Federico D'Agata

Functional connectivity of the insula in the resting brain

The human insula is hidden in the depth of the cerebral hemisphere by the overlying frontal and temporal opercula, and consists of three cytoarchitectonically distinct regions: the anterior agranular area, posterior granular area, and the transitional dysgranular zone; each has distinct histochemical staining patterns and specific connectivity. Even though there are several studies reporting the functional connectivity of the insula with the cingulated cortex, its relationships with other brain areas remain elusive in humans. Therefore, we decided to use resting state functional connectivity to elucidate in details its connectivity, in terms of cortical and subcortical areas, and also of lateralization. We investigated correlations in BOLD fluctuations between specific regions of interest of the insula and other brain areas of right-handed healthy volunteers, on both sides of the brain. Our findings document two major complementary networks involving the ventral-anterior and dorsal-posterior insula: one network links the anterior insula to the middle and inferior temporal cortex and anterior cingulate cortex, and is primarily related to limbic regions which play a role in emotional aspects; the second links the middle-posterior insula to premotor, sensorimotor, supplementary motor and middle-posterior cingulate cortices, indicating a role for the insula in sensorimotor integration. The clear bipartition of the insula was confirmed by negative correlation analysis. Correlation maps are partially lateralized: the salience network, related to the ventral anterior insula, displays stronger connections with the anterior cingulate cortex on the right side, and with the frontal cortex on the left side; the posterior network has stronger connections with the superior temporal cortex and the occipital cortex on the right side. These results are in agreement with connectivity studies in primates, and support the use of resting state functional analysis to investigate connectivity in the living human brain.

Meta-analytic clustering of the insular cortex: Characterizing the meta-analytic connectivity of the insula when involved in active tasks

The human insula has been parcellated on the basis of resting state functional connectivity and diffusion tensor imaging. Little is known about the organization of the insula when involved in active tasks. We explored this issue using a novel meta-analytic clustering approach. We queried the BrainMap database asking for papers involving normal subjects that recorded activations in the insular cortex, retrieving 1305 papers, involving 22,872 subjects and a total of 2957 foci. Data were analyzed with several different methodologies, some of which expressly designed for this work. We used meta-analytic connectivity modeling and meta-analytic clustering of data obtained from the BrainMap database. We performed cluster analysis to subdivide the insula in areas with homogeneous connectivity, and density analysis of the activated foci using Voronoi tessellation. Our results confirm and extend previous findings obtained investigating the resting state connectivity of the anterior-posterior and left-right insulae. They indicate, for the first time, that some blocks of the anterior insula play the role of hubs between the anterior and the posterior insulae, as confirmed by their activation in several different paradigms. This finding supports the view that the network to which the anterior insula belongs is related to saliency detection. The insulae of both sides can be parcellated in two clusters, the anterior and the posterior: the anterior is characterized by an attentional pattern of connectivity with frontal, cingulate, parietal, cerebellar and anterior insular highly connected areas, whereas the posterior is characterized by a more local connectivity pattern with connections to sensorimotor, temporal and posterior cingulate areas. This antero-posterior subdivision, better characterized on the right side, results sharper with the connectivity based clusterization than with the behavioral based clusterization. The circuits belonging to the anterior insula are very homogeneous and their blocks in multidimensional scaling of MACM-based profiles are in central position, whereas those belonging to the posterior insula, especially on the left, are located at the periphery and sparse, thus suggesting that the posterior circuits bear a more heterogeneous connectivity. The anterior cluster is mostly activated by cognition, whereas the posterior is mostly activated by interoception, perception and emotion.

Functional connectivity and coactivation of the nucleus accumbens: A combined functional connectivity and structure-based meta-analysis

This article investigates the functional connectivity patterns of the nucleus accumbens (NAcc) in 18 healthy participants using a resting state functional connectivity (rsFC) protocol. Also, a meta-analytic connectivity modeling (MACM) was used to characterize patterns of functional coactivations involving NAcc: The results of a structure-based meta-analyses of 57 fMRI and PET studies were submitted to activation likelihood estimation analysis to estimate consistent activation patterns across the different imaging studies. The results of the combined rsFC and MACM analyses show that spontaneous activity in NAcc predicts activity in regions implicated in reward circuitries, including orbitomedial prefrontal cortex, globus pallidus, thalamus, midbrain, amygdala, and insula. This confirms the key role of NAcc in the mesocorticolimbic system, which integrates inputs from limbic and cortical regions. We also detected activity in brain regions having few or no direct anatomical connections with NAcc, such as sensorimotor cortex, cerebellum, medial and posterior parietal cortex, and medial/inferior temporal cortex, supporting the view that not all functional connections can be explained by anatomical connections but can also result from connections mediated by third areas. Our rsFC findings are in line with the results of the structure-based meta-analysis: MACM maps are superimposable with NAcc rsFC results, and the reward paradigm class is the one that most frequently generates activation in NAcc. Our results overlap considerably with recently proposed schemata of the main neuron systems in the limbic forebrain and in the anterior part of the limbic midbrain in rodents and nonhuman primates.

Disrupted intrinsic functional connectivity in the vegetative state

It is debatable as to whether the spontaneous blood-oxygen-level dependent fluctuations that are observed in the resting brain in turn reflect consciously directed mental activity or, alternatively, constitute an intrinsic property of functional brain organisation persisting in the absence of consciousness. This report shows for the first time, in three patients, that the persistent vegetative state (PVS) is marked by a dysfunctional default mode network, with decreased connectivity in several brain regions, including the dorsolateral prefrontal cortex and anterior cingulated cortex, especially in the right hemisphere. This finding supports the view that the resting state is involved in self-consciousness, and that the right-hemisphere default state may play a major role in conscious processes. It is speculated that the default state may act as a surrogate marker of PVS with awareness contents and, therefore, could replace a more complex activation paradigm.

Grey matter abnormality in autism spectrum disorder: an activation likelihood estimation meta-analysis study

Background Autism spectrum disorder (ASD) is defined on a clinical basis by impairments in social interaction, verbal and non-verbal communication, and repetitive or stereotyped behaviours. Voxel based morphometry (VBM), a technique that gives a probabilistic measure of local grey matter (GM) and white matter concentration, has been used to study ASD patients: modifications in GM volume have been found in various brain regions, such as the corpus callosum, brainstem, amygdala, hippocampus and cerebellum. However, the findings are inconsistent with respect to the specific localisation and direction of GM modifications, and no paper has attempted to statistically summarise the results available in the literature. Methods The present study is a quantitative meta-analysis of the current VBM findings aimed at delineating the cortical regions with consistently increased or reduced GM concentrations. The activation likelihood estimation (ALE) was used, which is a quantitative voxel based meta-analysis method which can be used to estimate consistent activations across different imaging studies. Co-occurrence statistics of a PubMed query were generated, employing ‘autism spectrum disorder’ as the neuroanatomical lexicon. Results Significant ALE values related to GM increases were observed bilaterally in the cerebellum, in the middle temporal gyrus, in the right anterior cingulate cortex, caudate head, insula, fusiform gyrus, precuneus and posterior cingulate cortex, and in the left lingual gyrus. GM decreases were observed bilaterally in the cerebellar tonsil and inferior parietal lobule, in the right amygdala, insula, middle temporal gyrus, caudate tail and precuneus and in the left precentral gyrus.

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.

In vivo evidence of global and focal brain alterations in anorexia nervosa.

Brain alterations are known to be associated with anorexia nervosa (AN) and tend to be distributed across brain structures, with only a few reports describing focal damage. Magnetic resonance images of 21 anorexic patients with different disease duration and 27 control subjects were acquired and compared using voxel-based morphometry (VBM). Patients had a significant reduction of total white matter (WM) volume and focal gray matter (GM) atrophy in cerebellum, hypothalamus, caudate nucleus and frontal, parietal and temporal areas. The cerebellum was more affected in patients with longer disease duration, whereas the hypothalamic alterations were more pronounced in patients with shorter food restriction. A correlation with body mass index (BMI) and GM was found in the hypothalamus. Our data demonstrate a diffuse reduction of WM together with focal areas of GM atrophy in AN. The finding of a hypothalamic focal atrophy points to hormonal dysfunction and opens the possibility for a central dysregulation of homeostasis. The involvement of temporoparietal areas could account for body image distortion. Finally, the cerebellar GM atrophy confirms previous findings and seems to be a late consequence of AN that could play a role in the chronic phase of the disease.

Altered resting state attentional networks in diabetic neuropathic pain

Background Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. Methods The authors sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. Results NP patients showed a widespread reduction in connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. The authors also found a generalised reduction in the length of functional connections in the NP group: in all the examined networks, the Euclidean distance between connected voxels was significantly shorter in patients than in controls. Conclusion In diabetic NP, a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self-monitoring, pain processing and salience detection.

Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain

BackgroundIn this paper we explored thalamocortical functional connectivity in a group of eight patients suffering from peripheral neuropathic pain (diabetic pain), and compared it with that of a group of healthy subjects. We hypothesized that functional interconnections between the thalamus and cortex can be altered after years of ongoing chronic neuropathic pain.ResultsFunctional connectivity was studied through a resting state functional magnetic resonance imaging (fMRI) paradigm: temporal correlations between predefined regions of interest (primary somatosensory cortex, ventral posterior lateral thalamic nucleus, medial dorsal thalamic nucleus) and the rest of the brain were systematically investigated. The patient group showed decreased resting state functional connectivity between the thalamus and the cortex.ConclusionThis supports the idea that chronic pain can alter thalamocortical connections causing a disruption of thalamic feedback, and the view of chronic pain as a thalamocortical dysrhythmia.

Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex

Unawareness of deficits is a symptom of Alzheimers disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimers disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimers disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimers disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.