Neuroscience is experiencing unprecedented growth in dataset size both within individual brains and across populations. Large-scale, multimodal datasets are transforming our understanding of brain structure and function, creating opportunities to address previously unexplored questions. However, managing this increasing data volume requires new training and technology approaches. Modern data technologies are reshaping neuroscience by enabling researchers to tackle complex questions within a Ph.D. or postdoctoral timeframe. I will discuss cloud-based platforms such as brainlife.io, that provide scalable, reproducible, and accessible computational infrastructure. Modern data technology can democratize neuroscience, accelerate discovery and foster scientific transparency and collaboration. Concrete examples will illustrate how these technologies can be applied to mapping brain connectivity, studying human learning and development, and developing predictive models for traumatic brain injury (TBI). By integrating cloud computing and scalable data-sharing frameworks, neuroscience can become more impactful, inclusive, and data-driven..

Parvalbumin-positive GABAergic interneurons (PV-INs) provide inhibitory control of excitatory neuron activity, coordinate circuit function, and regulate behavior and cognition. PV-INs are uniquely susceptible to loss and dysfunction in traumatic brain injury (TBI) and epilepsy but the cause of this susceptibility is unknown. One hypothesis is that PV-INs use specialized metabolic systems to support their high-frequency action potential firing and that metabolic stress disrupts these systems, leading to their dysfunction and loss. Metabolism-based therapies can restore PV-IN function after injury in preclinical TBI models. Based on these findings, we hypothesize that (1) PV-INs are highly metabolically specialized, (2) these specializations are lost after TBI, and (3) restoring PV-IN metabolic specializations can improve PV-IN function as well as TBI-related outcomes. Using novel single-cell approaches, we can now quantify cell-type-specific metabolism in complex tissues to determine whether PV-IN metabolic dysfunction contributes to the pathophysiology of TBI.

Various clinical cases have provided evidence linking cardiovascular, neurological, and psychiatric disorders to changes in the brain-heart interaction. Our recent experimental evidence on patients with disorders of consciousness revealed that observing brain-heart interactions helps to detect residual consciousness, even in patients with absence of behavioral signs of consciousness. Those findings support hypotheses suggesting that visceral activity is involved in the neurobiology of consciousness and sum to the existing evidence in healthy participants in which the neural responses to heartbeats reveal perceptual and self-consciousness. Furthermore, the presence of non-linear, complex, and bidirectional communication between brain and heartbeat dynamics can provide further insights into the physiological state of the patient following severe brain injury. These developments on methodologies to analyze brain-heart interactions open new avenues for understanding neural functioning at a large-scale level, uncovering that peripheral bodily activity can influence brain homeostatic processes, cognition, and behavior.

Heiko Luhmann (Germany) – How neuronal activity builds the cerebral cortex; Mary Tolcos (Australia) – Cortical development and fetal brain injury; Silvia Velasco (Australia) – Human brain organoids to study neurodevelopment and disease

Inhibitory interneurons govern the sparse activation of principal cells that permits appropriate behaviors, but they among the most vulnerable to brain damage. Our recent work has demonstrated important roles for inhibitory neurons in disorders of brain development, injury and epilepsy. These studies have motivated our ongoing efforts to understand how these cells operate at the synaptic, circuit and behavioral levels and in designing new technologies targeting specific populations of interneurons for therapy. I will discuss our recent efforts examining the role of interneurons in traumatic brain injury and in designing cell transplantation strategies - based on the generation of new inhibitory interneurons - that enable precise manipulation of inhibitory circuits in the injured brain. I will also discuss our ongoing efforts using monosynaptic virus tracing and whole-brain clearing methods to generate brain-wide maps of inhibitory circuits in the rodent brain. By comprehensively mapping the wiring of individual cell types on a global scale, we have uncovered a fundamental strategy to sustain and optimize inhibition following traumatic brain injury that involves spatial reorganization of local and long-range inputs to inhibitory neurons. These recent findings suggest that brain damage, even when focally restricted, likely has a far broader affect on brain-wide neural function than previously appreciated.

Concussion (mild traumatic brain injury) affects approximately 50 million people annually. Headache is the most common symptom after concussion and persists in up to 50% of those affected for at least one-year. The biological underpinnings of and the efficacy and tolerability of treatments for post-traumatic headache has historically received little attention. While treatment in clinical practice is mostly directly at the underlying phenotype of the headache, persistent post-traumatic headache is considered to be less responsive to treatments used to treat migraine or tension-type headache. Over the past several years, significant pre-clinical research has begun to elucidate the mechanism(s) involved in the development of post-traumatic headache, and a concerted effort to evaluate the efficacy of selected treatments for persistent post-traumatic headache has begun. This presentation will review the epidemiology, pathophysiology, and emerging data on the prevention and treatment of post-traumatic headache.

An intriguing, relatively unexplored therapeutic avenue to investigate epilepsy is the interaction of sleep mechanisms and seizures. Multiple lines of clinical observations suggest a strong, bi-directional relationship between epilepsy and sleep. Epilepsy and sleep disorders are common comorbidities. Seizures occur more commonly in sleep in many types of epilepsy, and in turn, seizures can cause disrupted sleep. Sudden unexplained death in epilepsy (SUDEP) is strongly associated with sleep. The biological mechanisms underlying this relationship between seizures and sleep are poorly understood, but if better delineated, could offer novel therapeutic approaches to treating both epilepsy and sleep disorders. In this presentation, I will explore this sleep-seizure relationship in mouse models of epilepsy. First, I will present general approaches for performing detailed longitudinal sleep and vigilance state analysis in mice, including pre-weanling neonatal mice. I will then discuss recent data from my laboratory demonstrating an abnormal sleep phenotype in a mouse model of the genetic epilepsy, tuberous sclerosis complex (TSC), and its relationship to seizures. The potential mechanistic basis of sleep abnormalities and sleep-seizure interactions in this TSC model will be investigated, focusing on the role of the mechanistic target of rapamycin (mTOR) pathway and hypothalamic orexin, with potential therapeutic applications of mTOR inhibitors and orexin antagonists. Finally, similar sleep-seizure interactions and mechanisms will be extended to models of acquired epilepsy due to status epilepticus-related brain injury.

Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures and cognitive dysfunction. Targeting these cascades could prevent or reverse symptom progression and has the potential to provide viable disease-modifying treatments that could reduce the portion of TLE patients (>30%) not responsive to current medical therapies. Changes in GABA(A) receptor subunit expression have been implicated in the pathogenesis of TLE, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been shown to be a key regulator of these changes. The JAK/STAT pathway is known to be involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and synaptogenesis. Our laboratories have shown that a STAT3 inhibitor, WP1066, could greatly reduce the number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced status epilepticus (SE). This suggests promise for JAK/STAT inhibitors as disease-modifying therapies, however, the potential adverse effects of systemic or global CNS pathway inhibition limits their use. Development of more targeted therapeutics will require a detailed understanding of JAK/STAT-induced epileptogenic responses in different cell types. To this end, we have developed a new transgenic line where dimer-dependent STAT3 signaling is functionally knocked out (fKO) by tamoxifen-induced Cre expression specifically in forebrain excitatory neurons (eNs) via the Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. Most recently, we have demonstrated that STAT3 KO in excitatory neurons (eNSTAT3fKO) markedly reduces the progression of epilepsy (SRS frequency) in the intrahippocampal kainate (IHKA) TLE model and protects mice from kainic acid (KA)-induced memory deficits as assessed by Contextual Fear Conditioning. Using data from bulk hippocampal tissue RNA-sequencing, we further discovered a transcriptomic signature for the IHKA model that contains a substantial number of genes, particularly in synaptic plasticity and inflammatory gene networks, that are down-regulated after KA-induced SE in wild-type but not eNSTAT3fKO mice. Finally, we will review data from other models of brain injury that lead to epilepsy, such as TBI, that implicate activation of the JAK/STAT pathway that may contribute to epilepsy development.

Traumatic brain injury (TBI), a leading cause of acquired epilepsy, results in primary cellular injury as well as secondary neurophysiological and inflammatory responses which contribute to epileptogenesis. I will present our recent studies identifying a role for neuro-immune interactions, specifically, the innate immune receptor Toll-like receptor 4 (TLR4), in enhancing network excitability and cell loss in hippocampal dentate gyrus early after concussive brain injury. I will describe results indicating that the transient post-traumatic increases in dentate neurogenesis which occurs during the same early post-injury period augments dentate network excitability and epileptogenesis. I will provide evidence for the beneficial effects of targeting TLR4 and neurogenesis early after brain injury in limiting epileptogenesis. We will discuss potential mechanisms for convergence of the post-traumatic neuro-immune and neurogenic changes and the implications for therapies to reduce neurological deficits and epilepsy after brain injury.

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild cortical injury that does not directly damage subcortical structures (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are the source of thalamic C1q. Since the corticothalamic circuit is important for cognition and sleep, which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Both prematurity and IUGR are associated with perinatal systemic inflammation, a key factor associated with neuroinflammation and identified to be the best predictor of subsequent neurological impairments. Most of pharmacological candidates have failed to demonstrate any beneficial effect to prevent perinatal brain damage. In contrast, environmental enrichment based on developmental care, skin-to-skin contact and vocal/music intervention appears to confer positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the perinatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. Excessive cortisol release in response to perinatal stress induces pro-inflammatory and brain-programming effects. These deleterious effects are known to be balanced by Oxytocin (OT), a neuropeptide playing a key role during the perinatal period and parturition, in social behavior and regulating the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with perinatal brain damage, we recently reported that Carbetocin, a brain permeable long-lasting OT receptor (OTR) agonist, was associated with a significant reduction of activated microglia, the primary immune cells of the brain. Moreover this reduced microglia reactivity was associated to a long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the causality between the endogenous OT and central inflammation response to injury has not been established and will be further studied by the lab.

We will start our talk with a short video of our research, illustrating methods (some old and new) and findings that have provided our current understanding of how visual capabilities develop in infancy and early childhood. However, our research poses some outstanding questions. We will briefly discuss three issues, which are linked by a common focus on the development of visual attentional processing: (1) How do recurrent cortical loops contribute to development? Cortical selectivity (e.g., to orientation, motion, and binocular disparity) develops in the early months of life. However, these systems are not purely feedforward but depend on parallel pathways, with recurrent feedback loops playing a critical role. The development of diverse networks, particularly for motion processing, may explain changes in dynamic responses and resolve developmental data obtained with different methodologies. One possible role for these loops is in top-down attentional control of visual processing. (2) Why do hyperopic infants become strabismic (cross-eyes)? Binocular interaction is a particularly sensitive area of development. Standard clinical accounts suppose that long-sighted (hyperopic) refractive errors require accommodative effort, putting stress on the accommodation-convergence link that leads to its breakdown and strabismus. Our large-scale population screening studies of 9-month infants question this: hyperopic infants are at higher risk of strabismus and impaired vision (amblyopia and impaired attention) but these hyperopic infants often under- rather than over-accommodate. This poor accommodation may reflect poor early attention processing, possibly a ‘soft sign’ of subtle cerebral dysfunction. (3) What do many neurodevelopmental disorders have in common? Despite similar cognitive demands, global motion perception is much more impaired than global static form across diverse neurodevelopmental disorders including Down and Williams Syndromes, Fragile-X, Autism, children with premature birth and infants with perinatal brain injury. These deficits in motion processing are associated with deficits in other dorsal stream functions such as visuo-motor co-ordination and attentional control, a cluster we have called ‘dorsal stream vulnerability’. However, our neuroimaging measures related to motion coherence in typically developing children suggest that the critical areas for individual differences in global motion sensitivity are not early motion-processing areas such as V5/MT, but downstream parietal and frontal areas for decision processes on motion signals. Although these brain networks may also underlie attentional and visuo-motor deficits , we still do not know when and how these deficits differ across different disorders and between individual children. Answering these questions provide necessary steps, not only increasing our scientific understanding of human visual brain development, but also in designing appropriate interventions to help each child achieve their full potential.

Axons degenerate before the neuronal soma in many neurodegenerative diseases. Programmed axon death (Wallerian degeneration) is a widely-occurring mechanism of axon loss that is well understood and preventable in animals. Its aberrant activation by mutation of the pro-survival gene Nmnat2 directly causes axonopathy in mice with severity ranging from mild polyneuropathy to perinatal lethality. Rare biallelic mutations in the homologous human gene cause related phenotypes in patients. NMNAT2 is a negative regulator of the prodegenerative NADase SARM1. Constitutive activation of SARM1 is cytotoxic and the human SARM1 locus is significantly associated with sporadic ALS. Another negative regulator, STMN2, has also been implicated in ALS, where it is commonly depleted downstream of TDP-43. In mice, programmed axon death can be robustly blocked by deletion of Sarm1, or by overexpression, axonal targeting and/or stabilization of various NMNAT isoforms. This alleviates models of many human disorders including some forms of peripheral neuropathy, motor neuron diseases, glaucoma, Parkinson’s disease and traumatic brain injury, and it confers lifelong rescue on the lethal Nmnat2 null phenotype and other conditions. Drug discovery programs now aim to achieve similar outcomes in human disease. In order to optimize the use of such drugs, we have characterized a range of human NMNAT2 and SARM1 functional variants that underlie a spectrum of axon vulnerability in the human population. Individuals at the vulnerable end of this spectrum are those most likely to benefit from drugs blocking programmed axon death, and disorders associated with these genotypes are promising indications in which to apply them.

Learning by analogy is a powerful tool children’s developmental repertoire, as well as in educational contexts such as mathematics, where the key knowledge base involves building flexible schemas. However, noticing and learning from analogies develops over time and is cognitively resource intensive. I review studies that provide insight into the relationship between mechanisms driving children’s developing analogy skills, highlighting environmental inputs (parent talk and prior experiences priming attention to relations) and neuro-cognitive factors (Executive Functions and brain injury). I then note implications for mathematics learning, reviewing experimental findings that show analogy can improve learning, but also that both individual differences in EFs and environmental factors that reduce available EFs such as performance pressure can predict student learning.

Non-traumatic brain injury due to stroke, cerebral palsy and HIV often result in serious long-term disability worldwide, affecting more than 150 million persons globally; with the majority of persons living in low and middle income countries. These diseases often result in varying levels of motor and cognitive impairment due to brain injury which then affects the person’s ability to complete activities of daily living and fully participate in society. Increasingly advanced technologies are being used to support identification, diagnosis, assessment, and therapy for patients with brain injury. Specifically, robot and mechatronic systems can provide patients, physicians and rehabilitation clinical providers with additional support to care for and improve the quality of life of children and adults with motor and cognitive impairment. This talk will provide a brief introduction to the area of rehabilitation robotics and, via case studies, illustrate how computer/technology-assisted rehabilitation systems can be developed and used to assess motor and cognitive impairment, detect early evidence of functional impairment, and augment therapy in high and low-resource settings.