Increased Functional Connectivity between Prefrontal Cortex and Reward System in Pathological Gambling

Pathological gambling (PG) shares clinical characteristics with substance-use disorders and is thus discussed as a behavioral addiction. Recent neuroimaging studies on PG report functional changes in prefrontal structures and the mesolimbic reward system. While an imbalance between these structures has been related to addictive behavior, whether their dysfunction in PG is reflected in the interaction between them remains unclear. We addressed this question using functional connectivity resting-state fMRI in male subjects with PG and controls. Seed-based functional connectivity was computed using two regions-of-interest, based on the results of a previous voxel-based morphometry study, located in the prefrontal cortex and the mesolimbic reward system (right middle frontal gyrus and right ventral striatum). PG patients demonstrated increased connectivity from the right middle frontal gyrus to the right striatum as compared to controls, which was also positively correlated with nonplanning aspect of impulsiveness, smoking and craving scores in the PG group. Moreover, PG patients demonstrated decreased connectivity from the right middle frontal gyrus to other prefrontal areas as compared to controls. The right ventral striatum demonstrated increased connectivity to the right superior and middle frontal gyrus and left cerebellum in PG patients as compared to controls. The increased connectivity to the cerebellum was positively correlated with smoking in the PG group. Our results provide further evidence for alterations in functional connectivity in PG with increased connectivity between prefrontal regions and the reward system, similar to connectivity changes reported in substance use disorder.     

Functional Connectivity Alterations in Epilepsy from Resting-State Functional MRI

The study of functional brain connectivity alterations induced by neurological disorders and their analysis from resting state functional Magnetic Resonance Imaging (rfMRI) is generally considered to be a challenging task. The main challenge lies in determining and interpreting the large-scale connectivity of brain regions when studying neurological disorders such as epilepsy. We tackle this challenging task by studying the cortical region connectivity using a novel approach for clustering the rfMRI time series signals and by identifying discriminant functional connections using a novel difference statistic measure. The proposed approach is then used in conjunction with the difference statistic to conduct automatic classification experiments for epileptic and healthy subjects using the rfMRI data. Our results show that the proposed difference statistic measure has the potential to extract promising discriminant neuroimaging markers. The extracted neuroimaging markers yield 93.08% classification accuracy on unseen data as compared to 80.20% accuracy on the same dataset by a recent state-of-the-art algorithm. The results demonstrate that for epilepsy the proposed approach confirms known functional connectivity alterations between cortical regions, reveals some new connectivity alterations, suggests potential neuroimaging markers, and predicts epilepsy with high accuracy from rfMRI scans.     

Early Altered Resting-State Functional Connectivity Predicts the Severity of Post-Traumatic Stress Disorder Symptoms in Acutely Traumatized Subjects

The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject’s Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.     

Prefrontal Cortex Glutamate Correlates with Mental Perspective-Taking

Background

Dysfunctions in theory of mind and empathic abilities have been suggested as core symptoms in major psychiatric disorders including schizophrenia and autism. Since self monitoring, perspective taking and empathy have been linked to prefrontal (PFC) and anterior cingulate cortex (ACC) function, neurotransmitter variations in these areas may account for normal and pathological variations of these functions. Converging evidence indicates an essential role of glutamatergic neurotransmission in psychiatric diseases with pronounced deficits in empathy. However, the role of the glutamate system for different dimensions of empathy has not been investigated so far.

Methodology/Principal Findings

Absolute concentrations of cerebral glutamate in the ACC, left dorsolateral PFC and left hippocampus were determined by 3-tesla proton magnetic resonance spectroscopy (1H-MRS) in 17 healthy individuals. Three dimensions of empathy were estimated by a self-rating questionnaire, the Interpersonal Reactivity Index (IRI). Linear regression analysis showed that dorsolateral PFC glutamate concentration was predicted by IRI factor “perspective taking” (T = −2.710, p = 0.018; adjusted alpha-level of 0.017, Bonferroni) but not by “empathic concern” or “personal distress”. No significant relationship between IRI subscores and the glutamate levels in the ACC or left hippocampus was detected.

Conclusions/Significance

This is the first study to investigate the role of the glutamate system for dimensions of theory of mind and empathy. Results are in line with recent concepts that executive top-down control of behavior is mediated by prefrontal glutamatergic projections. This is a preliminary finding that needs a replication in an independent sample.     

Modulatory Interactions of Resting-State Brain Functional Connectivity

The functional brain connectivity studies are generally based on the synchronization of the resting-state functional magnetic resonance imaging (fMRI) signals. Functional connectivity measures usually assume a stable relationship over time; however, accumulating studies have reported time-varying properties of strength and spatial distribution of functional connectivity. The present study explored the modulation of functional connectivity between two regions by a third region using the physiophysiological interaction (PPI) technique. We first identified eight brain networks and two regions of interest (ROIs) representing each of the networks using a spatial independent component analysis. A voxel-wise analysis was conducted to identify regions that showed modulatory interactions (PPI) with the two ROIs of each network. Mostly, positive modulatory interactions were observed within regions involved in the same system. For example, the two regions of the dorsal attention network revealed modulatory interactions with the regions related to attention, while the two regions of the extrastriate network revealed modulatory interactions with the regions in the visual cortex. In contrast, the two regions of the default mode network (DMN) revealed negative modulatory interactions with the regions in the executive network, and vice versa, suggesting that the activities of one network may be associated with smaller within network connectivity of the competing network. These results validate the use of PPI analysis to study modulation of resting-state functional connectivity by a third region. The modulatory effects may provide a better understanding of complex brain functions.     

Evoked Extracellular Dopamine In Vivo in the Medial Prefrontal Cortex

Abstract: The measurement of evoked extracellular dopamine in the medial prefrontal cortex by using fast-scan cyclic voltammetry with carbon-fiber microelectrodes was established and release characteristics of mesoprefrontal dopamine neurons were examined in vivo in anesthetized rats. Despite the sparse dopaminergic innervation and the presence of more dense noradrenergic and serotonergic innervations overall in the medial prefrontal cortex, the measurement of extracellular dopamine was achieved by selective recording in dopamine-rich terminal fields and selective activation of ascending dopamine neurons. This was confirmed by electrochemical, pharmacological, and anatomical evidence. An increased release capacity for mesoprefrontal dopamine neurons was also demonstrated by the slower decay of the evoked dopamine response after inhibition of catecholamine synthesis and the maintenance of the evoked dopamine response at higher levels in the medial prefrontal cortex compared with the striatum during supraphysiological stimulation.     

内侧前额叶与社会认知

早期的研究表明杏仁核、前额叶、颞上沟、前扣带回等与人类的社会认知活动有关;随着多种新技术的应用。越来越多的研究发现其它一些脑区结构(如岛叶、基底节、白质等)也与社会认知和行为有关。本文综述了内侧前额叶在社会认知中的作用,重点介绍了内侧前额叶在心灵理论、情绪认知、社会推理与决策、道德判断、自我认知等社会认知活动中的作用。未来研究希望能从整体和动态上认识内侧前额叶在社会认知活动中的作用。     

Contribution of the Resting-State Functional Connectivity of the Contralesional Primary Sensorimotor Cortex to Motor Recovery after Subcortical Stroke

It remains uncertain if the contralesional primary sensorimotor cortex (CL_PSMC) contributes to motor recovery after stroke. Here we investigated longitudinal changes in the resting-state functional connectivity (rsFC) of the CL_PSMC and their association with motor recovery. Thirteen patients who had experienced subcortical stroke underwent a series of resting-state fMRI and clinical assessments over a period of 1 year at 5 time points, i.e., within the first week, at 2 weeks, 1 month, 3 months, and 1 year after stroke onset. Thirteen age- and gender-matched healthy subjects were recruited as controls. The CL_PSMC was defined as a region centered at the voxel that had greatest activation during hand motion task. The dynamic changes in the rsFCs of the CL_PSMC within the whole brain were evaluated and correlated with the Motricity Index (MI) scores. Compared with healthy controls, the rsFCs of the CL_PSMC with the bilateral PSMC were initially decreased, then gradually increased, and finally restored to the normal level 1 year later. Moreover, the dynamic change in the inter-hemispheric rsFC between the bilateral PSMC in these patients was positively correlated with the MI scores. However, the intra-hemispheric rsFC of the CL_PSMC was not correlated with the MI scores. This study shows dynamic changes in the rsFCs of the CL_PSMC after stroke and suggests that the increased inter-hemispheric rsFC between the bilateral PSMC may facilitate motor recovery in stroke patients. However, generalization of our findings is limited by the small sample size of our study and needs to be confirmed.     

Functional Connectivity of the Posteromedial Cortex

As different areas within the PMC have different connectivity patterns with various cortical and subcortical regions, we hypothesized that distinct functional modules may be present within the PMC. Because the PMC appears to be the most active region during resting state, it has been postulated to play a fundamental role in the control of baseline brain functioning within the default mode network (DMN). Therefore one goal of this study was to explore which components of the PMC are specifically involved in the DMN. In a sample of seventeen healthy volunteers, we performed an unsupervised voxelwise ROI-based clustering based on resting state functional connectivity. Our results showed four clusters with different network connectivity. Each cluster showed positive and negative correlations with cortical regions involved in the DMN. Progressive shifts in PMC functional connectivity emerged from anterior to posterior and from dorsal to ventral ROIs. Ventral posterior portions of PMC were found to be part of a network implicated in the visuo-spatial guidance of movements, whereas dorsal anterior portions of PMC were interlinked with areas involved in attentional control. Ventral retrosplenial PMC selectively correlated with a network showing considerable overlap with the DMN, indicating that it makes essential contributions in self-referential processing, including autobiographical memory processing. Finally, ventral posterior PMC was shown to be functionally connected with a visual network.The paper represents the first attempt to provide a systematic, unsupervised, voxelwise clustering of the human posteromedial cortex (PMC), using resting-state functional connectivity data. Moreover, a ROI-based parcellation was used to confirm the results.     

Characteristics of Resting-State Functional Connectivity in HIV-Associated Neurocognitive Disorder

BackgroundHIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND.MethodsWe evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied.ResultsAmong the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P<0.05). The functional connectivity with the right inferior frontal operculum and right superior frontal gyrus was positively correlated with memory and learning ability.ConclusionsThis cross-sectional study found a significant difference in fMRI patterns between patients with and without HAND. Decreased functional connectivity between precuneus and PFC could be possible functional substrate for cognitive dysfunction in HIV patients, which should be characterized in a longitudinal study.     

Amygdala Perfusion Is Predicted by Its Functional Connectivity with the Ventromedial Prefrontal Cortex and Negative Affect

Background

Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala-prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states.

Methods

Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects.

Results

BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety.

Conclusions

These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach.     

M1 Acetylcholine Receptor Stimulation Increases the Extracellular Concentrations of Glutamate and GABA in the Medial Prefrontal Cortex of the Rat

The present study was undertaken to examine the effects of different muscarinic receptor agonists on glutamate and GABA concentrations in the medial prefrontal cortex of the rat. In vivo perfusions were made in the conscious rat using a concentric push-pull cannulae system. Amino acid concentrations in samples were determined by HPLC with fluorometric detection. The intracortical perfusion of arecoline, a M1-M2 muscarinic receptor agonist, produced a significant increase in extracellular [GLU] and [GABA]. McN-A-343, a M1 muscarinic receptor agonist, but not the M2 muscarinic receptor agonist, oxotremorine, produced a significant increase in extracellular [GLU] and [GABA]. The effects of McN-A-343 on extracellular [GLU] and [GABA] were blocked by pirenzepine, a M1 muscarinic receptor antagonist. These results suggest that M1 muscarinic receptor stimulation increases the extracellular concentrations of GLU and GABA in the medial prefrontal cortex of the rat.     

Decreased Prefrontal Lobe Interhemispheric Functional Connectivity in Adolescents with Internet Gaming Disorder: A Primary Study Using Resting-State fMRI

Purposes

Recent neuroimaging studies have shown that people with Internet gaming disorder (IGD) have structural and functional abnormalities in specific brain areas and connections. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (rsFC) in participants with IGD. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric rsFC of the whole brain in participants with IGD.

Methods

We compared interhemispheric rsFC between 17 participants with IGD and 24 healthy controls, group-matched on age, gender, and education status. All participants were provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired for all participants. The rsFC between bilateral homotopic voxels was calculated. Regions showing abnormal VMHC in IGD participants were adopted as regions of interest for correlation analyses.

Results

Compared to healthy controls, IGD participants showed decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part), middle frontal gyrus and superior frontal gyrus. Further analyses showed Chen Internet Addiction Scale (CIAS)-related VMHC in superior frontal gyrus (orbital part) and CIAS (r = −0.55, p = 0.02, uncorrected).

Conclusions

Our findings implicate the important role of altered interhemispheric rsFC in the bilateral prefrontal lobe in the neuropathological mechanism of IGD, and provide further supportive evidence for the reclassification of IGD as a behavioral addiction.     

Time Course of Functional Connectivity in Primate Dorsolateral Prefrontal and Posterior Parietal Cortex during Working Memory

The dorsolateral prefrontal and posterior parietal cortex play critical roles in mediating attention, working memory, and executive function. Despite proposed dynamic modulation of connectivity strength within each area according to task demands, scant empirical data exist about the time course of the strength of effective connectivity, particularly in tasks requiring information to be sustained in working memory. We investigated this question by performing time-resolved cross-correlation analysis for pairs of neurons recorded simultaneously at distances of 0.2–1.5 mm apart of each other while monkeys were engaged in working memory tasks. The strength of effective connectivity determined in this manner was higher throughout the trial in the posterior parietal cortex than the dorsolateral prefrontal cortex. Significantly higher levels of parietal effective connectivity were observed specifically during the delay period of the task. These differences could not be accounted for by differences in firing rate, or electrode distance in the samples recorded in the posterior parietal and prefrontal cortex. Differences were present when we restricted our analysis to only neurons with significant delay period activity and overlapping receptive fields. Our results indicate that dynamic changes in connectivity strength are present but area-specific intrinsic organization is the predominant factor that determines the strength of connections between neurons in each of the two areas.     

Age-Related Differences in Test-Retest Reliability in Resting-State Brain Functional Connectivity

Resting-state functional MRI (rs-fMRI) has emerged as a powerful tool for investigating brain functional connectivity (FC). Research in recent years has focused on assessing the reliability of FC across younger subjects within and between scan-sessions. Test-retest reliability in resting-state functional connectivity (RSFC) has not yet been examined in older adults. In this study, we investigated age-related differences in reliability and stability of RSFC across scans. In addition, we examined how global signal regression (GSR) affects RSFC reliability and stability. Three separate resting-state scans from 29 younger adults (18–35 yrs) and 26 older adults (55–85 yrs) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available as part of the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 92 regions of interest (ROIs) with 5 cubic mm radius, derived from the default, cingulo-opercular, fronto-parietal and sensorimotor networks, were previously defined based on a recent study. Mean time series were extracted from each of the 92 ROIs from each scan and three matrices of z-transformed correlation coefficients were created for each subject, which were then used for evaluation of multi-scan reliability and stability. The young group showed higher reliability of RSFC than the old group with GSR (p-value = 0.028) and without GSR (p-value <0.001). Both groups showed a high degree of multi-scan stability of RSFC and no significant differences were found between groups. By comparing the test-retest reliability of RSFC with and without GSR across scans, we found significantly higher proportion of reliable connections in both groups without GSR, but decreased stability. Our results suggest that aging is associated with reduced reliability of RSFC which itself is highly stable within-subject across scans for both groups, and that GSR reduces the overall reliability but increases the stability in both age groups and could potentially alter group differences of RSFC.     

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.     

Resting-State Functional Connectivity Patterns Predict Chinese Word Reading Competency

Resting-state functional connectivity (RSFC) offers a novel approach to reveal the temporal synchronization of functionally related brain regions. Recent studies have identified several RSFCs whose strength was associated with reading competence in alphabetic languages. In the present study, we examined the role of intrinsic functional relations for reading a non-alphabetic language – Chinese – by correlating RSFC maps of nine Chinese reading-related seed regions and reaction time in the single-character reading task. We found that Chinese reading efficiency was positively correlated with the connection between left inferior occipital gyrus and left superior parietal lobule, between right posterior fusiform gyrus and right superior parietal lobule, and between left inferior temporal gyrus and left inferior parietal lobule. These results could not be attributed to inter-individual differences arising from the peripheral processes of the reading task such as visual input detection and articulation. The observed RSFC-reading correlation relationships are discussed in the framework of Chinese character reading, including visuospatial analyses and semantic/phonological processes.     

Control of Intermale Aggression by Medial Prefrontal Cortex Activation in the Mouse

Aggressive behavior is widely observed throughout the animal kingdom because of its adaptiveness for social animals. However, when aggressive behavior exceeds the species-typical level, it is no longer adaptive, so there should be a mechanism to control excessive aggression to keep it within the adaptive range. Using optogenetics, we demonstrate that activation of excitatory neurons in the medial prefrontal cortex (mPFC), but not the orbitofrontal cortex (OFC), inhibits inter-male aggression in mice. At the same time, optogenetic silencing of mPFC neurons causes an escalation of aggressive behavior both quantitatively and qualitatively. Activation of the mPFC suppresses aggressive bursts and reduces the intensity of aggressive behavior, but does not change the duration of the aggressive bursts. Our findings suggest that mPFC activity has an inhibitory role in the initiation and execution, but not the termination, of aggressive behavior, and maintains such behavior within the adaptive range.     

Abnormal Resting-State Connectivity at Functional MRI in Women with Premenstrual Syndrome

Objectives

Premenstrual syndrome (PMS) refers to a series of cycling and relapsing physical, emotion and behavior syndromes that occur in the luteal phase and resolve soon after the onset of menses. Although PMS is widely recognized, its neural mechanism is still unclear.

Design

To address this question, we measured brain activity for women with PMS and women without PMS (control group) using resting-state functional magnetic resonance imaging (rs-fMRI). In addition, the participants should complete the emotion scales (Beck Anxiety Inventory, BAI; Beck Depression Inventory, BDI, before the scanning) as well as the stress perception scale (Visual analog scale for stress, VAS, before and after the scanning).

Results

The results showed that compared with the control group, the PMS group had decreased connectivity in the middle frontal gyrus (MFG) and theparahippocampalgyrus (PHG), as well as increased connectivity in the left medial/superior temporal gyri (MTG/STG) and precentralgyrus within the default mode network (DMN); in addition, the PMS group had higher anxiety and depression scale scores, together with lower stress perception scores. Finally, there were significantly positive correlations between the stress perception scores and functional connectivity in the MFG and cuneus. The BDI scores in the PMS group were correlated negatively with the functional connectivity in the MFG and precuneus and correlated positively with the functional connectivity in the MTG.

Conclusion

These findings suggest that compared with normal women, women with PMS displayed abnormal stress sensitivity, which was reflected in the decreased and increased functional connectivity within the DMN, blunted stress perception and higher depression.