Neural networks of the mouse neocortex.

Numerous studies have examined the neuronal inputs and outputs of many areas within the mammalian cerebral cortex, but how these areas are organized into neural networks that communicate across the entire cortex is unclear. Over 600 labeled neuronal pathways acquired from tracer injections placed across the entire mouse neocortex enabled us to generate a cortical connectivity atlas. A total of 240 intracortical connections were manually reconstructed within a common neuroanatomic framework, forming a cortico-cortical connectivity map that facilitates comparison of connections from different cortical targets. Connectivity matrices were generated to provide an overview of all intracortical connections and subnetwork clusterings. The connectivity matrices and cortical map revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas. Together, these data provide a resource that can be used to further investigate cortical networks and their corresponding functions.

The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture.

Mobile version of the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA): Implementation and adult norms.

Timing and rhythm abilities are complex and multidimensional skills that are highly widespread in the general population. This complexity can be partly captured by the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). The battery, consisting of four perceptual and five sensorimotor tests (finger-tapping), has been used in healthy adults and in clinical populations (e.g., Parkinson's disease, ADHD, developmental dyslexia, stuttering), and shows sensitivity to individual differences and impairment. However, major limitations for the generalized use of this tool are the lack of reliable and standardized norms and of a version of the battery that can be used outside the lab. To circumvent these caveats, we put forward a new version of BAASTA on a tablet device capable of ensuring lab-equivalent measurements of timing and rhythm abilities. We present normative data obtained with this version of BAASTA from over 100 healthy adults between the ages of 18 and 87 years in a test-retest protocol. Moreover, we propose a new composite score to summarize beat-based rhythm capacities, the Beat Tracking Index (BTI), with close to excellent test-retest reliability. BTI derives from two BAASTA tests (beat alignment, paced tapping), and offers a swift and practical way of measuring rhythmic abilities when research imposes strong time constraints. This mobile BAASTA implementation is more inclusive and far-reaching, while opening new possibilities for reliable remote testing of rhythmic abilities by leveraging accessible and cost-efficient technologies.

Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators.

Transcriptional coactivators are a molecular recognition marvel because a single domain within these proteins, the activator binding domain or ABD, interacts with multiple compositionally diverse transcriptional activators. Also remarkable is the structural diversity among ABDs, which range from conformationally dynamic helical motifs to those with a stable core such as a ß-barrel. A significant objective is to define conserved properties of ABDs that allow them to interact with disparate activator sequences. The ABD of the coactivator Med25 (activator interaction domain or AcID) is unique in that it contains secondary structural elements that are on both ends of the spectrum: helices and loops that display significant conformational mobility and a seven-stranded ß-barrel core that is structurally rigid. Using biophysical approaches, we build a mechanistic model of how AcID forms binary and ternary complexes with three distinct activators; despite its static core, Med25 forms short-lived, conformationally mobile, and structurally distinct complexes with each of the cognate partners. Further, ternary complex formation is facilitated by allosteric communication between binding surfaces on opposing faces of the ß-barrel. The model emerging suggests that the conformational shifts and cooperative binding is mediated by a flexible substructure comprised of two dynamic helices and flanking loops, indicating a conserved mechanistic model of activator engagement across ABDs. Targeting a region of this substructure with a small-molecule covalent cochaperone modulates ternary complex formation. Our data support a general strategy for the identification of allosteric small-molecule modulators of ABDs, which are key targets for mechanistic studies as well as therapeutic applications.

Language Ability Predicts Cortical Structure and Covariance in Boys with Autism Spectrum Disorder.

There is significant clinical heterogeneity in language and communication abilities of individuals with Autism Spectrum Disorders (ASD). However, no consistent pathology regarding the relationship of these abilities to brain structure has emerged. Recent developments in anatomical correlation-based approaches to map structural covariance networks (SCNs), combined with detailed behavioral characterization, offer an alternative for studying these relationships. In this study, such an approach was used to study the integrity of SCNs of cortical thickness and surface area associated with language and communication, in 46 high-functioning, school-age children with ASD compared with 50 matched, typically developing controls (all males) with IQ > 75. Findings showed that there was alteration of cortical structure and disruption of fronto-temporal cortical covariance in ASD compared with controls. Furthermore, in an analysis of a subset of ASD participants, alterations in both cortical structure and covariance were modulated by structural language ability of the participants, but not communicative function. These findings indicate that structural language abilities are related to altered fronto-temporal cortical covariance in ASD, much more than symptom severity or cognitive ability. They also support the importance of better characterizing ASD samples while studying brain structure and for better understanding individual differences in language and communication abilities in ASD.

The effectiveness of styrene-maleic acid (SMA) copolymers for solubilisation of integral membrane proteins from SMA-accessible and SMA-resistant membranes.

Solubilisation of biological lipid bilayer membranes for analysis of their protein complement has traditionally been carried out using detergents, but there is increasing interest in the use of amphiphilic copolymers such as styrene maleic acid (SMA) for the solubilisation, purification and characterisation of integral membrane proteins in the form of protein/lipid nanodiscs. Here we survey the effectiveness of various commercially-available formulations of the SMA copolymer in solubilising Rhodobacter sphaeroides reaction centres (RCs) from photosynthetic membranes. We find that formulations of SMA with a 2:1 or 3:1 ratio of styrene to maleic acid are almost as effective as detergent in solubilising RCs, with the best solubilisation by short chain variants (<30kDa weight average molecular weight). The effectiveness of 10kDa 2:1 and 3:1 formulations of SMA to solubilise RCs gradually declined when genetically-encoded coiled-coil bundles were used to artificially tether normally monomeric RCs into dimeric, trimeric and tetrameric multimers. The ability of SMA to solubilise reaction centre-light harvesting 1 (RC-LH1) complexes from densely packed and highly ordered photosynthetic membranes was uniformly low, but could be increased through a variety of treatments to increase the lipid:protein ratio. However, proteins isolated from such membranes comprised clusters of complexes in small membrane patches rather than individual proteins. We conclude that short-chain 2:1 and 3:1 formulations of SMA are the most effective in solubilising integral membrane proteins, but that solubilisation efficiencies are strongly influenced by the size of the target protein and the density of packing of proteins in the membrane.

Auditory Pitch Perception in Autism Spectrum Disorder Is Associated With Nonverbal Abilities.

Atypical sensory perception and heterogeneous cognitive profiles are common features of autism spectrum disorder (ASD). However, previous findings on auditory sensory processing in ASD are mixed. Accordingly, auditory perception and its relation to cognitive abilities in ASD remain poorly understood. Here, children with ASD, and age- and intelligence quotient (IQ)-matched typically developing children, were tested on a low- and a higher level pitch processing task. Verbal and nonverbal cognitive abilities were measured using the Wechsler's Abbreviated Scale of Intelligence. There were no group differences in performance on either auditory task or IQ measure. However, there was significant variability in performance on the auditory tasks in both groups that was predicted by nonverbal, not verbal skills. These results suggest that auditory perception is related to nonverbal reasoning rather than verbal abilities in ASD and typically developing children. In addition, these findings provide evidence for preserved pitch processing in school-age children with ASD with average IQ, supporting the idea that there may be a subgroup of individuals with ASD that do not present perceptual or cognitive difficulties. Future directions involve examining whether similar perceptual-cognitive relationships might be observed in a broader sample of individuals with ASD, such as those with language impairment or lower IQ.

Rapid-onset hypoglycemia suppresses Fos expression in discrete parts of the ventromedial nucleus of the hypothalamus.

The consensus view of the ventromedial nucleus of the hypothalamus (VMH) is that it is a key node in the rodent brain network controlling sympathoadrenal counterregulatory responses to hypoglycemia. To identify the location of hypoglycemia-responsive neurons in the VMH, we performed a high spatial resolution Fos analysis in the VMH of rats made hypoglycemic with intraperitoneal injections of insulin. We examined Fos expression in the four constituent parts of VMH throughout its rostrocaudal extent and determined their relationship to blood glucose concentrations. Hypoglycemia significantly decreased Fos expression only in the dorsomedial and central parts of the VMH, but not its anterior or ventrolateral parts. Moreover, the number of Fos-expressing neurons was significantly and positively correlated in the two responsive regions with terminal blood glucose concentrations. We also measured Fos responses in the paraventricular nucleus of the hypothalamus (PVH) and in several levels of the periaqueductal gray (PAG), which receives strong projections from the VMH. We found the expected and highly significant increase in Fos in the neuroendocrine PVH, which was negatively correlated to terminal blood glucose concentrations, but no significant differences were seen in any part of the PAG. Our results show that there are distinct populations of VMH neurons whose Fos expression is suppressed by hypoglycemia, and their numbers correlate with blood glucose. These findings support a clear division of glycemic control functions within the different parts of the VMH.

Atypical functional brain connectivity during rest in autism spectrum disorders.

OBJECTIVE: Connectivity atypicalities in autism spectrum disorders (ASD) have been extensively proposed. The default mode network (DMN) is critical in this study, given the insight it provides for long-distance connectivity, and the importance of regions in this network for introspection and social emotion processing, areas affected in ASD. However, study of this network has largely been limited to adults; research earlier in development is lacking. The objective of this study was to examine DMN connectivity in children/adolescents with ASD. METHODS: A total of 115 children/adolescents, aged 6 to 17 years (71 males with ASD and 44 group age-matched TD males) were included in these analyses. We examined group differences in (1) functional connectivity between the posterior cingulate cortex and regions across the brain, (2) connectivity within the DMN as a function of age and intelligence quotient (IQ), and (3) the association between DMN connectivity and empathic accuracy. RESULTS: Individuals with ASD, relative to controls, showed either stronger or weaker connectivity between the posterior cingulate cortex (PCC) and DMN regions, depending on the region, but also showed stronger connectivity with non-DMN regions. A significant group-by-age interaction was observed in functional connectivity between the PCC and medial prefrontal cortex; connectivity increased with age in controls, but decreased in individuals with ASD. No effects of IQ were found. There was a significant group difference in the relation between DMN connectivity and empathic accuracy. INTERPRETATION: Differences in functional connectivity may suggest the presence of neural atypicalities that impact the development of typical connectivity in ASD. In addition to affecting DMN dynamics, these atypicalities may also impact social-cognitive abilities.

Sensorimotor integration is enhanced in dancers and musicians.

Studying individuals with specialized training, such as dancers and musicians, provides an opportunity to investigate how intensive practice of sensorimotor skills affects behavioural performance across various domains. While several studies have found that musicians have improved motor, perceptual and sensorimotor integration skills compared to untrained controls, fewer studies have examined the effect of dance training on such skills. Moreover, no study has specifically compared the effects of dance versus music training on perceptual or sensorimotor performance. To this aim, in the present study, expert dancers, expert musicians and untrained controls were tested on a range of perceptual and sensorimotor tasks designed to discriminate performance profiles across groups. Dancers performed better than musicians and controls on a dance imitation task (involving whole-body movement), but musicians performed better than dancers and controls on a musical melody discrimination task as well as on a rhythm synchronization task (involving finger tapping). These results indicate that long-term intensive dance and music training are associated with distinct enhancements in sensorimotor skills. This novel work advances knowledge of the effects of long-term dance versus music training and has potential applications in therapies for motor disorders.

Common parietal activation in musical mental transformations across pitch and time.

We previously observed that mental manipulation of the pitch level or temporal organization of melodies results in functional activation in the human intraparietal sulcus (IPS), a region also associated with visuospatial transformation and numerical calculation. Two outstanding questions about these musical transformations are whether pitch and time depend on separate or common processing in IPS, and whether IPS recruitment in melodic tasks varies depending upon the degree of transformation required (as it does in mental rotation). In the present study we sought to answer these questions by applying functional magnetic resonance imaging while musicians performed closely matched mental transposition (pitch transformation) and melody reversal (temporal transformation) tasks. A voxel-wise conjunction analysis showed that in individual subjects, both tasks activated overlapping regions in bilateral IPS, suggesting that a common neural substrate subserves both types of mental transformation. Varying the magnitude of mental pitch transposition resulted in variation of IPS BOLD signal in correlation with the musical key-distance of the transposition, but not with the pitch distance, indicating that the cognitive metric relevant for this type of operation is an abstract one, well described by music-theoretic concepts. These findings support a general role for the IPS in systematically transforming auditory stimulus representations in a nonspatial context.

The Neuroscience of Dance: A Conceptual Framework and Systematic Review.

Ancient and culturally universal, dance pervades many areas of life and has multiple benefits. In this article, we provide a conceptual framework and systematic review, as a guide for researching the neuroscience of dance. We identified relevant articles following PRISMA guidelines, and summarised and evaluated all original results. We identified avenues for future research in: the interactive and collective aspects of dance; groove; dance performance; dance observation; and dance therapy. Furthermore, the interactive and collective aspects of dance constitute a vital part of the field but have received almost no attention from a neuroscientific perspective so far. Dance and music engage overlapping brain networks, including common regions involved in perception, action, and emotion. In music and dance, rhythm, melody, and harmony are processed in an active, sustained pleasure cycle giving rise to action, emotion, and learning, led by activity in specific hedonic brain networks. The neuroscience of dance is an exciting field, which may yield information concerning links between psychological processes and behaviour, human flourishing, and the concept of eudaimonia.

Auditory global-local processing: effects of attention and musical experience.

In vision, global (whole) features are typically processed before local (detail) features ("global precedence effect"). However, the distinction between global and local processing is less clear in the auditory domain. The aims of the present study were to investigate: (i) the effects of directed versus divided attention, and (ii) the effect musical training on auditory global-local processing in 16 adult musicians and 16 non-musicians. Participants were presented with short nine-tone melodies, each comprised of three triplet sequences (three-tone units). In a "directed attention" task, participants were asked to focus on either the global or local pitch pattern and had to determine if the pitch pattern went up or down. In a "divided attention" task, participants judged whether the target pattern (up or down) was present or absent. Overall, global structure was perceived faster and more accurately than local structure. The global precedence effect was observed regardless of whether attention was directed to a specific level or divided between levels. Musicians performed more accurately than non-musicians overall, but non-musicians showed a more pronounced global advantage. This study provides evidence for an auditory global precedence effect across attention tasks, and for differences in auditory global-local processing associated with musical experience.

Visual cortex plasticity in cochlear implant users revealed in a visual motion detection task.

OBJECTIVE: The aim of this study was to investigate brain reorganization following cochlear implantation using electroencephalography, an implant-compatible technique to record electrical brain activity. METHODS: We investigated cortical plasticity in cochlear implant (CI) users using visual evoked potentials in response to visual motion changes. We estimated visual and auditory neural sources in CI users (n = 20) and normal hearing (NH) matched control participants (n = 22). RESULTS: Results showed intra-modal plasticity in the visual cortex of CI users, revealed by higher P1 and visual mismatch negativity amplitude, and greater contribution of the visual cortex during visual motion changes compared to NH controls. CONCLUSIONS: Our results suggest more efficient processing of visual information in CI users that may reflect enhanced multimodal compensatory strategies during speech processing. SIGNIFICANCE: This study showcases an objective, implant-compatible method that could be used in a clinical setting to measure and longitudinally track cortical plastic changes, enabling a better understanding of the link between individual patterns of cortical plasticity and CI outcomes.

A role for the intraparietal sulcus in transforming musical pitch information.

The present functional magnetic resonance imaging study investigates the neural substrates of relative pitch. Musicians and nonmusicians performed 2 same/different discrimination tasks (simple and transposed melody) that differed in whether they required precise encoding and comparison of relative pitch structure, along with 2 control tasks (rhythm and phoneme). The transposed melody task involved a musical transposition of 4 semitones between the target and comparison patterns, requiring listeners to use interval information rather than the absolute value of the individual pitches. Contrasting the transposed melody to the simple melody condition revealed greater activation in the cortex within the intraparietal sulcus (IPS) bilaterally; control tasks did not elicit significant activity in the IPS. Moreover, a whole-brain voxel-wise regression analysis of brain oxygenation level-dependent signal showed that activity within the right IPS predicted task performance for both musicians and nonmusicians specifically in the transposed melody condition. Successful performance of the transposed melody task requires encoding and comparison of auditory patterns having different tonal reference points-thus simple tonal memory is not sufficient. Our results point to a role for the IPS in transforming high-level auditory information. We suggest that this area may support a general capacity for transformation and comparison of systematically related stimulus attributes.

Accuracy of Tempo Judgments in Disk Jockeys Compared to Musicians and Untrained Individuals.

Professional disk jockeys (DJs) are an under-studied population whose performance involves creating new musical experiences by combining existing musical materials with a high level of temporal precision. In contemporary electronic dance music, these materials have a stable tempo and are composed with the expectation for further transformation during performance by a DJ for the audience of dancers. Thus, a fundamental aspect of DJ performance is synchronizing the tempo and phase of multiple pieces of music, so that over seconds or even minutes, they may be layered and transitioned without disrupting the rhythmic pulse. This has been accomplished traditionally by manipulating the speed of individual music pieces "by ear," without additional technological synchronization aids. However, the cumulative effect of this repeated practice on auditory tempo perception has not yet been evaluated. Well-known phenomena of experience-dependent plasticity in other populations, such as musicians, prompts the question of whether such effects exist in DJs in their domain of expertise. This pilot study examined auditory judgments of tempo in 10 professional DJs with experience mixing by ear, compared to 7 percussionists, 12 melodic instrumental musicians, and 11 untrained controls. Participants heard metronome sequences between 80 and 160 beats per minute (BPM) and estimated the tempo. In their most-trained tempo range, 120-139 BPM, DJs were more accurate (lower absolute percent error) than untrained participants. Within the DJ group, 120-139 BPM exhibited greater accuracy than slower tempos of 80-99 or 100-119 BPM. DJs did not differ in accuracy compared to percussionists or melodic musicians on any BPM range. Percussionists were more accurate than controls for 100-119 and 120-139 BPM. The results affirm the experience-dependent skill of professional DJs in temporal perception, with comparable performance to conventionally trained percussionists and instrumental musicians. Additionally, the pattern of results suggests a tempo-specific aspect to this training effect that may be more pronounced in DJs than percussionists and musicians. As one of the first demonstrations of enhanced auditory perception in this unorthodox music expert population, this work opens the way to testing whether DJs also have enhanced rhythmic production abilities, and investigating the neural substrates of this skill compared to conventional musicians.

An open access mouse brain flatmap and upgraded rat and human brain flatmaps based on current reference atlases.

Here we present a flatmap of the mouse central nervous system (CNS) (brain) and substantially enhanced flatmaps of the rat and human brain. Also included are enhanced representations of nervous system white matter tracts, ganglia, and nerves, and an enhanced series of 10 flatmaps showing different stages of rat brain development. The adult mouse and rat brain flatmaps provide layered diagrammatic representation of CNS divisions, according to their arrangement in corresponding reference atlases: Brain Maps 4.0 (BM4, rat) (Swanson, The Journal of Comparative Neurology, 2018, 526, 935-943), and the first version of the Allen Reference Atlas (mouse) (Dong, The Allen reference atlas, (book + CD-ROM): A digital color brain atlas of the C57BL/6J male mouse, 2007). To facilitate comparative analysis, both flatmaps are scaled equally, and the divisional hierarchy of gray matter follows a topographic arrangement used in BM4. Also included with the mouse and rat brain flatmaps are cerebral cortex atlas level contours based on the reference atlases, and direct graphical and tabular comparison of regional parcellation. To encourage use of the brain flatmaps, they were designed and organized, with supporting reference tables, for ease-of-use and to be amenable to computational applications. We demonstrate how they can be adapted to represent novel parcellations resulting from experimental data, and we provide a proof-of-concept for how they could form the basis of a web-based graphical data viewer and analysis platform. The mouse, rat, and human brain flatmap vector graphics files (Adobe Reader/Acrobat viewable and Adobe Illustrator editable) and supporting tables are provided open access; they constitute a broadly applicable neuroscience toolbox resource for researchers seeking to map and perform comparative analysis of brain data.

Wrist fusion using an induced membrane technique for forearm salvage in a patient with an infected open injury with segmental bone loss: A case report.

This case report describes the management of a 27-year-old male who, after a quadbike accident, presented with an open, infected, segmental both bone forearm injury with significant bone and soft tissue loss including the radio-carpal joint. Limb salvage was accomplished in the form of a single bone forearm fusion utilising Masquelet's two-stage induced membrane technique to reconstruct the segmental bone defect. The patient proceeded to uneventful bony union by 6 months and returned to driving and riding a quadbike. Despite significant deep infection, successful salvage was achieved using the induced membrane technique. Critical to success was aggressive, repeated debridement alongside restoration of vascular supply and reconstruction of soft tissue defects. We highlight the multidisciplinary approach to management including relevant specialists with a particular interest in limb reconstruction.