Hierarchical organization of functional connectivity in the mouse brain: a complex network approach

This paper represents a contribution to the study of the brain functional connectivity from the perspective of complex networks theory. More specifically, we apply graph theoretical analyses to provide evidence of the modular structure of the mouse brain and to shed light on its hierarchical organization. We propose a novel percolation analysis and we apply our approach to the analysis of a resting-state functional MRI data set from 41 mice. This approach reveals a robust hierarchical structure of modules persistent across different subjects. Importantly, we test this approach against a statistical benchmark (or null model) which constrains only the distributions of empirical correlations. Our results unambiguously show that the hierarchical character of the mouse brain modular structure is not trivially encoded into this lower-order constraint. Finally, we investigate the modular structure of the mouse brain by computing the Minimal Spanning Forest, a technique that identifies subnetworks characterized by the strongest internal correlations. This approach represents a faster alternative to other community detection methods and provides a means to rank modules on the basis of the strength of their internal edges.Comment: 11 pages, 9 figure

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Default Mode Network as a Neural Substrate of Acupuncture: Evidence, Challenges and Strategy

Acupuncture is widely applied all over the world. Although the neurobiological underpinnings of acupuncture still remain unclear, accumulating evidence indicates significant alteration of brain activities in response to acupuncture. In particular, activities of brain regions in the default mode network (DMN) are modulated by acupuncture. DMN is crucial for maintaining physiological homeostasis and its functional architecture becomes disrupted in various disorders. But how acupuncture modulates brain functions and whether such modulation constitutes core mechanisms of acupuncture treatment are far from clear. This Perspective integrates recent literature on interactions between acupuncture and functional networks including the DMN, and proposes a back-translational research strategy to elucidate brain mechanisms of acupuncture treatment

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation

Polymer-coated superparamagnetic iron oxide nanoparticles as T-2 contrast agent for MRI and their uptake in liver

Aim: To study the efficiency of multifunctional polymer-based superparamagnetic iron oxide nanoparticles (bioferrofluids) as a T-2 magnetic resonance contrast agent and their uptake and toxicity in liver. Materials & methods: Mice were intravenously injected with bioferrofluids and Endorem (R). The magnetic resonance efficiency, uptake and in vivo toxicity were investigated by means of magnetic resonance imaging (MRI) and histological techniques. Results: Bioferrofluids are a good T-2 contrast agent with a higher r(2)/r(1) ratio than Endorem. Bioferrofluids have a shorter blood circulation time and persist in liver for longer time period compared with Endorem. Both bioferrofluids and Endorem do not generate any noticeable histological lesions in liver over a period of 60 days post-injection. Conclusion: Our bioferrofluids are powerful diagnostic tool without any observed toxicity over a period of 60 days post-injection. Lay abstract: Several superparamagnetic iron oxide nanoparticles (SPIONs) preparations have been approved by US FDA for clinical use as MRI contrast agents. In recent years, we have been developing a synthetic multifunctional platform for SPIONs based on the use of polymers. In this report, we explored the diagnostic potential of these nanoparticles (herein called bioferrofluids) as an MRI contrast agent and their uptake in liver, without neglecting their toxicological effects. Results show that our bioferrofluids are a good T-2 contrast agent without any observed toxicity in liver

Functional ultrasound reveals effects of MRI acoustic noise on brain function

Loud acoustic noise from the scanner during functional magnetic resonance imaging (fMRI) can affect functional connectivity (FC) observed in the resting state, but the exact effect of the MRI acoustic noise on resting state FC is not well understood. Functional ultrasound (fUS) is a neuroimaging method that visualizes brain activity based on relative cerebral blood volume (rCBV), a similar neurovascular coupling response to that measured by fMRI, but without the audible acoustic noise. In this study, we investigated the effects of different acoustic noise levels (silent, 80 dB, and 110 dB) on FC by measuring resting state fUS (rsfUS) in awake mice in an environment similar to fMRI measurement. Then, we compared the results to those of resting state fMRI (rsfMRI) conducted using an 11.7 Tesla scanner. RsfUS experiments revealed a significant reduction in FC between the retrosplenial dysgranular and auditory cortexes (0.56 ± 0.07 at silence vs 0.05 ± 0.05 at 110 dB, p=.01) and a significant increase in FC anticorrelation between the infralimbic and motor cortexes (−0.21 ± 0.08 at silence vs −0.47 ± 0.04 at 110 dB, p=.017) as acoustic noise increased from silence to 80 dB and 110 dB, with increased consistency of FC patterns between rsfUS and rsfMRI being found with the louder noise conditions. Event-related auditory stimulation experiments using fUS showed strong positive rCBV changes (16.5% ± 2.9% at 110 dB) in the auditory cortex, and negative rCBV changes (−6.7% ± 0.8% at 110 dB) in the motor cortex, both being constituents of the brain network that was altered by the presence of acoustic noise in the resting state experiments. Anticorrelation between constituent brain regions of the default mode network (such as the infralimbic cortex) and those of task-positive sensorimotor networks (such as the motor cortex) is known to be an important feature of brain network antagonism, and has been studied as a biological marker of brain disfunction and disease. This study suggests that attention should be paid to the acoustic noise level when using rsfMRI to evaluate the anticorrelation between the default mode network and task-positive sensorimotor network.journal articl

Structural Basis of Large-Scale Functional Connectivity in the Mouse

Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients