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Abstract Bimanual coordination is impaired in Parkinson's disease (PD), affecting patients' quality of life. Besides dysfunction of the basal ganglia network, alterations of cortical oscillatory coupling, particularly between prefrontal and (pre-)motoric areas, are thought to underlie this impairment. Here, we studied 16 PD patients OFF and ON medication and age-matched healthy controls recording high-resolution electroencephalography (EEG) during performance of spatially coupled and uncoupled bimanual finger movements. Dynamic causal modeling (DCM) for induced responses was used to infer task-induced effective connectivity within a network comprising bilateral prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1). Performing spatially coupled movements, excitatory left-hemispheric PFC to lPM coupling was significantly stronger in controls compared to unmedicated PD patients. Levodopa-induced enhancement of this connection correlated with increased movement accuracy. During performance of spatially uncoupled movements, PD patients OFF medication exhibited inhibitory connectivity from left PFC to SMA. Levodopa intake diminished these inhibitory influences and restored excitatory PFC to lPM coupling. This restoration, however, did not improve motor function. Concluding, our results indicate that lateralization of prefrontal to premotor connectivity in PD can be augmented by levodopa substitution and is of compensatory nature up to a certain extent of complexity. Highlights • Bimanual coordination is impaired in Parkinson's Disease (PD). • In PD, β-activity in left primary motor cortex (M1) induces γ-activity in right M1. • β-γ-coupling between primary motor cortices is associated with poor motor performance. • Levodopa increases left prefrontal to lateral premotor coupling in PD. • This enhancement relates to improved motor control up to a certain complexity level. [ABSTRACT FROM AUTHOR]

Abstract Autobiographical memories (AMs) are often colored by emotions experienced during an event or those arising following further appraisals. However, how affective components of memories affect the brain-wide network recruited during the recollection of AMs remains largely unknown. Here, we examined effective connectivity during the elaboration of AMs - when retrieved episodic details are integrated to form a vivid construct - in the network composed by ventromedial prefrontal cortex (vmPFC), hippocampus and amygdala, three key regions associated with memory and affective processes. Functional MRI data was collected while volunteers recollected personal events of different types of valence and emotional intensity. Using dynamic causal modeling, we characterized the connections within the triadic network, and examined how they were modulated by the emotional intensity experienced during an event, and the valence of the affect evoked when recollecting the associated memory. Results primarily indicated the existence of a vmPFC to hippocampus effective connectivity during memory elaboration. Furthermore, the strength of the connectivity increased when participants relived memories of highly emotionally arousing events or that elicited stronger positive affect. These results indicate that the vmPFC drives hippocampal activity during memory elaboration, and plays a critical role in shaping affective responses that emanate from AMs. Highlights • Volunteers recollected autobiographical memories (AMs) of different emotional intensities and valence types in the scanner. • We used dynamic causal modeling to assess effective connectivity in the vmPFC-hippocampus-amygdala network. • Results indicated that the vmPFC is a driver of hippocampal activity during the elaboration of AMs. • Moreover, the strength of the vmPFC to hippocampus connectivity increased during the elaboration of emotional AMs. • These results show that the vmPFC plays an important role during the elaboration of AMs, in particular, emotional AMs. [ABSTRACT FROM AUTHOR]

Highlights • The causal connectivity among evolutionary different regions of the cortex is reported. • Resting-state data show a strong rightward bias in the regions’ interactions. • There is also a top-down bias with the only exception of the right hippocampus. • The right ventrolateral cortex seems to be a prominent source of causal influences. • Several levels of brain cognitive-affective organization are implied by these results. Abstract By taking into account Bruce Bridgeman's interest in an evolutionary framing of human cognition, we examine effective (cause-and-effect) connectivity among cortical structures related to different parts of the triune phylogenetic stratification: archicortex, paleocortex and neocortex. Using resting-state functional magnetic resonance imaging data from 25 healthy subjects and spectral Dynamic Causal Modeling, we report interactions among 10 symmetrical left and right brain areas. Our results testify to general rightward and top-down biases in excitatory interactions of these structures during resting state, when self-related contemplation prevails over more objectified conceptual thinking. The right hippocampus is the only structure that shows bottom-up excitatory influences extending to the frontopolar cortex. The right ventrolateral cortex also plays a prominent role as it interacts with the majority of nodes within and between evolutionary distinct brain subdivisions. These results suggest the existence of several levels of cognitive-affective organization in the human brain and their profound lateralization. [ABSTRACT FROM AUTHOR]

• Age-, reading-level-matched and developmental connectivity analyses in children. • Effective connectivity was assessed in children with and without dyslexia. • Connectivity was also assessed in development of children with and without dyslexia. • Feedforward connections from the visual word form area (VWFA) increased with age. • Connectivity from the inferior parietal lobule to the VWFA was altered in dyslexia. Altered brain connectivity between regions of the reading network has been associated with reading difficulties. However, it remains unclear whether connectivity differences between children with dyslexia (DYS) and those with typical reading skills (TR) are specific to reading impairments or to reading experience. In this functional MRI study, 132 children (M = 10.06 y, SD = 1.46) performed a phonological lexical decision task. We aimed to disentangle (1) disorder-specific from (2) experience-related differences in effective connectivity and to (3) characterize the development of DYS and TR. We applied dynamic causal modeling to age-matched (n dys = 25, n TR = 35) and reading-level-matched (n dys = 25, n TR = 22) groups. Developmental effects were assessed in beginning and advanced readers (TR: n beg = 48, n adv = 35, DYS: n beg = 24, n adv = 25). We show that altered feedback connectivity between the inferior parietal lobule and the visual word form area (VWFA) during print processing can be specifically attributed to reading impairments, because these alterations were found in DYS compared to both the age-matched and reading-level-matched TR. In contrast, feedforward connectivity from the VWFA to parietal and frontal regions characterized experience in TR and increased with age and reading skill. These directed connectivity findings pinpoint disorder-specific and experience-dependent alterations in the brain's reading network. [ABSTRACT FROM AUTHOR]

• Repeated face images cause decreased fMRI signal in early visual cortex (EVC), occipital face area (OFA), and fusiform face area (FFA). • The repetition suppression (RS) effect can be explained by the modulation of connectivity between EVC and OFA/FFA. • The between-region modulation supports synchronization and predictive coding theories of RS. • Face perception modulates nearly all within- and between-region connectivity, including direct connections from EVC to FFA. Stimulus repetition normally causes reduced neural activity in brain regions that process that stimulus. Some theories claim that this "repetition suppression" reflects local mechanisms such as neuronal fatigue or sharpening within a region, whereas other theories claim that it results from changed connectivity between regions, following changes in synchrony or top-down predictions. In this study, we applied dynamic causal modeling (DCM) on a public fMRI dataset involving repeated presentations of faces and scrambled faces to test whether repetition affected local (self-connections) and/or between-region connectivity in left and right early visual cortex (EVC), occipital face area (OFA) and fusiform face area (FFA). Face "perception" (faces versus scrambled faces) modulated nearly all connections, within and between regions, including direct connections from EVC to FFA, supporting a non-hierarchical view of face processing. Face "recognition" (familiar versus unfamiliar faces) modulated connections between EVC and OFA/FFA, particularly in the left hemisphere. Most importantly, immediate and delayed repetition of stimuli were also best captured by modulations of connections between EVC and OFA/FFA, but not self-connections of OFA/FFA, consistent with synchronization or predictive coding theories, though also possibly reflecting local mechanisms like synaptic depression. [ABSTRACT FROM AUTHOR]

The functional MRI (fMRI) signal is an indirect measure of neuronal activity. In order to deconvolve the neuronal activity from the experimental fMRI data, biophysical generative models have been proposed describing the link between neuronal activity and the cerebral blood flow (the neurovascular coupling), and further the hemodynamic response and the BOLD signal equation. These generative models have been employed both for single brain area deconvolution and to infer effective connectivity in networks of multiple brain areas. In the current paper, we introduce a new fMRI model inspired by experimental observations about the physiological underpinnings of the BOLD signal and compare it with the generative models currently used in dynamic causal modeling (DCM), a widely used framework to study effective connectivity in the brain. We consider three fundamental aspects of such generative models for fMRI: (i) an adaptive two-state neuronal model that accounts for a wide repertoire of neuronal responses during and after stimulation; (ii) feedforward neurovascular coupling that links neuronal activity to blood flow; and (iii) a balloon model that can account for vascular uncoupling between the blood flow and the blood volume. Finally, we adjust the parameterization of the BOLD signal equation for different magnetic field strengths. This paper focuses on the form, motivation and phenomenology of DCMs for fMRI and the characteristics of the various models are demonstrated using simulations. These simulations emphasize a more accurate modeling of the transient BOLD responses — such as adaptive decreases to sustained inputs during stimulation and the post-stimulus undershoot. In addition, we demonstrate using experimental data that it is necessary to take into account both neuronal and vascular transients to accurately model the signal dynamics of fMRI data. By refining the models of the transient responses, we provide a more informed perspective on the underlying neuronal process and offer new ways of inferring changes in local neuronal activity and effective connectivity from fMRI. [ABSTRACT FROM AUTHOR]

Reading is a complex process involving neural networks in which connections may be influenced by task demands and other factors. We employed functional magnetic resonance imaging and dynamic causal modeling to examine age-related influences on left-hemispheric kanji reading networks. During a homophone judgment task, activation in the middle frontal gyrus, and dorsal and ventral inferior frontal gyri were identified, representing areas involved in orthographic, phonological, and semantic processing, respectively. The young adults showed a preference for a semantically-mediated pathway from orthographic inputs to the retrieval of phonological representations, whereas the elderly preferred a direct connection from orthographic inputs to phonological lexicons prior to the activation of semantic representations. These sequential pathways are in line with the lexical semantic and non-semantic routes in the dual-route cascaded model. The shift in reading pathways accompanied by slowed reaction time for the elderly might suggest age-related declines in the efficiency of network connectivity. [ABSTRACT FROM AUTHOR]

Abstract: The standard account of motor control considers descending outputs from primary motor cortex (M1) as motor commands and efference copy. This account has been challenged recently by an alternative formulation in terms of active inference: M1 is considered as part of a sensorimotor hierarchy providing top–down proprioceptive predictions. The key difference between these accounts is that predictions are sensitive to the current proprioceptive context, whereas efference copy is not. Using functional electric stimulation to experimentally manipulate proprioception during voluntary movement in healthy human subjects, we assessed the evidence for context sensitive output from M1. Dynamic causal modeling of functional magnetic resonance imaging responses showed that FES altered proprioception increased the influence of M1 on primary somatosensory cortex (S1). These results disambiguate competing accounts of motor control, provide some insight into the synaptic mechanisms of sensory attenuation and may speak to potential mechanisms of action of FES in promoting motor learning in neurorehabilitation. [Copyright &y& Elsevier]

Abstract: Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG–functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that the FRN originates from the dACC. Furthermore, we clarified the functional role of the FRN, and determined the role of the dACC within the RPE network. These findings should enable us to study the processing of surprise and adjustment signals in the dACC in healthy and also in psychiatric patients. [Copyright &y& Elsevier]

Abstract: Neurofeedback based on real-time fMRI is an emerging technique that can be used to train voluntary control of brain activity. Such brain training has been shown to lead to behavioral effects that are specific to the functional role of the targeted brain area. However, real-time fMRI-based neurofeedback so far was limited to mainly training localized brain activity within a region of interest. Here, we overcome this limitation by presenting near real-time dynamic causal modeling in order to provide feedback information based on connectivity between brain areas rather than activity within a single brain area. Using a visual–spatial attention paradigm, we show that participants can voluntarily control a feedback signal that is based on the Bayesian model comparison between two predefined model alternatives, i.e. the connectivity between left visual cortex and left parietal cortex vs. the connectivity between right visual cortex and right parietal cortex. Our new approach thus allows for training voluntary control over specific functional brain networks. Because most mental functions and most neurological disorders are associated with network activity rather than with activity in a single brain region, this novel approach is an important methodological innovation in order to more directly target functionally relevant brain networks. [Copyright &y& Elsevier]

Abstract: Sensitivity to location and frequency of tactile stimuli is a characterizing feature of human primary (S1), and secondary (S2) somatosensory cortices. Recent evidence suggests that S1 is predominantly receptive to stimulus location, while S2 is attuned to stimulus frequency. Although it is well established in humans that tactile frequency information is relayed serially from S1 to S2, a recent study, using functional magnetic resonance imaging (fMRI) in combination with dynamic causal modeling (DCM), suggested that somatosensory inputs are processed in parallel in S1 and S2. In the present fMRI/DCM study, we revisited this controversy and investigated the specialization of the human somatosensory cortical areas with regard to tactile stimulus representations, as well as their effective connectivity. During brain imaging, 14 participants performed a somatosensory discrimination task on vibrotactile stimuli. Importantly, the model space for DCM was chosen to allow for direct inference on the question of interest by systematically varying the information transmission from pure parallel to pure serial implementations. Bayesian model comparison on the level of model families strongly favors a serial, instead of a parallel processing route for tactile stimulus information along the somatosensory pathway. Our fMRI/DCM data thus support previous suggestions of a sequential information transmission from S1 to S2 in humans. [Copyright &y& Elsevier]

Abstract: Adaptive behavior requires choosing effectively between options involving risks and potential rewards. Existing studies implicate lateral and medial prefrontal areas, striatum, insula, amygdala and parietal regions in specific aspects of decision-making. However, limited attention is given to how brain networks encode economic parameters in patterns of inter-regional interactions. Here, healthy participants underwent functional MRI while evaluating “mixed” gambles presenting potential gains, losses and associated outcome probabilities. Connectivity graphs were constructed from analyses of psychophysiological interactions across a comprehensive atlas of brain regions. Expected value correlated positively with activity within medial prefrontal and occipital cortices, and modulated effective connectivity across a network that extended substantially beyond these nodes. Value-sensitive effective connections were found to be arranged as a unitary, small world network in which medial and anterior–lateral prefrontal areas featured as hubs, characterized by dense connectivity and high shortest-path centrality. Further analyses revealed that the observed effective connectivity effects were more pertinent to dichotomous gain/loss comparisons than to continuous value determination. Factoring expected value into its constituent components, potential loss modulated connectivity across a subset of the value-sensitive network, whereas potential gain and outcome probability were not significantly embodied in functional interactions. Regional response non-linearity was excluded as an artifactual basis to the observed effects, and directionality inferences were confirmed by comparison of dynamic causal models. Our findings extend current literature demonstrating that the representation of value is dependent on distributed processing taking across a widespread network which feeds information into a limited set of integrative prefrontal nodes. This study also has more general paradigmatic implications for neuroeconomics, demonstrating the value of explicit modeling of inter-regional interactions for understanding the neural substrates of decisional processes. [Copyright &y& Elsevier]

Abstract: A remarkable act of memory entails binding different forms of information. We focus on the timeless question of how the bound engram is accessed such that its component features—item and context—are extracted. To shed light on this question, we investigate the dynamics between brain structures that together mediate the binding and extraction of item and context. Converging evidence has implicated the Parahippocampal cortex (PHc) in contextual processing, the Perirhinal cortex (PRc) in item processing, and the hippocampus in item-context binding. Effective connectivity analysis was conducted on fMRI data gathered during retrieval on tests that differ with regard to the to-be-extracted information. Results revealed that recall is initiated by context-related PHc activity, followed by hippocampal item-context engram activation, and completed with retrieval of the study-item by the PRc. The reverse path was found for recognition. We thus provide novel evidence for dissociative patterns of item-context unbinding during retrieval. [Copyright &y& Elsevier]

Abstract: Neural oscillations are thought to underlie coupling of spatially remote neurons and gating of information within the human sensorimotor system. Here we tested the hypothesis that different unimanual motor tasks are specifically associated with distinct patterns of oscillatory coupling in human sensorimotor cortical areas. In 13 healthy, right-handed subjects, we recorded task-induced neural activity with 122-channel electroencephalography (EEG) while subjects performed fast self-paced extension–flexion movements with the right index finger and an isometric contraction of the right forearm. Task-related modulations of inter-regional coupling within a core motor network comprising the left primary motor cortex (M1), lateral premotor cortex (lPM) and supplementary motor area (SMA) were then modeled using dynamic causal modeling (DCM). A network model postulating coupling both within and across frequencies best captured observed spectral responses according to Bayesian model selection. DCM revealed dominant coupling within the β-band (13–30Hz) between M1 and SMA during isometric contraction of the forearm, whereas fast repetitive finger movements were characterized by strong coupling within the γ-band (31–48Hz) and between the θ- (4–7Hz) and the γ-band. This coupling pattern was mainly expressed in connections from lPM to SMA and from lPM to M1. We infer that human manual motor control involves task-specific modulation of inter-regional oscillatory coupling both within and across distinct frequency bands. The results highlight the potential of DCM to characterize context-specific changes in coupling within functional brain networks. [Copyright &y& Elsevier]

Abstract: A leftward bias is well known in humans and animals, and commonly related to the right hemisphere dominance for spatial attention. Our previous fMRI study suggested that this bias is mediated by faster conduction from the right to left parietal cortices, than the reverse (Siman-Tov et al., 2007). However, the limited temporal resolution of fMRI and evidence on the critical involvement of sub-cortical regions in orienting of spatial attention suggested further investigation of the leftward bias using multi-scale measurement. In this simultaneous EEG–fMRI study, healthy participants were presented with face pictures in either the right or left visual fields while performing a central fixation task. Temporo-occipital event related potentials, time-locked to the stimulus onset, showed an association between faster conduction from the right to the left hemisphere and higher fMRI activation in the left pulvinar nucleus following left visual field stimulation. This combined-modal finding provides original evidence of the involvement of sub-cortical central attention-related regions in the leftward bias. This assertion was further strengthened by a DCM analysis designated at cortical (i.e., inferior parietal sulcus; IPS) and sub-cortical (pulvinar nucleus) attention-related nodes that revealed: 1. Stronger inter-hemispheric connections from the right to left than vice versa, already at the pulvinar level. 2. Stronger connections within the right than the left hemisphere, from the pulvinar to the IPS. This multi-level neural superiority can guide future efforts in alleviating attention deficits by focusing on improving network connectivity. [ABSTRACT FROM AUTHOR]

Abstract: Using Dynamic Causal Modeling (DCM) and functional magnetic resonance imaging (fMRI), we examined effective connectivity between three left hemisphere brain regions (inferior frontal gyrus, inferior parietal lobule, fusiform gyrus) and bilateral medial frontal gyrus in 12 children with reading difficulties (M age=12.4, range: 8.11–14.10) and 12 control children (M age=12.3, range: 8.9–14.11) during rhyming judgments to visually presented words. More difficult conflicting trials either had similar orthography but different phonology (e.g. pint-mint) or similar phonology but different orthography (e.g. jazz-has). Easier non-conflicting trials had similar orthography and phonology (e.g. dime-lime) or different orthography and phonology (e.g. staff-gain). The modulatory effect from left fusiform gyrus to left inferior parietal lobule was stronger in controls than in children with reading difficulties only for conflicting trials. Modulatory effects from left fusiform gyrus and left inferior parietal lobule to left inferior frontal gyrus were stronger for conflicting trials than for non-conflicting trials only in control children but not in children with reading difficulties. Modulatory effects from left inferior frontal gyrus to inferior parietal lobule, from medial frontal gyrus to left inferior parietal lobule, and from left inferior parietal lobule to medial frontal gyrus were positively correlated with reading skill only in control children. These findings suggest that children with reading difficulties have deficits in integrating orthography and phonology utilizing left inferior parietal lobule, and in engaging phonological rehearsal/segmentation utilizing left inferior frontal gyrus possibly through the indirect pathway connecting posterior to anterior language processing regions, especially when the orthographic and phonological information is conflicting. [Copyright &y& Elsevier]

Although most activities of daily life require simultaneous coordination of both proximal and distal joints, motor preparation during such movements has not been well studied. Previous results for motor preparation have focused on hand/finger movements. For simple hand/finger movements, results have found that such movements typically evoke activity primarily in the contralateral motor cortices. However, increasing the complexity of the finger movements, such as during a distal sequential finger-pressing task, leads to additional recruitment of ipsilateral resources. It has been suggested that this involvement of the ipsilateral hemisphere is critical for temporal coordination of distal joints. The goal of the current study was to examine whether increasing simultaneous coordination of multiple joints (both proximal and distal) leads to a similar increase in coupling with ipsilateral sensorimotor cortices during motor preparation compared to a simple distal movement such as hand opening. To test this possibility, 12 healthy individuals participated in a high-density EEG experiment in which they performed either hand opening or simultaneous hand opening while lifting at the shoulder on a robotic device. We quantified within- and cross-frequency cortical coupling across the sensorimotor cortex for the two tasks using dynamic causal modeling. Both hand opening and simultaneous hand opening while lifting at the shoulder elicited coupling from secondary motor areas to primary motor cortex within the contralateral hemisphere exclusively in the beta band, as well as from ipsilateral primary motor cortex. However, increasing the task complexity by combining hand opening while lifting at the shoulder also led to an increase in cross-frequency coupling within the ipsilateral hemisphere including theta, beta, and gamma frequencies, as well as a change in the coupling frequency of the interhemispheric coupling between the primary motor and premotor cortices. These findings demonstrate that increasing the demand of joint coordination between proximal and distal joints leads to increases in communication with the ipsilateral hemisphere as previously observed in distal sequential finger tasks. • EEG was measured to analyze frequency coupling during motor preparation using DCM. • Complexity was manipulated to examine changes in coupling with ipsilateral cortex. • Addition of lifting led to increased coupling with ipsilateral sensorimotor cortex. • Coupling expanded from beta to theta and gamma bands with the addition of lifting. • Increasing the number of joints controlled increases reliance on ipsilateral cortex. [ABSTRACT FROM AUTHOR]

Here we present our answers to a critical commentary by Elkhonon Goldberg on our recent publication (Velichkovsky et al., 2018). To avoid discussions about novelty effects in the human brain activity and memory processes, we narrowed down this response to a reanalysis of our data along the lines proposed in the commentary, namely to comparing the effective links between symmetrical brain structures during the first and the last parts of a prolonged resting-state fMRI experiment. We also tested for sex differences in our results and checked for a stability of top-down interactions during the course of experiment because learning is often expressed in the weakening of upper level control over low-level mechanisms. Our attempts to test the predictions based on the novelty hypothesis has led to mixed results suggesting that the discovered right-to-left dominance of causal connections at rest may have a deeper origin than supposed in the Goldberg's commentary. [ABSTRACT FROM AUTHOR]