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.

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.

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.

[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.

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.

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.

A hypothesis regarding possible interactions between the pressure-induced disorders in dopaminergic and amino-acidergic transmission.

When human divers or experimental animals are exposed to high pressure they develop the high pressure neurological syndrome (HPNS). The main symptoms include electroencephalographic changes and behavioral disturbances such as tremor, myoclonia, and hyperlocomotor activity. Recently, pressure-induced disorders in dopaminergic and amino-acidergic neurotransmission have been reported. In the present theoretical study, we review in vitro and in vivo neurochemical, electrophysiological, and pharmacobehavioral evidence concerning alterations in dopaminergic, glutamatergic, and GABAergic transmission occurring at high pressure, and their possible relationship to the symptoms of HPNS. Moreover, we also examine data concerning interactions, at normal pressure, between dopaminergic, glutamatergic, and GABAergic transmission that we suggest they could apply equally under high pressure between the pressure-induced disorders in dopaminergic and amino-acidergic transmission.

Pressure-induced disorders in neurotransmission and spontaneous behavior in rats: an animal model of psychosis.

Disorders in neurotransmission and spontaneous behavior in rats exposed to a high pressure helium-oxygen mixture that shows interesting parallels with the dopaminergic hypothesis of schizophrenia at both the biochemical and the therapeutic responding levels are reviewed. Furthermore, as human subjects exposed to a very high pressure have shown psychotic episodes, we conclude that the pressure-induced disorders in neurotransmission and spontaneous behavior in rats could constitute a valid animal model of schizophreniform psychosis and a useful tool for both the investigation of the biological mechanisms underlying schizophrenia and the development of new antipsychotic drugs.

The effects of kynurenic acid, quinolinic acid and other metabolites of tryptophan on the development of the high pressure neurological syndrome in the rat.

The effects of some biologically active metabolites of tryptophan on the high pressure neurological syndrome (HPNS) were studied. Kynurenic acid, quinolinic acid, 5-hydroxytryptophan, kynurenine and 3-hydroxyanthranilic acid, at doses within the physiological range, were administered exogenously to rats prior to exposure to increased pressure and any effects on the tremor, myoclonus and convulsion end points of the high pressure neurological syndrome were observed. Quinolinic acid (25 and 50 mg/kg) and kynurenine (50 mg/kg) reduced the onset pressure for tremor, but not myoclonus or convulsions. Kynurenic acid (100 mg/kg) increased tremor onset pressure; 5-hydroxytryptophan (20 mg/kg) slightly increased onset pressure for tremor but decreased that for myoclonus. 3-Hydroxyanthranilic acid (20 mg/kg) had no significant effect on any of the motor signs of the syndrome. These data provide further support for the idea that the motor events seen in the high pressure neurological syndrome are not produced by a single mechanism. Differences between the responses to related metabolites suggest that the precise balance between compounds such as kynurenic acid and quinolinic acid may be important in the appearance of the high pressure neurological syndrome.

The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.

Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.

Brain nuclei and neurotransmitters involved in the regulation of the high pressure neurological syndrome in the rat.

The role of glutamatergic (NMDA), cholinergic and purinergic neurotransmission in the pedunculopontine nucleus, red nucleus, ventrolateral thalamic nucleus, entopeduncular nucleus, and the substantia nigra in the development of the high pressure neurological syndrome (HPNS) was investigated in the rat. Focal injection of D-2-amino-7-phosphonoheptanoate (D-APH, 5 nmol per side) into the red nucleus or the pedunculopontine nucleus was protective against HPNS-induced convulsions. Carbachol (10 nmol), injected into the red nucleus, did not influence the severity of the symptoms of HPNS. Injection of carbachol into the pedunculopontine nucleus, significantly lowered the threshold pressure for convulsions and increased the threshold pressure for tremor. 2-Chloroadenosine (5 nmol), injected into the red nucleus, produced a potent antitremorgenic effect and a similar but less pronounced effect when injected into the pedunculopontine nucleus. 2-Chloroadenosine, injected into the substantia nigra (12.5 nmol) or the ventrolateral thalamic nucleus (25 nmol), facilitated the development of tremor and, in the entopeduncular nucleus (25 nmol), facilitated the occurrence of convulsions. These results show the complexity of neurotransmitter interactions in different regions of the brain, under high pressure. They also indicate that the biochemical and anatomical substrates, involved in the convulsions produced by HPNS, differ substantially from those in other experimental models of epilepsy.

Gamma-aminobutyric acid and the high pressure neurological syndrome.

Sodium valproate, nipecotic acid, diaminobutyric acid (DABA) and beta-alanine are drugs which enhance transmission mediated by gamma-aminobutyric acid (GABA) by a variety of mechanisms. They were used to study the role of GABA in the high pressure neurological syndrome (HPNS) in the rat. Sodium valproate, nipecotic acid and DABA reduced the increase in slow waves seen in the electroencephalogram (EEG) of control rats at pressures above 10-20 ATA; however, only sodium valproate had a beneficial effect on the behavioural signs of the high pressure neurological syndrome (tremor, myoclonus and convulsions). Sodium valproate is also thought to decrease neurotransmission produced by excitatory amino acids; thus, these results suggest that GABA is not one of the major neurotransmitters involved in all aspects of the high pressure neurological syndrome and that changes in excitatory neurotransmission may affect the behavioural signs.

The influence of helium pressure on the reduction induced in field potentials by various amino acids and on the GABA-mediated inhibition in the CA1 region of hippocampal slices in the rat.

In a previous study, it was shown that helium pressure depressed excitatory synaptic transmission mediated by the Schaffer-commissural afferents and increased the intrinsic excitability of pyramidal cells, in the CA1 region of hippocampal slices in the rat. In the present study, the neurochemical bases of these changes was investigated. Various excitatory amino acids were studied under normal and up to 80 atm of helium. At normal pressure, the amino acids tested induced a decrease in the field excitatory postsynaptic potential (EPSP) and antidromic field potential of CA1 pyramidal cells. These changes probably resulted from the well known depolarizing effect of the compounds. Quisqualate is supposed to activate the synaptic receptors of the pathway tested. Since the effect of this amino acid and other agonists were not significantly affected by helium pressure, it is suggested that the depressed hippocampal synaptic potentials under pressure did not result from reduced sensitivity of synaptic receptors. On the other hand, helium pressure enhanced the action of N-methyl-D-aspartate (NMDA) and depressed the GABA-mediated inhibition of CA1 pyramidal cells. Given that the excitability of these neurones is modulated by NMDA-related events and GABA inhibition, these results indicate that both neurochemical systems were probably involved in the helium pressure-induced hyperexcitability of the cells studied.

Interactions of the beta carboline abecarnil with the high pressure neurological syndrome in a primate model.

The neurophysiological interactions between the high pressure neurological syndrome (HPNS) and a new beta carboline, abecarnil, were studied in the non-human primate Papio anubis. Abecarnil is a partial agonist at the benzodiazepine site on the GABA/benzodiazepine receptor. Six animals were exposed on two occasions to pressures of 91 ATA in an environment of helium and oxygen. One exposure was pretreated with a total dose of abecarnil 1.0 mg/kg, the other with an equivalent volume of vehicle. Treatment with abecarnil prevented the severe signs of HPNS occurring between 51 and 91 ATA. Onset pressures of the various signs were unaffected. Some signs, e.g. myoclonus, became more frequent when abecarnil was used. A residual protective effect of abecarnil was present 4 weeks after the dose was given, active at pressures less than 71 ATA. Changes with pressure in the EEG were recorded primarily from the frontal cortex, but were also present in the parietal and occipital areas of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the four conventional wavebands, plus two others, analysed. The most striking change was the prevention by abecarnil of the pressure-induced 100% increase in alpha wave amplitude in the frontal region. It is concluded that modulation of GABA transmission is important in controlling the expression of HPNS.

Evidence for inert gas narcosis mechanisms in the occurrence of psychotic-like episodes at pressure environment.

Psychotic-like episodes in divers exposed to high pressure have been attributed to either the high-pressure neurological syndrome, confinement in pressure chamber, the subject's personality, or the addition of nitrogen or hydrogen to the basic helium-oxygen breathing mixture used for deep diving. Alternatively, it is suggested that these disorders are in fact paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture. This hypothesis is tested against a variety of lipid solubility theories of narcosis. The results clearly support the hypothesis and provide new information about the cellular interactions between inert gases at raised pressure and pressure itself.

Modulation by GABA transmission in the substantia nigra compacta and reticulata of locomotor activity in rats exposed to high pressure.

Helium pressure of > 20 bar causes neuroexcitatory changes referred to as the high pressure neurological syndrome. In rodents, symptoms include locomotor and motor activity (LMA), myoclonia and, at greater pressure, convulsions. We studied the effects of the GABA reuptake inhibitor nipecotic acid, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen. Whatever the drug used, bilateral administration in the substantia nigra reticulata (SNR) or in the substantia nigra compacta (SNC) showed no significant effects on myoclonia. In contrast, administration in the SNR of nipecotic acid, GVG, and baclofen resulted in a significant decrease of LMA; administration of muscimol in the SNR increased LMA. No significant effect was seen when drugs were injected in the SNC. These results suggest that changes in GABA transmission in the SNR, but not in the SNC, play a crucial role in the control of motor activity and the regulation of movement.