Failure to find residual memory deficits in monkeys after repeated HPNS.

Squirrel monkeys (n = 8) were equated on learning and memory tasks before sustaining 3 separate dives in a laboratory compression chamber. Associative memory was carefully monitored 1 wk before and 3 wk immediately after each dive. The first dive was a shallow, subseizure control dive and the subsequent 2 dives were deep, seizure-inducing dives. Half of the animals were always compressed in He-O2 and half in He-N2-O2 gas, which is known to increase the depth at which tremors and seizures occur. After the control dive there was a slight (10% average) decline in memory performance, but the decline was temporary and recovery was complete by the second postdive week. There was no evidence of residual memory impairments after either of the 2 subsequent seizure-inducing dives. Although addition of nitrogen to the breathing gas significantly elevated thresholds for tremors, it had no differential effect on memory scores. These results are in agreement with studies of human divers that show either no residual impairments or transient, fully recoverable cognitive symptoms after diving.

Thermoregulatory behavior and temperature gradient perception in a juvenile fish (Poecilia reticulata).

The thermoregulatory behavior of guppies in a temperature gradient was studied under conditions offering one degree of locomotor freedom, in which displacement of the fish was coupled to a change of occupied temperature, and two degrees of locomotor freedom, in which the added dimension allowed for thermally neutral movement, thus uncoupling any obligatory link between displacement and temperature change. More animals failed to thermoregulate in the second than in the first geometrical system (32% vs. 7%); however, the means of the temperature preferenda (Tp) were the same in both gradient configurations and the frequency distributions along the temperature axis were indistinguishable. In both geometrical systems, mean swimming speed along the temperature axis showed well-defined minima coinciding with the Tp. It was shown that the mean components of movement with respect to the thermal and thermally neutral axes both showed minima at Tp. Further analyses of the actual behavior confirm that in the vicinity of Tp the movements of the fish show little dependence on direction. The analyses thus suggest that thermoregulatory movements are not adjusted in response to movement-generated directional information derived from the temperature gradient. The primary determinant of thermoregulatory behavior in fish may require a more complex awareness of the thermal arrangement of the environment than can be furnished by the instantaneous perception of the local gradient structure.

Opposing effects of anesthetics on pressure tolerance and compression rate effect.

Inert gas narcotics increase intrinsic pressure tolerance (1,000Pc) in CD-1 mice but interfere with development of the protective responses raising seizure thresholds during slower compression (e.g., 60Pc). This secondary narcotic effect can block up to 40% of the total attainable increase in Pc. The narcosis susceptible moiety of this compression rate effect develops early, whereas a narcosis resistant remnant accounts for increase in Pc occurring after 90 min of compression or pressure exposure. Pressure conditioning by multiday pressure exposure entails increases in both 60Pc and 1,000Pc and in virtual annullment of the compression rate effect. The effect can be completely blocked by narcotic gases in the conditioning atmosphere. In addition to blocking part of the compression rate effect the presence of narcotic gases under these conditions can reverse the effects of previously established pressure conditioning. 60Pc regresses much more slowly under these conditions than 1,000Pc. Either reversal rate is much more rapid in air at 1 ATA than at 80 ATA under 0.9 atm N2O. The implications of these data are discussed with regard to evaluation of the hypothesis of antagonism between inert gas narcotics and high pressures and to elaboration of the monoamine hypothesis to account for the modification of the compression rate effect by narcotic gases.

Effect of habituation to subanesthetic N2 or N2O levels on pressure and anesthesia tolerance.

Exposure of CD-1 mice to subanesthetic partial pressures of N2O (0.5 atm) or N2 (10-20 atm) for periods up to 14 days results in up to 40% decreases in the mean threshold pressure eliciting type I high-pressure neurological syndrome (HPNS) seizures, and in increases up to 38% in the N2 partial pressure producing anesthesia. For all combinations of preexposure time, N2 partial pressure, as well as identity of the conditioning gas the relations between the convulsion threshold pressure (Pc) and the anesthesia N2 pressure (Pa) appear to be uniquely correlated by the equation Pa = 54.5 - 0.2(Pc - 60)1.2. The potency of N2O with respect to these habituation phenomena is between 28 and 33 times higher than that of N2, depending on the aspects compared. Evidence is presented indicating that after 14 days of habituation the animals have attained between 75 and 85% compensation for the anesthetic as well as the anticonvulsant effects of the conditioning gas. The bearing of the results on the problem of the nature of the antagonism between inert gas narcotic agents and high pressure and on the hypothesis that habituation tends toward restoration of isofluidity (or some analogous normalization process) are discussed.

Prolonged exposure of mice to He-O2 at high pressure: effects on seizure and anesthesia liability.

Multiday exposures of CD-1 mice to He-O2 atmospheres at pressures from 30 to 100 atm result in marked increases of threshold pressures for type I high-pressure neurological syndrome seizures. The effect develops with a half time (t1/2) of 12 h and is reversible (t1/2 = 7 h). The maximum enhancement of Pc is attained at a conditioning pressure of 80 ATA. Pressure conditioning also results in suppression of the compression rate effect on Pc. Furthermore, reserpine blocks the increase in Pc during prolonged pressure exposure. The entire effect thus appears to be an extension in time of the monoaminergic compression rate effect on Pc. Pressure conditioning does not modify anesthesia tolerance, unlike N2 habituation which affects anesthesia threshold pressure as well as Pc. The results are compared with the effects of habituation to inert-gas narcotics and the implications of the data for an understanding of inert-gas high-pressure antagonism in intact animals are discussed.

Effects of prolonged simultaneous exposure of CD-1 mice to high pressures and inert gas narcosis.

Addition of N2 to the heliox used in pressure conditioning exposures reduces or suppresses the increase in convulsion threshold pressure (Pc) as well as the change in compression rate effect resulting from pressure exposures in the absence of N2; 18 atm N2 neutralizes the effect of 80 ATA total pressure so that Pc remains at a constant level throughout the conditioning period. Since N2 habituation is much slower than pressure conditioning (t1/2 6 days vs. 12 h), this precludes mere addition of pressure and N2 effects in this situation. In contrast to Pc, anesthesia tolerance of mice exposed to 80 ATA in the presence of 18 atm N2 increases even more (25%) than at the same PN2 but at a total pressure of only 18 ATA, indicating that pressure reversal of anesthesia does not extend to the habituation events. The implications of the striking asymmetry between the effects of protracted high pressure and inert gas narcotic exposures for an understanding of the nature of the supposed IG/HP antagonism are discussed.

Hydrostatic pressure effects on the central nervous system: perspectives and outlook.

The high pressure neurological syndrome (h.p.n.s.) represents a complex of behavioural changes observed in all vertebrates when exposed to progressively increasing pressures. The general characteristics of the syndrome will be described and discussed in the light of alternative hypotheses about its aetiology and biophysical characteristics. Recent investigations in this area have dealt with the problem of the discretion of the several stages of the h.p.n.s. in their dependence on compression parameters; with the problem of individual variability in sensitivity to h.p.n.s. development, the genetic basis thereof, and its implications from the point of view of personnel selection; and with exploration of the characteristics and nature of the antagonism between high pressure and general anaesthetics in the production of h.p.n.s. symptoms. A final part of the discussion will deal with the current status of investigations into the problem of hazard assessment, and with the several possible approaches to controlling the h.p.n.s. associated hazards encountered in deep diving operations.

Effects of variations in time pattern of nitrogen addition on development of HPNS in mice.

The effect of change in injection pattern in nitrogen on threshold pressures of three symptoms associated with compression in helium/nitrogen atmospheres was explored. Excitement threshold pressures decrease with increasing concentrations of N2 and are not affected by changing from continuous to equivalent bolus N2 injection. Coarse tremor onset is delayed in direct proportion to the amount of N2 present with the same relative potency in compression at 60 atm/h as at 1000 atm/h. Bolus injection of N2 is less than half as effective as continuous injection in this respect. Threshold pressures of convulsion from high pressure neurological syndrome (HPNS) increase with increasing amounts of N2, the relative anticonvulsant potency of the gas being independent of compression rate when this is introduced by continuous injection. A bolus effect similar to, though smaller than with coarse tremors, is encountered at a compression rate of 60 atm/h but is absent at 1000 atm/h. Late injection of the bolus likewise abolishes this bolus effect. Possible mechanisms to give rise to these effects are discussed, and the bearing of the data on time sequence of HPNS development is explored.

Patterns of interaction of effects of light metabolically inert gases with those of hydrostatic pressure as such--a review.

This review of available literature attempts to interpret net effects of metabolically inert light gases (He, H2, and Ne) as the resultant of hydrostatic pressure and intrinsic pharmacological effects associated with exposure to these gases, and to assess the relative importance of each component with respect to a number of biological responses. A common pattern is recognizable for pressure reversal of anesthesia, high pressure convulsions, high pressure bradycardia, and certain characteristics of liposome model systems. Using the method of analysis proposed, these lightest gases can be shown to conform to the pattern of relation of potency to physical properties characteristic of more potent gaseous anesthetics, including N2, N2O, and Xe. The relations between effect produced and partial pressure of the acting gas are approximately linear to total pressures of 100 ATA for anesthesia or pressure reversal of anesthesia and (or to a much smaller extent) for the liposome model systems, but not for high pressure convulsions. As a result of these general factors no single gas can be expected to neutralize the effects of hydrostatic pressure with regard to all of the biological responses tested over any significant pressure range. A series of experiments with single cells and tissue cultures have revealed interactions between high pressure and inert gas that do not conform to the pattern set by the responses mentioned so far. These responses cannot yet be shown to constitute a homogeneous group and may represent at least two subgroups. Responses falling into this second heterogeneous category include cell motility, development of cell abnormalities and lysis, and cell and perhaps virus replication or multiplication. The implication of these results for the formulation of biophysical hypotheses to explain interactions between inert gas and high pressure, for considerations of high pressure effects as a safety hazard, and for the problem of experimental approaches to the study of pressure acclimation are discussed briefly.

Synergism of hyperoxia and high helium pressures in the causation of convulsions.

Hyperoxia beyond 1.8 ATA results in a striking reduction of high-pressure neurological syndrome (HPNS) type I convulsion threshold pressures but is without measurable effect on type II convulsions. The synergism is partially or completely reversed by increasing alveolar or tissue CO2 levels. High total pressures (PI) result in striking reductions in the duration of hyperoxic exposure preceding seizure onset (tc). The interaction of hyperoxia and high pressure gives rise to three zones on the PO2-Pt plane. In zone I, Pt less than 30 ATA, the duration of hyperoxia prior to convulsion onset is given by the equation PO2 -- PO2 lim = K/(tc -- tc lim), where PO2 lim and tc lim both decrease with increasing total pressure. Zone II, Pt = 30-50 ATA and PO2 1.8-2.3 ATA, is characterized by a sharp drop in tc, as Pt is increased beyond 30 ATA, to a value near 15 min that is constant within the PO2 limits given. In zone III, Pt greater than 50 ATA and PO2 greater than 0.2 ATA, tc is of the order of 2 min, and the seizures are essentially HPNS seizures only slightly modified by hyperoxia. The data are interpreted as suggesting that zone I represents hyperoxic seizures facilitated by high pressures, whereas zone II represents HPNS type I seizures facilitated by hyperoxia.

Correlation studies of individual variation in susceptibility to various components of HPNS in mice.

Individual convulsion threshold pressures were determined in mice exposed successively to type I and type II convulsions of the high-pressure neurological syndrome (HPNS), as well as in others exposed, in successive compressions, to type I convulsions under diverse conditions of replication of compression rate. Correlation analyses of the results showed the following degrees of correlation of individual convulsion-threshold pressures: type I with type II-negligible (r2 less than equal to 0.2); type I with type I at the same compression rate-closely correlated (r2 greater than or equal to 0.8); type I with type I at a different compression rate-negligible (r2 less than or equal to 0.2). Individual susceptibility to HPNS (type I) convulsions thus is a stable characteristic of individual seizures vary independently of one another. Likewise, the magnitude of the individual compression rate effect varies independently of intrinsic individual susceptibility to type I HPNS seizures. The results support the view that the HPNS is a composite entity, define constraints on personnel selection, and provide a basis for estimating the efficacy of various selection strategies.

Changes in CNS responses to high pressure during maturation of newborn mice.

From birth to maturity CD-2 mice were exposed to progressively increasing pressures of helium-oxygen. In all age groups a regular progression of changes in locomotor behavior was observed including, in sequence, increased locomotor activity and two types of convulsions designated as types I and II. The effects of altering compression rate and of reserpine pretreatment were recorded for all age groups. Maturation in these mice is associated with increased resistance to high-pressure neurological syndrome convulsions of either type, in contrast to what might have been expected from previous phylogenetic studies. The patterns in development of the two seizure types differ greatly in detail, further supporting the previously advanced inference that they represent neurological events that differ in kind rather than merely quantitatively. The effect of the results on theories that concern the mechanism of action of pressure on the vertebrate central nervous system is discussed.

Changes in heart rate associated with high-pressure convulsions in rodents.

The effect of compression in heliox atmospheres on heart rate in mice and in rats has been explored. In the absence of high-pressure neurological syndrome (NPNS) convulsions, the general relations between heart rate and pressure in mice from 14 days old to adulthood, as well as in 6- to 8-day-old rats, resemble each other, and also the results reported by others for liquid-breathing mice. Rats, 29 days old and adult, are different in that little bradycardia is observed. Type I (clonic) HPNS seizures are not associated with any additional changes in heart rate. Type II (tonic) seizures are invariably associated with profound transient bradycardia, recovery from which begins about the time the tonic seizure phase ends. The seizure-associated bradycardia can be abolished by atropine pretreatment. Data concerning relation of seizure-associated mortality, drug effects, and age and species differences are presented. The bearing of the results on the questions of seizure types in different species, neuroanatomical bases for HPNS seizures, and high-pressure death are discussed.

Comparative physiology of the high-pressure neurological syndrome--compression rate effects.

The effect of compression rate on onset of high-pressure convulsions has been studied in 14 vertebrate species, as well as in 10 mouse strains and 4 rat strains. Compression rate effects were observed in 9 of the 14 species. They appear to be independent of exposure temperature, correlate only very loosely with phylogenetic position, and appear to reflect species-specific compensatory mechanisms grafted onto an underlying convulsion-producing effect of high hydrostatic pressure. Five vertebrate species distributed among three of the four classes tested failed to show a significant degree of compression rate dependence of high-pressure neurological syndrome (HPNS) convulsion thresholds. The implications of this finding for the formulation of hypotheses regarding the biophysical basis for HPNS convulsions has been discussed. Comparison of intrinsic HPNS susceptibility in different species, in the light of these findings, requires that the comparison be made at a common compression rate. Four of the five lower vertebrate species fall consistently into the category showing high HPNS convulsion threshold pressures regardless of the compression rate employed, whereas the two primates and the one carnivore tested equally consistently fall in the low convulsion threshold pressure category. The data suggest a parallel between the degree of brain development and the relative HPNS susceptibility of a given species and contrast with the inverse relations observed during maturation of newborn mice and rats. The results are compared with data for other convulsants and suggest grouping HPNS and pentylenetetrazole seizures as against electroshock, hyperoxic, flurothyl, strychine, or picrotoxin convulsions.

Time, rate, and temperature factors in the onset of high-pressure convulsions.

An interrupted compression profile technique was used to develop data to separate the effects of time and pressure factors governing increase of high-pressure neurological syndrome (HPNS) convulsion threshold pressures (the compression rate effect) during different compression profiles. A single differential equation fits all data available to date for compression rate effect on convulsion thresholds of CD-1 mice (three distinct types of compression profile; mean compression rates 12-1,000 atm/h). The process leading to increase in HPNS convulsion pressure is initiated at the very beginning of compression, proceeds at increasingly rapid rates as higher pressures are attained, and approaches a limiting upper convulsion pressure. The convulsion threshold pressure in any given experiment is independent of the compression rate prevailing during the time immediately preceding onset of the seizure. The magnitude of the compression rate effect in the CD-1 mouse is independent of chamber temperature over a range of 27-36 degrees C, and rectal temperatures of 29.2-37.5 degrees C. The bearing of these results on the design of optimal compression schedules and on the analysis of the neurological mechanisms underlying the HPNS is discussed.

Interaction of central nervous system effects of high pressures with barbiturates.

The interactions of phenobarbital, barbital, and pentobarbital with high pressures of heliox were explored. Principal features of the complex results include: double peaks in the time course of convulsion thresholds (Pc); an early peak and a shoulder in the time course of pressures reversing anesthesia (Pa); far steeper dose-response curves for Pa than for Pc; selectively greater anticonvulsant effect for phenobarbital than for the other barbiturates; and enhancement of Pa with simultaneous depression of Pc by reserpine in phenobarbital-pretreated mice. The data indicate the existence of at least two discrete sites of interaction between barbiturates and high pressure, reflected by Pc and Pa. The implications of the data for the development of biophysical theories of pressure reversal of anesthesia and anti-high-pressure neurological syndrome action of anesthetics are discussed, together with implications for the experimental study of convulsant and anticonvulsant agents, and their applications to underwater physiology.

Sudden hearing loss due to diving and its prevention with heparin.

Vascular embolic and thrombotic problems postulated to be the cause of inner ear sudden deafness have been reported with decompression sickness also. Decompression sickness has been found to lead to cochlear potential loss in the guinea pig, and these losses are minimized by the prophylactic administration of heparin. Preliminary results show that inner ear hemorrhage may be associated with diving deafness, but plasma protein leakage into the perilymph of the ear may precede the hemorrhage. Inner ear hemorrhage in diving deafness seems to be restricted to the microcirculation. Until we gain a better understanding of the pathophysiology of diving induced deafness, it would be premature to consider agents such as heparin for the treatment of the problem in man.

Rate factors in development of the high-pressure neurological syndrome.

The effect of varying the pressure/time profile upon development of tremors and convulsions of the high-pressure neurological syndrome was studied in adult mice and squirrel monkeys and in baby mice. Two distinct response patterns were observed. In the adults rapid compression produces early onset of convulsions; convulsions subside rapidly when animals are held at constant pressure just above the convulsion point; and interrupted compression schedules show that total compression time rather than instantaneous compression rate at the moment seizures develop is the controlling parameter. Baby mice up to 12 days of age, by contrast, fail to show any perceptible relation between compression rate and convulsion threshold pressure (Pc); their seizures continue for a considerable period of time after a constant pressure level just above the convulsion threshold has been reached; and interrupted compressions of type a fail to change their convulsion threshold. Together with supplementary data regarding tremor thresholds and the transient increase of convulsion thresholds by prior seizures these results lead to a proposed schema describing these phenomena in terms of a pressure-dependent primary event predisposing to tremors and convulsions; a time-dependent event counteracting the convulsions (absent in baby mice); and a transient effect of prior convulsions, raising subsequent Pc.