The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice.

In Alzheimer's disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer's disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus-encompassing dorsal HIP-SS communication-in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

Functional Disconnectivity during Inter-Task Resting State in Dementia with Lewy Bodies.

AIMS: Limited research has been done on the functional connectivity in visuoperceptual regions in dementia with Lewy bodies (DLB) patients. This study aimed to investigate the functional connectivity differences between a task condition and an inter-task resting state condition within a visuoperceptual paradigm, in DLB patients compared with Alzheimer disease (AD) patients and healthy elderly control subjects. METHODS: Twenty-six DLB, 29 AD, and 22 healthy subjects underwent a detailed clinical and neuropsychological examination along with a functional MRI during the different conditions of a visuoperceptual paradigm. Functional images were analyzed using group-level spatial independent component analysis and seed-based connectivity analyses. RESULTS: While the DLB patients scored well and did not differ from the control and AD groups in terms of functional activity and connectivity during the task conditions, they showed decreased functional connectivity in visuoperceptual regions during the resting state condition, along with a temporal impairment of the default-mode network activity. Functional connectivity disturbances were also found within two attentional-executive networks and between these networks and visuoperceptual regions. CONCLUSION: We found a specific functional profile in the switching between task and resting state conditions in DLB patients. This result could help better characterize functional impairments in DLB and their contribution to several core symptoms of this pathology such as visual hallucinations and cognitive fluctuations.

Benefits from an autobiographical memory facilitation programme in relapsing-remitting multiple sclerosis patients: a clinical and neuroimaging study.

While the efficacy of mental visual imagery (MVI) to alleviate autobiographical memory (AM) impairment in multiple sclerosis (MS) patients has been documented, nothing is known about the brain changes sustaining that improvement. To explore this issue, 20 relapsing-remitting MS patients showing AM impairment were randomly assigned to two groups, experimental (n = 10), who underwent the MVI programme, and control (n = 10), who followed a sham verbal programme. Besides the stringent AM assessment, the patients underwent structural and functional MRI sessions, consisting in retrieving personal memories, within a pre-/post-facilitation study design. Only the experimental group showed a significant AM improvement in post-facilitation, accompanied by changes in brain activation (medial and lateral frontal regions), functional connectivity (posterior brain regions), and grey matter volume (parahippocampal gyrus). Minor activations and functional connectivity changes were observed in the control group. The MVI programme improved AM in MS patients leading to functional and structural changes reflecting (1) an increase reliance on brain regions sustaining a self-referential process; (2) a decrease of those reflecting an effortful research process; and (3) better use of neural resources in brain regions sustaining MVI. Functional changes reported in the control group likely reflected ineffective attempts to use the sham strategy in AM.

Functional and structural cerebral changes in key brain regions after a facilitation programme for episodic future thought in relapsing-remitting multiple sclerosis patients.

Increasingly studied, episodic future thought (EFT) impairment negatively affects patients' daily life. Along these lines, working with relapsing-remitting multiple sclerosis (RR-MS) patients, we documented the clinical effectiveness of a mental visual imagery (MVI)-based facilitation programme on EFT impairment related to executive function difficulties. We aimed at improving the characterisation of the cognitive and neural underpinnings of RR-MS patients' EFT amelioration, by exploring the structural and functional brain changes following the MVI programme. Seventeen non-depressed RR-MS patients were recruited and randomly assigned in the (i) experimental group (n=10), who followed the MVI programme or in the control group (n=7), who followed a verbal control programme. Using an adapted version of the Autobiographical Interview to assess EFT, after facilitation, significant improvement was observed in the experimental group only. This was accompanied by increased activation in the prefrontal region during the generation of future events and was positively correlated with grey matter volume increase in this same brain area. Increased activations in the parahippocampal and the middle temporal gyri were also observed in the experimental group in post-facilitation. Likewise, functional connectivity changes were observed in the posterior brain regions after facilitation. Only minor cerebral changes were observed in the control group, likely reflecting practice effects. Our study showed that EFT improvement following the MVI programme led to functional and structural changes in brain regions sustaining contextual processing, visual imagery, the integration and maintenance of multimodal information. Taken together, these findings suggest that a cognitive intervention focusing on scene construction can be efficient to alleviate EFT impairment related to executive dysfunction. As such, this study opens the way to the development of tailor-made rehabilitation programmes using the different cognitive mechanisms involved in EFT.

Manipulating ΔFOSB in D1-Type Medium Spiny Neurons of the Nucleus Accumbens Reshapes Whole-Brain Functional Connectivity.

BACKGROUND: The transcription factor ΔFOSB, acting in the nucleus accumbens, has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain, which are required for its regulation of complex behavior, remain unknown. METHODS: We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene and thereby decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the nucleus accumbens and tested whether these modifications affect the organization of functional connectivity (FC) in the brain. We acquired functional magnetic resonance imaging data at rest and in response to a morphine challenge and analyzed both stationary and dynamic FC patterns. RESULTS: The 2 manipulations modified brainwide communication markedly and differently. ΔFOSB down- and upregulation had overlapping effects on prefrontal- and retrosplenial cortex-centered networks, but also generated specific FC signatures for epithalamus (habenula) and dopaminergic/serotonergic centers, respectively. Analysis of dynamic FC patterns showed that increasing ΔFOSB essentially altered responsivity to morphine and uncovered striking modifications of the roles of the epithalamus and amygdala in brain communication, particularly upon ΔFOSB downregulation. CONCLUSIONS: These novel findings illustrate how it is possible to link activity of a transcription factor within a single cell type of an identified brain region to consequent changes in circuit function brainwide by use of functional magnetic resonance imaging, and they pave the way for fundamental advances in bridging the gap between transcriptional and brain connectivity mechanisms underlying opioid addiction.

MFCSC: Novel method to calculate mismatch between functional and structural brain connectomes, and its application for detecting hemispheric functional specialisations.

We introduce a novel connectomics method, MFCSC, that integrates information on structural connectivity (SC) from diffusion MRI tractography and functional connectivity (FC) from functional MRI, at individual subject level. The MFCSC method is based on the fact that SC only broadly predicts FC, and for each connection in the brain, the method calculates a value that quantifies the mismatch that often still exists between the two modalities. To capture underlying physiological properties, MFCSC minimises biases in SC and addresses challenges with the multimodal analysis, including by using a data-driven normalisation approach. We ran MFCSC on data from the Human Connectome Project and used the output to detect pairs of left and right unilateral connections that have distinct relationship between structure and function in each hemisphere; we suggest that this reflects cases of hemispheric functional specialisation. In conclusion, the MFCSC method provides new information on brain organisation that may not be inferred from an analysis that considers SC and FC separately.

Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity.

BACKGROUND: Opioid use disorder is a chronic relapsing disorder. The brain adapts to opioids that are taken for pain treatment or recreational use so that abstinence becomes a true challenge for individuals with opioid use disorder. Studying brain dysfunction at this stage is difficult, and human neuroimaging has provided highly heterogeneous information. METHODS: Here, we took advantage of an established mouse model of morphine abstinence together with functional magnetic resonance imaging to investigate whole-brain functional connectivity (FC) first at rest and then in response to an acute morphine challenge during image acquisition. RESULTS: Hierarchical clustering of seed pair correlation coefficients showed modified FC in abstinent animals, brainwide and regardless of the condition. Seed-to-voxel analysis and random forest classification, performed on data at rest, indicated that the retrosplenial cortex (a core component of the default mode network) and the amygdala (a major aversion center) are the best markers of abstinence, thus validating the translatability of the study. Seed pair network clustering confirmed disruption of a retrosplenial cortex-centered network, reflecting major reorganization of brain FC. The latter analysis also identified a persistent but unreported morphine signature in abstinent mice at rest, which involves cortical and midbrain components and characterizes the enduring morphine footprint. Finally, dynamic FC analysis revealed that the intrascanner acute morphine challenge modified FC faster and more broadly in abstinent animals, demonstrating brainwide adaptations of FC reactivity to an acute opioid challenge. CONCLUSIONS: This study used a unique experimental design to demonstrate that a prior history of chronic opioid exposure leaves a durable pharmacological signature on brain communication, with implications for pain management and recovery from opioid use disorder.

Thinking versus feeling: How interoception and cognition influence emotion recognition in behavioural-variant frontotemporal dementia, Alzheimer's disease, and Parkinson's disease.

Disease-specific mechanisms underlying emotion recognition difficulties in behavioural-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and Parkinson's disease (PD) are unknown. Interoceptive accuracy, accurately detecting internal cues (e.g., one's heart beating), and cognitive abilities are candidate mechanisms underlying emotion recognition. One hundred and sixty-eight participants (52 bvFTD; 41 AD; 24 PD; 51 controls) were recruited. Emotion recognition was measured via the Facial Affect Selection Task or the Mini-Social and Emotional Assessment Emotion Recognition Task. Interoception was assessed with a heartbeat detection task. Participants pressed a button each time they: 1) felt their heartbeat (Interoception); or 2) heard a recorded heartbeat (Exteroception-control). Cognition was measured via the Addenbrooke's Cognitive Examination-III or the Montreal Cognitive Assessment. Voxel-based morphometry analyses identified neural correlates associated with emotion recognition and interoceptive accuracy. All patient groups showed worse emotion recognition and cognition than controls (all P's ≤ .008). Only the bvFTD showed worse interoceptive accuracy than controls (P < .001). Regression analyses revealed that in bvFTD worse interoceptive accuracy predicted worse emotion recognition (P = .008). Whereas worse cognition predicted worse emotion recognition overall (P < .001). Neuroimaging analyses revealed that the insula, orbitofrontal cortex, and amygdala were involved in emotion recognition and interoceptive accuracy in bvFTD. Here, we provide evidence for disease-specific mechanisms for emotion recognition difficulties. In bvFTD, emotion recognition impairment is driven by inaccurate perception of the internal milieu. Whereas, in AD and PD, cognitive impairment likely underlies emotion recognition deficits. The current study furthers our theoretical understanding of emotion and highlights the need for targeted interventions.

Brain perfusion in dementia with Lewy bodies and Alzheimer's disease: an arterial spin labeling MRI study on prodromal and mild dementia stages.

BACKGROUND: We aimed to describe specific changes in brain perfusion in patients with dementia with Lewy bodies (DLB) at both the prodromal (also called mild cognitive impairment) and mild dementia stages, relative to patients with Alzheimer's disease (AD) and controls. METHODS: Altogether, 96 participants in five groups (prodromal DLB, prodromal AD, DLB with mild dementia, AD with mild dementia, and healthy elderly controls) took part in an arterial spin labeling MRI study. Three analyses were performed: a global perfusion value comparison, a voxel-wise analysis of both absolute and relative perfusion, and a linear discriminant analysis. These were used to assess the global decrease in perfusion, regional changes, and the sensitivity and specificity of these changes. RESULTS: Patterns of perfusion in DLB differed from AD and controls in both the prodromal stage and dementia, DLB having more deficits in frontal, insular, and temporal cortices whereas AD showed reduced perfusion in parietal and parietotemporal cortices. Decreases but also increases of perfusion in DLB relative to controls were observed in both absolute and relative measurements. All these regional changes of perfusion classified DLB patients with respect to either healthy controls or AD with sensitivity from 87 to 100 % and specificity from 90 to 96 % depending on the stage of the disease. CONCLUSIONS: Our results are consistent with previous studies. We extend the scope of those studies by integrating prodromal DLB patients and by describing both hypo- and hyperperfusion in DLB. While decreases in perfusion may relate to functional impairments, increases might suggest a functional compensation of some brain areas.

Identifying Dynamic Functional Connectivity Changes in Dementia with Lewy Bodies Based on Product Hidden Markov Models.

Exploring time-varying connectivity networks in neurodegenerative disorders is a recent field of research in functional MRI. Dementia with Lewy bodies (DLB) represents 20% of the neurodegenerative forms of dementia. Fluctuations of cognition and vigilance are the key symptoms of DLB. To date, no dynamic functional connectivity (DFC) investigations of this disorder have been performed. In this paper, we refer to the concept of connectivity state as a piecewise stationary configuration of functional connectivity between brain networks. From this concept, we propose a new method for group-level as well as for subject-level studies to compare and characterize connectivity state changes between a set of resting-state networks (RSNs). Dynamic Bayesian networks, statistical and graph theory-based models, enable one to learn dependencies between interacting state-based processes. Product hidden Markov models (PHMM), an instance of dynamic Bayesian networks, are introduced here to capture both statistical and temporal aspects of DFC of a set of RSNs. This analysis was based on sliding-window cross-correlations between seven RSNs extracted from a group independent component analysis performed on 20 healthy elderly subjects and 16 patients with DLB. Statistical models of DFC differed in patients compared to healthy subjects for the occipito-parieto-frontal network, the medial occipital network and the right fronto-parietal network. In addition, pairwise comparisons of DFC of RSNs revealed a decrease of dependency between these two visual networks (occipito-parieto-frontal and medial occipital networks) and the right fronto-parietal control network. The analysis of DFC state changes thus pointed out networks related to the cognitive functions that are known to be impaired in DLB: visual processing as well as attentional and executive functions. Besides this context, product HMM applied to RSNs cross-correlations offers a promising new approach to investigate structural and temporal aspects of brain DFC.