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.

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.

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.

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.

Spatial and object-based attention modulates broadband high-frequency responses across the human visual cortical hierarchy.

One of the puzzling aspects in the visual attention literature is the discrepancy between electrophysiological and fMRI findings: whereas fMRI studies reveal strong attentional modulation in the earliest visual areas, single-unit and local field potential studies yielded mixed results. In addition, it is not clear to what extent spatial attention effects extend from early to high-order visual areas. Here we addressed these issues using electrocorticography recordings in epileptic patients. The patients performed a task that allowed simultaneous manipulation of both spatial and object-based attention. They were presented with composite stimuli, consisting of a small object (face or house) superimposed on a large one, and in separate blocks, were instructed to attend one of the objects. We found a consistent increase in broadband high-frequency (30-90 Hz) power, but not in visual evoked potentials, associated with spatial attention starting with V1/V2 and continuing throughout the visual hierarchy. The magnitude of the attentional modulation was correlated with the spatial selectivity of each electrode and its distance from the occipital pole. Interestingly, the latency of the attentional modulation showed a significant decrease along the visual hierarchy. In addition, electrodes placed over high-order visual areas (e.g., fusiform gyrus) showed both effects of spatial and object-based attention. Overall, our results help to reconcile previous observations of discrepancy between fMRI and electrophysiology. They also imply that spatial attention effects can be found both in early and high-order visual cortical areas, in parallel with their stimulus tuning properties.

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.

In vivo free induction decay based 3D multivoxel longitudinal hadamard spectroscopic imaging in the human brain at 3 T.

We propose and demonstrate a full 3D longitudinal Hadamard spectroscopic imaging scheme for obtaining chemical shift maps, using adiabatic inversion pulses to encode the spins' positions. The approach offers several advantages over conventional Fourier-based encoding methods, including a localized point spread function; no aliasing, allowing for volumes of interest smaller than the object being imaged; an option for acquiring noncontiguous voxels; and inherent outer volume rejection. The latter allows for doing away with conventional outer volume suppression schemes, such as point resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM), and acquiring non-spin-echo spectra with short acquisition delay times, limited only by the excitation pulse's duration. This, in turn, minimizes T2 decay, maximizes the signal-to-noise ratio, and reduces J-coupling induced signal decay. Results are presented for both a phantom and an in vivo healthy volunteer at 3 T.

Non-spin-echo 3D transverse hadamard encoded proton spectroscopic imaging in the human brain.

A non-spin-echo multivoxel proton MR localization method based on three-dimensional transverse Hadamard spectroscopic imaging is introduced and demonstrated in a phantom and the human brain. Spatial encoding is achieved with three selective 90° radiofrequency pulses along perpendicular axes: The first two create a longitudinal ±M(Z) Hadamard order in the volume of interest. The third pulse spatially Hadamard-encodes the ±M(Z)s in the volume of interest in the third direction while bringing them to the transverse plane to be acquired immediately. The approaching-ideal point spread function of Hadamard encoding and very short acquisition delay yield signal-to-noise-ratios of 20 ± 8, 23 ± 9, and 31 ± 10 for choline, creatine, and N-acetylaspartate in the human brain at 1.5 T from 1 cm(3) voxels in 21 min. The advantages of transverse Hadamard spectroscopic imaging are that unlike gradient (Fourier) phase-encoding: (i) the volume of interest does not need to be smaller than the field of view to prevent aliasing; (ii) the number of partitions in each direction can be small, 8, 4, or even 2 at no cost in point spread function; (iii) the volume of interest does not have to be contiguous; and (iv) the voxel profile depends on the available B1 and pulse synthesis paradigm and can, therefore, at least theoretically, approach "ideal" "1" inside and "0" elsewhere.

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.

The habenula couples the dopaminergic and the serotonergic systems: application to depression in Parkinson's disease.

A high percentage of patients with Parkinson's disease suffer from depression in addition to their motor disabilities. However, the etiology of this depression and its relation to Parkinson's disease are unknown. Within the framework of the monoamine deficiency hypothesis of depression, we propose that the dopaminergic and serotonergic systems are coupled by the lateral habenula, and argue that altered basal ganglia activity leads to lateral habenula hyperactivity, which in turn down-regulates the serotonergic system, resulting in depressive symptoms in patients with Parkinson's disease. We tested this hypothesis using the unilateral 6-hydroxydopamine hemiparkinsonian rat model of Parkinson's disease. Behavior was assessed using the novelty suppressed feeding and forced swim tests, and the effective connectivity of the serotonergic system was estimated by manganese-enhanced magnetic resonance imaging of the raphe nuclei. The results show depression-like behaviors and reduced raphe connectivity with the lateral habenula, dentate gyrus of the hippocampus, thalamus and hypothalamus in the 6-hydroxydopamine rat groups. More importantly, partial restoration of the raphe connectivity and partial normalization of behavior were achieved by dopamine replacement therapy (apomorphine, 10 mg/kg, s.c. daily). Furthermore, nearly complete behavioral normalization was reached after a bilateral electric lesion of the lateral habenula. These findings provide a plausible link between Parkinson's disease and depression and open up avenues for new therapeutic interventions in depression and possibly in Parkinson's disease.

Hebrew brain vs. English brain: language modulates the way it is processed.

Is language processing universal? How do the specific properties of each language influence the way it is processed? In this study, we compare the neural correlates of morphological processing in Hebrew--a Semitic language with a rich and systematic morphology, to those revealed in English--an Indo-European language with a linear morphology. Using fMRI, we show that while in the bilingual brain both languages involve a common neural circuitry in processing morphological structure, this activation is significantly modulated by the different aspects of language. Whereas in Hebrew, morphological processing is independent of semantics, in English, morphological activation is clearly modulated by semantic overlap. These findings suggest that the processes involved in reading words are not universal, and therefore impose important constraints on current models of visual word recognition.

Imaging implicit morphological processing: evidence from Hebrew.

Is morphology a discrete and independent element of lexical structure or does it simply reflect a fine-tuning of the system to the statistical correlation that exists among orthographic and semantic properties of words? Hebrew provides a unique opportunity to examine morphological processing in the brain because of its rich morphological system. In an fMRI masked priming experiment, we investigated the neural networks involved in implicit morphological processing in Hebrew. In the lMFG and lIFG, activation was found to be significantly reduced when the primes were morphologically related to the targets. This effect was not influenced by the semantic transparency of the morphological prime, and was not found in the semantic or orthographic condition. Additional morphologically related decrease in activation was found in the lIPL, where activation was significantly modulated by semantic transparency. Our findings regarding implicit morphological processing suggest that morphology is an automatic and distinct aspect of visually processing words. These results also coincide with the behavioral data previously obtained demonstrating the central role of morphological processing in reading Hebrew.

Evidence for asymmetric intra substantia nigra functional connectivity-application to basal ganglia processing.

The growing uses of deep brain stimulation for various basal ganglia (BG) abnormalities have reinforced the need to better understand its functional circuitry and organization. Here we focus on cortico-basal-ganglia pathways to test the "parallel, segregated" versus "funneling, integrated" theories. Using manganese-enhanced MRI (MEMRI) together with principal component spatiotemporal analysis, we previously described two patterns of caudomedial striatum efferent connectivity to the substantia nigra pars reticulata (SNr) that were hypothesized to represent the coexistence of integrated and segregated processes. These patterns corresponded to a direct mono-synaptic projection to the dorsolateral core of the SN and to a di-synaptic projection covering the entire nucleus. In the current study, MEMRI of the rostrolateral striatum was carried out to test whether this coexistence remains in the mirror pathway, by measuring rostrolateral striatum efferent connectivity that is known to connect to the ventromedial SNr. Only one spatiotemporal pattern of manganese accumulation, corresponding to projections from the striatum, was observed. It corresponds to a mono-synaptic projection to the ventromedial SNr covering SNr laminas, but no manganese was observed at the dorsolateral SNr core. Together with our previous findings, this suggests functional asymmetry along the SNr which is consistent with the known anatomical organization of dendrite and axonal 3D arborization. Consequently, the polarized connectivity along the dorsolateral-ventromedial axis implies that funneling and integration occur in the core (dorsolateral SNr) to the lamina (ventromedial SNr) direction, whereas in the other direction, and within other parts of the SNr, segregation predominates.

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.