturbance is indeed basic and thereby underlies all other symptoms, one would expect it to be related to more global rather than local changes in the brain. Testing this hypothesis, we conducted a systematic review of fMRI studies on self in SZ. Our main findings are 1. Abnormal activity related to the self can be observed in a variety of different regions ranging from higher-order transmodal to lower-order unimodal regions, 2. These findings hold true across different tasks including self-reflection, self-referentiality, and self-agency, and 3. The global neural abnormalities related to the self in SZ correspond to all layers of the self, predominantly the mental and exteroceptive self. Such global neural disturbance of self converges well with the basic self-disturbance as described in phenomenology. [ABSTRACT FROM AUTHOR]

Despite intense neurobiological investigation in psychiatric disorders like major depressive disorder (MDD), the basic disturbance that underlies the psychopathological symptoms of MDD remains, nevertheless, unclear. Neuroimaging has focused mainly on the brain's extrinsic activity, specifically task-evoked or stimulus-induced activity, as related to the various sensorimotor, affective, cognitive, and social functions. Recently, the focus has shifted to the brain's intrinsic activity, otherwise known as its resting state activity. While various abnormalities have been observed during this activity, their meaning and significance for depression, along with its various psychopathological symptoms, are yet to be defined. Based on findings in healthy brain resting state activity and its particular spatial and temporal structure - defined in a functional and physiological sense rather than anatomical and structural - I claim that the various depressive symptoms are spatiotemporal disturbances of the resting state activity and its spatiotemporal structure. This is supported by recent findings that link ruminations and increased self-focus in depression to abnormal spatial organization of resting state activity. Analogously, affective and cognitive symptoms like anhedonia, suicidal ideation, and thought disorder can be traced to an increased focus on the past, increased past-focus as basic temporal disturbance o the resting state. Based on these findings, I conclude that the various depressive symptoms must be conceived as spatiotemporal disturbances of the brain's resting state's activity and its spatiotemporal structure. Importantly, this entails a new form of psychopathology, "Spatiotemporal Psychopathology" that directly links the brain and psyche, therefore having major diagnostic and therapeutic implications for clinical practice. [ABSTRACT FROM AUTHOR]

Empathy is a multicomponent function that includes sensorimotor, affective, and cognitive components. Although especially the affective component may implicate interoception and interoceptive awareness, the impact of interoception on empathy has never been evaluated behaviorally or neurophysiologically. Here, we tested how a preceding period of interoceptive awareness impacts and modulates neural activity during subsequent empathy. We used functional magnetic resonance imaging (fMRI) and measured the sequential interaction between interoception and empathy using fMRI in 18 healthy subjects. We found that the preceding interoceptive awareness period significantly enhanced neural activity during empathy in bilateral anterior insula and various cortical midline regions. The enhancement of neural activity during empathy in both interoceptive and empathy networks by preceding interoceptive awareness suggests a close relationship between interoception and empathy; thereby, interoception seems to be implicated to yielding empathy. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Heinzel A, Northoff G, Boeker H, Boesiger P, Grimm S. Emotional processing and executive functions in major depressive disorder: dorsal prefrontal activity correlates with performance in the intra-extra dimensional set shift. Major depressive disorder (MDD) is characterised by predominately negatively valenced emotional symptoms that are often accompanied by cognitive impairments. We posited that cognitive impairments in MDD are related to altered emotional processing in prefrontal cortex. We compared 20 medication-free patients with MDD and 29 matched healthy controls. Both groups performed an emotional task during functional magnetic resonance imaging (fMRI). Furthermore, they completed the intra-extra dimensional set shift (IED) test probing for cognitive impairments. Then we correlated the results of the IED with the changes in fMRI BOLD signal in MDD patients and healthy subjects. The subcategory of the IED applying extradimensional shift (EDS) showed a divergent performance of the MDD group committing significantly more errors than the control group. Correlating the EDS errors with fMRI signal changes, the healthy subjects showed a positive correlation with the right ventrolateral prefrontal cortex and the right orbitofrontal cortex. MDD subjects, in contrast, showed a positive correlation in right dorsolateral prefrontal cortex (DLPFC) and a negative correlation in the left dorsomedial prefrontal cortex (DMPFC). We hypothesise that the differential correlation in healthy controls and MDD patients may reflect the use of different strategies in their performance. The impaired executive functions, as reflected by altered processing in right DLPFC and left DMPFC, may implicitly influence emotional processing in patients suffering from MDD. [ABSTRACT FROM AUTHOR]

Abstract: Despite all the recent progress in neuroscience, we still do not understand the basic principles according to which the brain functions. This may be due, at least in part, to our lack of knowledge how the brain''s intrinsic activity, the brain''s input, impacts stimulus-induced changes in the brain. We here discuss the neuronal, experimental and methodological relevance of the brain''s resting state activity for future studies. Furthermore, we make several suggestions how to best define and include the brain''s resting state into our experimental designs. We conclude that experimental consideration of the brain''s resting state has major implications for setting up experimental designs and methodological strategies. This may also shed new light on some hitherto unresolved questions like the neuroscientific mechanisms underlying consciousness and psychiatric disorders. [Copyright &y& Elsevier]

Abstract: The nature of “the self” has been one of the central problems in philosophy and more recently in neuroscience. This raises various questions: (i) Can we attribute a self to animals? (ii) Do animals and humans share certain aspects of their core selves, yielding a trans-species concept of self? (iii) What are the neural processes that underlie a possible trans-species concept of self? (iv) What are the developmental aspects and do they result in various levels of self-representation? Drawing on recent literature from both human and animal research, we suggest a trans-species concept of self that is based upon what has been called a “core-self” which can be described by self-related processing (SRP) as a specific mode of interaction between organism and environment. When we refer to specific neural networks, we will here refer to the underlying system as the “core-SELF.” The core-SELF provides primordial neural coordinates that represent organisms as living creatures—at the lowest level this elaborates interoceptive states along with raw emotional feelings (i.e., the intentions in action of a primordial core-SELF) while higher medial cortical levels facilitate affective-cognitive integration (yielding a fully-developed nomothetic core-self). Developmentally, SRP allows stimuli from the environment to be related and linked to organismic needs, signaled and processed within core-self structures within subcorical-cortical midline structures (SCMS) that provide the foundation for epigenetic emergence of ecologically framed, higher idiographic forms of selfhood across different individuals within a species. These functions ultimately operate as a coordinated network. We postulate that core SRP operates automatically, is deeply affective, and is developmentally and epigenetically connected to sensory-motor and higher cognitive abilities. This core-self is mediated by SCMS, embedded in visceral and instinctual representations of the body that are well integrated with basic attentional, emotional and motivational functions that are apparently shared between humans, non-human mammals, and perhaps in a proto-SELF form, other vertebrates. Such a trans-species concept of organismic coherence is thoroughly biological and affective at the lowest levels of a complex neural network, and culturally and ecologically molded at higher levels of neural processing. It allows organisms to selectively adapt to and integrate with physical and social environments. Such a psychobiologically universal, but environmentally diversified, concept may promote novel trans-species studies of the core-self across mammalian species. [Copyright &y& Elsevier]

Background: Based on animal data, NMDA receptor hypofunction has been suggested as a model for positive symptoms in schizophrenia. NMDA receptor hypofunction affects several corticolimbic brain regions, of which the posterior cingulate seems to be the most sensitive. However, empirical support for a crucial role of posterior cingulate NMDA hypofunction in the pathophysiology of positive symptoms is still missing in humans. We therefore conducted an fMRI study using the NMDA antagonist ketamine in healthy human subjects during episodic memory retrieval, which is supposed to activate the posterior cingulate. Methods: We investigated 16 healthy subjects which were assigned to either placebo (n = 7; saline) or ketamine (n = 9; 0.6 mg/kg/h) group in a double-blind study design. All subjects received their infusion while performing an episodic memory retrieval task in the scanner. Immediately after the fMRI session, psychopathological effects of ketamine were measured using the Altered States of Consciousness Questionnaire. Results: The placebo group showed BOLD signal increases in the posterior and anterior cingulate during retrieval. Signal increases were significantly lower in the ketamine group. Lower signal increases in the posterior cingulate correlated significantly with positive (i.e. psychosis-like) symptoms induced by ketamine. Conclusion: The present study for the first time demonstrates a relationship between NMDA receptors, posterior cingulate and positive (i.e. psychosis-like) symptoms in humans. Confirming findings from animal studies, it supports the hypothesis of a pathophysiological role of NMDA receptor hypofunction in the posterior cingulate in schizophrenia. [ABSTRACT FROM AUTHOR]

Age‐related variations in many regions and/or networks of the human brain have been uncovered using resting‐state functional magnetic resonance imaging. However, these findings did not account for the dynamical effect the brain's global activity (global signal [GS]) causes on local characteristics, which is measured by GS topography. To address this gap, we tested GS topography including its correlation with age using a large‐scale cross‐sectional adult lifespan dataset (n = 492). Both GS topography and its variation with age showed frequency‐specific patterns, reflecting the spatiotemporal characteristics of the dynamic change of GS topography with age. A general trend toward dedifferentiation of GS topography with age was observed in both spatial (i.e., less differences of GS between different regions) and temporal (i.e., less differences of GS between different frequencies) dimensions. Further, methodological control analyses suggested that although most age‐related dedifferentiation effects remained across different preprocessing strategies, some were triggered by neuro‐vascular coupling and physiological noises. Together, these results provide the first evidence for age‐related effects on global brain activity and its topographic‐dynamic representation in terms of spatiotemporal dedifferentiation. [ABSTRACT FROM AUTHOR]

Social anxiety disorder (SAD) is characterized by social anxiety/fear, self-attention, and interoception. Functional magnetic resonance imaging studies demonstrate increased activity during symptom-sensitive tasks in regions of the default-mode network (DMN), amygdala (AMG), and salience network (SN). What is the source of this task-unspecific symptom-sensitive hyperactivity in DMN? We address this question by probing SAD resting state (rs) changes in DMN including their relation to other regions as possible source of task-unspecific hyperactivity in the same regions. Our findings show the following: (1) rs-hypoconnectivity within-DMN regions; (2) rs-hyperconnectivity between DMN and AMG/SN; (3) task-evoked hyperactivity in the abnormal rs-regions of DMN and AMG/SN during different symptom-sensitive tasks; (4) negative relationship of rest and task changes in especially anterior DMN regions as their rs-hypoconnectivity is accompanied by task-unspecific hyperactivity; (5) abnormal top-down/bottom-up modulation between anterior DMN regions and AMG during rest and task. Findings demonstrate that rs-hypoconnectivity among DMN regions is negatively related to task-unspecific hyperactivity in DMN and AMG/SN. We propose a model of "Topography of the Anxious Self" in SAD (TAS-SAD). Abnormal DMN-AMG/SN topography during rest, as trait feature of an "unstable social self", is abnormally aggravated during SAD-sensitive situations resulting in task-related hyperactivity in the same regions with an "anxious self" as state feature. [ABSTRACT FROM AUTHOR]

The low‐frequency (<0.1 Hz) fluctuation in sustained attention attracts enormous interest in cognitive neuroscience and clinical research since it always leads to cognitive and behavioral lapses. What is the source of the spontaneous fluctuation in sustained attention in neural activity, and how does the neural fluctuation relate to behavioral fluctuation? Here, we address these questions by collecting and analyzing two independent fMRI and behavior datasets. We show that the neural (fMRI) fluctuation in a key brain network, the default‐mode network (DMN), mediate behavioral (reaction time) fluctuation during sustained attention. DMN shows the increased amplitude of fluctuation, which correlates with the behavioral fluctuation in a similar frequency range (0.01–0.1 Hz) but not in the lower (<0.01 Hz) or higher (>0.1 Hz) frequency range. This was observed during both auditory and visual sustained attention and was replicable across independent datasets. These results provide a novel insight into the neural source of attention‐fluctuation and extend the former concept that DMN was deactivated in cognitive tasks. More generally, our findings highlight the temporal dynamic of the brain–behavior relationship. [ABSTRACT FROM AUTHOR]

Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. [ABSTRACT FROM AUTHOR]

The integration of multiple imaging modalities is becoming an increasingly well used research strategy for studying the human brain. The neurotransmitters glutamate and GABA particularly lend themselves towards such studies. This is because these transmitters are ubiquitous throughout the cortex, where they are the key constituents of the inhibition/excitation balance, and because they can be easily measured in vivo through magnetic resonance spectroscopy, as well as with select positron emission tomography approaches. How these transmitters underly functional responses measured with techniques such as fMRI and EEG remains unclear though, and was the target of this review. Consistently shown in the literature was a negative correlation between GABA concentrations and stimulus-induced activity within the measured region. Also consistently found was a positive correlation between glutamate concentrations and inter-regional activity relationships, both during tasks and rest. These findings are outlined along with results from populations with mental disorders to give an overview of what brain imaging has suggested to date about the biochemical underpinnings of functional activity in health and disease. We conclude that the combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key methodological and interpretive issues be addressed before can meet its potential. [ABSTRACT FROM AUTHOR]

Objective Catatonia is a psychomotor syndrome characterized by concomitant emotional, behavioural and motor symptoms. In many cases clinical symptoms disappear almost immediately with administration of lorazepam, which acts on GABAA receptors. Methods Using functional magnetic resonance imaging (fMRI) we investigated prefrontal activation patterns during emotion processing in catatonic patients with and without lorazepam in a double-blind study design. For emotional stimulation the International Affective Picture System (IAPS) was used. BOLD-signals were determined using regions of interest (ROI) and were statistically compared between groups. Results For negative emotional pictures lorazepam induced higher signal decreases in the orbitofrontal cortex (OFC) in catatonic patients than in healthy subjects resulting in a regularization of activity patterns comparable to healthy subjects with placebo. Conclusions Results indicate disturbances in the functioning of OFC in catatonia. GABAergic modified emotion regulation with decreased inhibition of affective stimuli could lead to the intense emotions reported by many catatonic patients. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Various studies demonstrate a special role of the right compared to the left anterior insula in mediating our self. However, the neural features of the right insula that allow for its special role remain unclear. Presupposing a spatiotemporal model of self—"Basis model of self-specificity" (BMSS)—we here address the following question: what spatial-topographic and temporal-dynamic features render neural activity in the right insula to be more suitable in mediating self-specificity than the left insula? First, applying fMRI, we demonstrate that the right insula (i) exhibits higher degrees of centrality in rest, and (ii) higher context-dependent functional connectivity in a self-specific task among regions of distinct layers of self (intero-, extero-proprioceptive, and mental). Second, using EEG in rest and task, we show that the right insula shows longer autocorrelation window (ACW) in its neural activity than both left insula and other regions of the different layers of self. Together, we demonstrate special topographic, i.e., high functional connectivity, and dynamic, i.e., long ACW, neural features of the right insula compared to both left insula and other regions of the distinct layers of self. This suits neural activity in the right insula ideally for high functional integration and temporal continuity as key features of the self including its intero-, extero-proprioceptive, and mental layers. [ABSTRACT FROM AUTHOR]

• VR environments help improve rehabilitation of impaired complex cognitive functions. • Combining neuroimaging and VR boosts ecological validity, generates practical gains. • These are the first neurofunctional predictive biomarkers of VR cognitive training. As Virtual reality (VR) is increasingly used in neurological disorders such as stroke, traumatic brain injury, or attention deficit disorder, the question of how it impacts the brain's neuronal activity and function becomes essential. VR can be combined with neuroimaging to offer invaluable insight into how the targeted brain areas respond to stimulation during neurorehabilitation training. That, in turn, could eventually serve as a predictive marker for therapeutic success. Functional magnetic resonance imaging (fMRI) identified neuronal activity related to blood flow to reveal with a high spatial resolution how activation patterns change, and restructuring occurs after VR training. Portable and quiet, electroencephalography (EEG) conveniently allows the clinician to track spontaneous electrical brain activity in high temporal resolution. Then, functional near-infrared spectroscopy (fNIRS) combines the spatial precision level of fMRIs with the portability and high temporal resolution of EEG to constitute an ideal measuring tool in virtual environments (VEs). This narrative review explores the role of VR and concurrent neuroimaging in cognitive rehabilitation. [ABSTRACT FROM AUTHOR]

Previous neuroimaging studies have examined the association between changes in brain structure and gastrointestinal symptoms (GIS), seen in disorders such as Irritable Bowel Syndrome and Irritable Bowel Disease. Studies in adults have found changes in white and grey matter volume (GMV) in patients with various gastrointestinal disorders. However, it is unclear whether GIS‐related structural changes in the brain are limited to adults or could be present throughout the lifespan. Given that gastrointestinal disorders are typically diagnosed between 4 and 18 years old, we investigated GIS‐induced morphological changes in pre‐adolescents (8–10), adolescents (12–16 years) and young adults (17–21 years). Using a voxel‐based morphometry (VBM) analysis, we compared regional grey matter volume (GMV) between participants with GIS and controls, using structural brain images from the Philadelphia Neurodevelopmental Cohort (PNC) database. A total of 211 participants (107 participants with GISs and 104 control participants) who had undergone structural magnetic resonance imaging were analysed. VBM analysis was used to objectively analyse GMV across the whole brain and compare between participants with GIS and controls. Participants experiencing GIS showed smaller GMV in regions within the limbic system/basal ganglia (bilateral caudate, bilateral ventral hippocampus, bilateral amygdala and bilateral superior orbital frontal cortex), and larger GMV in regions within the pain‐matrix (thalamus, bilateral putamen, right mid‐frontal gyrus) compared to controls. These differences were most prominent in the adolescent and young adult groups compared to pre‐adolescents. In conclusion, the structural differences found in participants with GIS support the need for further research into the neurophysiological impact of these symptoms. [ABSTRACT FROM AUTHOR]

• The ascending and descending phases of BOLD signal modulates face recognition. • Inter-regional phase lag distinguishes the face processing and frontoparietal systems. • Inter-regional phase lag in the infra-slow frequency range is essential for cognitive performance. Low frequency phase synchronization is an essential mechanism of information communication among brain regions. In the infra-slow frequency range (<0.1 Hz), inter-regional phase lag is of importance for brain function (e.g., anti-phase between the default mode network and task positive network). However, the role of phase lag in cognitive processing remains unclear. Based on the frequency tagging experimental paradigm and functional magnetic resonance imaging (fMRI) technique, we investigated inter-regional phase lag and phase coherence using a face recognition task (n = 30, 15 males/15 females). Phase coherence within the face processing system was significantly increased during task state, highlighting the importance of regular inter-regional phase relationship for face recognition. Moreover, results showed decreased phase lag within the core and extended face areas (face processing system) and increased phase lag between the face processing system and frontoparietal network, indicating a reorganization of inter-regional relationships of the two systems. Inter-regional phase lag was modulated by the task at ascending and descending phases of the fMRI signal, suggesting a phase-dependent inter-regional relationship. Furthermore, phase lags between visual cortex and amygdala and between visual cortex and motor area were positively related to reaction time, indicating better task performance depends on both rapid emotional detection pathway and visual-motor pathway. Overall, inter-regional phase synchronization in the infra-slow frequency range is of important for effective information communication and cognitive performance. [ABSTRACT FROM AUTHOR]

Variability quenching is a widespread neural phenomenon in which trial‐to‐trial variability (TTV) of neural activity is reduced by repeated presentations of a sensory stimulus. However, its neural mechanism and functional significance remain poorly understood. Recurrent network dynamics are suggested as a candidate mechanism of TTV, and they play a key role in consciousness. We thus asked whether the variability‐quenching phenomenon is related to the level of consciousness. We hypothesized that TTV reduction would be compromised during reduced level of consciousness by propofol anesthetics. We recorded functional magnetic resonance imaging signals of resting‐state and stimulus‐induced activities in three conditions: wakefulness, sedation, and unconsciousness (i.e., deep anesthesia). We measured the average (trial‐to‐trial mean, TTM) and variability (TTV) of auditory stimulus‐induced activity under the three conditions. We also examined another form of neural variability (temporal variability, TV), which quantifies the overall dynamic range of ongoing neural activity across time, during both the resting‐state and the task. We found that (a) TTM deceased gradually from wakefulness through sedation to anesthesia, (b) stimulus‐induced TTV reduction normally seen during wakefulness was abolished during both sedation and anesthesia, and (c) TV increased in the task state as compared to resting‐state during both wakefulness and sedation, but not anesthesia. Together, our results reveal distinct effects of propofol on the two forms of neural variability (TTV and TV). They imply that the anesthetic disrupts recurrent network dynamics, thus prevents the stabilization of cortical activity states. These findings shed new light on the temporal dynamics of neuronal variability and its alteration during anesthetic‐induced unconsciousness. [ABSTRACT FROM AUTHOR]

Two aspects of the low frequency fluctuations of spontaneous brain activity have been proposed which reflect the complex and dynamic features of resting-state activity, namely temporal variability and signal synchronization. The relationship between them, especially its role in consciousness, nevertheless remains unclear. Our study examined the temporal variability and signal synchronization of spontaneous brain activity, as well as their relationship during loss of consciousness. We applied an intra-subject design of resting-state functional magnetic resonance imaging (rs-fMRI) in two conditions: during wakefulness, and under anesthesia with clinical unconsciousness. In addition, an independent group of patients with disorders of consciousness (DOC) was included in order to test the reliability of our findings. We observed a global reduction in the temporal variability, local and distant brain signal synchronization for subjects during anesthesia. Importantly, we found a link between temporal variability and both local and distant signal synchronizations during wakefulness: the higher the degree of temporal variability, the higher its intra-regional homogeneity and inter-regional functional connectivity. In contrast, this link was broken down under anesthesia, implying a decoupling between temporal variability and signal synchronization; this decoupling was reproduced in patients with DOC. Our results suggest that there exist some as yet unclear physiological mechanisms of consciousness which “couple” the two mathematically independent measures, temporal variability and signal synchronization of spontaneous brain activity. Our findings not only extend our current knowledge of the neural correlates of anesthetic-induced unconsciousness, but have implications for both computational neural modeling and clinical practice, such as in the diagnosis of loss of consciousness in patients with DOC. [ABSTRACT FROM AUTHOR]

We live in a dynamic environment, constantly confronted with approaching objects that we may either avoid or be forced to address. A multisensory and sensorimotor interface, the peripersonal space (PPS), mediates every physical interaction between our body and the environment. Behavioral investigations show high variability in the extension of PPS across individuals, but there is a lack of evidence on the neural underpinnings of these large individual differences. Here, we used approaching auditory stimuli and fMRI to capture the individual boundary of PPS and examine its neural underpinnings. Precisely, we tested the hypothesis that intertrial variability (ITV) in brain regions coding PPS predicts individual differences of its boundary at the behavioral level. Selectively in the premotor cortex, we found that ITV, rather than trial-averaged amplitude, of BOLD responses to far rather than near dynamic stimuli predicts the individual extension of PPS. Our results provide the first empirical support for the relevance of ITV of brain responses for individual differences in human behavior. [ABSTRACT FROM AUTHOR]

Recent studies at the cellular and regional levels have pointed out the multifaceted importance of neural synchronization and temporal variance of neural activity. For example, neural synchronization and temporal variance has been shown by us to be altered in patients in the vegetative state (VS). This finding nonetheless leaves open the question of whether these abnormalities are specific to VS or rather more generally related to the absence of consciousness. The aim of our study was to investigate the changes of inter- and intra-regional neural synchronization and temporal variance of resting state activity in anesthetic-induced unconsciousness state. Applying an intra-subject design, we compared resting state activity in functional magnetic resonance imaging (fMRI) between awake versus anesthetized states in the same subjects. Replicating previous studies, we observed reduced functional connectivity within the default mode network (DMN) and thalamocortical network in the anesthetized state. Importantly, intra-regional synchronization as measured by regional homogeneity (ReHo) and temporal variance as measured by standard deviation (SD) of the BOLD signal were significantly reduced in especially the cortical midline regions, while increased in the lateral cortical areas in the anesthetized state. We further found significant frequency-dependent effects of SD in the thalamus, which showed abnormally high SD in Slow-5 (0.01-0.027 Hz) in the anesthetized state. Our results show for the first time of altered temporal variance of resting state activity in anesthesia. Combined with our findings in the vegetative state, these findings suggest a close relationship between temporal variance, neural synchronization and consciousness. Hum Brain Mapp 35:5368-5378, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Multi-variate pattern analysis (MVPA) applied to BOLD-fMRI has proven successful at decoding complicated fMRI signal patterns associated with a variety of cognitive processes. One cognitive process, not yet investigated, is the mental representation of "Yes/No" thoughts that precede the actual overt response to a binary "Yes/No" question. In this study, we focus on examining: (1) whether spatial patterns of the hemodynamic response carry sufficient information to allow reliable decoding of "Yes/No" thoughts; and (2) whether decoding of "Yes/No" thoughts is independent of the intention to respond honestly or dishonestly. To achieve this goal, we conducted two separate experiments. Experiment 1, collected on a 3T scanner, examined the whole brain to identify regions that carry sufficient information to permit significantly above-chance prediction of "Yes/No" thoughts at the group level. In Experiment 2, collected on a 7T scanner, we focused on the regions identified in Experiment 1 to examine the capability of achieving high decoding accuracy at the single subject level. A set of regions - namely right superior temporal gyrus, left supra-marginal gyrus, and left middle frontal gyrus - exhibited high decoding power. Decoding accuracy for these regions increased with trial averaging. When 18 trials were averaged, the median accuracies were 82.5%, 77.5%, and 79.5%, respectively. When trials were separated according to deceptive intentions (set via experimental cues), and classifiers were trained on honest trials, but tested on trials where subjects were asked to deceive, the median accuracies of these regions still reached 66%, 75%, and 78.5%. These results provide evidence that concealed "Yes/No" thoughts are encoded in the BOLD signal, retaining some level of independence from the subject's intentions to answer honestly or dishonestly. These findings also suggest the theoretical possibility for more efficient brain-computer interfaces where subjects only need to think their answers to communicate. [ABSTRACT FROM AUTHOR]

Distinguishing potentially harmful or beneficial stimuli is necessary for the self-preservation and well-being of all organisms. This assessment requires the ongoing valuation of environmental stimuli. Despite much work on the processing of aversive- and appetitive-related brain signals, it is not clear to what degree these two processes interact across the brain. To help clarify this issue, this report used a cross-species comparative approach in humans (i.e. meta-analysis of imaging data) and other mammals (i.e. targeted review of functional neuroanatomy in rodents and non-human primates). Human meta-analysis results suggest network components that appear selective for appetitive (e.g. ventromedial prefrontal cortex, ventral tegmental area) or aversive (e.g. cingulate/supplementary motor cortex, periaqueductal grey) processing, or that reflect overlapping (e.g. anterior insula, amygdala) or asymmetrical, i.e. apparently lateralized, activity (e.g. orbitofrontal cortex, ventral striatum). However, a closer look at the known value-related mechanisms from the animal literature suggests that all of these macroanatomical regions are involved in the processing of both appetitive and aversive stimuli. Differential spatiotemporal network dynamics may help explain similarities and differences in appetitive- and aversion-related activity. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated resting-state abnormalities in midline regions in vegetative state/unresponsive wakefulness syndrome and minimally conscious state patients. However, the functional implications of these resting-state abnormalities remain unclear. Recent findings in healthy subjects have revealed a close overlap between the neural substrate of self-referential processing and the resting-state activity in cortical midline regions. As such, we investigated task-related neural activity during active self-referential processing and various measures of resting-state activity in 11 patients with disorders of consciousness (DOC) and 12 healthy control subjects. Overall, the results revealed that DOC patients exhibited task-specific signal changes in anterior and posterior midline regions, including the perigenual anterior cingulate cortex (PACC) and posterior cingulate cortex (PCC). However, the degree of signal change was significantly lower in DOC patients compared with that in healthy subjects. Moreover, reduced signal differentiation in the PACC predicted the degree of consciousness in DOC patients. Importantly, the same midline regions (PACC and PCC) in DOC patients also exhibited severe abnormalities in the measures of resting-state activity, that is functional connectivity and the amplitude of low-frequency fluctuations. Taken together, our results provide the first evidence of neural abnormalities in both the self-referential processing and the resting state in midline regions in DOC patients. This novel finding has important implications for clinical utility and general understanding of the relationship between the self, the resting state, and consciousness. Hum Brain Mapp 35:1997-2008, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The insula has been identified as a key region involved in interoceptive awareness. Whilst imaging studies have investigated the neural activation patterns in this region involved in intero- and exteroceptive awareness, the underlying biochemical mechanisms still remain unclear. In order to investigate these, a well-established fMRI task targeting interoceptive awareness (heartbeat counting) and exteroceptive awareness (tone counting) was combined with magnetic resonance spectroscopy (MRS). Controlling for physiological noise, neural activity in the insula during intero- and exteroceptive awareness was confirmed in an independent data sample using the same fMRI design. Focussing on MRS values from the left insula and combining them with neural activity during intero- and exteroceptive awareness in the same healthy individuals, we demonstrated that GABA concentration in a region highly involved in interoceptive processing is correlated with neural responses to interoceptive stimuli, as opposed to exteroceptive stimuli. In addition, both GABA and interoceptive signal changes in the insula predicted the degree of depressed affect, as measured by the Beck Hopelessness Scale. On the one hand, the association between GABA concentration and neural activity during interoceptive awareness provides novel insight into the biochemical underpinnings of insula function and interoception. On the other, through the additional association of both GABA and neural activity during interoception with depressed affect, these data also bear potentially important implications for psychiatric disorders like depression and anxiety, where GABAergic deficits, altered insula function and abnormal affect coincide. [Copyright &y& Elsevier]

Highlights: [•] Provide an overview of factors to consider when planning multi-modal imaging studies. [•] Discuss technical and methodological issues for hypothesis generation. [•] Discuss issues of specificity that arise in multi-modal imaging. [ABSTRACT FROM AUTHOR]

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [18F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders. Hum Brain Mapp 35:173-184, 2014. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex – specifically the medial prefrontal cortex (mPFC) – and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc), dorsomedial thalamus (DMT), and periaqueductal grey (PAG). It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia. [ABSTRACT FROM AUTHOR]

Somatoform disorder patients suffer from impaired emotion recognition and other emotional deficits. Emotional empathy refers to the understanding and sharing of emotions of others in social contexts. It is likely that the emotional deficits of somatoform disorder patients are linked to disturbed empathic abilities; however, little is known so far about empathic deficits of somatoform patients and the underlying neural mechanisms. We used fMRI and an empathy paradigm to investigate 20 somatoform disorder patients and 20 healthy controls. The empathy paradigm contained facial pictures expressing anger, joy, disgust, and a neutral emotional state; a control condition contained unrecognizable stimuli. In addition, questionnaires testing for somatization, alexithymia, depression, empathy, and emotion recognition were applied. Behavioral results confirmed impaired emotion recognition in somatoform disorder and indicated a rather distinct pattern of empathic deficits of somatoform patients with specific difficulties in 'empathic distress.' In addition, somatoform patients revealed brain areas with diminished activity in the contrasts 'all emotions'-'control,' 'anger'-'control,' and 'joy'-'control,' whereas we did not find brain areas with altered activity in the contrasts 'disgust'-'control' and 'neutral'-'control.' Significant clusters with less activity in somatoform patients included the bilateral parahippocampal gyrus, the left amygdala, the left postcentral gyrus, the left superior temporal gyrus, the left posterior insula, and the bilateral cerebellum. These findings indicate that disturbed emotional empathy of somatoform disorder patients is linked to impaired emotion recognition and abnormal activity of brain regions responsible for emotional evaluation, emotional memory, and emotion generation. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Interdependent cultures (such as the Chinese) and independent cultures (such as the German) differ in their attitude towards harmony that is more valued in interdependent cultures. Interdependent and independent cultures also differ in their appreciation of anger — an emotion that implies the disruption of harmony. The present study investigated if interdependent and independent cultures foster distinct brain activity associated with empathic processing of familiar angry, familiar neutral, and unfamiliar neutral faces. Using functional MRI, we scanned Chinese and German healthy subjects during an intentional empathy task, a control task (the evaluation of skin color), and a baseline condition. The subject groups were matched with regard to age, gender, and education. Behaviorally, Chinese subjects described themselves as significantly more interdependent compared to German subjects. The contrast ‘intentional empathy for familiar angry’>‘baseline’ revealed several regions, including the left inferior frontal cortex, the left supplementary motor area, and the left insula, that showed comparable hemodynamic responses in both groups. However, the left dorsolateral prefrontal cortex had stronger hemodynamic responses in Chinese subjects in the contrast ‘intentional empathy for familiar angry’>‘baseline’. Germans, in contrast, showed stronger hemodynamic responses in the right temporo-parietal junction, right inferior and superior temporal gyrus, and left middle insula for the same contrast. Hemodynamic responses in the latter three brain regions correlated with interdependences scores over all subjects. Our results suggest that enhanced emotion regulation during empathy with anger in the interdependent lifestyle is mediated by the left dorsolateral prefrontal cortex. Increased tolerance towards the expression of anger in the independent lifestyle, in contrast, is associated with increased activity of the right inferior and superior temporal gyrus and the left middle insula. [Copyright &y& Elsevier]

Although empathic responses to stimuli with emotional contents may occur automatically, humans are capable to intentionally empathize with other individuals. Intentional empathy for others is even possible when they do not show emotional expressions. However, little is known about the neuronal mechanisms of this intentionally controlled empathic process. To investigate the neuronal substrates underlying intentional empathy, we scanned 20 healthy Chinese subjects, using fMRI, when they tried to feel inside the emotional states of neutral or angry faces of familiar (Asian) and unfamiliar (Caucasian) models. Skin color evaluation of the same stimuli served as a control task. Compared to a baseline condition, the empathy task revealed a network of established empathy regions, including the anterior cingulate cortex, bilateral inferior frontal cortex and bilateral anterior insula. The contrast of intentional empathy vs skin color evaluation, however, revealed three regions: the bilateral inferior frontal cortex, whose hemodynamic responses were independent of perceived emotion and familiarity and the right-middle temporal gyrus, whose activity was modulated by emotion but not by familiarity. These findings extend our understanding of the role of the inferior frontal cortex and the middle temporal gyrus in empathy by demonstrating their involvement in intentional empathy. [ABSTRACT FROM PUBLISHER]

Objectives. Somatoform disorder patients demonstrate a disturbance in the balance between internal and external information processing, with a decreased focus on external stimulus processing. We investigated brain activity of somatoform disorder patients, during the processing of rewarding external events, paying particular attention to the effects of inpatient multimodal psychodynamic psychotherapy. Methods. Using fMRI, we applied a reward task that required fast reactions to a target stimulus in order to obtain monetary rewards; a control condition contained responses without the opportunity to gain rewards. Twenty acute somatoform disorder patients were compared with twenty age-matched healthy controls. In addition, 15 patients underwent a second scanning session after participation in multimodal psychodynamic psychotherapy. Results. Acute patients showed diminished hemodynamic differentiation between rewarding and non rewarding events in four regions, including the left postcentral gyrus and the right ventroposterior thalamus. After multimodal psychodynamic psychotherapy, both regions showed a significant normalization of neuronal differentiation. Conclusion. Our results suggest that diminished responsiveness of brain regions involved in the processing of external stimuli underlies the disturbed balance of internal and external processing of somatoform disorder patients. By providing new approaches to cope with distressing events, multimodal psychodynamic psychotherapy led to decreased symptoms and normalization of neuronal activity. [ABSTRACT FROM AUTHOR]

Abstract: Imaging studies investigating the default-mode network (DMN) of the brain revealed the phenomenon of elevated neural responses during periods of rest. This effect has been shown to be abnormally elevated in regions of the DMN concerning mood disorders like major depressive disorder (MDD). Since these disorders are accompanied by impaired emotional functioning, this leads to the suggestion of an association between activity during rest conditions and emotions, which remains to be demonstrated in a healthy and clinical population. Controlling for interoceptive processing, a process often closely connected to emotional functioning, we here demonstrate in an fMRI study of 30 healthy subjects the connection between activity during rest conditions in regions of the DMN and emotions in a psychologically, regionally, and stimulus specific way. Our findings provide further insight into the psychological functions underlying rest activity. Our findings in healthy subjects may also have future implications for a better understanding of mood disorders. [Copyright &y& Elsevier]

Abstract: Whilst recent neuroimaging studies have identified a series of different brain regions as being involved in empathy, it remains unclear concerning the activation consistence of these brain regions and their specific functional roles. Using MKDA, a whole-brain based quantitative meta-analysis of recent fMRI studies of empathy was performed. This analysis identified the dACC-aMCC-SMA and bilateral anterior insula as being consistently activated in empathy. Hypothesizing that what are here termed affective–perceptual and cognitive–evaluative forms of empathy might be characterized by different activity patterns, the neural activations in these forms of empathy were compared. The dorsal aMCC was demonstrated to be recruited more frequently in the cognitive–evaluative form of empathy, whilst the right anterior insula was found to be involved in the affective–perceptual form of empathy only. The left anterior insula was active in both forms of empathy. It was concluded that the dACC-aMCC-SMA and bilateral insula can be considered as forming a core network in empathy, and that cognitive–evaluative and affective–perceptual empathy can be distinguished at the level of regional activation. [ABSTRACT FROM AUTHOR]

Abstract: Life choices (e.g., occupational choice) often include situations with two or more possible correct answers, thereby putting us in a situation of conflict. Recent reports have described that the evaluation of conflict might be crucially mediated by neural activity in the dorsal anterior cingulate cortex (dACC), although the reduction of conflict might rather be associated with neural activity in the medial prefrontal cortex (MPFC). What remains unclear is whether these regions mutually interact, thereby raising the question of their functional connectivity during conflict situations. Using psychophysiological interaction (PPI) analyses of functional magnetic resonance imaging (fMRI) data, this study shows that the dACC co-varied significantly higher with the MPFC during an occupational choice task with two possible correct answers when compared to the control task: a word-length task with one possible correct answer. These results suggest that the MPFC has a functional relation with dACC, especially in conflict situations where there is no objective correct answer. Taken together, this lends support to the assumption that the MPFC might be crucial in biasing the decision, thereby reducing conflict. [ABSTRACT FROM AUTHOR]

Abstract: Self-referential processing involves a complex set of cognitive functions, posing challenges to delineating its independent neural correlates. While self-referential processing has been considered functionally intertwined with episodic memory, the present study explores their overlap and dissociability. Standard tasks for self-referential processing and episodic memory were combined into a single fMRI experiment. Contrasting the effects of self-relatedness and retrieval success allowed for the two processes to be delineated. Stimuli judged as self-referential specifically activated the posterior cingulate/anterior precuneus, the medial prefrontal cortex, and an inferior division of the inferior parietal lobule. In contrast, episodic memory retrieval specifically involved the posterior precuneus, the right anterior prefrontal cortex, and a superior division of the inferior parietal lobule (extending into superior parietal lobule). Overlapping activations were found in intermediate zones in the precuneus and the inferior parietal lobule, but not in the prefrontal cortex. While our data show common networks for both processes in the medial and lateral parietal cortex, three functional differentiations were also observed: (1) an anterior–posterior differentiation within the medial parietal cortex; (2) a medial–anterolateral differentiation within the prefrontal cortex; and, (3) an inferior–superior differentiation within the lateral parietal cortex for self-referential processing versus episodic memory retrieval. [Copyright &y& Elsevier]

Abstract: Patients with depression show an impaired ability to modulate emotional states and to process positive emotional information. Here we examined expectancy-induced modulation of emotional picture processing in major depression. We hypothesized alterations in the medial prefrontal cortex. During fMRI, 15 depressed and 21 healthy control subjects passively viewed affective photographs. Half of the pictures were preceded by an expectancy cue signaling whether an emotionally salient or neutral picture would follow. The contrast ‘cued versus uncued emotional picture viewing’ was used to study modulation of emotional picture processing by preceding attention. Healthy individuals showed enhanced activation in the dorsomedial prefrontal cortex and decreased activation in the dorsolateral prefrontal cortex during cued compared to uncued emotional picture perception. The group comparison revealed that these modulatory effects were significantly attenuated in depressed patients. This attenuation was particularly observed in the positive compared to the negative picture condition and tended to normalize in the dorsomedial prefrontal cortex after remission of symptoms. Altered prefrontal modulation in depression may contribute to impaired affect modulation and related clinical symptoms, such as anhedonia. [Copyright &y& Elsevier]

Abstract: Objective: The Beck Depression Inventory (BDI) is probably the most widely used depression scale. It has been suggested that it contains a two-factor structure measuring cognitive-affective (i.e. psychological) and somatic-vegetative depressive symptoms. In this study we aim to evaluate these factors by probing for their neural correlates. Methods: Neural responses evoked by emotional perception, relative to an emotional judgment task, were measured using functional magnetic resonance imaging (fMRI) in 20 medication-free patients with severe MDD. Psychological and somatic-vegetative symptoms were evaluated with the BDI. Results: Psychological symptoms correlated with signal changes in the dorsomedial and right ventrolateral prefrontal cortex, while somatic-vegetative symptoms correlated with signal changes in the pre-genual anterior cingulate cortex. Conclusions: These preliminary findings demonstrate segregated neural representation of psychological and somatic-vegetative symptoms of MDD in different cortical regions. Thus, our results indicate that the two-factor structure of the BDI is related to distinct neural correlates. [Copyright &y& Elsevier]

Background: Although pedophilia is of high public concern, little is known about underlying neural mechanisms. Although pedophilic patients are sexually attracted to prepubescent children, they show no sexual interest toward adults. This study aimed to investigate the neural correlates of deficits of sexual and emotional arousal in pedophiles. Methods: Thirteen pedophilic patients and 14 healthy control subjects were tested for differential neural activity during visual stimulation with emotional and erotic pictures with functional magnetic resonance imaging. Results: Regions showing differential activations during the erotic condition comprised the hypothalamus, the periaqueductal gray, and dorsolateral prefrontal cortex, the latter correlating with a clinical measure. Alterations of emotional processing concerned the amygdala–hippocampus and dorsomedial prefrontal cortex. Conclusions: Hypothesized regions relevant for processing of erotic stimuli in healthy individuals showed reduced activations during visual erotic stimulation in pedophilic patients. This suggests an impaired recruitment of key structures that might contribute to an altered sexual interest of these patients toward adults. [Copyright &y& Elsevier]

Abstract: Emotions are frequently characterized by distinct dimensions such as valence, intensity, and recognition. However, the exact neural representation of these dimensions in different prefrontal cortical regions remains unclear. One of the problems in revealing prefrontal cortical representation is that the very same regions are also involved in cognitive functions associated with emotion processing. We therefore conducted an fMRI study involving the viewing of emotional pictures (using the International Affective Picture System; IAPS) and controlled for associated cognitive processing like judgment and preceding attention. Functional activation was correlated with subjective post-scanning ratings of valence, intensity, and recognition. Valence significantly correlated with the functional response in ventromedial prefrontal cortex (VMPFC) and dorsolateral prefrontal cortex (DLPFC), intensity with activation in ventrolateral prefrontal cortex (VLPFC) and dorsomedial prefrontal cortex (DMPFC), and recognition with the functional response in perigenual anterior cingulate cortex (PACC). In conclusion, our results indicate segregated neural representation of the different emotion dimensions in different prefrontal cortical regions. [Copyright &y& Elsevier]

Determining the level of consciousness in patients with disorders of consciousness (DOC) remains challenging. To address this challenge, resting-state fMRI (rs-fMRI) has been widely used for detecting the local, regional, and network activity differences between DOC patients and healthy controls. Although substantial progress has been made towards this endeavor, the identification of robust rs-fMRI-based biomarkers for level of consciousness is still lacking. Recent developments in machine learning show promise as a tool to augment the discrimination between different states of consciousness in clinical practice. Here, we investigated whether machine learning models trained to make a binary distinction between conscious wakefulness and anesthetic-induced unconsciousness would then be capable of reliably identifying pathologically induced unconsciousness. We did so by extracting rs-fMRI-based features associated with local activity, regional homogeneity, and interregional functional activity in 44 subjects during wakefulness, light sedation, and unresponsiveness (deep sedation and general anesthesia), and subsequently using those features to train three distinct candidate machine learning classifiers: support vector machine, Extra Trees , artificial neural network. First, we show that all three classifiers achieve reliable performance within-dataset (via nested cross-validation), with a mean area under the receiver operating characteristic curve (AUC) of 0.95, 0.92, and 0.94, respectively. Additionally, we observed comparable cross-dataset performance (making predictions on the DOC data) as the anesthesia-trained classifiers demonstrated a consistent ability to discriminate between unresponsive wakefulness syndrome (UWS/VS) patients and healthy controls with mean AUC's of 0.99, 0.94, 0.98, respectively. Lastly, we explored the potential of applying the aforementioned classifiers towards discriminating intermediate states of consciousness, specifically, subjects under light anesthetic sedation and patients diagnosed as having a minimally conscious state (MCS). Our findings demonstrate that machine learning classifiers trained on rs-fMRI features derived from participants under anesthesia have potential to aid the discrimination between degrees of pathological unconsciousness in clinical patients. • Anesthetic-induced unconsciousness informs pathological unconsciousness. • Rs-fMRI-based machine learning is applied to distinguish conscious from unconscious subjects. • Machine learning models achieve reliable performance in cross-dataset generalizations. • Hyperparameter optimization significantly improves model performance. • Network-level functional connectivity features are most informative for classification. [ABSTRACT FROM AUTHOR]