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Over the last decade, synchronized resting-state fluctuations of blood oxygenation level-dependent (BOLD) signals between remote brain areas [so-called BOLD resting-state functional connectivity (rs-FC)] have gained enormous relevance in systems and clinical neuroscience. However, the neural underpinnings of rs-FC are still incompletely understood. Using simultaneous positron emission tomography/ magnetic resonance imaging we here directly investigated the relationship between rs-FC and local neuronal activity in humans. Computational models suggest a mechanistic link between the dynamics of local neuronal activity and the functional coupling among distributed brain regions. Therefore, we hypothesized that the local activity (LA) of a region at rest determines its rs-FC. To test this hypothesis, we simultaneously measured both LA (glucose metabolism) and rs-FC (via synchronized BOLD fluctuations) during conditions of eyes closed or eyes open. During eyes open, LA increased in the visual system, and the salience network (i.e., cingulate and insular cortices) and the pattern of elevated LA coincided almost exactly with the spatial pattern of increased rs-FC. Specifically, the voxelwise regional profile of LA in these areas strongly correlated with the regional pattern of rs-FC among the same regions (e.g., LA in primary visual cortex accounts for~50%, andLAin anterior cingulate accounts for~20%of rs-FC with the visual system). These data provide the first direct evidence in humans that local neuronal activity determines BOLD FC at rest. Beyond its relevance for the neuronal basis of coherent BOLD signal fluctuations, our procedure may translate into clinical research particularly to investigate potentially aberrant links between local dynamics and remote functional coupling in patients with neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

The visual cortex is sensitive to emotional stimuli. This sensitivity is typically assumed to arise when amygdala modulates visual cortex via backwards connections. Using human fMRI, we compared dynamic causal connectivity models of sensitivity with fearful faces. This model comparison tested whether amygdala modulates distinct cortical areas, depending on dynamic or static face presentation. The ventral temporal fusiform face area showed sensitivity to fearful expressions in static faces. However, for dynamic faces, we found fear sensitivity in dorsal motion-sensitive areas within hMT+/V5 and superior temporal sulcus. The model with the greatest evidence included connections modulated by dynamic and static fear from amygdala to dorsal and ventral temporal areas, respectively. According to this functional architecture, amygdala could enhance encoding of fearful expression movements from video and the form of fearful expressions from static images. The amygdala may therefore optimize visual encoding of socially charged and salient information. [ABSTRACT FROM AUTHOR]

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin-prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells. [ABSTRACT FROM AUTHOR]

To behave adaptively, an organism must balance the accurate maintenance of information stored in working memory with the ability to update that information when the context changes. This trade-off between fidelity and flexibility may depend upon the anticipated likelihood that updating will be necessary. To address the neurobiological basis of anticipatory optimization, we acquired functional magnetic resonance imaging data, while healthy human subjects performed a modified delayed-response task. This task used cues that predicted memory updating, with high or low probability, followed by a contingent updating or maintenance event. This enabled us to compare behavior and neuronal activity during conditions in which updating was anticipated with high and low probability, and measure responses to expected and unexpected memory updating. Based on the known role of dopamine in cognitive flexibility and working memory updating, we hypothesized that differences in anticipatory set would be manifest in the dopaminergic midbrain and striatum. Consistent with our predictions, we identified sustained activation in the dopaminergic midbrain and the striatum, associated with anticipations of high versus low updating probability. We also found that this anticipatory factor affected neural responses to subsequent updating processes, which suppressed, rather than elevated, midbrain and striatal activity. Our study addresses for the first time an important and hitherto understudied aspect of working memory. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that ACh enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimizing the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore, using dynamic causal modeling, we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that ACh adaptively enhances sensory precision by boosting bottom-up signaling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty. [ABSTRACT FROM AUTHOR]

This study addresses the neuronal representation of aversive sounds that are perceived as unpleasant. Functional magnetic resonance imaging in humans demonstrated responses in the amygdala and auditory cortex to aversive sounds. We show that the amygdala encodes both the acoustic features of a stimulus and its valence (perceived unpleasantness). Dynamic causal modeling of this system revealed that evoked responses to sounds are relayed to the amygdala via auditory cortex. While acoustic features modulate effective connectivity from auditory cortex to the amygdala, the valence modulates the effective connectivity from amygdala to the auditory cortex. These results support a complex (recurrent) interaction between the auditory cortex and amygdala based on object-level analysis in the auditory cortex that portends the assignment of emotional valence in amygdala that in turn influences the representation of salient information in auditory cortex. [ABSTRACT FROM AUTHOR]

Attentional orientation to a spatial cue and reorientation--after invalid cueing--are mediated by two distinct networks in the human brain. A bilateral dorsal frontoparietal network, comprising the intraparietal sulcus (IPS) and the frontal eye fields (FEF), controls the voluntary deployment of attention and may modulate visual cortex in preparation for upcoming stimulation. In contrast, reorienting attention to invalidly cued targets engages a right-lateralized ventral frontoparietal network comprising the temporoparietal junction (TPJ) and ventral frontal cortex. The present fMRI study investigated the functional architecture of these two attentional systems by characterizing effective connectivity during lateralized orienting and reorienting of attention, respectively. Subjects performed a modified version of Posner's location-cueing paradigm. Dynamic causal modeling (DCM) of regional responses in the dorsal and ventral network, identified in a conventional (SPM) whole-brain analysis, was used to compare different functional architectures. Bayesian model selection showed that top-down connections from left and right IPS to left and right visual cortex, respectively, were modulated by the direction of attention. Moreover, model evidence was highest for a model with directed influences from bilateral IPS to FEF, and reciprocal coupling between right and left FEF. Invalid cueing enhanced forward connections from visual areas to right TPJ, and directed influences from right TPJ to right IPS and IFG (inferior frontal gyrus). These findings shed further light on the functional organization of the dorsal and ventral attentional network and support a context-sensitive lateralization in the top-down (backward) mediation of attentional orienting and the bottom-up (forward) effects of invalid cueing. [ABSTRACT FROM AUTHOR]

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson's disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those >30 Hz is particularly unclear. Do they improve movement, and, if so, in what way? We acquired simultaneously magnetoencephalography and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (Ml ) and STN and on the coherence between the two structures. We observed discrete peaks in Ml and STN power at 60 -90 Hz and at 300 - 400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity at 60 -90 Hz was coherent with activity in Ml. Directionality analysis showed that STN gamma activity at 60 -90 Hz tended to drive gamma activity in Ml. The effects of levodopa on both local and distant synchronization at 60 -90 Hz correlated with the degree of improvement in bradykinesia-rigidity as did local STN activity at 300 - 400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and Ml. We conclude that synchronization at 60-90 Hz in the basal ganglia cortical network is prokinetic but likely through a modulatory effect rather than any involvement in explicit motor processing. [ABSTRACT FROM AUTHOR]

Humans have the arguably unique ability to understand the mental representations of others. For success in both competitive and cooperative interactions, however, this ability must be extended to include representations of others' belief about our intentions, their model about our belief about their intentions, and so on. We developed a "stag hunt" game in which human subjects interacted with a computerized agent using different degrees of sophistication (recursive inferences) and applied an ecologically valid computational model of dynamic belief inference. We show that rostral medial prefrontal (paracingulate) cortex, a brain region consistently identified in psychological tasks requiring mentalizing, has a specific role in encoding the uncertainty of inference about the other's strategy. In contrast, dorsolateral prefrontal cortex encodes the depth of recursion of the strategy being used, an index of executive sophistication. These findings reveal putative computational representations within prefrontal cortex regions, supporting the maintenance of cooperation in complex social decision making. [ABSTRACT FROM AUTHOR]

Individuals with autism spectrum conditions (ASCs) have a core difficulty in recursively inferring the intentions of others. The precise cognitive dysfunctions that determine the heterogeneity at the heart of this spectrum, however, remains unclear. Furthermore, it remains possible that impairment in social interaction is not a fundamental deficit but a reflection of deficits in distinct cognitive processes. To better understand heterogeneity within ASCs, we employed a game-theoretic approach to characterize unobservable computational processes implicit in social interactions. Using a social hunting game with autistic adults, we found that a selective difficulty representing the level of strategic sophistication of others, namely inferring others' mindreading strategy, specifically predicts symptom severity. In contrast, a reduced ability in iterative planning was predicted by overall intellectual level. Our findings provide the first quantitative approach that can reveal the underlying computational dysfunctions that generate the autistic "spectrum." [ABSTRACT FROM AUTHOR]

The synchronous discharge of neuronal assemblies is thought to facilitate communication between areas within distributed networks in the human brain. This oscillatory activity is especially interesting, given the pathological modulation of specific frequencies in diseases affecting the motor system. Many studies investigating oscillatory activity have focused on same frequency, or linear, coupling between areas of a network. In this study, our aim was to establish a functional architecture in the human motor system responsible for induced responses as measured in normal subjects with magnetoencephalography. Specifically, we looked for evidence for additional nonlinear (between-frequency) coupling among neuronal sources and, in particular, whether nonlinearities were found predominantly in connections within areas (intrinsic), between areas (extrinsic) or both. We modeled the event-related modulation of spectral responses during a simple hand-grip using dynamic casual modeling. We compared models with and without nonlinear connections under conditions of symmetric and asymmetric interhemispheric connectivity. Bayesian model comparison suggested that the task-dependent motor network was asymmetric during right hand movements. Furthermore, it revealed very strong evidence for nonlinear coupling between sources in this distributed network, but interactions among frequencies within a source appeared linear in nature. Our results provide empirical evidence for nonlinear coupling among distributed neuronal sources in the motor system and that these play an important role in modulating spectral responses under normal conditions. [ABSTRACT FROM AUTHOR]

An important and unresolved question is how the human brain processes speech for meaning after initial analyses in early auditory cortical regions. A variety of left-hemispheric areas have been identified that clearly support semantic processing, although a systematic analysis of directed interactions among these areas is lacking. We applied dynamic causal modeling of functional magnetic resonance imaging responses and Bayesian model selection to investigate, for the first time, experimentally induced changes in coupling among three key multimodal regions that were activated by intelligible speech: the posterior and anterior superior temporal sulcus (pSTS and aSTS, respectively) and pars orbitalis (POrb) of the inferior frontal gyrus. We tested 216 different dynamic causal models and found that the best model was a "forward" system that was driven by auditory inputs into the pSTS, with forward connections from the pSTS to both the aSTS and the POrb that increased considerably in strength (by 76 and 150%, respectively) when subjects listened to intelligible speech. Task-related, directional effects can now be incorporated into models of speech comprehension. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is an established technique for non-invasive stimulation of human cortex. Although studies have shown an influence of rTMS on single cortical regions and on simple behavioral response patterns, its influences on the dynamics of task-related activity in cortical networks have not been characterized. We provide such a characterization by showing that 5 Hz rTMS over primary somatosensory cortex (SI) induces a reconfiguration of activity patterns in a sensorimotor network, comprising the stimulated region and ipsilateral primary motor cortex (MI). These plastic changes endure for up to 120 min and are correlated with behavioral improvement in discrimination. Dynamic causal modeling showed that this reconfiguration could be explained by an rTMS-induced increase in SI excitability (self-connection) and an increase in the effective connectivity from SI to MI. Thus, our data demonstrate that rTMS can temporarily induce behaviorally relevant reorganization within a complex cortical network underlying human somatosensory experience. [ABSTRACT FROM AUTHOR]

The morphology of the human cortex varies remarkably across individuals, regardless of overall brain size. It is currently unclear whether related cortical regions covary in gray matter density, as a result of mutually trophic influences or common experience-related plasticity. We acquired a structural magnetic resonance imaging scan from 172 subjects and extracted the regional gray matter densities from 12 readily identifiable regions of interest involved in sensorimotor or higher-order cognitive functions. We then used these values to predict regional densities in the remaining areas of the cortex, using voxel-based morphometry. This revealed patterns of positive and negative covariance that provide insight into the topographical organization of multiple cortical regions. We report that the gray matter density of a region is a good predictor of the density of the homotopic region in the contralateral hemisphere, with the striking exception of primary visual cortex. Whereas some regions express patterns of regional covariance that are mirror symmetrical relative to the interhemispheric fissure, other regions express asymmetric patterns of regional covariance. Finally, patterns of covariance are remarkably consistent between males and females, with the exception of the left amygdala, which is positively associated with the left and right anterior inferior temporal cortex in males and with the right angular gyrus in females. Our study establishes that the density of different cortical regions is coordinated within an individual. The coordinated variations we report are likely to be determined by both genetic and environmental factors and may be the basis for differences in individual behavior. [ABSTRACT FROM AUTHOR]

Lesion and functional imaging studies in humans have suggested that the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and intraparietal sulcus (IPS) are involved in orienting attention. A functional magnetic resonance imaging study supplemented by a behavioral experiment examined the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) conditioning to the right and left DLPFC on reaction times and synaptic activity as indexed by changes in the blood oxygenation level-dependent (BOLD) signal during a cued choice reaction time task. Orienting precues were either correct (valid) or incorrect (invalid) with respect to the subsequent move cue. The effects of real and sham rTMS were compared for each site of stimulation. Invalid trials showed a significant increase in response times and increases in the BOLD signal in right frontal and parietal regions when compared with valid trials. Conditioning left DLPFC with rTMS led to decreased BOLD signal during performance of this reorienting task in areas including left VLPFC and left IPS. Comparing invalid to valid trials after right DLPFC conditioning revealed decreased BOLD signal in right VLPFC. Data from the behavioral study showed that right DLPFC rTMS selectively increases response times in invalid trials. This effect was only present in the first 10 min after rTMS conditioning. No effect was found in either validly or invalidly cued trials with left DLPFC conditioning. These results suggest that 5Hz rTMS over right DLPFC exerts remote effects on the activity of areas that functionally interact with the DLPFC during attentional processes, particularly when the reorienting of attention is more demanding as in invalid trials. [ABSTRACT FROM AUTHOR]

To behave adaptively, an organism must balance the accurate maintenance of information stored in working memory with the ability to update that information when the context changes. This trade-off between fidelity and flexibility may depend upon the anticipated likelihood that updating will be necessary. To address the neurobiological basis of anticipatory optimization, we acquired functional magnetic resonance imaging data, while healthy human subjects performed a modified delayed-response task. This task used cues that predicted memory updating, with high or low probability, followed by a contingent updating or maintenance event. This enabled us to compare behavior and neuronal activity during conditions in which updating was anticipated with high and low probability, and measure responses to expected and unexpected memory updating. Based on the known role of dopamine in cognitive flexibility and working memory updating, we hypothesized that differences in anticipatory set would be manifest in the dopaminergic midbrain and striatum. Consistent with our predictions, we identified sustained activation in the dopaminergic midbrain and the striatum, associated with anticipations of high versus low updating probability. We also found that this anticipatory factor affected neural responses to subsequent updating processes, which suppressed, rather than elevated, midbrain and striatal activity. Our study addresses for the first time an important and hitherto understudied aspect of working memory.

The synchronous discharge of neuronal assemblies is thought to facilitate communication between areas within distributed networks in the human brain. This oscillatory activity is especially interesting, given the pathological modulation of specific frequencies in diseases affecting the motor system. Many studies investigating oscillatory activity have focused on same frequency, or linear, coupling between areas of a network. In this study, our aim was to establish a functional architecture in the human motor system responsible for induced responses as measured in normal subjects with magnetoencephalography. Specifically, we looked for evidence for additional nonlinear (between-frequency) coupling among neuronal sources and, in particular, whether nonlinearities were found predominantly in connections within areas (intrinsic), between areas (extrinsic) or both. We modeled the event-related modulation of spectral responses during a simple hand-grip using dynamic casual modeling. We compared models with and without nonlinear connections under conditions of symmetric and asymmetric interhemispheric connectivity. Bayesian model comparison suggested that the task-dependent motor network was asymmetric during right hand movements. Furthermore, it revealed very strong evidence for nonlinear coupling between sources in this distributed network, but interactions among frequencies within a source appeared linear in nature. Our results provide empirical evidence for nonlinear coupling among distributed neuronal sources in the motor system and that these play an important role in modulating spectral responses under normal conditions.