Directed functional connectivity of the default-mode-network of young and older healthy subjects.

Alterations in the default mode network (DMN) are associated with aging. We assessed age-dependent changes of DMN interactions and correlations with a battery of neuropsychological tests, to understand the differences of DMN directed connectivity between young and older subjects. Using a novel multivariate analysis method on resting-state functional MRI data from fifty young and thirty-one healthy older subjects, we calculated intra- and inter-DMN 4-nodes directed pathways. For the old subject group, we calculated the partial correlations of inter-DMN pathways with: psychomotor speed and working memory, executive function, language, long-term memory and visuospatial function. Pathways connecting the DMN with visual and limbic regions in older subjects engaged at BOLD low frequency and involved the dorsal posterior cingulate cortex (PCC), whereas in young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) cortex and the DMN, were SM efferent in the young subjects and SM afferent in the older subjects. Most DMN efferent pathways correlated with reduced speed and working memory. We suggest that the reduced sensorimotor efferent and the increased need to control such activities, cause a higher dependency on external versus internal cues thus suggesting how physical activity might slow aging.

Directed functional connectivity of the sensorimotor system in young and older individuals.

Introduction: Studies in the sensorimotor system of older versus young individuals have shown alterations in functional connectivity and organization. Our objective was to explore the implications of these differences in terms of local organizations, and to identify processes that correlate with neuropsychological parameters. Methods: Using a novel multivariate analysis method on resting-state functional MRI data obtained from 50 young and 31 older healthy individuals, we identified directed 4-node functional pathways within the sensorimotor system and examined their correlations with neuropsychological assessments. Results: In young individuals, the functional pathways were unidirectional, flowing from the primary motor and sensory cortices to higher motor and visual regions. In older individuals, the functional pathways were more complex. They originated either from the calcarine sulcus or the insula and passed through mutually coupled high-order motor areas before reaching the primary sensory and motor cortices. Additionally, the pathways in older individuals that resembled those found in young individuals exhibited a positive correlation with years of education. Discussion: The flow pattern of young individuals suggests efficient and fast information transfer. In contrast, the mutual coupling of high-order motor regions in older individuals suggests an inefficient and slow transfer, a less segregated and a more integrated organization. The differences in the number of sensorimotor pathways and of their directionality suggests reduced efferent degenerated pathways and increased afferent compensated pathways. Furthermore, the positive effect of years of education may be associated with the Cognitive Reserve Hypothesis, implying that cognitive reserve could be maintained through specific information transfer pathways.

Aberrant Intrinsic Brain Network Functional Connectivity During a Face-Matching Task in Women Diagnosed With Premenstrual Dysphoric Disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is characterized by affective, cognitive, and physical symptoms, suggesting alterations at the brain network level. Women with PMDD demonstrate aberrant discrimination of facial emotions during the luteal phase of the menstrual cycle and altered reactivity to emotional stimuli. However, previous studies assessing emotional task-related brain reactivity using region-of-interest or whole-brain analysis have reported conflicting findings. Therefore, we utilized both region-of-interest task-reactivity and seed-voxel functional connectivity (FC) approaches to test for differences in the default mode network, salience network, and central executive network between women with PMDD and control participants during an emotional-processing task that yields an optimal setup for investigating brain network changes in PMDD. METHODS: Twenty-four women with PMDD and 27 control participants were classified according to the Daily Record of Severity of Problems. Participants underwent functional magnetic resonance imaging scans while completing the emotional face-matching task during the midfollicular and late-luteal phases of their menstrual cycle. RESULTS: No significant between-group differences in brain reactivity were found using region-of-interest analysis. In the FC analysis, a main effect of diagnosis was found showing decreased default mode network connectivity, increased salience network connectivity, and decreased central executive network connectivity in women with PMDD compared with control participants. A significant interaction between menstrual cycle phase and diagnosis was found in the central executive network for right posterior parietal cortex and left inferior lateral occipital cortex connectivity. A post hoc analysis revealed stronger FC during the midfollicular than the late-luteal phase of PMDD. CONCLUSIONS: Aberrant FC in the 3 brain networks involved in PMDD may indicate vulnerability to experience affective and cognitive symptoms of the disorder.

Emotional states as distinct configurations of functional brain networks.

The conceptualization of emotional states as patterns of interactions between large-scale brain networks has recently gained support. Yet, few studies have directly examined the brain's network structure during emotional experiences. Here, we investigated the brain's functional network organization during experiences of sadness, amusement, and neutral states elicited by movies, in addition to a resting-state. We tested the effects of the experienced emotion on individual variability in the brain's functional connectome. Next, for each state, we defined a community structure of the brain and quantified its segregation and integration. We found that sadness, relative to amusement, was associated with higher modular integration and increased connectivity of cognitive control networks: the salience and fronto-parietal networks. Moreover, in both the functional connectome and the emotional report, the similarity between individuals was dependent on the sex. Our results suggest that the experience of emotion is linked to a reconfiguration of whole-brain distributed, not emotion-specific, functional networks and that the brain's topological structure carries information about the subjective emotional experience.

Asymmetry of the insula-sensorimotor circuit in Parkinson's disease.

Patients with Parkinson's disease (PD) experience motor and non-motor symptoms, suggesting alterations of the motor and/or limbic system or more probably of their communications. We hypothesized that the communication between the insula (part of the limbic system) and sensorimotor cortex in PD is altered and hemispheric asymmetric. Furthermore, that this asymmetry relates to non-motor symptoms, and specifically, that apathy-related asymmetry is unique to PD. To test these hypotheses, we used a novel multivariate time-frequency analysis method applied to resting-state functional magnetic resonance imaging (MRI) data of 28 controls and 25 participants with PD measured in their OFF medication state. The analysis infers directionality of coupling, that is, afferent or efferent, among four anatomical regions, thus defining directed pathways of information flow, which enables the extension of symmetry measures to include directionality. A major right asymmetry reduction of the dorsal-posterior insula efferent and a slight bilateral increase of insula afferent pathways were observed in participants with PD versus controls. Between-group pathways that correlated with mild cognitive impairments combined the central-executive and default-mode networks through the right insula. Apathy-correlated pathways of the posterior insula in participants with PD versus controls exhibited reduced right efferent and increased left afferent. Because apathy scores were comparable between the groups and effects of the other motor and non-motor symptoms were statistically removed by the analysis, the differences in apathy-correlated pathways were suggested as unique to PD. These pathways could be predictors in the pre-symptomatic phase in patients with apathy.

Altered sensorimotor fMRI directed connectivity in Parkinson's disease patients.

Dopamine depletion in the axons of Parkinson's disease (PD) patients precedes depletion in cell bodies thus proposing that macroscopic connectivity can be used to understand disease mechanism. A novel multivariate functional connectivity analysis, based on high order coherence among four fMRI BOLD signals was applied on resting-state fMRI data of controls and PD patients (OFF and ON medication states) and unidirectional multiple-region pathways in the sensorimotor system were identified. Pathways were classified as "preserved" (unaffected by the disease), "damaged" (not observed in patients) and "corrected" (observed in controls and in PD-ON state). The majority of all pathways were feedforward, most of them with the pattern "S1→M1→SMA." Of these pathways, 67% were "damaged," 28% "preserved," and 5% "corrected." Prefrontal cortex (PFC) afferent and efferent pathways that corresponded to goal directed and habitual activities corresponded to recurrent circuits. Eighty-one percent of habitual afferent had internal cue (i.e., M1→S1→), of them 79% were "damaged" and the rest "preserved." All goal-directed afferent had external cue (i.e., S1→M1→) with third "damaged," third "preserved," and third "corrected." Corrected pathways were initiated in the dorsolateral PFC. Reduced connectivity of the SMA and PFC resulted from reduced sensorimotor afferent to these regions. Reduced sensorimotor internal cues to the PFC resulted with reduced habitual processes. Levodopa effects were for pathways that started in region reach with dopamine receptors. This methodology can enrich understudying of PD mechanisms in other (e.g., the default mode network) systems.

Trait-related changes in brain network topology in premenstrual dysphoric disorder.

The female predominance in the prevalence of depression is partially accounted by reactivity to hormonal fluctuations. Premenstrual dysphoric disorder (PMDD) is a reproductive subtype of depression characterized by cyclic emotional and somatic symptoms that recur before menstruation. Despite the growing understanding that most psychiatric disorders arise from dysfunctions in distributed brain circuits, the brain's functional connectome and its network properties of segregation and integration were not investigated in PMDD. To this end, we examined the brain's functional network organization in PMDD using graph theoretical analysis. 24 drug naïve women with PMDD and 27 controls without premenstrual symptoms underwent 2 resting-state fMRI scans, during the mid-follicular and late-luteal menstrual cycle phases. Functional connectivity MRI, graph theory metrics, and levels of sex hormones were computed during each menstrual phase. Altered network topology was found in PMDD across symptomatic and remitted stages in major graph metrics (characteristic path length, clustering coefficient, transitivity, local and global efficiency, centrality), indicating decreased functional network segregation and increased functional network integration. In addition, PMDD patients exhibited hypoconnectivity of the anterior temporal lobe and hyperconnectivity of the basal ganglia and thalamus, across menstrual phases. Furthermore, the relationship between difficulties in emotion regulation and PMDD was mediated by specific patterns of functional connectivity, including connections of the striatum, thalamus, and prefrontal cortex. The shifts in the functional connectome and its topology in PMDD may suggest trait vulnerability markers of the disorder.

Impact of dopamine and cognitive impairment on neural reactivity to facial emotion in Parkinson's disease.

Emotional and cognitive impairments in Parkinson's disease (PD) are prevalent, hamper interpersonal relations and reduce quality of life. It is however unclear to what extent these domains interplay in PD-related deficits and how they are influenced by dopaminergic availability. This study examined the effect of cognitive impairment and dopaminergic medication on neural and behavioral mechanisms of facial emotion recognition in PD patients. PD patients on and off dopaminergic medication and matched healthy controls underwent an emotional face matching task during functional MRI. In addition, a comprehensive neuropsychological evaluation of cognitive function was conducted. Increased BOLD response to emotional faces was found in the visual cortex of PD patients relative to controls irrespective of cognitive function and medication status. Administration of dopaminergic medication in PD patients resulted in restored behavioral accuracy for emotional faces relative to controls and decreased retrosplenial cortex BOLD response to emotion relative to off-medication state. Furthermore, cognitive impairment in PD patients was associated with reduced behavioral accuracy for non-emotional stimuli and predicted BOLD response to emotion in the anterior and posterior cingulate cortices, depending on medication status. Findings of aberrant visual and retrosplenial BOLD response to emotion are suggested to stem from altered attentional and/or emotion-driven modulation from subcortical and higher cortical regions. Our results indicate neural disruptions and behavioral deficits in emotion processing in PD patients that are dependent on dopaminergic availability and independent of cognitive function. Our findings highlight the importance of dopaminergic treatment not only for the motor symptoms but also the emotional disturbances in PD.

Bidirectional signal exchanges and their mechanisms during joint attention interaction - A hyperscanning fMRI study.

Social interactions are essential to our daily life. We tested the hypothesis that social interactions during joint attention (JA) require bidirectional communication, each with a different mechanism. We used a novel multivariate functional connectivity analysis, which enables obtaining directed pathways between four regions at each time-frequency point, with hyper-scanning MRI data of real-time JA interaction. Constructing multiple "4-regional directed pathways" and counting the number of times, regions engaged in feedforward or feedback processes in the 'sender' or the 'receiver brains, we obtained the following. (1) There were more regions in feedforward than in feedback processes (125 versus 99). (2) The right hemisphere was more involved in feedforward (74 versus 33), while the left hemisphere in feedback (66 versus 51). (3) The dmPFC was more engaged in feedforward (73 versus 44) while the TPJ in both (49 versus 45). (4) The dmPFC was more involved in the sending processes (i.e. initiation of feedforward and feedback) while the TPJ in the receiving processes. (5) JA interaction was involved with high MRI frequencies (0.04-0.1 Hz), while continues interactions by low MRI frequencies (0.01-0.04 Hz). (6) Initiation and responding to JA (i.e. IJA and RJA) evolved with composite neural systems: similar systems for pathways that included the dmPFC, vmPFC and the STS, and different systems for pathways that included the TPJ, vmPFC, PCC and the STS. These findings have important consequences in the basic understanding of social interaction and could help in diagnose and follow-up of social impairments.

Sex differences during emotion processing are dependent on the menstrual cycle phase.

Sex differences in the neural processing of emotion are of special interest considering that mood and anxiety disorders predominant in females. However, these sex-related differences were typically studied without considering the hormonal status of female subjects, although emotion processing in the brain was shown to differ between phases of the menstrual cycle. In this functional MRI study, we demonstrated the influence of the menstrual cycle phase on sex differences in brain activity and functional connectivity during negative and positive emotions, using two different paradigms: emotion perception and emotion experience. Twenty naturally cycling healthy women without premenstrual symptoms were scanned twice: during the mid-follicular and late-luteal menstrual phases, and compared to a matched group of twenty healthy men. During negative emotion perception, men showed increased neural activity in the right hippocampal formation relative to women in the mid-follicular phase, and increased activity in the right cerebellum relative to women in the late-luteal phase. During experience of amusement, reduced putamen-ventrolateral prefrontal cortex and putamen-dorsomedial prefrontal cortex functional connectivity were observed for women in the late-luteal phase relative to men and associated with levels of sex hormones. These neural and hormonal findings were complemented by behavioral reports of reduced amusement and increased sadness in late-luteal women. Our results demonstrate menstrual phase-dependent sex differences in emotion perception and experience and may suggest a biological tendency for a deficient experience of pleasure and reward during the late-luteal phase. These findings may further shed light on the underlying pathophysiology of premenstrual dysphoric disorder.

Characterizing directed functional pathways in the visual system by multivariate nonlinear coherence of fMRI data.

A multivariate measure of directed functional connectivity is used with resting-state fMRI data of 40 healthy subjects to identify directed pathways of signal progression in the human visual system. The method utilizes 4-nodes networks of mutual interacted BOLD signals to obtains their temporal hierarchy and functional connectivity. Patterns of signal progression were defined at frequency windows by appealing to a hierarchy based upon phase differences, and their significance was assessed by permutation testing. Assuming consistent phase relationship between neuronal and fMRI signals and unidirectional coupling, we were able to characterize directed pathways in the visual system. The ventral and dorsal systems were found to have different functional organizations. The dorsal system, particularly of the left hemisphere, had numerous feedforward pathways connecting the striate and extrastriate cortices with non-visual regions. The ventral system had fewer pathways primarily of two types: (1) feedback pathways initiated in the fusiform gyrus that were either confined to the striate and the extrastriate cortices or connected to the temporal cortex, (2) feedforward pathways initiated in V2, excluded the striate cortex, and connected to non-visual regions. The multivariate measure demonstrated higher specificity than bivariate (pairwise) measure. The analysis can be applied to other neuroimaging and electrophysiological data.

Separate neural representations of depression, anxiety and apathy in Parkinson's disease.

Depression, anxiety and apathy are distinct neuropsychiatric symptoms that highly overlap in Parkinson's disease (PD). It remains unknown whether each symptom is uniquely associated with a functional network dysfunction. Here, we examined whether individual differences in each neuropsychiatric symptom predict functional connectivity patterns in PD patients while controlling for all other symptoms and motor function. Resting-state functional connectivity MRI were acquired from 27 PD patients and 29 healthy controls. Widespread reduced functional connectivity was identified in PD patients and explained by either the neuropsychiatric or motor symptoms. Depression in PD predicted increased functional connectivity between the orbitofrontal, hippocampal complex, cingulate, caudate and thalamus. Apathy in PD predicted decreased caudate-thalamus and orbitofrontal-parahippocampal connectivity. Anxiety in PD predicted three distinct types of functional connectivity not described before: (i) increased limbic-orbitofrontal cortex; (ii) decreased limbic-dorsolateral prefrontal cortex and orbitofrontal-dorsolateral prefrontal cortices and (iii) decreased sensorimotor-orbitofrontal cortices. The first two types of functional connectivity suggest less voluntary and more automatic emotion regulation. The last type is argued to be specific to PD and reflect an impaired ability of the orbitofrontal cortex to guide goal-directed motor actions in anxious PD patients.

Frequency-phase analysis of resting-state functional MRI.

We describe an analysis method that characterizes the correlation between coupled time-series functions by their frequencies and phases. It provides a unified framework for simultaneous assessment of frequency and latency of a coupled time-series. The analysis is demonstrated on resting-state functional MRI data of 34 healthy subjects. Interactions between fMRI time-series are represented by cross-correlation (with time-lag) functions. A general linear model is used on the cross-correlation functions to obtain the frequencies and phase-differences of the original time-series. We define symmetric, antisymmetric and asymmetric cross-correlation functions that correspond respectively to in-phase, 90° out-of-phase and any phase difference between a pair of time-series, where the last two were never introduced before. Seed maps of the motor system were calculated to demonstrate the strength and capabilities of the analysis. Unique types of functional connections, their dominant frequencies and phase-differences have been identified. The relation between phase-differences and time-delays is shown. The phase-differences are speculated to inform transfer-time and/or to reflect a difference in the hemodynamic response between regions that are modulated by neurotransmitters concentration. The analysis can be used with any coupled functions in many disciplines including electrophysiology, EEG or MEG in neuroscience.

Multiple-region directed functional connectivity based on phase delays.

Network analysis is increasingly advancing the field of neuroimaging. Neural networks are generally constructed from pairwise interactions with an assumption of linear relations between them. Here, a high-order statistical framework to calculate directed functional connectivity among multiple regions, using wavelet analysis and spectral coherence has been presented. The mathematical expression for 4 regions was derived and used to characterize a quartet of regions as a linear, combined (nonlinear), or disconnected network. Phase delays between regions were used to obtain network's temporal hierarchy and directionality. The validity of the mathematical derivation along with the effects of coupling strength and noise on its outcomes were studied by computer simulations of the Kuramoto model. The simulations demonstrated correct directionality for a large range of coupling strength and low sensitivity to Gaussian noise compared with pairwise coherences. The analysis was applied to resting-state fMRI data of 40 healthy young subjects to characterize the ventral visual system, motor system and default mode network (DMN). It was shown that the ventral visual system was predominantly composed of linear networks while the motor system and the DMN were composed of combined (nonlinear) networks. The ventral visual system exhibits its known temporal hierarchy, the motor system exhibits center ↔ out hierarchy and the DMN has dorsal ↔ ventral and anterior ↔ posterior organizations. The analysis can be applied in different disciplines such as seismology, or economy and in a variety of brain data including stimulus-driven fMRI, electrophysiology, EEG, and MEG, thus open new horizons in brain research. Hum Brain Mapp 38:1374-1386, 2017. © 2016 Wiley Periodicals, Inc.

Emotional regulation difficulties and premenstrual symptoms among Israeli students.

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) reported to affect 3-8 % of women of reproductive age and resulting in marked emotional and occupational impairment. Despite its prevalence, the etiology of PMDD is largely unknown, and patients remain mostly undiagnosed and poorly treated. It has been suggested that PMDD is a manifestation of underlying depressive disorder which is associated with the inability to regulate emotions in an adaptive manner. Therefore, we hypothesized that women with PMDD would exhibit increased difficulty with emotional regulation. A total of 648 female Israeli college students were assessed by the Premenstrual Symptoms Screening Tool (PSST) and the Difficulties in Emotion Regulation Scale (DERS). Of these women, 166 (25.6 %) met the criteria for PMS. Sixty-four (9.9 %) suffered from PMDD. More emotion regulation deficits were observed in the PMDD and PMS groups compared to the control group. Furthermore, there were more emotional regulation deficits among the predominantly psychological and mixed symptom subtype compared to the predominantly physical symptom subtype group. This is the first study to report an association between emotional dysregulation and PMDD. These findings may lead to development of more individually tailored treatment protocols focused on improving emotional regulation techniques.

Understanding alterations in serotonin connectivity in a rat model of depression within the monoamine-deficiency and the hippocampal-neurogenesis frameworks.

The monoamine-deficiency and the hippocampal-neurogenesis hypotheses of depression propose that alterations in the serotonin system and of hippocampal functionality are critical in the pathogenesis of depression. We measured the alterations in the connectivity level of the raphe nucleus in the chronic mild stress (CMS) rat model of depression using the manganese enhanced MRI method (MEMRI). Manganese ions were injected into the median raphe and their anterograde intracellular propagation was followed. Depression-like behavior was demonstrated using the sucrose preference tests. We show that the raphe's connectivity is differentially altered through chronic stress. In line with the monoamine-deficiency hypothesis, the connectivity of the raphe with the basal ganglia (BG) output nuclei, the hippocampus, the habenula and the entorhinal and insular cortices was reduced in CMS rats, suggesting an overall reduction in raphe excitability. Connectivity reductions were predominantly found in the right hemisphere, strengthening previous evidence pointing at a-symmetric hemispheric involvement in depression. Despite the general reduction in raphe connectivity, enhanced connectivity was found between the raphe and the septum, suggesting that alterations are connection-specific. On the basis of our results - while yet equivocal - we further discuss the possible coupling between the serotonergic and dopaminergic systems and two distinct mechanisms (direct and indirect) in which alterations in raphe connectivity may affect hippocampal dysfunction in chronic stress, thus linking the monoamine-deficiency and the hippocampal-neurogenesis hypotheses.

Maximizing negative correlations in resting-state functional connectivity MRI by time-lag.

This paper aims to better understand the physiological meaning of negative correlations in resting state functional connectivity MRI (r-fcMRI). The correlations between anatomy-based brain regions of 18 healthy humans were calculated and analyzed with and without a correction for global signal and with and without spatial smoothing. In addition, correlations between anatomy-based brain regions of 18 naïve anesthetized rats were calculated and compared to the human data. T-statistics were used to differentiate between positive and negative connections. The application of spatial smoothing and global signal correction increased the number of significant positive connections but their effect on negative connections was complex. Positive connections were mainly observed between cortical structures while most negative connections were observed between cortical and non-cortical structures with almost no negative connections between non-cortical structures. In both human and rats, negative connections were never observed between bilateral homologous regions. The main difference between positive and negative connections in both the human and rat data was that positive connections became less significant with time-lags, while negative connections became more significant with time-lag. This effect was evident in all four types of analyses (with and without global signal correction and spatial smoothing) but was most significant in the analysis with no correction for the global signal. We hypothesize that the valence of r-fcMRI connectivity reflects the relative contributions of cerebral blood volume (CBV) and flow (CBF) to the BOLD signal and that these relative contributions are location-specific. If cerebral circulation is primarily regulated by CBF in one region and by CBV in another, a functional connection between these regions can manifest as an r-fcMRI negative and time-delayed correlation. Similarly, negative correlations could result from spatially inhomogeneous responses of rCBV or rCBF alone. Consequently, neuronal regulation of brain circulation may be deduced from the valence of r-fcMRI connectivity.

Exemplar selectivity reflects perceptual similarities in the human fusiform cortex.

While brain imaging studies emphasized the category selectivity of face-related areas, the underlying mechanisms of our remarkable ability to discriminate between different faces are less understood. Here, we recorded intracranial local field potentials from face-related areas in patients presented with images of faces and objects. A highly significant exemplar tuning within the category of faces was observed in high-Gamma (80-150 Hz) responses. The robustness of this effect was supported by single-trial decoding of face exemplars using a minimal (n = 5) training set. Importantly, exemplar tuning reflected the psychophysical distance between faces but not their low-level features. Our results reveal a neuronal substrate for the establishment of perceptual distance among faces in the human brain. They further imply that face neurons are anatomically grouped according to well-defined functional principles, such as perceptual similarity.