Caffeine and Modafinil Ameliorate the Neuroinflammation and Anxious Behavior in Rats during Sleep Deprivation by Inhibiting the Microglia Activation.

Background: Sleep deprivation (SD) plagues modern society due to the professional demands. It prevails in patients with mood and neuroinflammatory disorders. Although growing evidence suggests the improvement in the cognitive performance by psychostimulants during sleep-deprived conditions, the impending involved mechanism is rarely studied. Thus, we hypothesized that mood and inflammatory changes might be due to the glial cells activation induced modulation of the inflammatory cytokines during SD, which could be improved by administering psychostimulants. The present study evaluated the role of caffeine/modafinil on SD-induced behavioral and inflammatory consequences. Methods: Adult male Sprague-Dawley rats were sleep deprived for 48 h using automated SD apparatus. Caffeine (60 mg/kg/day) or modafinil (100 mg/kg/day) were administered orally to rats once every day during SD. Rats were subjected to anxious and depressive behavioral evaluation after SD. Subsequently, blood and brain were collected for biochemical, immunohistochemical and molecular studies. Results: Sleep deprived rats presented an increased number of entries and time spent in closed arms in elevated plus maze test and decreased total distance traveled in the open field (OF) test. Caffeine/modafinil treatment significantly improved these anxious consequences. However, we did not observe substantial changes in immobility and anhedonia in sleep-deprived rats. Caffeine/modafinil significantly down-regulated the pro- and up-regulated the anti-inflammatory cytokine mRNA and protein expression in the hippocampus during SD. Similar outcomes were observed in blood plasma cytokine levels. Caffeine/modafinil treatment significantly decreased the microglial immunoreactivity in DG, CA1 and CA3 regions of the hippocampus during SD, however, no significant increase in immunoreactivity of astrocytes was observed. Sholl analysis signified the improvement in the morphological alterations of astrocytes and microglia after caffeine/modafinil administration during SD. Stereological analysis demonstrated a significant improvement in the number of ionized calcium binding adapter molecule I (Iba-1) positive cells (different states) in different regions of the hippocampus after caffeine or modafinil treatment during SD without showing any significant change in total microglial cell number. Eventually, the correlation analysis displayed a positive relationship between anxiety, pro-inflammatory cytokines and activated microglial cell count during SD. Conclusion: The present study suggests the role of caffeine or modafinil in the amelioration of SD-induced inflammatory response and anxious behavior in rats. Highlights - SD induced mood alterations in rats. - Glial cells activated in association with the changes in the inflammatory cytokines. - Caffeine or modafinil improved the mood and restored inflammatory changes during SD. - SD-induced anxious behavior correlated with the inflammatory consequences.

Tyrosine ameliorates heat induced delay in event related potential P300 and contingent negative variation.

The efficacy of tyrosine, a catecholamine precursor, as a countermeasure in the reduction of cognitive decline during heat exposure (HE) using event-related potential P300, and contingent negative variation (CNV) was evaluated. Ten healthy males, age 20-30years participated in the study. Volunteers received placebo or tyrosine (6.5g) 90min prior to HE (1.5h in 45°C+30% RH). P300 latency was significantly increased (p<0.01) during exposure with placebo, which was reduced significantly (p<0.01) after tyrosine supplementation. There was an increase in CNV M100 latency (p<0.05) and reaction time (p<0.01) and decrease in M100 amplitude (p<0.01) during HE with placebo, which returns to near normal level with the tyrosine administration. A significantly higher plasma norepinephrine (p<0.05), dopamine and epinephrine levels were detected in tyrosine supplemented group post heat exposure. HE increases the brain catecholamine activity thereby reduces the plasma norepinephrine and dopamine level leading to a reduction in cognitive performances. Tyrosine supplementation increases the catecholamine level and reduces the impairment of cognitive performance during HE.

Modafinil improves event related potentials P300 and contingent negative variation after 24 h sleep deprivation.

AIMS: The efficacy of modafinil as a countermeasure in the reduction of cognitive decline following 24 h of sleep deprivation (SD) on subjective sleepiness scales, event-related potential (ERP) P300, and contingent negative variation (CNV) was evaluated. MAIN METHODS: Eleven healthy males, age 25-30 years participated. The experiment was performed in five sessions on different days between 7 and 8a.m. Session 1, baseline recordings; Session 2, after one night's SD; Session 3, 48 h of recovery from SD; Session 4, after 1 week of Session 1, following one night's SD along with modafinil (400mg/day); Session 5, 48 h of recovery after SD+modafinil. KEY FINDINGS: Subjective sleepiness scores increased significantly after SD as compared to baseline (P<0.01), but remained unaltered after modafinil supplementation. There was an increase in N100 and P300 peak latencies of ERP following SD (P<0.01), which was reduced with modafinil (P<0.05). There was an increase in CNV M100 and P300 peak latencies after SD (P<0.01) which decreased with the use of modafinil (P<0.05). The CNV reaction time increased following SD (P<0.01) and decreased with the use of modafinil (P<0.05). No significant effects on ERP N200, P200 latencies and P200, P300 amplitudes and CNV N100, M200 peak latencies and M100, M200 amplitudes were observed. SIGNIFICANCE: The results strongly suggest that modafinil in a dose of 400mg/day, reduces the subjective sleepiness and cognitive decline following 24 h of SD.

Meditation as an intervention for cognitive disturbances following total sleep deprivation.

BACKGROUND & OBJECTIVES: Decline in cognitive functions is a major challenge for professionals during sustained wakefulness. We used middle latency response (MLR), event related potentials P300-ERP and contingent negative variation (CNV) and Raven's Advanced Progressive Matrices (RAPM) - a standard neuropsychological test were used to evaluate cognitive impairment after total sleep deprivation (SD); and to study the impact of meditation as an intervention for this impairment. METHODS: Healthy male volunteers (n=10) drawn randomly from the Indian Army participated in a 6-night study design executed before and after two months of meditation practice: night 1-adaptation, night 2-baseline, night 3-24 h SD, night 4-recovery sleep, night 5-24 h SD after 60 days meditation, night 6-recovery sleep after SD. A 36 h SD was obtained by keeping the subject awake for 12 h after 24 h SD. RESULTS: The latency and amplitude of P300 increased after 36 h SD. Amplitudes and latencies of both early and late CNV increased after 24 and 36 h SD, indicating deficient orientation and impairment of attention and perception. Prolonged CNV reaction time after 36 h SD manifested deficient motor response following second (imperative) stimulus. Latency of MLR Na registered significant change following 36 h SD compared to baseline (P<0.01) and recovery (P<0.05). RAPM score showed significant decrease after 36 h of wakefulness indicating impaired analytical ability and difficulty in problem solving. None of these parameters showed any significant alteration after SD, following meditation practice. INTERPRETATION & CONCLUSIONS: The present results showed that SD impaired cognitive performance to graded extents significantly, but this deterioration could be improved to a significant extent using meditation.

Sleep architecture at 4300 m altitude in a sample of Indian lowlanders.

The present study aimed to evaluate sleep architecture at 4300 m in a sample of 10 healthy Indian lowlanders, mean age 25.7 +/- 5.1 yrs. Polysomnography on two consecutive nights each was performed at sea level and 4300 m, the first night for adaptation and the second one for actual recording. Total sleep time reduced from 433.33 +/- 8.95 to 412.06 +/- 13.13 minutes (P < 0.0005), sleep latency increased from 11.56 +/- 6.85 to 22.22 +/- 7.95 minutes (P < 0.0025), deep NREM sleep (S3 + S4) reduced from 79.56 +/- 28.45 to 45.39 +/- 25.32 minutes (P < 0.01), light NREM sleep (S1 + S2) increased from 272.94 +/- 20.63 to 296.72 +/-23.24 minutes (P < 0.05), REM decreased from 80.89 +/- 7.65 to 69.94 +/- 11.30 minutes (P < 0.02) and periodic breathing was present in 4 of 10 participants on the second night at 4300 m. Decreased sleep quality (P < 0.0005) and increased sleep disturbances (P < 0.0005) were reported in subjective ratings at high altitude. Changes in sleep architecture similar to but of a greater magnitude are present on the second night of staged induction to 4300 m, than reported at 3500 m in our earlier study.

Event related potential (ERP) P300 after 6 months residence at 4115 meter.

BACKGROUND & OBJECTIVES: The P300 wave is an event related potential (ERP) elicited by infrequent, task-relevant stimuli and appeared at about 300 ms, represents higher cognitive function of information processing, working memory or stimulus categorization. Hypobaric hypoxia deteriorates the cognitive function during the short term stay (days to few weeks) at high altitude. The present study was carried out to evaluate the P300 responses during long duration stay (1 month and 6 months) at high altitude (HA, 4115 m) in a sample of Indian lowlanders. METHODS: The study was carried out on 18 healthy male volunteers at sea level (SL). The volunteers were stage inducted to 4115 m altitude in the Eastern Himalayas. The P300 was recorded after 1 and 6 months of their stay at HA. RESULTS: The latencies of peaks N100, P200 and N200 waves did not show any significant changes after 1 and 6 months of stay at HA as compared to SL. The P300 latency was significantly delayed after 1 month and further delayed after 6 month of residence at 4115 m. The P200 and P300 amplitudes did not show any changes. INTERPRETATION & CONCLUSIONS: The increase in P300 latency indicated that long duration of stay at high altitude slows the stimulus evaluation processes. The observations suggest that hypoxia causes slowing of the signal processing at HA. The magnitude of the effects of hypobaric hypoxia may be dependent upon the duration of residence at high altitude.

Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture.

Sojourners to high altitude experience poor-quality of sleep due to hypobaric hypoxia (HH). Brain neurotransmitters are the key regulators of sleep wakefulness. Scientific literature has limited information on the role of brain neurotransmitters involved in sleep disturbance in HH. The present study aimed to investigate the time dependent changes in neurotransmitter levels and enzymes involved in the biosynthesis of brain neurotransmitters in frontal cortex, brain stem, cerebellum, pons and medulla and the effect of these alterations on sleep architecture in HH. Thirty adult Sprague-Dawley rats, body weight of 230-250 g were exposed to simulated altitude ∼7620 m, 282 mm Hg, partial pressure of O(2) 59 mm Hg for 7 and 14 days continuously in an animal decompression chamber. After 7 and 14 days of HH, brain nor-epinephrine and dopamine levels were significantly increased in frontal cortex, brain stem, cerebellum and pons and medulla whereas serotonin level was significantly reduced in frontal cortex and pons and medulla after 14 days of HH. Tyrosine hydroxylase level in locus coeruleus (LC) was significantly increased whereas Choline Acetyl Transferase and Glutamic Acid Decarboxylase (GAD) levels were significantly reduced in laterodorsal-tegmentum and pedunculopontine-tegmentum after 7 days of HH. GAD was also reduced in LC after 7 days HH. Alteration in these neurotransmitters and enzyme levels was accompanied with reduction in quality and quantity of sleep. There was a significant increase in sleep latency, rapid eye movement (REM) latency, duration of active awake, quiet awake, quiet sleep and a significant decrease in duration of REM sleep and deep sleep on day 7 and 14 of HH. It was concluded that HH alters the expression of enzymes linked to sleep neurotransmitter synthesis pathway and subsequent loss of homeostasis at neurotransmitter level disrupts the sleep pattern in hypobaric hypoxia.

Effect of L-carnitine supplementation on endurance exercise in normobaric/normoxic and hypobaric/hypoxic conditions.

OBJECTIVE: To evaluate the effect of L-carnitine supplementation on improving endurance exercise in normobaric/normoxic and hypobaric/hypoxic environments. METHODS: Six-week-endurance-trained male Sprague-Dawley rats (n = 24) were randomly divided into 2 groups: control and experimental; the latter group was supplemented with L-carnitine, administered orally in a dose of 100 mg x kg(-1) body weight. The animals were supplemented for 25 days under ambient normobaric/normoxic conditions and thereafter were exposed to 72 hours of hypobaric hypoxia equivalent to 6100 m. The supplementation was continued during the exposure. "Run to exhaustion" was recorded on day 1 (R1) (presupplementation) and on days 7 (R2), 14 (R3), 21 (R4), and 28 (R5, which followed the last 72 hours of hypoxic exposure) of supplementation. Food intake, body weight, and the biochemical measures of plasma glucose, total cholesterol, and high-density lipoprotein (HDL) cholesterol were recorded. RESULTS: There was a significant improvement in endurance exercise, as indicated by an increase in run to exhaustion following L-carnitine supplementation under normobaric normoxia (36%-39%) and hypobaric hypoxia (50%). L-carnitine supplementation had no effect on plasma glucose levels either at sea level or after hypoxic exposure. Total cholesterol was decreased in normoxic and HDL cholesterol was increased in normoxic and hypoxic conditions, indicating a beneficial effect of exercise. CONCLUSION: L-carnitine supplementation improved exercise endurance in rats exposed to normobaric normoxic and hypobaric hypoxic conditions. Such supplementation would be beneficial in delaying the onset of fatigue during prolonged exercise in both conditions, indicating its potentially beneficial use at high altitude.

Effect of simulated ascent to 3500 meter on neuro-endocrine functions.

Ascent to extreme High Altitude (HA) is in steps and it entails acclimatization at moderately HA locations. In terms of acclimatization, it is pertinent to understand the physiological changes, which occur on immediate ascent to moderate HA. The study aimed to evaluate the effect of ascent to 3500 m on neuro-endocrine responses in the first hour of induction. The plasma levels of catecholamines and cortisol were measured before and after one hour of ascent to high altitude. The peripheral oxygen saturation (SpO2), Galvanic Skin Resistance (GSR), Heart Rate (HR) and Blood Pressure (BP) were simultaneously monitored. The plasma epinephrine, norepinephrine, dopamine and cortisol were increased after one-hour exposure to 3500 m altitude as compared to before exposure. The SpO2 showed a significant decrease during and after high altitude induction. The heart rate and diastolic BP increased at 3500 m whereas the GSR did not show significant changes. There are changes in neuroendocrine responses, which reflect a sympathetic over activity in the first hour of exposure to 3500 m.

Effect of hypobaric hypoxia on visual evoked potential at high altitude.

The effect of hypobaric hypoxia on visual evoked potential (VEP) was studied in 27 male volunteers at sea level (SL), during the 1st and 3rd weeks of their stay at high altitude (HA) of 3,500 m and in the 1st week of their return to the sea level (RSL). Exposure to high altitude (HA) led to significant changes in VEP. The N1 wave latency of both right and left eye was significantly increased (P<0.05) during 3rd week of stay at the altitude which persisted even after the return to the sea level. The latency of P1 wave of both right and left eye was higher in 3rd week at high altitude but not significant statistically. But the delay in P1 latency persisted in 1st week of their return to sea level which was significant (p<0.05) statistically as compared to sea level. The latency of N2 wave was significantly decreased (P<0.05) during the 1st week of stay at HA and returned back to basal value in the 3rd week of stay at HA in both right and left eye. However, the changes observed in NPN complex in terms of wave latencies were within the physiological limits. The amplitude of wave N1-P1 of both the right and left eye did not show any change. The changes observed reflect the process of acclimatisation to 3500m high altitude.

Brainstem auditory evoked responses in young urban and rural boys--a comparison.

Brainstem auditory evoked responses (BAER) were studied in a total of 194 boys in the age group between 10-15 yrs taken from a busy metropolitan city and also from a relatively quiet town in order to compare their values and to look into the probable cause of the difference between them, if any. BAER were tested with the help of Compact-4 (Nicolet, USA) instrument using the standard technique. In general, the BAER values of the two sample populations were found to be almost similar with no gross differences in terms of peak latency and inter peak latencies. The values were found to be comparable to adult male values as reported earlier.