Convergent data from various scientific approaches strongly implicate cerebellar systems in nonmotor functions. The functional anatomy of these systems has been pieced together from disparate sources, such as animal studies, lesion studies in humans, and structural and functional imaging studies in humans. To better define this distinct functional anatomy, in the current study we delineate the role of the cerebellum in several nonmotor systems simultaneously and in the same subjects using resting state functional connectivity MRI. Independent component analysis was applied to resting state data from two independent datasets to identify common cerebellar contributions to several previously identified intrinsic connectivity networks (ICNs) involved in executive control, episodic memory/selfreflection, salience detection, and sensorimotor function. We found distinct cerebellar contributions to each of these ICNs. The neocerebellum participates in (1) the right and left executive control networks (especially crus I and II), (2) the salience network (lobule VI), and (3) the default-mode network (lobule IX). Little to no overlap was detected between these cerebellar regions and the sensorimotor cerebellum (lobules V-VI). Clusters were also located in pontine and dentate nuclei, prominent points of convergence for cerebellar input and output, respectively. The results suggest that the most phylogenetically recent part of the cerebellum, particularly crus I and II, make contributions to parallel cortico-cerebellar loops involved in executive control, salience detection, and episodic memory/self-reflection. The largest portions of the neocerebellum take part in the executive control network implicated in higher cognitive functions such as working memory.

Objective Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. We recently reported in healthy volunteers that the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. We also showed that this process is specific to the regulation of emotional, compared to non-emotional, conflict. Here we examined whether this form of non-instructed emotion regulation is perturbed in generalized anxiety disorder. Methods 17 patients and 24 healthy comparison subjects, were studied using functional magnetic resonance imaging while they performed an emotional conflict task, which involved categorizing facial affect while ignoring overlaid affect label words. We compared trial-by-trial changes in conflict regulation using behavioral and neural measures. Results Healthy subjects effectively regulated emotional conflict from trial-to-trial, even though they were unaware of having done so. By contrast, generalized anxiety disorder patients were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation correlated with symptoms and could be used to accurately classify the two groups. Conclusions Our data demonstrate that patients with generalized anxiety disorder show significant deficits in the non-instructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.

Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

While resting state functional connectivity has been shown to decrease in patients with mild/moderate Alzheimer’s disease, it is not yet known how functional connectivity changes in patients as the disease progresses. Furthermore, it has been noted that the default mode network is not as homogenous as previously assumed and several fractionations of the network have been proposed. Here, we separately investigated the modulation of three default mode sub-networks, as identified with group ICA, by comparing Alzheimer’s disease patients to healthy controls and by assessing connectivity changes over time. Our results showed decreased connectivity at baseline in patients versus controls in the posterior default mode network, and increased connectivity in the anterior and ventral default mode networks. At follow-up, functional connectivity decreased across all default mode systems in patients. Our results suggest that earlier in the disease, regions of the posterior default mode network start to disengage whereas regions within the anterior and ventral networks enhance their connectivity. However, as the disease progresses connectivity within all systems eventually deteriorates.

Functional and structural maturation of networks comprised of discrete regions is an important aspect of brain development. The default-mode network (DMN) is a prominent network which includes the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), medial temporal lobes (MTL), and angular gyrus (AG). Despite increasing interest in DMN function, little is known about its maturation from childhood to adulthood. Here we examine developmental changes in DMN connectivity using a multimodal imaging approach by combining resting-state fMRI, voxel-based morphometry and diffusion tensor imaging-based tractography. We found that the DMN undergoes significant developmental changes in functional and structural connectivity, but these changes are not uniform across all DMN nodes. Convergent structural and functional connectivity analyses suggest that PCC-mPFC connectivity along the cingulum bundle is the most immature link in the DMN of children. Both PCC and mPFC also showed gray matter volume differences, as well as prominent macrostructural and microstructural differences in the dorsal cingulum bundle linking these regions. Notably, structural connectivity between PCC and left MTL was either weak or non-existent in children, even though functional connectivity did not differ from that of adults. These results imply that functional connectivity in children can reach adult-like levels despite weak structural connectivity. We propose that maturation of PCC-mPFC structural connectivity plays an important role in the development of self-related and social-cognitive functions that emerge during adolescence. More generally, our study demonstrates how quantitative multimodal analysis of anatomy and connectivity allows us to better characterize the heterogeneous development and maturation of brain networks.

Background Generalized social anxiety disorder (gSAD) is characterized by exaggerated amygdala reactivity to social signals of threat, but if and how the amygdala interacts with functionally and anatomically connected prefrontal cortex (PFC) remains largely unknown. Recent evidence points to aberrant amygdala connectivity to medial PFC in gSAD at rest, but it is difficult to attribute functional relevance without the context of threat processing. Here, we address this by studying amygdala-frontal cortex connectivity during viewing of fearful faces and at rest in gSAD patients. Methods Twenty patients with gSAD and 17 matched healthy controls (HCs) participated in functional magnetic resonance imaging of an emotional face matching task, and a resting state task. Functional connectivity and psychophysiological interaction analysis were used to assess amygdala connectivity. Results Compared to HCs, gSAD patients exhibited less connectivity between amygdala and the rostral anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) while viewing fearful faces. gSAD patients also showed less connectivity between amygdala and rostral ACC at rest in the absence of fearful faces. DLPFC connectivity was negatively correlated with LSASFear. Conclusions Task and rest paradigms provide unique and important information about discrete and overlapping functional networks. In particular, amygdala coupling to DLPFC may be a phasic abnormality, emerging only in the presence of a social predictor of threat, whereas amygdala coupling to the rostral ACC may reflect both phasic and tonic abnormalities. These findings prompt further studies to better delineate intrinsic and externally-evoked brain connectivity in anxiety and depression in relation to amygdala dysfunction.

Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia [...

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety-and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.fibroblast growth factor 9 | major depression | anxiety | hippocampus | affect T he neurotrophic hypothesis of major depressive disorder (MDD) posits that the neurobiological basis for mood disorders may be due to the dysregulation of growth factors and their effects on brain circuitry (1, 2). This hypothesis is supported by gene expression profiling experiments in postmortem human brains that implicate the fibroblast growth factor (FGF) family and other neurotrophins in MDD (3, 4). To date, only a few growth factors involved in mood disorders, such as brain-derived neurotrophic factor (BDNF) and FGF2, have been studied extensively.Our laboratory and others have demonstrated that FGF2 is down-regulated in the frontal cortices (3), hippocampus (5), and locus coeruleus (4) in depressed individuals. This consistent decrease in FGF2 expression across regions is striking and underscores the likely importance of FGF2 in mediating affect.Follow-up studies from our laboratory and others have focused on the FGF family and have demonstrated a key role of FGF2 in the control of emotional behavior. Rats exposed to chronic social defeat stress, an animal model recapitulating some aspects of MDD, showed decreased hippocampal FGF2 expression relative to unstressed controls (6), whereas subchronic and chronic administration of FGF2 had antidepressant properties (7,8). Moreover, adminis...