Dynamic brain networks explored by structure-revealing methods

The research field of functional magnetic resonance imaging (fMRI) has made possible a remarkable progress in the understanding of the human brain enabling neuroscientists to study spatio-temporal alterations in the healthy and the diseased brain. While current theories of schizophrenia stress the critical role that plays aberrant connectivity among brain regions, other theories point towards the crucial role that plays functional excitation-inhibition (E-I) balance. Indeed, recent neuroscientific research has revealed increasing evidence that taking functional brain connectivity into account is essential to understand how the human brain works, and many studies have reviewed that serious behavioural impairments in mental disorders such as schizophrenia result from increases in the functional (E-I) balance within the neural microcircuitry. Particularly, the connection between the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF) during working memory (WM) was found to be increased in carriers of schizophrenia risk genes and patients. However, less is known about causality, i.e. which region drives the altered connection. Stochastic Dynamic Causal Modelling (sDCM) is a novel mathematical algorithm for studying the causal connectivity among higher cognitive brain regions from fMRI data. The main purpose of this study is to identify alterations on genetic risk carriers and patients from the DLPFC-HF network estimated with sDCM and describe how these alterations have an impact on the behavior. Over the study, we strive to give to the sDCM parameter estimates a neurobiological explanation by linking the concepts of causal connectivity with functional (E-I) balance. In this work, we applied this methodology in two samples by constructing a systematic set of sDCMs describing interactions between right DLPFC and left HF. In a first sample, 180 healthy subjects were measured by fMRI during a standard working memory N-Back task at three different sites (Mannheim, Bonn, Berlin; each with 60 participants). Bayes Model Selection (BMS) revealed the same causal pattern or winning model across the three sites, with the 2-Back working memory condition as driving input to both DLPFC and HF and with a connection from DLPFC to HF. Furthermore, a genome-wide risk variant for schizophrenia: ZNF804A (rs1344706), showed a strong impact on the DLPFC-HF network. On the one hand, risk homozygotes showed higher effective connectivity or higher functional (E-I) balance between DLPFC and HF. On the other hand, risk allele carriers showed higher functional (E-I) balance on the self-connection in the DLPFC. In a second sample, 33 schizophrenia patients were measured by fMRI during the same working memory N-Back task. We pair-wise matched healthy volunteers of the first sample and patients and applied the same methodology. BMS revealed the same winning model in patients but sDCM parameter estimates differed significantly between groups. Patients showed higher functional (E-I) balance on both self-connections in comparison to healthy volunteers. In summary, we observed that risk allele carriers and patients have a higher functional (E-I) balance within the DLPFC-HF network. In view of these research findings, we hypothesized a possible biological functioning of ZNF804A (rs1344706) on the DLPFC-HF network and suggested a mechanistic model for explaining the underlying neurobiology of schizophrenia within this network. Then, we reported causal relations between sDCM parameter estimates and behavior in terms of functional (E-I) balance in both samples. On the one hand, we observed that risk allele carriers and patients require lower functional (E-I) balance on the DLPFC-HF network in order to achieve the best performance during the task. On the other hand, we found that healthy volunteers require higher functional (E-I) balance on the network in order to achieve the optimal behavior. This study investigated the applicability of computational models like sDCM to establish the functional significance of specific genetic polymorphisms for schizophrenia and identify causal mechanisms associated with the disease in relation to the underlying neurobiology and behavior. In forthcoming studies, we plan to investigate whether subject-specific directed connections strengths between DLPFC and HF, and genotype, contain sufficiently rich information to enable accurate predictions of behavior. In order to study how temporal patterns in the neuronal ensembles and genotype convey robust information about behavior, multivariate regressors or statistical decoding algorithms will be used in both samples.

Many real-life decision making problems incorporate higher-order structure, involving interdependencies between different stimuli, actions, and subsequent rewards. It is not known whether brain regions implicated in decision making, such as ventromedial prefrontal cortex, employ a stored model of the task structure to guide choice (model-based decision making) or merely learn action or state values without assuming higher-order structure, as in standard reinforcement learning. To discriminate between these possibilities we scanned human subjects with fMRI while they performed two different decision making tasks with higher-order structure: probabilistic reversal learning, in which subjects had to infer which of two choices was the more rewarding and then flexibly switch their choice when contingencies changed; and the inspection game, in which subjects had to successfully compete against an intelligent adversary by mentalizing the opponent’s state of mind in order to anticipate the opponent’s behavior in future. For both tasks we found that neural activity in a key decision making region: ventromedial prefrontal cortex, was more consistent with computational models that exploit higher-order structure, than with simple reinforcement learning. Moreover, in the social interaction game, subjects were found to employ a sophisticated strategy whereby they used knowledge of how their actions would influence the actions of their opponent to guide their choices. Specific computational signals required for the implementation of such a strategy were present in medial prefrontal cortex and superior temporal sulcus, providing insight into the basic computations underlying competitive strategic interactions. These results suggest that brain regions such as ventromedial prefrontal cortex employ an abstract model of task structure to guide behavioral choice, computations that may underlie the human capacity for complex social interactions and abstract strategizing.

This thesis is concerned with two studies which have the common pursuit to improve the investigation of pathomechanisms underlying schizophrenic and affective disorders. They were motivated by the fact, that the diagnosis of mental disorders is a complex process and despite advances still error prone. It is proposed that during the pathogenesis of mental disorders interaction of genes and environment lead to functional changes in brain regions and related brain networks. Indeed, abnormalities in reward, stress and emotion processing are described for mental disorders. It is expected that neuroimaging studies might identify brain activation or connectivity patterns that could aid their differential diagnosis disorders or guide treatment selection. The first study investigated if living in big cities could affect the mesolimbic reward system and densely connected cortical and subcortical structures. 147 healthy subjects provided information about current and residency during their first years of life and performed the Desire-Reason-Dilemma paradigm during functional magnetic resonance imaging. Compared with subjects from less urban areas, city dwellers showed an altered activation and modulation capability of the midbrain dopamine system. City dwellers also revealed exaggerated responses in other brain regions involved in reward processing, and in the regulation of stress and emotions such as amygdala, orbitofrontal and pregenual anterior cingulate cortex. This study provided evidence for an influence of an environmental risk factor on cortico-subcortical networks involved in reward and emotion processing. Dysfunctions of these brain networks are involved in the development of schizophrenic and affective disorders. The aim of the second study was to investigate dynamic functional interactions between amygdala, nucleus accumbens and prefrontal cortex that underlie the influences of emotions, desires and rationality on human decisions because quite little is known about dynamic functional interactions between these brain circuits that underlie reward processing, self-controlled pursuit of long-term goals and emotions. For this purpose, the Desire-Reason-Dilemma paradigm was extended by an affective component. One half of the stimuli showed a gray ellipse representing non-emotional stimuli and the other half showed an emotional face in its center. Seventeen healthy volunteers were included in the study and nine additional subjects were excluded due to excessive head movements. The behavioral data revealed that fearful faces generally increased avoidance tendency to non-reward stimuli leading to significantly slower acceptance and faster rejection of these stimuli. But reward counteracted the avoidance tendency of fearful faces. The functional MRI analysis showed that increased functional connectivity between amygdala and nucleus accumbens facilitated the approach of immediate reward in the presence of emotional information. This was not observed in the absence of reward. Further, increased functional interactions of the anteroventral prefrontal cortex with amygdala and nucleus accumbens were associated with rational decisions in dilemma situations. The second work provided an experimental paradigm that for the first time enabled the in vivo investigation of the interaction between amygdala, nucleus accumbens und antero-ventral prefrontal cortex when emotional-, reward related information and self-controlled pursuit of long-term goals guided human decisions and reward-directed actions. It was shown that the activity in the amygdala, which is hypothesized as an integration region of cognition and emotion, is influenced by a risk factor contributing to development of mental disorders and that the amygdala interacts with cortical regions and the mesolimbic dopamine system to coordinate goal directed behavior. Future application of the affective DRD paradigm and the inclusion of additional information, e.g. genetic variation might provide additional insight in the underlying neuro-mechanisms of schizophrenic and affective disorders.

Unprecedented 4D spatiotemporal infant regional cerebral blood flow framework and region-specific physiology–function coupling across infancy were elucidated, highlighting strong physiology–function coupling specifically at the default-mode network to meet extraneuronal metabolic demand for network emergence.

Objective To study the resting-state functional connectivity(FC) changes of anterior cingulate cortex(ACC) and amygdala in adolescent patients with medication-naive first-episode major depressive disorder(MDD). Methods Medication-naive first-episode MDD adolescents(n=30) and pair-wise matched healthy controls(HCs, n=29) underwent resting-state functional magnetic resonance images(fMRI). To study whether there were different in FC changes between amygdala and ACC and whole brain regions, and whether abnormal FC was related to clinical characteristics. Results Compared with HCs, the adolescent MDD patients showed decreased FC between the left amygdala and right thalamus(MNI x, y, z: 15, -21, 18)(t=-2.85)and increased FC between the left amygdala and the bilateral temporal middle gyrus, left occipital gyrus, right medial prefrontal cortex(MPFC)(MNI x, y, z: 9, 66, 15)(t=2.80). The right amygdale showed decreased FC with bilateral middle frontal gyrus, left caudate(MNI x, y, z: -15, -9, 21)(t=-2.53), right thalamus(MNI x, y, z: 12, -36, 12)(t=-3.01), right cerebellum(MNI x, y, z: 3, -84, -33)(t=-2.45) and increased FC with right temporal middle gyrus, right MPFC(MNI x, y, z: 6, 69, 12)(t=2.41). The left ACC showed decreased FC with left cerebellum(MNI x, y, z: 12, -87, -24)(t=-2.36), left frontal inferior triangle gyrus, right frontal inferior orbital gyrus and increased FC with right frontal middle orbital gyrus.The right ACC showed decreased FC with left caudate(MNI x, y, z: -15, 21, 6)(t=-2.29), right temporal middle gyrus, right MPFC(MNI x, y, z: 9, 54, 36)(t=-2.29), right frontal inferior orbital gyrus, right angular(MNI x, y, z: 45, -51, 21)(t=-3.01), left dorsolateral prefrontal cortex(MNI x, y, z: -21, 33, 36)(t=-2.61). The increased FC between the left amygdale and bilateral temporal middle gyrus showed positive correlation with the score of HAMD(r=0.50, P<0.05; r=0.45, P<0.05). And the FC between the right amygdale and right middle frontal gyrus was positive correlation with duration of disease(r=0.63, P<0.05). Conclusion There is widespread FC disorder in amygdala and ACC in adolescents patients with first-episode depression.Abnormal FC changes may be the neuropathological mechanism of depression. Key words: Adolescent major depressive disorder; Resting-state fMRI; Functional connectivity; Amygdala; Anterior cingulated cortex

To determine whether modification of the connections between cerebellar and prefrontal areas might vary among multiple sclerosis (MS) phenotypes and might be associated with cognitive failure. Approval of the institutional review boards and written informed consent were obtained from each participant. Stroop-related functional magnetic resonance (MR) imaging activations and effective connectivity abnormalities between the right cerebellum and any other brain regions were assessed by using a psychophysiologic interaction (PPI) analysis from 17 patients with relapsing-remitting (RR), 17 with benign, and 23 with secondary progressive (SP) MS and 18 healthy control subjects (P < .05, corrected at cluster level). Correlations with disease duration, T2 lesion volume, brain volume, and response times (RTs) during the incongruent condition were estimated (P < .001, uncorrected). Activation and PPI analyses showed that, compared with the other groups, RR MS group had abnormal recruitment of regions of the left frontoparietal lobes, whereas compared with RR MS group, SP MS group had abnormal recruitment of the cingulum or precuneus. Benign MS group had increased activation of the right prefrontal cortex, and increased interaction between these regions and the right cerebellum. In healthy controls, RTs inversely correlated with activity of right cerebellum and several frontoparietal regions. In MS, RTs inversely correlated with bilateral cerebellar activity and directly correlated with right precuneus activity. In MS, disease duration inversely correlated with right cerebellar activity and directly correlated with left inferior frontal gyrus and right precuneus activity. Higher T2 lesion volume and lower brain volumes were related to activity in these areas. Patients with MS who have various clinical phenotypes experience different abnormalities in activation and effective connectivity between the right cerebellum and frontoparietal areas, which contribute to inefficient cortical reorganization, with increasing cognitive load. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120216/-/DC1.

To evaluate brain changes after cognitive rehabilitation in patients with clinically stable relapsing-remitting (RR) multiple sclerosis (MS) by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques. The study was conducted with approval of the involved institutional review boards. Written informed consent was obtained from each participant. Twenty patients with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on three-dimensional T1-weighted images and changes in normal-appearing white matter (NAWM) architecture on diffusion-weighted images were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated by using linear models. As compared with their performance at baseline, the patients in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of the posterior cingulate cortex (PCC)/precuneus and dorsolateral prefrontal cortex (PFC) during the Stroop task, as well as modifications of the activity of the anterior cingulum, PCC and/or precuneus, left dorsolateral PFC, and right inferior parietal lobule at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01). Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions.

Objective To provide a new approach to further elucidate the underlying pathogenesis of major depressive disorder by using resting-state functional connectivity strengths(FCS) in unmedicated patients with major depressive disorder(MDD). Methods Thirty-three unmedicated patients with MDD and thirty-three normal controls underwent the resting-state functional magnetic resonance imaging(rs-fMRI).After preprocessing of rs-fMRI, the whole brain FCS values were constructed. Two-sample t-test was used to compare the FCS values of both groups to locate the regions with significant change. And correlation analysis was performed between the FCS values extracted from significantly different brain regions and Hamilton Depression Scale (HAMD24) scores. Results One sample t test had shown that high FCS values brain areas (hubs) of MDD patients and normal controls were mainly located in the default mode network (the prefrontal cortex, anterior cingulate gyrus, posterior cingulate gyrus, precuneus/cuneus, angular gyrus) and parietal cortex, lateral temporal cortex as well as occipital cortex. In comparison to the normal controls, the MDD patients had FCS values significantly decreased in the bilateral posterior cerebellar lobe (right posterior cerebellar t=-4.57, P<0.05; left posterior cerebellar t=-3.40,P<0.05), and FCS values increased in the right superior temporal gyrus (t=3.71,P<0.05) and left anterior insular lobe (t=3.91, P<0.05). There were no significant correlations between the HAMD24 scores and the FCS values in right/left posterior cerebellar (r=0.081, P=0.654; r=-0.028, P=0.877), right superior temporal gyrus (r=0.211, P=0.239) and left anterior insular lobe (r=-0.017,P=0.924). Conclusions These findings suggest abnormal functional connectivity in the bilateral posterior cerebellar lobe, right temporal lobe and left insular lobe in MDD. The FCS analysis may be used as a new research method to explore the pathogenesis of MDD. Key words: Depressive disorder; Resting state; Functional connectivity strengths

Basic emotional states (such as anger, fear, and joy) can be similarly conveyed by the face, the body, and the voice. Are there human brain regions that represent these emotional mental states regardless of the sensory cues from which they are perceived? To address this question, in the present study participants evaluated the intensity of emotions perceived from face movements, body movements, or vocal intonations, while their brain activity was measured with functional magnetic resonance imaging (fMRI). Using multivoxel pattern analysis, we compared the similarity of response patterns across modalities to test for brain regions in which emotion-specific patterns in one modality (e.g., faces) could predict emotion-specific patterns in another modality (e.g., bodies). A whole-brain searchlight analysis revealed modality-independent but emotion category-specific activity patterns in medial prefrontal cortex (MPFC) and left superior temporal sulcus (STS). Multivoxel patterns in these regions contained information about the category of the perceived emotions (anger, disgust, fear, happiness, sadness) across all modality comparisons (face-body, face-voice, body-voice), and independently of the perceived intensity of the emotions. No systematic emotion-related differences were observed in the overall amplitude of activation in MPFC or STS. These results reveal supramodal representations of emotions in high-level brain areas previously implicated in affective processing, mental state attribution, and theory-of-mind. We suggest that MPFC and STS represent perceived emotions at an abstract, modality-independent level, and thus play a key role in the understanding and categorization of others' emotional mental states.

Magnetic resonance imaging of cerebellar–prefrontal and cerebellar–parietal functional connectivity

To make economic choices between goods, the brain needs to compute representations of their values. A great deal of research has been performed to determine the neural correlates of value representations in the human brain. However, it is still unknown whether there exists a region of the brain that commonly encodes decision values for different types of goods, or if, in contrast, the values of different types of goods are represented in distinct brain regions. We addressed this question by scanning subjects with functional magnetic resonance imaging while they made real purchasing decisions among different categories of goods (food, nonfood consumables, and monetary gambles). We found activity in a key brain region previously implicated in encoding goal-values: the ventromedial prefrontal cortex (vmPFC) was correlated with the subjects' value for each category of good. Moreover, we found a single area in vmPFC to be correlated with the subjects' valuations for all categories of goods. Our results provide evidence that the brain encodes a "common currency" that allows for a shared valuation for different categories of goods.

How do parcellation size and short-range connectivity affect dynamics in large-scale brain network models?

Toward a biochemistry of mind?

Objective To investigate the correlation between activated brain regions examined by functional magnetic resonance imaging (fMRI) after rectal balloon distention and intestinal symptoms, psychological status, and quality of life in patients with diarrhea type irritable bowel syndrome (IBS-D) at different stages of disease. Methods According to the symptoms status, patients with IBS-D were divided into onset group (seven patients), remission group (five patients) and persistence group (six patients), and six healthy individuals were selected as healthy controls at the same time. After stimulated with rectal balloon distention at first sensation thresholds, continual defecation thresholds or 80% of maximum tolerable thresholds, patients received fMRI examination. Analysis of variance and two-sample t test were used to compare the difference in activated brain areas between two groups. Pearson analysis was performed to analyze the correlations between activated brain areas and scores of irritable bowel syndrome (IBS) intestinal symptom, Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA) and irritable bowel syndrome special quality of life scale (IBS-QOL). Results There was no significant difference in first sensation thresholds, continual defecation thresholds or 80% of maximum tolerable thresholds between patients of different groups. After rectal balloon distention, there were differences in such brain areas: bilateral anterior cingulate cortex (ACC), left inferior parietal lobe, and left middle frontal gyrus. Compared with those of control group, the activation of ACC, inferior parietal lobe and middle frontal gyrus lowered in patients of onset group (both P<0.05). There was positive correlation between the activation of middle frontal gyrus and intestinal symptom scores in persistence group(r=0.823, P=0.048). There were negative correlations between the activation of inferior parietal lobe (r =-0.816, P=0.048), middle frontal gyrus(r=-0.860, P=0.028) of persistence group, activation of middle frontal gyrus (r=-0.892, P=0.042) of remission group and HAMD score. There were positive correlations between the activation of inferior parietal lobe (r =0.818, P=0.047), middle frontal gyrus(r = 0.907, P=0.013) of persistence group, activation of midfrontal gyrus (r = 0.914, P=0.030) of remission group and scores of IBS-QOL. Conclusion The brain regions were activated during the rectal balloon distention both in IBS-D patients and healthy controls, and there were differences in activated brain regions among different stages of IBS-D. Key words: Irritable bowel syndrome; diarrhea; Magnetic resonance imaging; Brain region activities; Rectal balloon distention

目的 探讨精神分裂症患者脑静息态默认网络、中心执行网络及突显网络的网络内及网络间的功能连接特点.方法 对74例精神分裂症患者(患者组)和79名相匹配的健康者(对照组)进行静息态fMRI扫描.采取功能连接分析方法,以内侧前额叶皮质及右侧前岛叶为感兴趣区域分别提取默认网络、中心执行网络及突显网络,分析3个网络内及网络间静息态功能连接情况;并对有差异的功能连接与精神症状及病程等进行偏相关分析.结果 与对照组相比,患者组内侧前额叶皮质与双侧背外侧前额叶皮质(左侧-0.02±0.18与-0.12±0.12,t=4.25,P＜0.01;右侧-0.02±0.11与-0.10±0.10,t=5.40,P＜0.01)、双侧豆状壳核(左侧0.14±0.12与0.04±0.10,t=5.03,P＜0.01;右侧0.13±0.11与0.03±0.98,t=4.96,P＜0.01)的功能连接增强;右侧前岛叶与左侧额中回(-0.05±0.17与-0.07±0.17,t=4.60,P＜0.01)及楔前叶/后扣带回(0.01±0.13与-0.09±0.14,t=4.01,P＜0.01)的功能连接增强(均采用高斯随机场理论校正,体素水平P＜0.01,簇水平P＜0.05);默认网络与中心执行网络、突显网络间的负向功能连接减小甚至消失(Bonferroni校正P＜0.05).患者组PANSS阳性症状分与右侧前岛叶与楔前叶/后扣带回皮质间的功能连接呈正相关(r=0.232,P=0.025);患者组病程与右侧前岛叶与左侧额中回(r=0.288,P=0.007)、楔前叶/后扣带回(r=0.196,P=0.049)间的功能连接呈正相关.结论 精神分裂症患者存在静息态默认网络、中心执行网络及突显网络3个网络间的连接异常,可能与精神分裂症的病理机制有关.