Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
Cerebrospinal fluid leaks (CSF) result from an abnormal communication between the subarachnoid space and the extracranial space. Approximately 90% of CSF leak at the anterior skull base manifests as rhinorrhea and can become life-threatening condition. Endoscopic sinus surgery (ESS) has become a common otolaryngologist procedure. The aim of this article is to consider our experience and to evaluate the outcomes in patients who underwent a purely endoscopic repair of CSF leaks of the anterior skull base.
The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.
Cerebrospinal fluid (CSF) plays an essential role in maintaining the homeostasis of the central nervous system. The functions of CSF include: (1) buoyancy of the brain, spinal cord, and nerves; (2) volume adjustment in the cranial cavity; (3) nutrient transport; (4) protein or peptide transport; (5) brain volume regulation through osmoregulation; (6) buffering effect against external forces; (7) signal transduction; (8) drug transport; (9) immune system control; (10) elimination of metabolites and unnecessary substances; and finally (11) cooling of heat generated by neural activity. For CSF to fully mediate these functions, fluid-like movement in the ventricles and subarachnoid space is necessary. Furthermore, the relationship between the behaviors of CSF and interstitial fluid in the brain and spinal cord is important. In this review, we will present classical studies on CSF circulation from its discovery over 2,000 years ago, and will subsequently introduce functions that were recently discovered such as CSF production and absorption, water molecule movement in the interstitial space, exchange between interstitial fluid and CSF, and drainage of CSF and interstitial fluid into both the venous and the lymphatic systems. Finally, we will summarize future challenges in research. This review includes articles published up to February 2016.
Canine Chiari-like malformation (CM) is a complex abnormality of the skull and craniocervical junction associated with miniaturization and brachycephaly which can result in the spinal cord disease syringomyelia (SM). This study investigated the inheritance of CM in a Griffon Bruxellois (GB) family and feasibility of crossbreeding a brachycephalic CM affected GB with a mesaticephalic normal Australian terrier and then backcrossing to produce individuals free of the malformation and regain GB breed characteristics. The study family cohort (n = 27) included five founder dogs from a previous baseline study of 155 GB which defined CM as a global malformation of the cranium and craniocervical junction with a shortened skull base and increased proximity of the cervical vertebrae to the skull. T1-weighted sagittal DICOM images of the brain and craniocervical junction were analysed for five significant traits (two angles, three lines) identified from the previous study and subsequent Qualitative Trait Loci analysis. Mean measurements for mixed breed, pure-breed and baseline study groups were compared. Results indicated that mixed breed traits posed less risk for CM and SM and were useful to distinguish the phenotype. Moreover on the MR images, the filial relationships displayed by the traits exhibited segregation and those presenting the greatest risk for CM appeared additive towards the severity of the condition. The external phenotypes revealed that by outcrossing breed types and with careful selection of appropriate conformation characteristics in the first generation, it is possible to regain the GB breed standard and reduce the degree of CM. The four GB affected with SM in the study all exhibited reduced caudal skull development compared to their relatives. The craniocervical traits may be useful for quantifying CM and assessing the possibility of SM thus assisting breeders with mate selection. However, such a system requires validation to ensure appropriateness for all breeds at risk.
To determine the feasibility of next-generation sequencing (NGS) microbiome approaches in the diagnosis of infectious disorders in brain or spinal cord biopsies in patients with suspected CNS infections.
Brain function relies on communication between large populations of neurons across multiple brain areas, a full understanding of which would require knowledge of the time-varying activity of all neurons in the central nervous system. Here we use light-sheet microscopy to record activity, reported through the genetically encoded calcium indicator GCaMP5G, from the entire volume of the brain of the larval zebrafish in vivo at 0.8 Hz, capturing more than 80% of all neurons at single-cell resolution. Demonstrating how this technique can be used to reveal functionally defined circuits across the brain, we identify two populations of neurons with correlated activity patterns. One circuit consists of hindbrain neurons functionally coupled to spinal cord neuropil. The other consists of an anatomically symmetric population in the anterior hindbrain, with activity in the left and right halves oscillating in antiphase, on a timescale of 20 s, and coupled to equally slow oscillations in the inferior olive.
Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.
Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions.