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Previously, using simultaneous resting-state functional magnetic resonance imaging (fMRI) and photometry-based neuronal calcium recordings in the anesthetized rat, we identified blood oxygenation level-dependent (BOLD) responses directly related to slow calcium waves, revealing a cortex-wide and spatially organized correlate of locally recorded neuronal activity (Schwalm et al., 2017). Here, using the same techniques, we investigate two distinct cortical activity states: persistent activity, in which compartmentalized network dynamics were observed; and slow wave activity, dominated by a cortex-wide BOLD component, suggesting a strong functional coupling of inter-cortical activity. During slow wave activity, we find a correlation between the occurring slow wave events and the strength of functional connectivity between different cortical areas. These findings suggest that down-up transitions of neuronal excitability can drive cortex-wide functional connectivity. This study provides further evidence that changes in functional connectivity are dependent on the brain's current state, directly linked to the generation of slow waves.

Spontaneous slow oscillation-associated slow wave activity represents an internally generated state which is characterized by alternations of network quiescence and stereotypical episodes of neuronal activity - slow wave events. However, it remains unclear which macroscopic signal is related to these active periods of the slow wave rhythm. We used optic fiber-based calcium recordings of local neural populations in cortex and thalamus to detect neurophysiologically defined slow calcium waves in isoflurane anesthetized rats. The individual slow wave events were used for an event-related analysis of simultaneously acquired whole-brain BOLD fMRI. We identified BOLD responses directly related to onsets of slow calcium waves, revealing a cortex-wide BOLD correlate: the entire cortex was engaged in this specific type of slow wave activity. These findings demonstrate a direct relation of defined neurophysiological events to a specific BOLD activity pattern and were confirmed for ongoing slow wave activity by independent component and seed-based analyses. When a person is in a deep non-dreaming sleep, neurons in their brain alternate slowly between periods of silence and periods of activity. This gives rise to low-frequency brain rhythms called slow waves, which are thought to help stabilize memories. Slow wave activity can be detected on multiple scales, from the pattern of electrical impulses sent by an individual neuron to the collective activity of the brain’s entire outer layer, the cortex. But does slow wave activity in an individual group of neurons in the cortex affect the activity of the rest of the brain? To find out, Schwalm, Schmid, Wachsmuth et al. took advantage of the fact that slow waves also occur under general anesthesia, and placed anesthetized rats inside miniature whole-brain scanners. A small region of cortex in each rat had been injected with a dye that fluoresces whenever the neurons in that region are active. An optical fiber was lowered into the rat’s brain to transmit the fluorescence signals to a computer. Monitoring these signals while the animals lay inside the scanner revealed that slow-wave activity in any one group of cortical neurons was accompanied by slow-wave activity across the cortex as a whole. This relationship was seen only for slow waves, and not for other brain rhythms. Slow waves seem to occur in all species of animal with a backbone, and in both healthy and diseased brains. While it is not possible to inject fluorescent dyes into the human brain, it is possible to monitor neuronal activity using electrodes. Comparing local electrode recordings with measures of whole-brain activity from scanners could thus allow similar experiments to be performed in people. There is growing evidence – from animal models and from studies of patients – that slow waves may be altered in Alzheimer’s disease. Further work is required to determine whether detecting these changes could help diagnose disease at earlier stages, and whether reversing them may have therapeutic potential.

Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms. Huntington’s disease is a devastating brain disorder that causes severe mood disorders, problems with moving, and dementia. Most people develop the condition between their thirties and fifties, and die a decade or two after the symptoms first appear. The disease emerges because of a mutation in the gene for the Huntingtin protein, which leads to neurons slowly dying in the brain. While genetic testing can reveal who carries the faulty gene, no treatment addresses the root of the disorder or prevents it from appearing. Instead, most therapies for Huntington’s disease aim to reduce brain damage once the telltale symptoms are already present. However, the disease-causing protein is expressed early during the life of a patient, which could give it time to damage the brain long before neurons die and the disorder reveals itself. Treatments that start after the first signs of the disease may be too late to reverse the damage. Detecting and preventing early brain changes in people that carry the mutation may thus help to stop the disease from progressing. Here, Arnoux, Willam, Griesche et al. set out to detect the minute changes that the faulty Huntingtin protein may cause in the brain network of young mice with the mutation. State-of-the-art imaging tools helped to examine individual neurons in the brain area that processes visual information. These experiments revealed that a group of brain cells had become hyperactive; once this change had occurred, the mutant animals were less anxious than is typical for mice. Metformin is a drug used to treat diabetes, but it also interferes with a structure that is required to produce the disease-causing Huntingtin protein. Arnoux et al. therefore explored whether the compound could rescue the early brain alterations observed in mutant mice. Adding metformin in the water of the animals for three weeks halted the production of the mutant protein, reversed the brain changes and stopped the abnormal behavior. Further work is now required in humans to confirm that Huntington’s disease starts with a change in the activity of networks in the brain, and to verify that metformin can stop the disorder in its track.

•Neurons in a local cortical microcircuit are active exclusively in a slow wave event.•Visually evoked slow wave events travel from occipital to frontal cortical areas.•Integrating fast line scanning fMRI with photometry increases the sensitivity of fMRI.•Fast line scanning can resolve propagation dynamics of slow wave events.•Slow wave event-associated BOLD responses propagate continuously over the cortex. Population up-states, also referred to as slow wave events (SWEs), are a hallmark of the slow wave brain state in mammalian cortex, typically occurring during deep sleep or under certain types of anesthesia. We explore the neuronal recruitment and propagation of SWEs on observational scales ranging from single neurons to the entire cortex, intertwining optical and translationally relevant functional MRI (fMRI). By two-photon calcium imaging in mouse visual cortex, we demonstrate that all active cells of the observed local micronetwork participate in a population wide SWE. Implementing an optomagnetic-integration concept, involving simultaneous fiber photometry with fast cortical line-scanning fMRI in rats, we identify and follow propagating SWEs across the cortex. We can demonstrate continuous cortical propagation of a SWE by non-invasive line-scanning fMRI. This opens the door for monitoring the spatiotemporal dynamics of a neurophysiological-defined signal - here SWEs. Non-invasive monitoring of SWE propagation might represent a proxy for the functional integrity of local and global cortical networks in rodents and humans. [Display omitted]

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Inhibitory interneurons play central roles in the modulation of spontaneous network activity and in processing of neuronal information. In sensory neocortical areas, parvalbumin-positive (PV+) GABAergic interneurons control the representation and processing of peripheral sensory inputs. We studied the functional role of PV+ interneurons in the barrel cortex of anesthetized adult PVCre mice by combining extracellular multi-electrode recordings with optogenetic silencing of a small fraction of PV+ interneurons. In all cortical layers, optogenetic inhibition caused an increase in spontaneous network activity from theta to gamma frequencies. The spatio-temporal representation of sensory inputs was studied by stimulating one or two whiskers at different intervals and analyzing the resulting local field potential (LFP) and single unit (SU) response. Silencing PV+ interneurons caused an increase in LFP response to sensory stimulation and a decrease in temporal discrimination of consecutive whisker deflections. The combined effect of whisker deflection and optogenetic inhibition was highly similar to the linear sum of the individual effects of these two manipulations. SU recordings revealed that optogenetic silencing reduced stimulus detectability by increasing stimulus-evoked firing rate by a constant offset, suggesting that PV+ interneurons improve signal-to-noise ratio by reducing ongoing spiking activity, thereby sharpening the spatio-temporal representation of sensory stimuli.

We propose a pipeline for synthetic generation of personalized Computer Tomography (CT) images, with a radiation exposure evaluation and a lifetime attributable risk (LAR) assessment. We perform a patient-specific performance evaluation for a broad range of denoising algorithms (including the most popular deep learning denoising approaches, wavelets-based methods, methods based on Mumford–Shah denoising, etc.), focusing both on accessing the capability to reduce the patient-specific CT-induced LAR and on computational cost scalability. We introduce a parallel Probabilistic Mumford–Shah denoising model (PMS) and show that it markedly-outperforms the compared common denoising methods in denoising quality and cost scaling. In particular, we show that it allows an approximately 22-fold robust patient-specific LAR reduction for infants and a 10-fold LAR reduction for adults. Using a normal laptop, the proposed algorithm for PMS allows cheap and robust (with a multiscale structural similarity index >90%) denoising of very large 2D videos and 3D images (with over 107 voxels) that are subject to ultra-strong noise (Gaussian and non-Gaussian) for signal-to-noise ratios far below 1.0. The code is provided for open access.

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces (BCIs) should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions.

The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs.