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The goal of this study was to identify features in mouse electrocorticogram recordings that indicate the depth of anesthesia as approximated by the administered anesthetic dosage. Anesthetic depth in laboratory animals must be precisely monitored and controlled. However, for the most common lab species (mice) few indicators useful for monitoring anesthetic depth have been established. We used electrocorticogram recordings in mice, coupled with peripheral stimulation, in order to identify features of brain activity modulated by isoflurane anesthesia and explored their usefulness in monitoring anesthetic depth through machine learning techniques. Using a gradient boosting regressor framework we identified interhemispheric somatosensory coherence as the most informative and reliable electrocorticogram feature for determining anesthetic depth, yielding good generalization and performance over many subjects. Knowing that interhemispheric somatosensory coherence indicates the effectively administered isoflurane concentration is an important step for establishing better anesthetic monitoring protocols and closed-loop systems for animal surgeries., Frontiers in Neuroinformatics, 16, ISSN:1662-5196

Real-time analysis and classification of bio-signals measured using wearable devices is computationally costly and requires dedicated low-power hardware. One promising approach is to use spiking neural networks implemented using in-memory computing architectures and neuromorphic electronic circuits. However, as these circuits process data in streaming mode without the possibility of storing it in external buffers, a major challenge lies in the processing of spatio-temporal signals that last longer than the time constants present in the network synapses and neurons. Here we propose to extend the memory capacity of a spiking neural network by using parallel delay chains. We show that it is possible to map temporal signals of multiple seconds into spiking activity distributed across multiple neurons which have time constants of few milliseconds. We validate this approach on an ECG anomaly detection task and present experimental results that demonstrate how temporal information is properly preserved in the network activity.

Brain-inspired event-based neuromorphic processing systems have emerged as a promising technology in particular for bio-medical circuits and systems. However, both neuromorphic and biological implementations of neural networks have critical energy and memory constraints. To minimize the use of memory resources in multi-core neuromorphic processors, we propose a network design approach inspired by biological neural networks. We use this approach to design a new routing scheme optimized for small-world networks and, at the same time, to present a hardware-aware placement algorithm that optimizes the allocation of resources for small-world network models. We validate the algorithm with a canonical small-world network and present preliminary results for other networks derived from it, arXiv admin note: substantial text overlap with arXiv:2203.00655

Funder: Academy of Medical Sciences; Id: http://dx.doi.org/10.13039/501100000691, Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272, Funder: University College London; Id: http://dx.doi.org/10.13039/501100000765, Funder: Neuroscience Center Zurich, University of Zurich, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155, Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269, Manganese neurotoxicity is a hallmark of hypermanganesemia with dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity, we performed transcriptome analysis of slc39a14-/- mutant zebrafish that were exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that Ca2+ dyshomeostasis and activation of the unfolded protein response are key features of manganese neurotoxicity. Consistent with this interpretation, MnCl2 exposure led to decreased whole-animal Ca2+ levels, locomotor defects and changes in neuronal activity within the telencephalon and optic tectum. In accordance with reduced tectal activity, slc39a14-/- zebrafish showed changes in visual phototransduction gene expression, absence of visual background adaptation and a diminished optokinetic reflex. Finally, numerous differentially expressed genes in mutant larvae normalised upon MnCl2 treatment indicating that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. Overall, we assembled a comprehensive set of genes that mediate manganese-systemic responses and found a highly correlated and modulated network associated with Ca2+ dyshomeostasis and cellular stress. This article has an associated First Person interview with the first author of the paper.

Predictability is a prerequisite for effective human control of artificial intelligence (AI). For example, the inability to predict the malfunctioning of AI impedes timely human intervention. In this paper, we employ a computerized navigation task, a lunar lander game, to investigate empirically how AI's predictability compares to humans' predictability. To this end, we ask participants to guess whether the landings of a spaceship in this game performed by AI and humans will succeed. We show that humans are worse at predicting AI performance than at predicting human performance in this environment. Significantly, participants underestimate the differences in the relative predictability of AI and, at times, overestimate their prediction skills. We link the difference in predictability to differences in the approaches, i.e. different landing patterns, employed by AI and humans to succeed in the task. These results highlight important differences in perception of AI and human with implications for human-computer interaction.

The hippocampus of many mammals contains a histoarchitectural region that is not present in laboratory mice and rats—the reflected blade of the CA3 pyramidal cell layer. Pyramidal cells of the reflected blade do not extend dendrites into the hippocampal molecular layer, and recent evidence indicates that they, like the proximal CA3 pyramids in laboratory rats and mice, partially integrate functionally with the dentate circuitry in pattern separation. Quantitative assessments of phylogenetic or disease-related changes in the hippocampal structure and function treat the reflected blade heterogeneously. Depending on the ease with which it can be differentiated, it is either assigned to the dentate hilus or to the remainder of CA3. Here, we investigate the impact that the differential assignment of reflected blade neurons may have on the outcomes of quantitative comparisons. We find it to be massive. If reflected blade neurons are treated as a separate entity or pooled with dentate hilar cells, the quantitative makeup of hippocampal cell populations can differentiate between species in a taxonomically sensible way. Assigning reflected blade neurons to CA3 greatly diminishes the differentiating power of all hippocampal principal cell populations, which may point towards a quantitative hippocampal archetype. A heterogeneous assignment results in a differentiation pattern with little taxonomic semblance. The outcomes point towards the reflected blade as either a major potential player in hippocampal functional and structural differentiation or a region that may have cloaked that hippocampi are more similarly organized across species than generally believed., Frontiers in Neuroanatomy, 16, ISSN:1662-5129

Artificial vision systems of autonomous agents face very difficult challenges, as their vision sensors are required to transmit vast amounts of information to the processing stages, and to process it in real-time. One first approach to reduce data transmission is to use event-based vision sensors, whose pixels produce events only when there are changes in the input. However, even for event-based vision, transmission and processing of visual data can be quite onerous. Currently, these challenges are solved by using high-speed communication links and powerful machine vision processing hardware. But if resources are limited, instead of processing all the sensory information in parallel, an effective strategy is to divide the visual field into several small sub-regions, choose the region of highest saliency, process it, and shift serially the focus of attention to regions of decreasing saliency. This strategy, commonly used also by the visual system of many animals, is typically referred to as ``selective attention''. Here we present a digital architecture implementing a saliency-based selective visual attention model for processing asynchronous event-based sensory information received from a DVS. For ease of prototyping, we use a standard digital design flow and map the architecture on an FPGA. We describe the architecture block diagram highlighting the efficient use of the available hardware resources demonstrated through experimental results exploiting a hardware setup where the FPGA interfaced with the DVS camera., Comment: 5 pages, 5 figures

Anorexia nervosa (AN) is difficult to treat with up to half of patients failing to gain weight during treatment. Neurobiological factors predicting treatment response in AN are poorly understood. In this longitudinal study, we aimed to identify morphological characteristics in the grey matter which predict treatment success in patients with AN. Fifty patients with severe AN participated in an eating disorder-specific inpatient treatment. On admission, T1-weighted magnetic resonance images were acquired from all patients. Half of the patients successfully gained weight, reaching a body-mass index ≥ 17.5 kg/m2. Using voxel-based morphometry, local grey matter volumes were compared between the two groups of patients who gained weight and those who did not. This approach allowed us to identify anatomical characteristics which predict treatment success in terms of post-treatment weight status. Patients who did not reach the weight threshold at discharge had a smaller volume in the right cerebellar crus I at the time of admission. In this group, smaller volume was associated with a greater alexithymia score. The findings suggest that a trophic state within the cerebellum before treatment might be prognostic for treatment success. Consistent with previous reports, this result further substantiates the possible role of the cerebellum in the psychopathology of AN.

Embodiment research is at a turning point. There is an increasing amount of data and studies investigating embodiment phenomena and their role in mental processing and functions from across a wide range of disciplines and theoretical schools within the life sciences. However, the integration of behavioral data with data from different biological levels is challenging for the involved research fields such as movement psychology, social and developmental neuroscience, computational psychosomatics, social and behavioral epigenetics, human-centered robotics, and many more. This highlights the need for an interdisciplinary framework of embodiment research. In addition, there is a growing need for a cross-disciplinary consensus on level-specific criteria of embodiment. We propose that a developmental perspective on embodiment is able to provide a framework for overcoming such pressing issues, providing analytical tools to link timescales and levels of embodiment specific to the function under study, uncovering the underlying developmental processes, clarifying level-specific embodiment criteria, and providing a matrix and platform to bridge disciplinary boundaries among the involved research fields., Frontiers in Systems Neuroscience, 15, ISSN:1662-5137

We derive a theoretical construct that allows for the characterisation of both scalable and scale free systems within the dynamic causal modelling (DCM) framework. We define a dynamical system to be “scalable” if the same equation of motion continues to apply as the system changes in size. As an example of such a system, we simulate planetary orbits varying in size and show that our proposed methodology can be used to recover Kepler’s third law from the timeseries. In contrast, a “scale free” system is one in which there is no characteristic length scale, meaning that images of such a system are statistically unchanged at different levels of magnification. As an example of such a system, we use calcium imaging collected in murine cortex and show that the dynamical critical exponent, as defined in renormalization group theory, can be estimated in an empirical biological setting. We find that a task-relevant region of the cortex is associated with higher dynamical critical exponents in task vs. spontaneous states and vice versa for a task-irrelevant region.

Significance: The reliability of functional near-infrared spectroscopy (fNIRS) measurements is reduced by systemic physiology. Short-channel regression algorithms aim at removing systemic “noise” by subtracting the signal measured at a short source–detector separation (mainly scalp hemodynamics) from the one of a long separation (brain and scalp hemodynamics). In literature, incongruent approaches on the selection of the optimal regressor signal are reported based on different assumptions on scalp hemodynamics properties. Aim: We investigated the spatial and temporal distribution of scalp hemodynamics over the sensorimotor cortex and evaluated its influence on the effectiveness of short-channel regressions. Approach: We performed hand-grasping and resting-state experiments with five subjects, measuring with 16 optodes over sensorimotor areas, including eight 8-mm channels. We performed detailed correlation analyses of scalp hemodynamics and evaluated 180 hand-grasping and 270 simulated (overlaid on resting-state measurements) trials. Five short-channel regressor combinations were implemented with general linear models. Three were chosen according to literature, and two were proposed based on additional physiological assumptions [considering multiple short channels and their Mayer wave (MW) oscillations]. Results: We found heterogeneous hemodynamics in the scalp, coming on top of a global close-to-homogeneous behavior (correlation 0.69 to 0.92). The results further demonstrate that short-channel regression always improves brain activity estimates but that better results are obtained when heterogeneity is assumed. In particular, we highlight that short-channel regression is more effective when combining multiple scalp regressors and when MWs are additionally included. Conclusion: We shed light on the selection of optimal regressor signals for improving the removal of systemic physiological artifacts in fNIRS. We conclude that short-channel regression is most effective when assuming heterogeneous hemodynamics, in particular when combining spatial- and frequency-specific information. A better understanding of scalp hemodynamics and more effective short-channel regression will promote more accurate assessments of functional brain activity in clinical and research settings., Neurophotonics, 7 (03)

Aberrant emotion processing is a core characteristic of panic disorder (PD). Findings concerning the underlying neural pathways remain inconsistent. We applied functional magnetic resonance imaging (fMRI) in the context of a task based on the circumplex model of affect. This model links affective states to two underlying neurophysiological systems: arousal and valence. Twenty-two healthy participants and 20 participants with PD rated arousal and valence in response to affective faces during fMRI. In healthy controls, we found that arousal modulated the hemodynamic response in the parahippocampus, the ventromedial prefrontal cortex and the cuneus during face perception. Valence and extreme ratings of valence modulated the hemodynamic response in temporal, parietal, somatosensory, premotor and cerebellar regions. Comparing healthy controls to participants with PD, we found that healthy controls showed a stronger modulation of the hemodynamic response during face perception associated with extreme ratings of valence in the parahippocampus and the supplementary motor area. This suggests parahippocampal dysfunction in the processing of highly valenced affective faces in PD, which may underlie aberrant contextualization of strong affective stimuli. Our findings need to be interpreted with care as they were adjusted for multiple comparisons using a liberal correction procedure.

Large-scale research integration is contingent on seamless access to data in standardized formats. Standards enable researchers to understand external experiment structures, pool results, and apply homogeneous preprocessing and analysis workflows. Particularly, they facilitate these features without the need for numerous potentially confounding compatibility add-ons. In small animal magnetic resonance imaging, an overwhelming proportion of data is acquired via the ParaVision software of the Bruker Corporation. The original data structure is predominantly transparent, but fundamentally incompatible with modern pipelines. Additionally, it sources metadata from free-field operator input, which diverges strongly between laboratories and researchers. In this article we present an open-source workflow which automatically converts and reposits data from the ParaVision structure into the widely supported and openly documented Brain Imaging Data Structure (BIDS). Complementing this workflow we also present operator guidelines for appropriate ParaVision data input, and a programmatic walk-through detailing how preexisting scans with uninterpretable metadata records can easily be made compliant after the acquisition., Frontiers in Neuroinformatics, 14, ISSN:1662-5196

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the stratum corneum. It results from mutations in the SPINK5 gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of Spink5 knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the stratum corneum and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes in vivo and in vitro, respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients. This article has an associated First Person interview with the first author of the paper., Summary: Nrf2 activation ameliorates the epidermal barrier defect and cutaneous inflammation in a mouse model of Netherton syndrome, suggesting the utility of NRF2-activating compounds in patients with this genetic disease.

Human intelligence has been theorized since the ancient Greeks. Plato and Aristotle incorporated theories of human intelligence into their metaphysical and cosmological theories which informed the social and medical sciences for centuries. With the advent of the 20th century, human intelligence became increasingly standardized based on Intelligence Quotients (IQ). Moreover, multiple theories of human intelligence were posited on morphological features of the human brain, focusing on cranial volume and size of the pre-frontal cortex which was suggestive of superior human cognitive abilities. This article argues that fixation with anatomical features of the brain was tended to ignore the importance of neuro-hormonal regulation which is a more appropriate indicator of human cognitive abilities. The article challenges the correlation between brain size and human cognitive abilities while offering an alternate theory of human cognitive abilities which emphasizes the roles of neurotransmitters, neurotrophins, and enteric gut microbiome (EGM) regulation.

Significance: Our study reveals that frontal cerebral oxygenation asymmetry (FCOA), i.e. a difference in the oxygenation between the right and left prefrontal cortex (PFC), is a real phenomenon in healthy human subjects at rest. Aim: To investigate FCOA, we performed a study with 134 healthy right-handed subjects with the systemic physiology augmented functional near infrared spectroscopy (SPA-fNIRS) approach. Approach: Subjects were measured 2 to 4 times on different days resulting in an unprecedented number of 518 single measurements of the absolute values of tissue oxygen saturation ( ) and total hemoglobin concentration ([tHb]) of the right and left PFC. Measurements were performed with frequency-domain functional near-infrared spectroscopy. In addition, the cardiorespiratory parameters were measured simultaneously. Results: We found that (i) subjects showed an FCOA (higher on the right PFC), but not for tHb; (ii) intrasubject variability was excellent for both and tHb, and fair for FCOA; (iii) correlated significantly with blood concentration, [tHb] with heart rate, respiration rate (RR), and the pulse-respiration quotient (PRQ), and FCOA with RR and PRQ; (iv) FCOA and were dependent on season and time of day, respectively; (v) FCOA was negatively correlated with the room temperature; and (vi) and tHb were not correlated with the subjects mood but with their chronotype, whereas FCOA was not dependent on the chronotype. Conclusion: Our study demonstrates that FCOA is real, and it provides unique insights into this remarkable phenomenon.

How neurovascular coupling develops in preterm-born neonates has been largely neglected in scientific research. We measured visually evoked (flicker light) hemodynamic responses (HRs) in preterm-born neonates ( n = 25 , gestational age: 31.71 ± 3.37 weeks, postnatal age: 25.48 ± 23.94 days) at the visual cortex (VC) and left frontotemporal lobe (FTL) using functional near-infrared spectroscopy (fNIRS) neuroimaging. We found that the HR characteristics show a large intersubject variability but could be classified into three groups according to the changes of oxyhemoglobin concentration at the VC [(A) increase, (B) decrease, or (C) inconclusive]. In groups A and B, the HRs at the left FTL were correlated with those at the VC, indicating the presence of a frontotemporal-occipital functional connectivity. Neonates in group A had a higher weight at measurement compared to those in group B, and had the lowest baseline total hemoglobin concentration and hematocrit compared to group C. To the best of our knowledge, this is the first fNIRS study showing (1) that the HRs of preterm-born neonates need to be classified into subgroups, (2) that the subgroups differed in terms of weight at measurement, and (3) that HRs can be observed also at the FTL during visual stimulation. These findings add insights into how neurovascular coupling develops in preterm-born neonates.

Spontaneous canine simple mammary carcinomas (mCA) are often viewed as models of human mCA. Cancer-associated stroma (CAS) is central for initiation and progression of human cancer, and is likely to play a key role in canine tumours as well. However, canine CAS lacks characterisation and it remains unclear how canine and human CAS compare. Formalin-fixed paraffin embedded (FFPE) tissue constitutes a valuable resource of patient material, but chemical crosslinking has largely precluded its analysis by next-generation RNA sequencing (RNAseq). We have recently established a protocol to isolate CAS and normal stroma from archival FFPE tumours using laser-capture microdissection followed by RNAseq. Using this approach, we have analysed stroma from 15 canine mCA. Our data reveal strong reprogramming of canine CAS. We demonstrate a high-grade molecular homology between canine and human CAS, and show that enrichment of upregulated canine CAS genes strongly correlates with the enrichment of an independently derived human stromal signature in the TCGA breast tumour dataset. Relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Finally, we establish the prognostic potential of the canine CAS signature in human samples, emphasising the relevance of studying canine CAS as a model of the human disease. In conclusion, we provide a proof-of-principle to analyse specific subsections of FFPE tissue by RNAseq, and compare stromal gene expression between human and canine mCA to reveal molecular drivers in CAS supporting tumour growth and malignancy., Summary: This study offers proof-of-principle for a novel protocol to analyse gene expression in subsections of FFPE patient tissue, supporting the use of spontaneous canine mammary tumours as models for the human disease.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

The inherent complexity of brain tissue, with brain cells intertwining locally and projecting to distant regions, has made three-dimensional visualization of intact brains a highly desirable but challenging task in neuroscience. The natural opaqueness of tissue has traditionally limited researchers to techniques short of single cell resolution such as computer tomography or magnetic resonance imaging. By contrast, techniques with single-cell resolution required mechanical slicing into thin sections, which entails tissue distortions that severely hinder accurate reconstruction of large volumes. Recent developments in tissue clearing and light sheet microscopy have made it possible to investigate large volumes at micrometer resolution. The value of tissue clearing has been shown in a variety of tissue types and animal models. However, its potential for examining the songbird brain remains unexplored. Songbirds are an established model system for the study of vocal learning and sensorimotor control. They share with humans the capacity to adapt vocalizations based on auditory input. Song learning and production are controlled in songbirds by the song system, which forms a network of interconnected discrete brain nuclei. Here, we use the CUBIC and iDISCO+ protocols for clearing adult songbird brain tissue. Combined with light sheet imaging, we show the potential of tissue clearing for the investigation of connectivity between song nuclei, as well as for neuroanatomy and brain vasculature studies., Frontiers in Neuroanatomy, 13, ISSN:1662-5129

The prosomeric brain model contemplates progressive regionalization of the central nervous system (CNS) from a molecular and morphological ontogenetic perspective. It defines the forebrain axis relative to the notochord, and contemplates intersecting longitudinal (zonal, columnar) and transversal (neuromeric) patterning mechanisms. A checkboard pattern of histogenetic units of the neural wall results, where each unit is differentially fated by an unique profile of active genes. These natural neural units later expand their radial dimension during neurogenesis, histogenesis, and correlative differential morphogenesis. This fundamental topologic framework is shared by all vertebrates, as a Bauplan, each lineage varying in some subtle aspects. So far the prosomeric model has been applied only to neural structures, but we attempt here a prosomeric analysis of the hypothesis that major vessels invade the brain wall in patterns that are congruent with its intrinsic natural developmental units, as postulated in the prosomeric model. Anatomic and embryologic studies of brain blood vessels have classically recorded a conserved pattern of branches (thus the conventional terminology), and clinical experience has discovered a standard topography of many brain arterial terminal fields. Such results were described under assumptions of the columnar model of the forebrain, prevalent during the last century, but this is found insufficient in depth and explanatory power in the modern molecular scenario. We have thus explored the possibility that brain vascularization in rodents and humans may relate systematically to genoarchitectonic forebrain subdivisions contemplated in the prosomeric model. Specifically, we examined first whether early vascular invasion of some molecularly characterized prosomeric domains shows heterochrony. We indeed found a heterochronic pattern of vascular invasion that distinguishes between adjacent brain areas with differential molecular profiles. We next mapped topologically on the prosomeric model the major arterial branches serving the human brain. The results of this approach bear on the possibility of a developmentally-based modern arterial terminology.

Neurophotonics, 6 (2)

Expansion microscopy and light sheet imaging (ExLSM) provide a viable alternative to existing tissue clearing and large volume imaging approaches. The analysis of intact volumes of brain tissue presents a distinct challenge in neuroscience. Recent advances in tissue clearing and light sheet microscopy have re-addressed this challenge and blossomed into a plethora of protocols with diverse advantages and disadvantages. While refractive index matching achieves near perfect transparency and allows for imaging at large depths, the resolution of cleared brains is usually limited to the micrometer range. Moreover, the often long and harsh tissue clearing protocols hinder preservation of native fluorescence and antigenicity. Here we image large expanded brain volumes of zebra finch brain tissue in commercially available light sheet microscopes. Our expansion light sheet microscopy (ExLSM) approach presents a viable alternative to many clearing and imaging methods because it improves on tissue processing times, fluorophore compatibility, and image resolution. ISSN:1662-5129

The lower stations of the auditory system display a complex anatomy. The inner ear labyrinth is composed of several interconnecting membranous structures encased in cavities of the temporal bone, and the cerebellopontine angle contains fragile structures such as meningeal folds, the choroid plexus (CP), and highly variable vascular formations. For this reason, most histological studies of the auditory system have either focused on the inner ear or the CNS by physically detaching the temporal bone from the brainstem. However, several studies of neuroimmune interactions have pinpointed the importance of structures such as meninges and CP; in the auditory system, an immune function has also been suggested for inner ear structures such as the endolymphatic duct (ED) and sac. All these structures are thin, fragile, and have complex 3D shapes. In order to study the immune cell populations located on these structures and their relevance to the inner ear and auditory brainstem in health and disease, we obtained a clarified-decalcified preparation of the rat hindbrain still attached to the intact temporal bone. This preparation may be immunolabeled using a clearing protocol (based on iDISCO+) to show location and functional state of immune cells. The observed macrophage distribution suggests the presence of CP-mediated communication pathways between the inner ear and the cochlear nuclei., Frontiers in Neuroanatomy, 13, ISSN:1662-5129

Borderline personality disorder (BPD) is associated with disturbed emotion regulation. Psychotherapeutic interventions using mindfulness elements have shown effectiveness in reducing clinical symptoms, yet little is known about their underlying neurobiology. In this functional magnetic resonance imaging (fMRI) study, 19 female BPD patients and 19 healthy controls were compared during mindful introspection, cognitive self-reflection and a neutral condition. The activation pattern in the right dorsomedial prefrontal cortex (DMPFC) in BPD patients was different from that in healthy subject when directing attention onto their emotions and bodily feelings in contrast to cognitively thinking about themselves. Mindful introspection compared with the neutral condition was associated with higher activations in bilateral motor/pre-motor regions, left inferior frontal gyrus (IFG), and left posterior cingulate cortex (PCC), while cognitive self-reflection activated the right motor and somatosensory cortex, extending into the right supramarginal gyrus (SMG) and superior temporal gyrus (STG) in BPD patients compared with the controls. Results indicate that self-referential cognitive and emotional processes are not clearly differentiated in BPD patients at the neurobiological level. In particular, altered neural mechanism underlying self-referential thinking may be related to some aspects of the typical emotion dysregulation in BPD. Current data support the finding that mindful self-focused attention is effective in regulating amygdala activity in BPD as well as in healthy subjects.

Sampling is a critical step in procedures that generate quantitative morphological data in the neurosciences. Samples need to be representative to allow statistical evaluations, and samples need to deliver a precision that makes statistical evaluations not only possible but also meaningful. Sampling generated variability should, e.g., not be able to hide significant group differences from statistical detection if they are present. Estimators of the coefficient of error (CE) have been developed to provide tentative answers to the question if sampling has been “good enough” to provide meaningful statistical outcomes. We tested the performance of the commonly used Gundersen-Jensen CE estimator, using the layers of the mouse hippocampal dentate gyrus as an example (molecular layer, granule cell layer and hilus). We found that this estimator provided useful estimates of the precision that can be expected from samples of different sizes. For all layers, we found that a smoothness factor (m) of 0 generally provided better estimates than an m of 1. Only for the combined layers, i.e., the entire dentate gyrus, better CE estimates could be obtained using an m of 1. The orientation of the sections impacted on CE sizes. Frontal (coronal) sections are typically most efficient by providing the smallest CEs for a given amount of work. Applying the estimator to 3D-reconstructed layers and using very intense sampling, we observed CE size plots with m = 0 to m = 1 transitions that should also be expected but are not often observed in real section series. The data we present also allows the reader to approximate the sampling intervals in frontal, horizontal or sagittal sections that provide CEs of specified sizes for the layers of the mouse dentate gyrus., Frontiers in Neuroanatomy, 11, ISSN:1662-5129

Elderly people at risk of developing cognitive decline; e.g., following surgery, may benefit from structured, challenging, and repetitive cognitive video training. This study assessed usability and acute effects of a newly developed bedside console (COPHYCON). Fifteen healthy elderly individuals performed a one-time 80-min intervention, including cognitive video games aimed at improving awareness and selective attention. Perceived usefulness and perceived ease of use (Technology Acceptance Model) were assessed together with measures of the achieved game level, reaction times, (in-) correct responses during ALERT and SELECT game play. Further, prefrontal cortical involvement of the regional cerebral hemoglobin saturation (rS02%) assessed with functional near infrared spectroscopy (fNIRS) (n = 5) and EEG power (n = 10) was analyzed. All participants completed the study without any adverse events. Perceived usefulness and perceived ease of use (TAM scores range 1-7) of the system varied between 3.9 and 6.3. The game levels reached for awareness varied between 9 and 11 (initial score 8-10), for reaction speed between 439 and 469 ms, and for correct responses between 74.1 and 78.8%. The highest level for the selective attention games was 2 (initial score 1), where reaction speed varied between 439 and 469 ms, correct responses between 96.2 and 98.5%, respectively. The decrease of rS02% in the right prefrontal cortex during gameplay was significantly (p < 0.001) lower, compared to the left prefrontal cortex. Four participants yielded significant lower rS02% measures after exergaming with the ALERT games (p < 0.000), but not with the SELECT games. EEG recordings of theta power significantly decreased in the averaged ~0.25-0.75 time interval for the left prefrontal cortex sensor across the cognitive game levels between the ALERT 1 and SELECT 1, as well as between SELECT 1 and 2 games. Participants rated the usability of the COPHYCON training positively. Further results indicate that video gaming may be an effective measure to affect prefrontal cortical functioning in elderly. The results warrant a clinical explorative study investigating the feasibility of the COPHYCON in a clinical setting., Frontiers in Systems Neuroscience, 11, ISSN:1662-5137

There is not yet a comprehensive view of how the color of light affects the cerebral and systemic physiology in humans. The aim was to address this deficit through basic research. Since cerebral and systemic physiological parameters are likely to interact, it was necessary to establish an approach, which we have termed "systemic-physiology-augmented functional near-infrared spectroscopy (SPA-fNIRS) neuroimaging." This multimodal approach measures the systemic and cerebral physiological response to exposure to light of different colors. In 14 healthy subjects (9 men, 5 women, age: [Formula: see text] years, range: 24 to 57 years) exposed to red, green, and blue light (10-min intermittent wide-field visual color stimulation; [Formula: see text] blocks of visual stimulation), brain hemodynamics and oxygenation were measured by fNIRS on the prefrontal cortex (PFC) and visual cortex (VC) simultaneously, in addition with systemic parameters. This study demonstrated that (i) all colors elicited responses in the VC, whereas only blue evoked a response in the PFC; (ii) there was a color-dependent effect on cardiorespiratory activity; (iii) there was significant change in neurosystemic functional connectivity; (iv) cerebral hemodynamic responses in the PFC and changes in the cardiovascular system were gender and age dependent; and (v) electrodermal activity and psychological state showed no stimulus-evoked changes, and there was no dependence on color of light, age, and gender. We showed that short-term light exposure caused color-dependent responses in cerebral hemodynamics/oxygenation as well as cardiorespiratory dynamics. Additionally, we showed that neurosystemic functional connectivity changes even during apparently stress-free tasks-an important consideration when using any of the hemodynamic neuroimaging methods (e.g. functional magnetic resonance imaging, positron emission tomography, and fNIRS). Our findings are important for future basic research and clinical applications as well as being relevant for everyday life.

With the aim of transitioning functional near-infrared spectroscopy (fNIRS) technology from the laboratory environment to everyday applications, the field has seen a recent push toward the development of wearable/miniaturized, multiwavelength, multidistance, and modular instruments. However, it is challenging to unite all these requirements in a precision instrument with low noise, low drift, and fast sampling characteristics. We present the concept and development of a wearable fNIRS instrument that combines all these key features with the goal of reliably and accurately capturing brain hemodynamics. The proposed instrument consists of a modular network of miniaturized optode modules that include a four-wavelength light source and a highly sensitive silicon photomultiplier detector. Simultaneous measurements with short-separation (7.5 mm; containing predominantly extracerebral signals) and long-separation (20 mm or more; containing both extracerebral and cerebral information) channels are used with short-channel regression filtering methods to increase robustness of fNIRS measurements. Performance of the instrument was characterized with phantom measurements and further validated in human in vivo measurements, demonstrating the good raw signal quality (signal-to-noise ratio of 64 dB for short channels; robust measurements up to 50 mm; dynamic optical range larger than 160 dB), the valid estimation of concentration changes (oxy- and deoxyhemoglobin, and cytochrome-c-oxidase) in muscle and brain, and the detection of task-evoked brain activity. The results of our preliminary tests suggest that the presented fNIRS instrument outperforms existing instruments in many aspects and bears high potential for real-time single-trial fNIRS applications as required for wearable brain–computer interfaces., Proceedings of SPIE, 4 (4), ISSN:0277-786X

Dynamic neural fields (DNFs) are dynamical systems models that approximate the activity of large, homogeneous, and recurrently connected neural networks based on a mean field approach. Within dynamic field theory, the DNFs have been used as building blocks in architectures to model sensorimotor embedding of cognitive processes. Typically, the parameters of a DNF in an architecture are manually tuned in order to achieve a specific dynamic behavior (e.g., decision making, selection, or working memory) for a given input pattern. This manual parameters search requires expert knowledge and time to find and verify a suited set of parameters. The DNF parametrization may be particular challenging if the input distribution is not known in advance, e.g., when processing sensory information. In this paper, we propose the autonomous adaptation of the DNF resting level and gain by a learning mechanism of intrinsic plasticity (IP). To enable this adaptation, an input and output measure for the DNF are introduced, together with a hyper parameter to define the desired output distribution. The online adaptation by IP gives the possibility to pre-define the DNF output statistics without knowledge of the input distribution and thus, also to compensate for changes in it. The capabilities and limitations of this approach are evaluated in a number of experiments., Frontiers in Computational Neuroscience, 11 (AUG), ISSN:1662-5188

Calsyntenins form a family of linker proteins between distinct populations of vesicles and kinesin motors for axonal transport. They were implicated in synapse formation and synaptic plasticity by findings in worms, mice and humans. These findings were in accordance with the postsynaptic localization of the Calsyntenins in the adult brain. However, they also affect the formation of neural circuits, as loss of Calsyntenin-1 (Clstn1) was shown to interfere with axonal branching and axon guidance. Despite the fact that Calsyntenins were discovered originally in embryonic chicken motoneurons, their distribution in the developing nervous system has not been analyzed in detail so far. Here, we summarize our analysis of the temporal and spatial expression patterns of the cargo-docking proteins Clstn1, Clstn2 and Clstn3 during neural development by comparing the dynamic distribution of their mRNAs by in situ hybridization in the spinal cord, the cerebellum, the retina and the tectum, as well as in the dorsal root ganglia (DRG).

Objective: To investigate clinical efficacy as well as the incidence and extent of complications regarding intrathecal baclofen (ITB) therapy in children.Methods: This is a retrospective medical chart review of three paediatric patients with acquired brain injuries (ABI) resulting from drowning who underwent ITB pump implantation for treatment of severe spasticity.Results: Compared to the pre-operative state, ITB therapy reduced spasticity with a corresponding decrease of modified Ashworth scale in upper (3.2 ± 1.4 to 1.3 ± 0.6) and lower extremities (3.5 ± 0.9 to 2.0 ± 1.0). Overall, six complications, five device-related and one accidental, were found in two out of three patients.Conclusion: Intrathecal baclofen is an effective therapy option for paediatric patients with ABI after drowning to significantly reduce spasticity of upper and lower extremities. A word of caution must be addressed to the incidence and extent of complications related to ITB therapy.

The central importance of translational control by posttranslational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and subsequently cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, by mass spectrometry we observed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool to manipulate hypusine modification in a temporal and spatial manner, both to analyze how this unique modification normally functions in vivo, as well as how it contributes to different pathological conditions.

Anxiety disorders are characterized by deficient emotion regulation prior to and in anxiety-evoking situations. Patients with social anxiety disorder (SAD) have increased brain activation also during the anticipation and perception of non-specific emotional stimuli pointing to biased general emotion processing. In the current study we addressed the neural correlates of emotion regulation by cognitive control during the anticipation and perception of non-specific emotional stimuli in patients with SAD. Thirty-two patients with SAD underwent functional magnetic resonance imaging during the announced anticipation and perception of emotional stimuli. Half of them were trained and instructed to apply reality-checking as a control strategy, the others anticipated and perceived the stimuli. Reality checking significantly (p0.01) reduced activity in insular, amygdalar and medial thalamic areas during the anticipation and perception of negative emotional stimuli. The medial prefrontal cortex was comparably active in both groups (p0.50). The results suggest that cognitive control in patients with SAD influences emotion processing structures, supporting the usefulness of emotion regulation training in the psychotherapy of SAD. In contrast to studies in healthy subjects, cognitive control was not associated with increased activation of prefrontal regions in SAD. This points to possibly disturbed general emotion regulating circuits in SAD.

Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R). Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78) was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.

fMRI studies in mice typically require the use of anesthetics. Yet, it is known that anesthesia alters responses to stimuli or functional networks at rest. In this work, we have used Dual Regression analysis Network Modeling to investigate the effects of two commonly used anesthetics, isoflurane and medetomidine, on rs-fMRI derived functional networks, and in particular to what extent anesthesia affected the interaction within and between these networks. Experimental data have been used from a previous study (Grandjean et al., 2014). We applied multivariate ICA analysis and Dual Regression to infer the differences in functional connectivity between isoflurane- and medetomidine-anesthetized mice. Further network analysis was performed to investigate within- and between-network connectivity differences between these anesthetic regimens. The results revealed five major networks in the mouse brain: lateral cortical, associative cortical, default mode, subcortical, and thalamic network. The anesthesia regime had a profound effect both on within- and between-network interactions. Under isoflurane anesthesia predominantly intra- and inter-cortical interactions have been observed, with only minor interactions involving subcortical structures and in particular attenuated cortico-thalamic connectivity. In contrast, medetomidine-anesthetized mice displayed subcortical functional connectivity including interactions between cortical and thalamic ICA components. Combining the two anesthetics at low dose resulted in network interaction that constituted the superposition of the interaction observed for each anesthetic alone. The study demonstrated that network modeling is a promising tool for analyzing the brain functional architecture in mice and comparing alterations therein caused by different physiological or pathological states. Understanding the differential effects of anesthetics on brain networks and their interaction is essential when interpreting fMRI data recorded under specific physiological and pathological conditions., Frontiers in Neural Circuits, 11, ISSN:1662-5110

Erythropoietic protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH), which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ∼5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (∼97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C), which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3′ splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas) show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing., Summary: A new mouse model reproduces the predominant genetic disposition of patients affected by erythropoietic protoporphyria, a rare disease associated with extreme pain after light exposure.

In the brain, D-amino acid oxidase (DAO/DAAO) mainly oxidizes D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptors. Thus, DAO can regulate the function of NMDA receptors via D-serine breakdown. Furthermore, DAO activator (DAOA)/G72 has been reported as both DAOA and repressor. The co-expression of DAO and DAOA genes and proteins in the human brain is not yet elucidated. The aim of this study was to understand the regional and age span distribution of DAO and DAOA (mRNA and protein) in a concomitant manner. We determined DAO and DAOA mRNA and protein expression across six brain regions in normal human post-mortem brain samples (16 weeks of gestation to 91 years) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. We found higher expression of DAO mRNA in the cerebellum, whereas lower expression of DAO protein in the cerebellum compared to the other brain regions studied, which suggests post-transcriptional regulation. We detected DAOA protein but not DAOA mRNA in all brain regions studied, suggesting a tightly regulated expression. To understand this regulation at the transcriptional level, we analyzed DNA methylation levels at DAO and DAOA CpG sites in the cerebellum and frontal cortex of control human post-mortem brain obtained from Gene Expression Omnibus datasets. Indeed, DAO and DAOA CpG sites in the cerebellum were significantly more methylated than those in the frontal cortex. While investigating lifespan effects, we found that DAO mRNA levels were positively correlated with age, Frontiers in Neuroanatomy, 11, ISSN:1662-5129

Despite an abundance of computational models for learning of synaptic weights, there has been relatively little research on structural plasticity, i.e., the creation and elimination of synapses. Especially, it is not clear how structural plasticity works in concert with spike-timing-dependent plasticity (STDP) and what advantages their combination offers. Here we present a fairly large-scale functional model that uses leaky integrate-and-fire neurons, STDP, homeostasis, recurrent connections, and structural plasticity to learn the input encoding, the relation between inputs, and to infer missing inputs. Using this model, we compare the error and the amount of noise in the network's responses with and without structural plasticity and the influence of structural plasticity on the learning speed of the network. Using structural plasticity during learning shows good results for learning the representation of input values, i.e., structural plasticity strongly reduces the noise of the response by preventing spikes with a high error. For inferring missing inputs we see similar results, with responses having less noise if the network was trained using structural plasticity. Additionally, using structural plasticity with pruning significantly decreased the time to learn weights suitable for inference. Presumably, this is due to the clearer signal containing less spikes that misrepresent the desired value. Therefore, this work shows that structural plasticity is not only able to improve upon the performance using STDP without structural plasticity but also speeds up learning. Additionally, it addresses the practical problem of limited resources for connectivity that is not only apparent in the mammalian neocortex but also in computer hardware or neuromorphic (brain-inspired) hardware by efficiently pruning synapses without losing performance., Frontiers in Computational Neuroscience, 10, ISSN:1662-5188

Low numeracy skills have a negative impact on the employment prospects and mental and physical health of individuals, and on the economic status of countries. Clearly, this is a high priority area where efficient strategies for intervention can lead to a better outcome, especially when implemented at an early age. We discuss here present and future directions for intervention. The development of such interventions has been based on the study of numerical difficulties through methods ranging from standardized tests to behavioral measures to neuroimaging. The intervention techniques range from group-based interventions targeted at strengths and weaknesses in specific components of arithmetic, to educational computer-games, to non-invasive brain-stimulation. We discuss the principles behind each method, the current evidence, and future directions. © 2013 Elsevier GmbH.

While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis (AHN) in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates) are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non-rodent species, and support emerging concepts of functional and structural interactions between CA3 and the dentate gyrus., Frontiers in Neuroanatomy, 10, ISSN:1662-5129

The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF) method to detect differences in the pharmacological MRI (phMRI) response in rats to treatment with an analgesic drug (buprenorphine) as compared to control (saline). Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD), and high dose (HD), and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus, and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow a supervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies., Frontiers in Computational Neuroscience, 10, ISSN:1662-5188

Major depressive disorder (MDD) has been associated with alterations in several functional brain networks. Previous studies investigating brain networks in MDD during the performance of a task have yielded inconsistent results with the function of the brain at rest. In this study, we used functional magnetic resonance imaging at rest and during a goal-directed task to investigate dynamics of functional connectivity in 19 unmedicated patients with MDD and 19 healthy controls across both experimental paradigms. Patients had spatial differences in the default mode network (DMN), in the executive network (EN), and in the dorsal attention network (DAN) compared to controls at rest and during task performance. In patients the amplitude of the low frequency (LFO) oscillations was reduced in the motor and in the DAN networks during both paradigms. There was a diagnosis by paradigm interaction on the LFOs amplitude of the salience network, with increased amplitude change between task and rest in patients relative to controls. Our findings suggest that the function of several networks could be intrinsically affected in MDD and this could be viable phenotype for the investigation on the neurobiological mechanisms of this disorder and its treatment., Psychiatry research. Neuroimaging, 259, ISSN:0925-4927