Mammalian CNS barosensitivity: studied by brain-stem auditory-evoked potential in mice.

High pressure nervous syndrome (HPNS) is an instinctive response of mammalian high-class nervous functions to increased hydrostatic pressure. Electrophysiological activity of mammalian central nervous system (CNS), including brainstem auditory-evoked potential (BAEP), has characteristic changes under pressure. Here we recorded BAEP of 63 mice exposed to 0-4.0 MPa. The results showed that interpeak latencies between wave I and wave IV (IPL1-4) and their changes under pressures (deltaIPL1-4) responded to increasing pressure in a biphase pattern, shortened under pressure from 0 to 0.7MPa, then prolonged later. There were significantly negative correlations between base IPL1-4s and deltaIPL1-4s (p < 0.01). Individual IPL1-4s were supposed to respond to increasing pressure in a relative steady pattern in accordance with its base IPL1-4s. Those with shorter-base IPL1-4 presented direct increases in IPL1-4. However, those with longer-base IPL1-4 had a decreased IPL1-4 under small to moderate pressure then rebounded later. Our results suggested that mammalian CNS functions were susceptible to small to moderate pressure, as well as a higher pressure than 1.0MPa. Mice, as a statistical mass, had an "optimum" pressure about 0.7MPa, rather than atmospheric pressure, referred as shortest IPL1-4s. An individual's response to high pressure might be relied on his base biological condition. Our results highlighted a new approach to investigate a practical strategy to medical selecting barotolerant candidates for deep divers. Diversity of individual susceptibility to hydrostatic pressure was under discussed. Underlying mechanisms of the "optimum" pressure for CNS function and its significance to neurophysiology remain open to further exploration.

Relationship between barotolerance and fatty acids constitution of brain cell membrane.

OBJECTIVE: It is suggested that one of the mechanisms for high pressure nervous syndrome (HPNS) is related to nervous cell membranous fluidity. Both pressure and fatty acid components of cell membranes would influence membrane fluidity. The present research probed into the relationship between different fatty acid components of brain cell membrane and individuals' degree of HPNS. METHODS: Four groups of mice were compressed to 4.1 MPa with an He-O2 mixture over a period of two hours. These animals had been fed with different diets for a period of months prior to the procedure. We recorded interpeak latency of Wave 1 to Wave 4 (IPL1-4) of brainstem auditory-evoked potential (BAEP) at different stages of compression. Animals were sacrificed immediately after surfacing. Both polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) of brain cell membranes were analyzed by HPLC. RESULTS: Upon arriving at 4 MPa, the IPL1-4 readings of the four groups were prolonged 0.294 +/- 0.400 milliseconds (ms), 0.156 +/- 0.200 ms, 0.009 +/- 0.182 ms and 0.025 +/- 0.137 ms separately; each corresponded to its own PUFA-percent constitution of 16.2 +/- 4.5%, 24.8 +/- 4.3%, 33.5 +/- 8.8% and 32.3 +/- 2.9% respectively on the basis of total fatty acids. DISCUSSION AND CONCLUSION: Varying fractions of PUFAs, implying different membrane fluidity, interfered with disturbance of synaptic transmission during hyperbaric exposure. In other words, the higher the ratio of PUFAs/SFAs to the brain cell membrane, the stronger the ability for animals to antagonize the pressure effect.

The efficacy of physiological and pharmacological N-methyl-D-aspartate receptor block is greatly reduced under hyperbaric conditions.

Human divers exposed to hyperbaric pressure may suffer from cognitive and motor impairments thought to be related to high pressure effects per ce. These effects, termed high pressure neurological syndrome (HPNS), appear at pressure above 1.1 MPa. HPNS involves CNS hyperexcitability that is partially attributed to augmented responses of the glutamatergic N-methyl-d-aspartate receptor (NMDAR). NMDAR is blocked by Mg(2+) (physiologically) and by dl-2-Amino-5-phosphonopentanoic acid (AP5, pharmacologically). We have recently reported that hyperbaric pressure augments rat hippocampus NMDAR synaptic response and generates hyperexcitability. We now test pressure effects on the blockade efficacy of Mg(2+)and AP5. Under high pressure conditions more than double [Mg(2+)](o) and [AP5](o) were needed to achieve similar effects on NMDAR synaptic response's amplitude, decay time, and time integral comparable to control conditions. [Mg(2+)](o) and [AP5](o) concentration-response curves and the concentration for 50% responses' inhibition (IC(50)s) showed similar normalized pattern at control and pressure for each parameter. We conclude that hyperbaric pressure reduces the efficacy of these NMDAR blockers that may be associated with the receptor conformational change(s). This provides additional mechanism for pressure over activation of NMDAR. Taken together with our previous reports, high pressure modification of NMDAR activity significantly contributes to CNS hyperexcitability and possibly for long term vulnerability.

Low susceptibility to inert gases and pressure symptoms in TREK-1-deficient mice.

Nervous disorders may occur after an organism is saturated with inert gases, which may alter the lipid bilayer structure, according to their liposolubility coefficient. Increase in the nitrogen partial pressure induces a neurological syndrome called 'nitrogen narcosis'. By contrast, high pressures of helium induce epilepsy, an high-pressure nervous syndrome symptom. On the basis of an analogy with anaesthetic mechanisms, we used TREK-1 knockout mice, earlier described to volatile the anaesthetics resistance. These mice had a higher threshold of resistance to the narcotic effects of nitrogen and to the death after recurrent epileptic seizure induced by high pressure. TREK-1 channels seem to play a key role in modulating the anaesthetic potential of inert gases and in neuroprotection.

Neurological decompression illness and hematocrit: analysis of a consecutive series of 200 recreational scuba divers.

Neurological complications are common in recreational divers diagnosed with decompression illness (DCI). Prior reports suggest that hemoconcentration, with hematocrit values of 48 or greater, increase the risk for more severe and persistent neurological deficits in divers with DCI. Herein we describe our experience with neurological DCI and hematocrit values in a large series of consecutively treated divers. We performed a retrospective chart review of 200 consecutive recreational divers that received treatment for DCI. Standard statistical analyses were performed to determine if there were any significant relationships between diving-related or demographic parameters, neurological manifestations, and hematocrit. In 177 of the 200 divers (88.5%), at least one manifestation of neurological DCI (mild, moderate, or severe) was present. The median hematocrit value was 43, for both male and female divers, with a range of 30 to 61. Hematocrit values did not correlate with diver age or level of diving experience. In male divers, the hematocrit did not correlate with neurological symptoms, including the sub-group with values of 48 or greater. In contrast, female divers with hematocrit values of 48 or greater were significantly more likely to develop motor weakness (p=0.002, Fisher's exact test) and an increased number of severe sensory symptoms (p=0.001, Kendall's tau statistic). Neurological complications are common in recreational divers treated for DCI. Hematocrit values of 48 or higher were correlated with the presence of motor weakness and severity of sensory symptoms in female divers. The hematocrit did not correlate with neurological DCI in male divers.

Cellular and neurophysiological effects of high ambient pressure.

The observed cellular effects of pressure are entirely compatible with the acute manifestations of CNS hyperexcitability. Inhibition of the glycine receptor will reduce post-synaptic inhibition, leading to increased excitability (cf 'Startle Disease', an hereditary disease with increased excitability arising from a genetic modification to the glycine receptor (Becker et al., 2002)). Since glycine-mediated neurotransmission is particularly associated with motor reflex circuits (Lynch, 2004) it is not surprising that many of the acute manifestations of pressure involve motor dysfunction. Potentiation by pressure of the NR1-NR2C subtype of the NMDA-sensitive glutamate receptor will lead to increased excitability within the cerebellum (where this receptor sub-type is most highly expressed (Monyer et al., 1994)). Although the cerebellum receives input from many parts of the nervous system, it projects primarily to the motor and frontal lobe cognitive areas. Thus dysfunction of the glutamate-mediated excitatory neurotransmission in this area is most likely to result in locomotor and cognitive symptoms, characteristic of acute pressure effects. Finally, the effects observed on AC/cAMP intracellular signalling, probably mediated via dopamine receptors, is also likely to produce motor dysfunction (cf Parkinson's disease). The observed cellular effects also suggest potential mechanisms that could result in long-term CNS dysfunction. Potentiation of glutamate neurotransmission is likely to lead to excessive calcium entry into those neurons. This may trigger excitotoxicity via a signal cascade in which neuronal NO synthase is activated producing the toxic free radical peroxynitrite and activation of the proapoptotic protein poly(ADP-ribose) polymerase (Aarts & Tymianski, 2005). An additional mechanism, also initially triggered by a rise in intracellular calcium through NR1-NR2C receptors, involves activation of a member of the Transient Receptor Potential (TRP) channel superfamily, the TRPM-7 channel. Activation of these channels will cause a further rise in intracellular calcium, creating a positive feedback and generating more neuronal death through the toxic signal cascade (Aarts & Tymianski, 2005). Neuronal cell death within the cerebellum might be expected to give rise to delayed motor and cognitive dysfunction the magnitude of which would tend to be related to the extent of hyperbaric exposure. There is at present no evidence that these excitotoxic mechanisms are triggered by exposure to pressure but future experimental work should investigate the extent to which pressure might activate them.

[High pressure neurological syndrome]. / Sindrome neurológico de alta presión.

INTRODUCTION: Pressure is a thermodynamic variable that, like temperature, affects the states of matter. High pressure is an environmental characteristic of the deep sea. Immersion to depth brings about an increase in pressure of 0.1 MPa (1 atm) for each 10 m of seawater. Humans exposed to high pressure, mostly professional divers, suffer effects that are proportional to their exposure. DEVELOPMENT: The nervous system is one of the most sensitive targets of high pressure. The high pressure neurological syndrome (HPNS) begins to show signs at about 1.3 MPa (120 m) and its effects intensify at greater depths. HPNS starts with tremor at the distal extremities, nausea, or moderate psychomotor and cognitive disturbances. More severe consequences are proximal tremor, vomit, hyperreflexia, sleepiness, and psychomotor or cognitive compromise. Fasciculations and myoclonia may occur during severe HPNS. Extreme cases may show psychosis bouts, and focalized or generalized convulsive seizures. Electrophysiological studies during HPNS display an EEG characterized by reduction of high frequency activity (alpha and beta waves) and increased slow activity, modification of evoked potentials of various modalities (auditory, visual, somatosensory), reduced nerve conduction velocity and changes in latency. Studies using experimental animals have shown that these signs and symptoms are progressive and directly dependent on the pressure. HPNS features at neuronal and network levels are depression of synaptic transmission and paradoxical hyperexcitability. CONCLUSION: HPNS is associated with exposure to high pressure and its related technological means. Experimental findings suggest etiological hypotheses, prevention and therapeutic approaches for this syndrome.

Postural control in a simulated saturation dive to 240 msw.

INTRODUCTION: There is evidence that increased ambient pressure causes an increase in postural sway. This article documents postural sway at pressures not previously studied and discusses possible mechanisms. METHODS: Eight subjects participated in a dry chamber dive to 240 msw (2.5 MPa) saturation pressure. Two subjects were excluded due to unilateral caloric weakness before the dive. Postural sway was measured on a force platform. The path length described by the center of pressure while standing quietly for 60 seconds was used as test variable. Tests were repeated 38 times in four conditions: with eyes open or closed, while standing on bare platform or on a foam rubber mat. RESULTS: Upon reaching 240 msw, one subject reported vertigo, disequilibrium and nausea, and in all subjects, mean postural sway increased 26% on bare platform with eyes open (p < 0.05) compared to predive values. There was no significant improvement in postural sway during the bottom phase, but a trend was seen toward improvement when the subjects were standing with eyes closed on foam rubber (p = 0.1). Postural sway returned to predive values during the decompression phase. DISCUSSION: Postural imbalance during deep diving has been explained previously as HPNS possibly including a specific effect on the vestibulo-ocular reflex. Although vertigo and imbalance are known to be related to compression rate, this study shows that there remains a measurable increase in postural sway throughout the bottom phase at 240 msw, which seems to be related to absolute pressure.

CNS manifestations of HPNS: revisited.

Exposure to high pressures (HP) has been associated with the development of the high pressure neurological syndrome (HPNS) in deep-divers and experimental animals. In contrast, many diving mammals are naturally able to withstand very high pressures. Although at a certain pressure range humans are also able to perform to some extent, the severe signs of HPNS at higher pressures motivated the research on the pathophysiology underlying this syndrome rather than on possible adaptive mechanisms. Thermodynamically, high pressure resembles cooling. Both conditions usually involve reduction in the entropy and slowing down of kinetic rates. We have observed in rat corticohippocampal brain slices that high pressure slows and reduces excitatory synaptic activity. However, this was associated with increased gain of the system, allowing the depressed inputs to elicit regular firing in their target cells. This increased gain was partially mediated by elevated excitability of their dendrites and reduction in the background inhibition. This compensation is efficient at low-medium frequencies. However, it induces abnormal spike reverberation at the high frequency band (> 50 Hz). Synaptic depression that requires less vesicles/transmitter turn over may serve as an energy-saving mechanism when enzymes and membrane pumps activity are slowed down at pressure. It is even more efficient if a similar reduction is induced in inhibitory synaptic activity. Unfortunately, the frequency response characteristics at this mode of operation may make the system vulnerable to external signals (noise, auditory, visual, etc) at frequencies that elicit 'resonance' responses. Therefore, it is expected that humans exposed to pressures above 1.5 MPa display lethargy and fatigue, certain reduction in cognitive and memory functions when the system is working in an 'economic' mode. The more serious signs of HPNS such as nausea, vomiting, severe tremor, disturbance of motor coordination, and seizures, may be the consequence of an interaction between the 'economic' mode of operation and resonance-inducing environmental disturbances.

[Diving: barometric pressure and neurochemical mechanisms]. / La plongée: pression barométrique et mécanismes neurochimiques.

The studies of Paul Bert, presented in his book "La Pression Barométrique" in 1878, were at the origin of the modern hyperbaric physiology. Indeed his research demonstrated the effects of oxygen at high pressure, that compression effects must be dissociated from decompression effects, and that neurological troubles and death of divers during or after decompression were due to the fast rate of decompression. However, it is only in 1935 that the work of Behnke et al. attributed the complaints reported at 3 bars and above in compressed air or nitrogen-oxygen mixture to the increase in partial pressure of nitrogen which induces nitrogen narcosis. Little is known about the origins and mechanisms of this narcosis. The traditional view was that anaesthesia or narcosis occurred when the volume of a hydrophobic membrane site was caused to expand beyond a critical amount by the absorption of molecules of a narcotic gas. The observation of the pressure reversal effect during general anaesthesia has long supported this lipid theory. However, recently, protein theories have met with increasing recognition since results with gaseous anaesthetics have been interpreted as evidence for a direct gas-protein interaction. The question is to know whether inert gases, that disrupt dopamine and GABA neurotransmissions and probably glutamatergic neurotransmission, act by binding to neurotransmitter protein receptors.

Modulation of isolated N-methyl-d-aspartate receptor response under hyperbaric conditions.

In humans, hyperbaric pressure induces the high-pressure neurological syndrome (HPNS). HPNS is characterized by tremor, sleep disorders, electroencephalographic changes, and impairment of cognitive and motor performances. In animals, higher pressures result in convulsions and death. An increased N-methyl-d-aspartate receptor (NMDAR) response has been implicated with HPNS. We studied high-pressure effects on pharmacologically isolated NMDAR field excitatory postsynaptic potentials (fEPSPs). Hippocampal coronal brain slices from male Sprague-Dawley rats were prepared, constantly superfused with physiological solutions, gas-saturated at normobaric pressure and compressed up to 10.1 MPa with helium. fEPSPs were recorded from the dendritic layer of CA1 pyramidal neurones. High pressure significantly increased the single fEPSP delay, maximal initial slope, amplitude, decay time and time integral (elevated Na(+) and Ca(2+) influx) despite the known general decrease in glutamatergic synaptic release. The estimated negative and positive activation volumes (DeltaV*) for various kinetic segments of the fEPSP suggest a complex response of the receptor to pressure. The NMDAR frequency response was tested by a train of five stimuli. At 50-100 Hz, high pressure did not increase the fEPSPs' frequency-dependent depression and the train's time integral remained unchanged. At 25 Hz, pressure induced a larger frequency-dependent depression and significantly increased the time integral. Our results provide, for the first time, direct information on the isolated brain NMDAR response under hyperbaric conditions. These observations may explain some increase in the excitability of single normal glutametergic fEPSPs and their frequency responses.

Effect of 2.1 MPa and 4.1 MPa H2O2 exposure on auditory brain stem evoked potential in mice.

Brain auditory evoked potential (BAEP) in mice exposed to hyperbaric H2O2 pressure was monitored to reveal the correlation between altered synaptic transmission and hydrogen narcosis or isobaric HPNS. Inter peak latencies and wave amplitudes were selected as indices of assessment. The animals were exposed either to He-O2 or H2-O2 at 2.1 MPa and 4.1 MPa. Results showed that synaptic transmission was inhibited to various extents. The inhibition was partly due to the narcotic effect of hydrogen, which was added to the effect caused by hydrostatic pressure. On the other hand, asymmetrical reaction of each segment in the neuro-network might be responsible for the occurrence of HPNS.

Microdialysis study of striatal dopaminergic dysfunctions induced by 3 MPa of nitrogen- and helium-oxygen breathing mixtures in freely moving rats.

Previous studies have demonstrated opposite effects of high-pressure helium and nitrogen on extracellular dopamine (DA) levels, which may reflect disturbances on the synthesis, release or metabolic mechanisms. Intrastriatal microdialysis was used to measure the precursor (tyrosine), DA and its metabolites (DOPAC, HVA) levels under nitrogen- or helium- at pressure up to 3 MPa. Under 3 MPa of helium-oxygen breathing mixtures, the extracellular concentration of tyrosine is decreased while the extracellular concentration of DA is increased. On the contrary, nitrogen-oxygen breathing mixture at the same pressure increased extracellular tyrosine concentration and decreased DA release. Under both conditions, an increment of the DOPAC and HVA levels could be noted. Our results suggest that changes in DA release and metabolism during high-pressure helium exposure reflect the effect of the pressure per se, whereas the intrinsic effects of narcotic gases, although sensitive to pressure, would be revealed by hyperbaric nitrogen exposure.

Pressure (< or=4 ATA) increases membrane conductance and firing rate in the rat solitary complex.

Neuronal sensitivity to pressure, barosensitivity, is illustrated by high-pressure nervous syndrome, which manifests as increased central nervous system excitability when heliox or trimix is breathed at >15 atmospheres absolute (ATA). We have tested the hypothesis that smaller levels of pressure (

Modulation of rat corticohippocampal synaptic activity by high pressure and extracellular calcium: single and frequency responses.

High pressure (>1.5 MPa) induces a series of disturbances of the nervous system that are generically termed high-pressure nervous syndrome (HPNS). HPNS is characterized by motor and cognitive impairments. The neocortex and the hippocampus are presumably involved in this last disorder. The medial perforant path (MPP) synapse onto the granule cells of the dentate gyrus is the main connection between these structures. We have studied high-pressure (HP) effects on single and frequency response of this synapse. Since effects of HP on various synapses were mimicked by reducing [Ca2+]o, results under these conditions were compared. Medial perforant path-evoked field excitatory postsynaptic potentials (fEPSPs) were recorded from granule cells in rat brain slices. Slices were exposed to high pressure of helium (0.1-10.1 MPa) at 30 degrees C. HP depressed single fEPSPs by 35 and 55% at 5.1 and 10.1 MPa, respectively, and increased paired-pulse facilitation (PPF) at 10- to 40-ms inter-stimulus intervals. Frequency-dependent depression (FDD) was enhanced by HP during trains of stimuli at 50 but not at 25 Hz. Depression of single fEPSPs by reduction of [Ca2+]o from 2 mM control to 1 mM at normal pressure was equivalent to the effect of 10.1 MPa at control [Ca2+]o. However, this low [Ca2+]o induced greater enhancement of PPF, and in contrast, turned FDD at 25-50 Hz into frequency-dependent potentiation. These results suggest that HP depresses single synaptic release by reducing Ca2+ entry, whereas slowing of synaptic frequency response is independent of Ca2+. These findings increase our understanding of HPNS experienced by deep divers.

Helium-oxygen pressure induces striatal glutamate increase: a microdialysis study in freely-moving rats.

In rat, helium pressures induce locomotor and motor activity which requires dopaminergic and N-methyl-D-aspartate (NMDA) receptor activities at striatal level. However, biochemical studies have suggested that pressure exposure may increase striatal glutamate level. We used microdialysis technique to study the effects of pressure on glutamate level in the striatum and the effects of local administration of D1 (SCH23390) or D2 (sulpiride) on these changes. Pressures increase both glutamate and glutamine levels in striatal microdialysates. Administration of sulpiride (1 microM) or SCH23390 (1 microM) by reverse microdialysis did not affect significantly pressure induced glutamate increase. So, protective effects of D1 and D2 antagonists against locomotor and motor hyperactivity (LMA) are probably independent of the processes involved in the striatal glutamate increase evoked by pressure.

High pressure enhanced NMDA activity in the striatum and the globus pallidus: relationships with myoclonia and locomotor and motor activity in rat.

In mammals high pressure of helium-oxygen (He-O2) breathing mixture leads to the high pressure neurological syndrome (HPNS) which includes a set of behavioural disorders such as locomotor and motor hyperactivity (LMA) and myoclonia. In rats, i.c.v. administrations of competitive NMDA antagonists decrease some of these symptoms suggesting that He-O2 pressure could enhance NMDA neurotransmission within the central nervous system. More recently, we have shown using microdialysis that the extracellular glutamate level is increased in the striatum by He-O2 pressure. Neurochemical data have suggested that this structure is probably involved in the LMA development but not in the myoclonia expression. When considering myoclonia, recent neuropathological studies performed at normal pressure in humans suggest that the globus pallidus extern (equivalent to the globus pallidus in the rat) could be involved in this behavioural disorder. The aim of this study was to compare the role of striatal and pallidal NMDA activity on the LMA development and the myoclonia expression in the model of rat exposed to 8 MPa of He-O2 mixture. The intrastriatal administration of D(-)-2-amino-7-phosphonoheptanoic acid (2-APH) (10 nmol/slide) reduced the LMA development but only slightly reduced myoclonia. In contrast, the intrapallidal administration of 2-APH (10 nmol/slide) reduced both LMA and myoclonia. These results suggest that the LMA development requires NMDA activity at both striatal and pallidal level. In contrast, the myoclonia expression mainly requires NMDA activity at pallidal level. Consequently, NMDA neurotransmission at input and output levels of the striato-pallidal pathway play different roles in some of the behavioural disorders induced by He-O2 pressure.