Cerebrospinal Fluid-Contacting Neurons Sense pH Changes and Motion in the Hypothalamus.

CSF-contacting (CSF-c) cells are present in the walls of the brain ventricles and the central canal of the spinal cord and found throughout the vertebrate phylum. We recently identified ciliated somatostatin-/GABA-expressing CSF-c neurons in the lamprey spinal cord that act as pH sensors as well as mechanoreceptors. In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively. Here, we investigate the functional properties of the ciliated somatostatin-/GABA-positive CSF-c neurons in the hypothalamus by performing whole-cell recordings in hypothalamic slices. Depolarizing current pulses readily evoked action potentials, but hypothalamic CSF-c neurons had no or a very low level of spontaneous activity at pH 7.4. They responded, however, with membrane potential depolarization and trains of action potentials to small deviations in pH in both the acidic and alkaline direction. Like in spinal CSF-c neurons, the acidic response in hypothalamic cells is mediated via ASIC3-like channels. In contrast, the alkaline response appears to depend on connexin hemichannels, not on PKD2L1 channels. We also show that hypothalamic CSF-c neurons respond to mechanical stimulation induced by fluid movements along the wall of the third ventricle, a response mediated via ASIC3-like channels. The hypothalamic CSF-c neurons extend their processes dorsally, ventrally, and laterally, but as yet, the effects exerted on hypothalamic circuits are unknown. With similar neurons being present in rodents, the pH- and mechanosensing ability of hypothalamic CSF-c neurons is most likely conserved throughout vertebrate phylogeny.SIGNIFICANCE STATEMENT CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.

Changes in sensorimotor-related thalamic diffusion properties and cerebrospinal fluid hydrodynamics predict gait responses to tap test in idiopathic normal-pressure hydrocephalus.

OBJECTIVES: To compare diffusion tensor (DT)-derived indices from the thalamic nuclei and cerebrospinal fluid (CSF) hydrodynamic parameters for the prediction of gait responsiveness to the CSF tap test in early iNPH patients. METHODS: In this study, 22 patients with iNPH and 16 normal controls were enrolled with the approval of an institutional review board. DT imaging and phase-contrast magnetic resonance imaging were performed in patients and controls to determine DT-related indices of the sensorimotor-related thalamic nuclei and CSF hydrodynamics. Gait performance was assessed in patients using gait scale before and after the tap test. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were applied to compare group differences between patients and controls and assess the predictive performance of gait responsiveness to the tap test in the patients. RESULTS: Fractional anisotropy (FA) and axial diffusivity showed significant increases in the ventrolateral (VL) and ventroposterolateral (VPL) nuclei of the iNPH group compared with those of the control group (p < 0.05). The predictions of gait responsiveness of ventral thalamic FA alone (area under the ROC curve [AUC] < 0.8) significantly outperformed those of CSF hydrodynamics alone (AUC < 0.6). The AUC curve was elevated to 0.812 when the CSF peak systolic velocity and FA value were combined for the VPL nucleus, yielding the highest sensitivity (0.769) and specificity (0.778) to predict gait responses. CONCLUSIONS: Combined measurements of sensorimotor-related thalamic FA and CSF hydrodynamics can provide potential biomarkers for gait response to the CSF tap test in patients with iNPH. KEY POINTS: • Ventrolateral and ventroposterolateral thalamic FA may predict gait responsiveness to tap test. • Thalamic neuroplasticity can be assessed through DTI in idiopathic normal-pressure hydrocephalus. • Changes in the CST associated with gait control could trigger thalamic neuroplasticity. • Activities of sensorimotor-related circuits could alter in patients with gait disturbance. • Management of patients with iNPH could be more appropriate.

[Progress in diagnosis of and therapy for idiopathic normal-pressure hydrocephalus--Lymphatic drainage of CSF and ISF from the brain: recent concept and hypothesis].

Cerebrospinal fluid (CSF) drains via the cribriform plate and nasal mucosa to cervical lymph nodes. There are no conventional lymphatics in the brain but physiological studies have revealed a substantial and immunologically significant lymphatic drainage from brain to cervical lymph nodes. Interstitial fluid (ISF) and solutes from brain parenchyma drain along capillary and perivascular space of artery, and path through the skull base, then reach to the cervical lymph nodes. CSF and ISF appear to drain by separate routes from the brain, especially in humans. However, there are interrelationships between the two fluid compartments that become more significant when drainage of CSF or ISF is impaired by disease processes. Vessel pulsations appear to be the driving force for the perivascular lymphatic drainage along artery walls, and as vessels stiffen with age, amyloid peptides (Aß) deposit in the drainage pathways as cerebral amyloid angiopathy (CAA). Blockage of lymphatic drainage of ISF and solutes from the brain by CAA may result in loss of homeostasis of the neuronal environment that may contribute to neuronal malfunction and dementia. Such failure of perivascular drainage may associated with the pathoetiology of Alzheimer's disease, cerebral small artery disease and idiopathic normal pressure hydrocephalus (iNPH).

Reassessing cerebrospinal fluid (CSF) hydrodynamics: a literature review presenting a novel hypothesis for CSF physiology.

The traditional model of cerebrospinal fluid (CSF) hydrodynamics is being increasingly challenged in view of recent scientific evidences. The established model presumes that CSF is primarily produced in the choroid plexuses (CP), then flows from the ventricles to the subarachnoid spaces, and is mainly reabsorbed into arachnoid villi (AV). This model is seemingly based on faulty research and misinterpretations. This literature review presents numerous evidence for a new hypothesis of CSF physiology, namely, CSF is produced and reabsorbed throughout the entire CSF-Interstitial fluid (IF) functional unit. IF and CSF are mainly formed and reabsorbed across the walls of CNS blood capillaries. CP, AV and lymphatics become minor sites for CSF hydrodynamics. The lymphatics may play a more significant role in CSF absorption when CSF-IF pressure increases. The consequences of this complete reformulation of CSF hydrodynamics may influence applications in research, publications, including osteopathic manual treatments.

Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma.

PURPOSE: To evaluate the evidence supporting a role for senescent changes in cerebrospinal fluid (CSF) circulatory physiology in the pathogenesis of normal-tension glaucoma (NTG). DESIGN: Literature review and personal perspective of the authors. METHODS: Analysis of selected articles in the peer-reviewed literature with interpretation and perspective. RESULTS: Recent studies have reported that intracranial pressure is lower in patients with NTG when compared with patients with primary open-angle glaucoma and nonglaucomatous control subjects. It has been suggested that a low intracranial pressure in patients with normal intraocular pressure could lead to glaucomatous damage. This low intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, could result in barotraumatically induced optic nerve damage at the lamina cribrosa. However, several experimental studies do not support the speculation that low intracranial pressure and the resulting pressure-dependent effects cause bowing back of the lamina cribrosa and optic disc cupping. On the other hand, CSF production and turnover have been shown to be decreased in aging and in pathologic conditions, such as Alzheimer disease and normal pressure hydrocephalus. Interestingly, recent studies have revealed that both Alzheimer disease patients and patients with normal pressure hydrocephalus may have a higher risk of developing glaucoma. Therefore, we believe that CSF circulatory failure, ultimately resulting in reduced neurotoxin clearance along the optic nerves, could be an alternative explanation as to why glaucoma develops in patients with low intracranial pressure. CONCLUSIONS: On the basis of the evidence available from the peer-reviewed literature, our tentative conclusion is that age-related changes in CSF circulatory physiology and the subsequent decrease in CSF turnover, with diminished clearance of toxic substances, can account for, at least in part, the pathogenesis of NTG. It should be stressed that for the moment at least, the present hypothesis remains unproven. Further research will be necessary to determine the possible role of CSF circulatory dysfunction in NTG. If confirmed, this hypothesis could provide new, important insights into the pathogenesis of NTG.

Effects of tissue dielectric properties on the electric field induced in tDCS: a sensitivity analysis.

Numerical modeling studies remain the only viable way to accurately predict the electric field (E-field) distribution in transcranial direct current stimulation (tDCS). Despite the existence of multiple studies of this kind, a wide range of different values and properties for the electrical conductivities of the tissues represented is employed. This makes it difficult to predict whether the changes observed between models are due to differences in the geometries of the volume conductors or to the different electrical properties of the tissues. In this study we used the finite element method to calculate the E-field distribution in several spherical head models whose tissues were represented with different isotropic and anisotropic conductivity profiles. Results show that the distribution of the E-field is especially sensitive to the conductivity of the skull, skin and GM. These results might help comparing numerical modeling studies that employ different conductivity values.

The correlation between cauda equina nerve root volume and sensory block height after spinal anaesthesia with glucose-free bupivacaine.

We examined the association between cauda equina nerve root volume and sensory block height in 15 patients undergoing spinal anaesthesia with 0.5% glucose-free bupivacaine. Magnetic resonance imaging and a separate image segmentation program were used to calculate the volume of the nerve roots. Nerve root volume was also correlated with lumbosacral cerebrospinal fluid volume and with patients' physical characteristics. Nerve root volume correlated negatively with sensory block height (Spearman rho -0.61 (95% CI -0.85 to -0.14)) and body mass index (Spearman rho -0.66 (95% CI -0.87 to -0.24)) but positively with cerebrospinal fluid volume (Spearman rho 0.76 (95% CI 0.43-0.91)). Factors that are thought to influence cerebrospinal fluid volume, such as body mass index, might similarly affect the volume of the nerve roots. The size of the nerve roots may influence the spread of spinal anaesthesia.

The microanatomical structure of the cistern of the lamina terminalis.

Microanatomical dissection was performed on 14 formalin-fixed human cadaveric head specimens to provide information relevant for surgical procedures involving the cistern of the lamina terminalis (LT). The cistern of the LT was located in the midline of the telencephalon and was tent-shaped. The superior wall was located between the septal areas bilaterally, the lateral walls leaned laterally downwards, the anterior wall was the integrated line of the bilateral leptomeninges, the posterior and the inferoposterior walls were composed of the LT, the inferior margin was the arachnoid membrane between the optic nerves, and the inferoanterior wall usually formed a recess in front of the optic chiasm. In summary, the shape of the cistern of the LT is relatively constant, which is helpful for predicting the direction of hemorrhage of an aneurysm of the anterior communicating artery; in distinguishing its neural, vascular, and fibrous contents; and guiding surgical procedures.

Evidence of endoplasmic reticular stress in the spinal motor neurons exposed to CSF from sporadic amyotrophic lateral sclerosis patients.

We have earlier reported that intrathecal injection of cerebrospinal fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (ALS-CSF) into neonatal rats and supplementation of rat spinal cord cultures with ALS-CSF induces motor neuron degeneration via aberrant neurofilament phosphorylation and Golgi apparatus fragmentation. Intracellular aggregates immunoreactive to ubiquitin, phosphorylated neurofilaments and choline acetyl transferase (ChAT) were prominently seen in NSC-34 cells exposed to ALS-CSF. Protein aggregation could cause stress on endoplasmic reticulum (ER) and may precede Golgi fragmentation. Here we assessed the effect of ALS-CSF on the expression of GRP-78 and caspase-12 proteins, the markers of ER stress responses, in NSC-34 cells and rat spinal cords by immunochemistry and immunoblotting. Both in vitro and in vivo, increased expression of these proteins accompanied elevated active caspase-12 levels. Apoptotic nuclei and nuclear translocation of caspase-12 were noted in some cells. In vitro, the occurrence of ER stress was supported by electron microscopic observations of numerous free polyribosomes and fragmented ER cisternae. Aggregated mSOD1 protein causes ER stress in familial ALS. ER stress is also reported in the autopsy samples of sporadic ALS. Thus our observation of ER stress may be linked to the protein aggregation, viz. phosphorylated neurofilaments and ChAT, reported earlier.

Hypothalamic osmoregulation is maintained across the wake-sleep cycle in the rat.

In different species, rapid eye movement sleep (REMS) is characterized by a thermoregulatory impairment. It has been postulated that this impairment depends on a general insufficiency in the hypothalamic integration of autonomic function. This study aims to test this hypothesis by assessing the hypothalamic regulation of body fluid osmolality during the different wake-sleep states in the rat. Arginine-vasopressin (AVP) plasma levels were determined following intracerebroventricular (ICV) infusions of artificial cerebrospinal fluid (aCSF), either isotonic or made hypertonic by the addition of NaCl at three different concentrations (125, 250 and 500 mM). Animals were implanted with a cannula within a lateral cerebral ventricle for ICV infusions and with electrodes for the recording of the electroencephalogram. ICV infusions were made in different animals during Wake, REMS or non-REM sleep (NREMS). The results show that ICV infusion of hypertonic aCSF during REMS induced an increase in AVP plasma levels that was not different from that observed during either Wake or NREMS. These results suggest that the thermoregulatory impairment that characterizes REMS does not depend on a general impairment in the hypothalamic control of body homeostasis.

The effects of the interthalamic adhesion position on cerebrospinal fluid dynamics in the cerebral ventricles.

The interthalamic adhesion is a unique feature of the third ventricle in the brain. It differs in shape and size and its location varies between individuals. In this study, computational fluid dynamics was performed on 4 three-dimensional models of the cerebral ventricular system with the interthalamic adhesion modeled in different locations in the third ventricle. Cerebrospinal fluid (CSF) was modeled as incompressible Newtonian fluid and flow was assumed laminar. The periodic motion of CSF flow as a function of the cardiac cycle starting from diastole was prescribed as the inlet boundary condition at the foramen of Monroe. Results from this study show how the location of the interthalamic adhesion influences the pattern of pressure distribution in the cerebral ventricles. In addition, the highest CSF pressure in the third ventricle can vary by approximately 50% depending on the location of the interthalamic adhesion. We suggest that the interthalamic adhesion may have functional implications on the development of hydrocephalus and it is important to model this anatomical feature in future studies.

Cerebrospinal fluid stasis and its clinical significance.

We hypothesize that stasis of the cerebrospinal fluid (CSF) occurs commonly and is detrimental to health. Physiologic factors affecting the normal circulation of CSF include cardiovascular, respiratory, and vasomotor influences. The CSF maintains the electrolytic environment of the central nervous system (CNS), influences systemic acid-base balance, serves as a medium for the supply of nutrients to neuronal and glial cells, functions as a lymphatic system for the CNS by removing the waste products of cellular metabolism, and transports hormones, neurotransmitters, releasing factors, and other neuropeptides throughout the CNS. Physiologic impedance or cessation of CSF flow may occur commonly in the absence of degenerative changes or pathology and may compromise the normal physiologic functions of the CSF. CSF appears to be particularly prone to stasis within the spinal canal. CSF stasis may be associated with adverse mechanical cord tension, vertebral subluxation syndrome, reduced cranial rhythmic impulse, and restricted respiratory function. Increased sympathetic tone, facilitated spinal segments, dural tension, and decreased CSF flow have been described as closely related aspects of an overall pattern of structural and energetic dysfunction in the axial skeleton and CNS. Therapies directed at affecting CSF flow include osteopathic care (especially cranial manipulation), craniosacral therapy, chiropractic adjustment of the spine and cranium, Network Care (formerly Network Chiropractic), massage therapy (including lymphatic drainage techniques), yoga, therapeutic breath-work, and cerebrospinal fluid technique. Further investigation into the nature and causation of CSF stasis, its potential effects upon human health, and effective therapies for its correction is warranted.

The cranial rhythmic impulse and excessive crying of infancy.

BACKGROUND: Osteopathic physicians believe that the birthing process causes cranial dysfunction that may be manifested in somatic symptoms, one of which is excessive crying of infancy. Cranial dysfunction can be determined by assessing the cranial rhythmic impulse (CRI). OBJECTIVE: The objective of this study is to examine whether an abnormal CRI is associated with excessive crying of infancy. DESIGN: Full-term infants in the well-baby nursery of an urban public hospital in the Bronx, New York were enrolled. Two (2) osteopathic physicians independently measured the CRI in infants before discharge. One (1) osteopath repeated the CRI measurement at 2 weeks. At 6 weeks, an investigator blinded to the CRI and birth data assessed infant crying using the modified Ames Cry Score via telephone interview with the primary caretaker. The caretaker was also asked about maternal stress, use of home or cultural remedies, and the infant's diet. The main outcome measure was the presence of excessive crying. RESULTS: One hundred and thirty-nine (139) patients were included in the final sample. The overall incidence of excessive crying was 41.7%. Excessive crying was associated with an abnormal CRI at 2 weeks (p < 0.001) but not with the CRI at birth (p = 0.23). Infants with an abnormal CRI at 2 weeks were 6.8 times (95% confidence intervals 2.2, 20.6) more likely to develop excessive crying than infants with a normal CRI. Infant diet was independently associated with excessive crying. Inter-rater agreement for CRI measurement was 0.70 using the kappa statistic. CONCLUSIONS: These data suggest that an abnormal CRI at 2 weeks of age may be associated with excessive crying.

Impact of anesthetic agents on cerebrovascular physiology in children.

The role of the pediatric neuroanesthetist is to provide comprehensive care to children with neurologic pathologies. The cerebral physiology is influenced by the developmental stage of the child. The understanding of the effects of anesthetic agents on the physiology of cerebral vasculature in the pediatric population has significantly increased in the past decade allowing a more rationale decision making in anesthesia management. Although no single anesthetic technique can be recommended, sound knowledge of the principles of cerebral physiology and anesthetic neuropharmacology will facilitate the care of pediatric neurosurgical patients.

MR imaging and quantification of the movement of the lamina terminalis depending on the CSF dynamics.

BACKGROUND AND PURPOSE: Brain pulsation is a well-known observation in neurosurgery, but methods for its visualization on MR imaging, like phase imaging, do not provide a detailed structural view. We prospectively investigated electrocardiographic (ECG)-gated cine true fast imaging with steady-state precession (FISP) sequence on volunteers to test a sequence for demonstrating brain pulsation and movements of intracranial structures related to CSF dynamics. MATERIALS AND METHODS: Eleven healthy volunteers were investigated with prospectively ECG-gated cine true-FISP in the midsagittal plane. A total of 50 phases were recorded per cardiac cycle and per volunteer. The lamina terminalis was chosen to study the pulsatility of the brain, and the optic recess diameter was chosen for means of objective quantification of the degree of pulsatility. RESULTS: Pulsatile motion of the lamina terminalis was apparent in all volunteers on the cine mode. The mean diameter of the optic recess was 2.5 mm. The greatest change in diameter in 1 volunteer was 1.5 mm. The mean change in diameter was 40% during 1 cardiac cycle. CONCLUSIONS: Cine true-FISP sequence is a well-suited method for investigations of passive movements of the ventricular system. It shows pulsations of the brain as well as passive changes caused by CSF dynamics with high temporal and spatial resolution.

Descending brain-spinal cord projections in a primitive vertebrate, the lamprey: cerebrospinal fluid-contacting and dopaminergic neurons.

We used Neurobiotin as a retrograde tract tracer in both larval and adult sea lampreys and observed a number of neuronal brainstem populations (mainly reticular and octaval populations and some diencephalic nuclei) that project to the spinal cord, in agreement with the results of previous tracer studies. We also observed small labeled neurons in the ventral hypothalamus, the mammillary region, and the paratubercular nucleus, nuclei that were not reported as spinal projecting. Notably, most of the labeled cells of the mammillary region and some of the ventral hypothalamus were cerebrospinal fluid-contacting (CSF-c) neurons. Combined tract tracing and immunocytochemistry showed that some of the labeled neurons of the mammillary and paratubercular nuclei were dopamine immunoreactive. In addition, some CSF-c cells were labeled in the caudal rhombencephalon and rostral spinal cord, and many were also dopamine immunoreactive. Results with other tracers (biotinylated dextran amines, horseradish peroxidase, and the carbocyanine dye DiI) also demonstrated that the molecular weight or the molecular nature of the tracer was determinant in revealing diencephalic cells with very thin axons. The results show that descending systems afferent to the spinal cord in lampreys are more varied than previously reported, and reveal a descending projection from CSF-c cells, which is unknown in vertebrates. The present results also reveal the existence of large differences between agnathans and gnathostomes in the organization of the dopaminergic cells that project to the spinal cord.

In vivo detection of gray and white matter differences in GABA concentration in the human brain.

A novel selective multiple quantum filtering-based chemical shift imaging method was developed for acquiring GABA images in the human brain at 3 T. This method allows a concomitant acquisition of an interleaved total creatine image with the same spatial resolution. Using T(1)-based image segmentation and a nonlinear least square regression analysis of GABA-to-total creatine concentration ratios in frontal and parietal lobes of healthy adult volunteers as a function of the tissue gray matter fraction, the mean GABA concentration in gray and white matter was determined to be 1.30+/-0.36 micromol/g and 0.16+/-0.16 micromol/g (mean+/-SD, n=13), respectively. It is expected that this method will become a useful tool for studying GABAergic function in the human brain in vivo.

White matter abnormalities in autism detected through transverse relaxation time imaging.

While neuroimaging studies have reported neurobiological abnormalities in autism, the underlying tissue abnormalities remain unclear. Quantitative transverse relaxation time (T2) imaging permits the examination of tissue abnormalities in vivo, with increased T2 largely reflecting increased tissue water. Blood flow and the presence of tissue iron may also affect T2. In this study, we used voxel-based relaxometry of the cerebrum and global averages to examine T2 abnormalities in autism. Nineteen males with autism (age: 9.2 +/- 3.0 years) and 20 male controls (age: 10.7 +/- 2.9 years) underwent magnetic resonance imaging at 3.0 T. Quantitative T2 maps, generated through gradient echo sampling of the free induction decay and echo, were segmented into gray matter, white matter, and cerebrospinal fluid. Average cerebral gray and white matter T2 were determined and compared between groups. To assess localized T2 differences, the quantitative T2 maps were warped to a template created for this study, smoothed, and compared using statistical parametric mapping. Patients with autism had an increase in average cerebral white matter T2, although no group differences were seen in average cerebral gray matter T2. Patients with autism also had bilateral regional T2 increases in the gray matter and associated white matter of the parietal lobes (primary sensory association areas) and occipital lobes (visual association areas) and in the white matter within the supplementary motor areas in the frontal lobes. The regional and global elevations in white matter T2 suggest abnormalities of white matter tissue water content in autism, which may represent a neurobiological basis for the aberrant cortical connectivity hypothesized to underlie the disorder.

The perineurial vessel: a possible candidate for the structural basis of the meridian (Jing-Luo) in Chinese medicine.

A new concept is proposed of the 'perineurial vessel' as another vascular system of the body. The effects of acupuncture and moxibustion are explained as mechanical or thermal stimulation of intraperineurial cerebrospinal fluid (CSF). Fenestrated venous capillaries of circumventricular organs, including the choroid plexus, instead of arachnoid granulations, are shown to be the main site of CSF absorption. A new concept is also presented of a double circulatory system of the body, namely, in addition to the cardiovascular system, a lympho-liquid system with complete fluid circulation throughout the entire body.