Pupillary response to percutaneous auricular vagus nerve stimulation in alcohol withdrawal syndrome: A pilot trial.

BACKGROUND: Autonomic symptoms in alcohol withdrawal syndrome (AWS) are associated with a sympathetic-driven imbalance of the autonomic nervous system. To restore autonomic balance in AWS, novel neuromodulatory approaches could be beneficial. We conducted a pilot trial with percutaneous auricular vagus nerve stimulation (pVNS) in AWS and hypothesized that pVNS will enhance the parasympathetic tone represented by a reduction of pupillary dilation in a parasympatholytic pharmacological challenge. METHODS: Thirty patients suffering from alcohol use disorder, undergoing AWS, and stable on medication, were recruited in this open-label, single-arm pilot trial with repeated-measure design. Peripheral VNS (monophasic volt impulses of 1 msec, alternating polarity, frequency 1 Hz, amplitude 4 mV) was administered at the left cymba conchae for 72 h, followed by pupillometry under a tropicamide challenge. We assessed craving with a visual analog scale. We used pupillary mean as the dependent variable in a repeated-measures ANOVA (rmANOVA). RESULTS: A repeated-measures ANOVA resulted in a significant difference for pupillary diameter across time and condition (F(2,116) = 27.97, p < .001, ηp2 > .14). Tukey-adjusted post hoc analysis revealed a significant reduction of pupillary diameter after pVNS. Alcohol craving was significantly reduced after pVNS (p < .05, Cohen's d = 1.27). CONCLUSION: Our study suggests that pVNS activates the parasympathetic nervous system in patients with acute AWS, and that this activation is measurable by pupillometry. To this end, pVNS could be beneficial as a supportive therapy for AWS. Potential confounding effects of anti-craving treatment should be kept in mind.

Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen-progestin regimen versus estrogen alone on performance, mood and personality of menopausal syndrome patients.

The influence of a combined estrogen-progestin regimen (Climodien) on noopsyche, thymopsyche, personality and psychophysiological measures of menopausal syndrome patients was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3 = estradiol valerate (CAS 979-32-8) 2 mg + the progestin dienogest (CAS 65928-58-7) 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P) followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg + dienogest 2 mg) = regimen A*. 49 women (16, 17, 16 valid patients per arm) aged between 46 and 67 years (mean 58, 58, 56 years, respectively) with the diagnoses of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1) were included in the analysis of the double-blind phase. Both the double-blind and the open-label phase lasted 2 months. Noopsychic investigations demonstrated an improvement in associative verbal memory after 2 months of regimen A, which was significant as compared with both baseline and placebo. Regarding visual memory, regimen A* induced an improvement, which was significantly different from the decline in correct reproductions in the Benton Test observed under estradiol. Errors in the Benton Test decreased significantly after regimen A* as compared with regimen EV. These findings suggest that hormone replacement therapy with estradiol, and even more in combination with dienogest, improves verbal and visual memory, which is in line with the improvement in information processing speed and capacity objectified by event-related potentials (ERP). Thymopsychic investigations demonstrated a significant improvement in somatic complaints and trait anxiety after both regimen A and regimen EV as compared with baseline. State anxiety decreased significantly under regimen A* as compared with EV. The Freiburger Personality Inventory showed an improvement in aggressivity after regimen A* as compared with the preceding placebo as well as an improvement in striving after dominancy after both regimen A and regimen EV as compared with pre-treatment, but also after regimen A* as compared with regimen EV. Extraversion increased after 2 months of regimen A as compared to regimen P. Psychophysiological findings including pupillary and skin conductance variables were not significant.

[Central nervous system activation in opioid dependent patients, evaluation with Fourier analysis of pupillary oscillations]. / Zentralnervöse Aktiviertheit bei opioidabhängigen Patienten, evaluiert durch Fourieranalyse der Pupillenoszillationen.

The aim of the present investigation was to determine whether Fourier analysis of pupillary oscillations permits detection of differences in the activation of the central nervous system of opioid-addicted patients. We analysed pupillary oscillations during the recording period of static pupillometry, which lasted 25.6 s. Using Fourier analysis, the spectrum was divided into five frequency bands (0.0-0.20, 0.21-0.40, 0.41-0.60, 0.61-0.80, 0.81-1.0 Hz); the total spectrum (0-1 Hz) was also assessed. Three groups of patients were selected: the group addicted to heroin (consuming exclusively heroin) consisted of 26 patients with a mean age of 25.0 +/- 6.3 years, the methadone substitution group of 20 patients with a mean age of 30.9 +/- 8.2 years, and the morphine substitution group of 20 patients with a mean age of 33.2 +/- 4.6 years. The 3 patient groups were compared with normal controls of similar age (25.1 +/- 4.6 years). In the frequency band of 0.0-0.20 Hz the morphine group showed significantly lower amplitudes than the heroin group. Also in the frequency band of 0.41-0.60 Hz the morphine group differed significantly from the other groups concerning lower amplitudes, reflecting deactivation. In the total spectrum of 0 to 1 Hz the differences between these two groups were significant. Comparison with normal controls also showed significant differences. The groups were further divided according to dose (high/low): Patients of the heroin group as well as those of the methadone and morphine groups who had consumed higher doses showed greater activation of the central nervous system. In conclusion the morphine group was more deactivated than the methadone and heroin group and patients who received higher doses of the substances showed greater central nervous activation. Thus, the measurement of central nervous activation by means of Fourier analysis of pupillary oscillations might be useful in monitoring substitution therapy.

Receptor test (pupillary dilatation after application of 0.01% tropicamide solution) and determination of central nervous activation (Fourier analysis of pupillary oscillations) in patients with Alzheimer's disease.

Memory loss and severe cognitive deficits in Alzheimer patients are supposed to be related to a reduction of acetylcholine as well as to central nervous deactivation. For the investigation of cholinergic deficits and deactivation, we used computer-assisted pupillometry. Cholinergic deficits caused by a particularly severe loss of cholinergic neurons may be responsible for cognitive and mnemonic performance deficits. The control of the pupillary diameter represents a balance between cholinergic and adrenergic innervation and is influenced directly or indirectly by central and autonomic nervous system inputs. Either of these systems could be affected in Alzheimer patients. A reduced innervation of the target muscle through neuronal cell death, axon retraction, reduced release, increased reuptake of altered amounts or function of neurotransmitter receptors seems to affect the pupillary response to cholinergic antagonists in Alzheimer patients. There is, however, no relationship between pupillary diameter and central deactivation, but between central nervous activation and pupillary oscillations which reflect the physiological corticodiencephalic activity, a relationship has to be assumed. Frequencies and amplitudes of pupillary oscillations measured by means of Fourier analysis are modulated corticodiencephalically. Therefore, Alzheimer patients were compared to healthy controls with respect to their pupillary diameters and responses to an acetylcholine antagonist. Twenty-nine patients, aged between 55 and 85 years, suffering from mild to moderate Alzheimer's disease (AD) and 29 normal controls of similar age (56-85 years) participated in the study. The cholinergic receptors of the pupil were blocked by the acetylcholine antagonist tropicamide. It could be assumed that the larger the pupillary dilatation, the larger the extent of cognitive deficits. Alzheimer patients show abnormal acetylcholine neurotransmission. Changes of pupillary diameter after instillation of 1 drop of 0.01% tropicamide solution were measured and Fourier analysis of pupillary oscillations was performed. Times of measurement were: 0 (baseline), 20, 40, 60, 80, and 100 min. After 4 min tropicamide was instilled. Forty min after the instillation of tropicamide into the left eye, the Alzheimer patients showed a pronounced dilatation of 41.57%. The dilatation in normal controls was 28.5%. Fourier analysis of pupillary oscillations (sum of frequency bands = power) demonstrated a marked deactivation (low amplitudes in low-frequency bands, but in contrast to our expectations no higher amplitudes in the higher frequency bands) in patients with AD which remained constant at all times of measurement. By means of discriminant analysis of pupillary diameter and pupillary oscillations (frequency band 0.00-1 Hz), 89. 7% were correctly predicted to be Alzheimer patients, 89% to be normal controls.

[Fourier analysis of pupil oscillations for measuring central activation in psychosomatic patients]. / Fourieranalyse der Pupillenoszillationen zur Messung der zentralen Aktiviertheit bei psychosomatischen Patienten.

The aim of the study was to answer the question if there are any differences in the central activation of different groups of psychosomatic patients and patients with eating disorders, which was measured by means of Fourier analysis of pupillary oscillations. A total of 132 patients (110 f, 22 m) with a mean age of 29.69 years (standard deviation: 9.9) participated in the study. In anorectic and bulimic patients high central activation was observed. Different groups of psychosomatic patients showed significant differences in their central nervous activation. In the group of subjects with the ICD-10 diagnosis F 41.3 (mixed anxiety disorders) the highest amplitudes was observed not only in the particular frequency bands but also in the total spectrum (power), which reflects high central activation. Reduced activation was found in subjects with somatoform autonomic function disorder of the upper and lower gastrointestinal tract (F 45.3). The measurement of central activation in psychosomatic disorders could have consequences for therapeutic interventions.

Psychophysiological diagnostics in alcohol dependency: Fourier analysis of pupillary oscillations and the receptor test for determination of cholinergic deficiency.

Mnestic disturbances in alcoholics may be related to cholinergic deficiency as well as to central nervous system inactivation. After instillation of tropicamide, cholinergic receptors are blocked and pupillary dilatation occurs. It is assumed that the more severe the cognitive deterioration, the wider the pupillary dilatation. Pupillary oscillations reflect central activation. Changes of pupillary diameter after topical instillation of tropicamide and pupillary oscillations were measured in 44 alcohol-dependent patients aged 40-55 years, diagnosed according to the DSM-III-R as severe alcoholics (>7 symptoms), having been abstinent for at least 3 weeks (objectively tested with carbohydrate-deficient transferrin), compared with 18 healthy controls. The pupillary diameter of the left eye was measured eight times within 103 min, as were pupillary oscillations. Using Fourier analysis, the amplitudes of oscillations were measured in five frequency bands and the sum of the frequency bands was calculated. In addition, central activation was measured during a calculation test at 3 and 103 min. The pupillary dilatation of 22% in alcoholics compared to 14% of normal controls after tropicamide raises the question of a cholinergic deficit in alcohol dependence. With regard to basic activation, measured by Fourier analysis of pupillary oscillations, alcoholics demonstrated significantly lower power (sum of the frequency bands) than controls at baseline and at 3, 20, and 40 min (P < 0.01) as well as at 60, 80, 100, and 103 min (P < 0.05). After a cognitive task, a difference between alcoholics and healthy controls was found at 3 min. Alcoholics showed lower basic activation and decreased cognitive activation. By means of cross-validation, a differentiation between alcohol-dependent patients (n = 44 and n = 42 respectively) and normal controls (n = 18) was possible.

[Pupillary diameter and pupillary reactions in heroin dependent patients and in patients participating in a methadone and morphine replacement program]. / Pupillenweite und Pupillenreagibilität bei Heroinabhängigen sowie Patienten, die an einem Methadon- bzw. Morphinsubstitutionsprogramm teilnehmen.

The computer-assisted static and dynamic light evoked pupillometry (TV-pupillometer 1050, Whittaker Corp.) had been proved to be a sensitive procedure for assessment of the effect of psychoactive drugs. Therefore, this method was used in 26 heroin dependent patients (mean age 24.42 years), 20 methadone substituted patients (mean age 29.75), and 20 morphine-substituted patients (mean age 30.65 years) to answer the question whether there were no differences within the patient groups but significant differences between the patients and healthy normals. Indeed, pupillary diameter (vegetative activation) as well as relative change (pupillary reagibility) showed no significant differences between the heroin dependents, the methadone substitution group and the morphine substitution group. However concerning pupillary diameter and relative change the patient groups differed significantly from the healthy controls. Onset latency revealed no differences within the patient groups and between patient groups and healthy controls respectively. Thus the variable pupillary diameter and relative change could be used to assess the additional application of opiates in patients participating in a substitution program.

Nonorganic insomnia in generalized anxiety disorder. 1. Controlled studies on sleep, awakening and daytime vigilance utilizing polysomnography and EEG mapping.

Objective and subjective sleep and awakening quality as well as daytime vigilance of insomniac patients with generalized anxiety disorder (GAD) were investigated, as compared with normal controls. Forty-four outpatients (25 females, 19 males), aged 24-65 (mean 43) years, diagnosed with non-organic insomnia (ICD-10: F 51.0), related to mild GAD (F 41.1), with a Hamilton anxiety (HAMA) score of 22 +/- 6 and a Zung self-rating anxiety (SAS) score of 37 +/- 6 were included. After 1 adaptation night, sleep induction, maintainance and architecture were measured objectively by polysomnography, subjective sleep and awakening quality were assessed by self-rating scales and visual analog scales, objective awakening quality was measured by a psychometric test battery, and diurnal tiredness was measured by a 3-min vigilance-controlled EEG (V-EEG) and a 4-min resting EEG mapping. In polysomnography patients demonstrated-as compared with normals-significantly increased wake time during the total sleep period and more early-morning awakening, decreased total sleep and sleep efficiency. Subjective sleep quality was deteriorated as well, as were well-being, drive, mood, and wakefulness in the morning. In noopsychic performance, GAD patients did rather well in attention, concentration, attention variability, and numerical memory, while fine-motor activity and reaction time were deteriorated. In psychophysiology, critical flicker frequency was decreased in the morning, while muscle strength, blood pressure and pulse rate showed no differences. EEG mapping during the late morning hours (10.00-12.00 h) demonstrated hypervigilance in the V-EEG, while in the resting recording an increased sleep pressure was detected. The latter was correlated significantly to the SAS score, but less so to the observer-rated Hamilton anxiety score. Our findings suggest that CNS hypervigilance and hyperarousal, as actual symptoms of GAD, lead to nocturnal insomnia, which in turn may cause-as a consequence of sleep pressure not slept off-diurnal tiredness.

Nonorganic insomnia in generalized anxiety disorder. 2. Comparative studies on sleep, awakening, daytime vigilance and anxiety under lorazepam plus diphenhydramine (Somnium) versus lorazepam alone, utilizing clinical, polysomnographic and EEG mapping methods.

Previous human pharmacological and toxicological studies demonstrated advantages of the combination drug Somnium [SOM, lorazepam (LOR) 1 mg plus diphenhydramine 25 mg] over 1 mg LOR alone, as it showed synergistic effects in hypnotic properties and antagonistic effects in regard to toxicity. In the present double-blind, parallel-group study, hypnotic and anxiolytic effects of SOM were studied in 44 patients with non-organic insomnia related to mild generalized anxiety disorder (GAD), as compared with LOR alone. After a placebo run-in phase of 1 week, they received active treatment (1 tablet SOM or LOR 1 mg) for 4 weeks and thereafter placebo again for 1 week. Clinical evaluations included the physician's general assessment of efficacy, tolerance and adverse effects, the Hamilton anxiety rating scale (HAMA), the Zung self-rating anxiety scale (SAS) and depression scale, the withdrawal symptom scale (WSS), hematology and blood chemistry. Sleep laboratory evaluations included objective and subjective sleep and awakening quality, measured by polysomnography, self-rating of sleep and awakening quality (SSA) and a psychometric test battery in the morning, as well as measurement of daytime brain function, objectivated by EEG mapping. Physicians' global evaluation of insomnia demonstrated no changes in the pre-drug placebo period, moderate improvement under both drugs, with a marginal advantage of SOM over LOR in the first 2 weeks, and a return to pre-drug values in the post-drug placebo period. Anxiety improved in observer ratings (HAMA) under both drugs, in self-rating (SAS) under the combination drug only, with the scores returning to pre-drug placebo values after post-drug placebo substitution. There were no significant findings in the self-rating depression scale and the WSS, with the exception of an improvement in the WSS score 4 weeks after SOM, as compared with pre-drug placebo. There were no rebound phenomena. Both drugs were well tolerated-in regard to both adverse effects and laboratory findings. Confirmatory statistics on the polysomnographically recorded target variable latency to sleep onset stage 2 demonstrated a significant shortening of sleep latency after SOM and a significant superiority of the combination drug SOM over LOR after acute dosing, as compared with pre-drug placebo. Descriptive statistics demonstrated further a significant improvement of sleep efficiency and total sleep time after SOM and of wakefulness time and number of awakenings during the total sleep period after both drugs, but no interdrug differences. Sleep architecture remained unchanged. Subjective sleep quality improved with both drugs, morning drowsiness and the total SSA score only with SOM, while LOR was superior to SOM regarding morning somatic complaints. There were neither changes nor interdrug differences in the morning noopsyche. In psychophysiology, critical flicker frequency decreased more under SOM than LOR. After 4 weeks therapy, no significant findings in polysomnography and subjective sleep and awakening were seen, except for an increase in movement time under LOR (tolerance development). In objective awakening quality, psychometry revealed an improvement of reaction time under SOM and a decrease of attention variability and an increase in fine-motor activity under LOR, with an interdrug comparison showing a significant superiority of SOM over LOR in regard to reaction time, reaction time variability and reaction time performance. After placebo substitution, rebound phenomena were seen in polysomnography and subjective sleep and awakening in the 1st night of the SOM group only, which were gone in the 7th placebo night, however. Noopsychic performance remained improved in both groups, with a superiority of SOM to LOR in regard to reaction time and reaction time variability. (ABSTRACT TRUNCATED)

Comparative studies on the effects of the combination drug lorazepam plus diphenhydramine (Somnium) versus lorazepam on the noopsyche, thymopsyche and psychophysiology in nonorganic insomnia related to generalized anxiety disorder.

In a double-blind, parallel-group design study on hypnotic and anxiolytic effects of the combination drug Somnium (lorazepam 1 mg + diphenhydramine 25 mg) (SOM) as compared with 1 mg lorazepam (LOR) alone, daytime behavioral effects were studied in 44 patients with nonorganic insomnia related to a mild generalized anxiety disorder. After a placebo run-in phase of 1 week, they received active treatment for 4 weeks. Psychometric evaluations included 6 thymopsychic variables (somatic complaints, state anxiety, trait anxiety, self-rating anxiety and depression scale and adjective mood scale), 6 noopsychic variables (general, associative, numerical and total verbal memory; correct reproductions and errors-Benton visual memory test), 4 pupillary measures (pupillary diameter, latency, relative change in % and half recovery time in pupillary response) and 6 skin conductance measures (baseline, latency, ascending time, time to peak, skin conductance response and skin conductance response maximum). Multivariate statistical analysis of the thymopsyche demonstrated significant improvement after both compounds, with the combination drug significantly superior to its single component lorazepam. Also regarding noopsychic measures, Somnium was significantly superior to the single component lorazepam, as specifically verbal memory was improved after Somnium, while opposite changes occurred after lorazepam alone. Pupillary measures revealed no significant overall inter-drug differences, whereas skin conductance findings demonstrated that the combination drug Somnium was superior to the single component lorazepam also in regard to the anxiolytic effect at the autonomic nervous system level.

On the cerebro-protective effects of caroverine, a calcium-channel blocker and antiglutamatergic drug: double-blind, placebo-controlled, EEG mapping and psychometric studies under hypoxia.

1. In a double-blind, placebo-controlled study, the acute antihypoxidotic properties of the calcium-channel blocking and antiglutamatergic caroverine were investigated utilizing blood gas analysis, EEG mapping and psychometry under a transient, reversible, hypoxic hypoxidosis. 2. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found in 6000 m altitude), which was inhaled for 23 min under normobaric conditions by 16 healthy, young volunteers. They received randomized after an adaptation session, single oral doses of placebo, 40, 80 and 120 mg caroverine. Evaluation of blood gases, EEG mapping and psychometry were carried out 0, 2, 4, 6 and 8 h post-drug, during hypoxia. 3. Blood gas analysis demonstrated a drop in PO2 from 95 to 33 and 30 mmHg, in PCO2 from 38 to 30 and 30 mmHg in the 14th and 23rd minute of inhalation, respectively, while pH increased from 7.41 to 7.50 and 7.51. Base excess and standard bicarbonate remained stable. 4. EEG mapping under hypoxia exhibited a marked increase of delta/theta, decrease of alpha and an increase of superimposed beta activity, which reflects deterioration of vigilance. 5. Caroverine attenuated this hypoxia-induced vigilance decrement in a dose- and time-dependent manner 6-8 h after 80 mg and 2-8 h after 120 mg. 6. Hypoxic hypoxidosis induced a deterioration of memory and attention variability, which was mitigated by 80 and 120 mg caroverine. However, there was an augmentation of the hypoxia-induced decrement in psychomotor performance after 120 mg. 7. The drug was well tolerated, and there were no significant differences compared with placebo with regard to pulse and blood pressure.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED: The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS: One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS: EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS: Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

[The "cognitive pupillary oscillation hypothesis" in patients with neurotic disorders and organic psychosyndrome: reliability and validity of a new psychophysiologic method]. / Die "Kognitive Pupillenoszillationshypothese" bei Patienten mit neurotischen Störungen bzw. organischem Psychosyndrom: Reliabilität und Validität eines neuen psychophysiologischen Verfahrens.

A new psychophysiological method called "cognitive pupillary oscillation hypothesis" is introduced. Under the influence of a cognitive test (simple calculations) changes of the maximal amplitudes of pupillary oscillations, reflecting central nervous activation, are observed. In healthy subjects a retest reliability of 0.75-0.85 was calculated. Furthermore, the data after FFT (Fast Fourier Transform) of pupillary oscillations of two populations of patients (n = 509 and 396, respectively) showed a high stability. The validity of the method was determined by means of a procedure similar to cross validation. The use of the "cognitive pupillary oscillation hypothesis" for the differential diagnosis between patients with neurotic disorders (ICD 9: 300) (n = 73) and patients with organic brain syndrome (ICD 9: 290, ICD 291.2) (n = 34) is demonstrated.

Pupillary dilatation test and Fourier analysis of pupillary oscillations in patients with multiple sclerosis.

Recently we investigated 29 patients aged between 31 and 60 years with multiple sclerosis by means of two new techniques. The first technique was based on pupillary dilatation response to the topical application of the cholinergic antagonist tropicamide. The second technique was the Fourier analysis of pupillary oscillations for measurement of central activation, carried out without and under the influence of a cognitive task. The multiple sclerosis group had a pupillary dilatation of 31.9% after 40 min. Under the influence of a cognitive task the patient group revealed lower amplitudes of pupillary oscillations reflecting a decreased capacity for cognitive activation.

Effects of the novel neuroprotective agent, riluzole, on human brain function and behavior: I. Double-blind, placebo-controlled EEG mapping and psychometric studies under normoxia.

In a double-blind, placebo-controlled, crossover study, the encephalotropic and psychotropic properties of single oral doses of the novel neuroprotective agent, riluzole, were investigated utilizing EEG mapping and psychometry. Twenty healthy young volunteers received randomly at weekly intervals, placebo, 50, 100 and 200 mg riluzole. EEG recordings and evaluation of 9 noopsychic and 5 thymopsychic variables were carried out at 0, 2, 4, 6 and 8 h after oral drug administration. EEG maps on the multivariate analysis demonstrated that all three doses induced significant changes in human brain function, as compared with placebo, between 2 and 8 h, with effect only increasing slightly with dose. EEG maps on univariate analysis demonstrated generally an increase of delta/theta, decrease of alpha and beta power, as well as a slowing of the centroid of the total power spectrum, which suggests sedative properties of the drug. Only after the two highest doses at 6 h were some different findings observed. Multivariate statistics on psychometry failed to show any significant effects on the noopsyche, while for the thymopsyche, all three doses of riluzole produced a deterioration. The latter was characterized by a decrease in drive and wakefulness as well as deterioration in well-being, mood and affectivity. Thus, under normoxia, in all three doses riluzole produced neurophysiologically a sedative effect, accompanied at the behavioral level by a deterioration in the thymopsyche, which may be expected from a drug with antiglutamatergic effects in normals.

Effects of the novel neuroprotective agent, riluzole, on human brain function and behavior: II. Double-blind, placebo-controlled EEG mapping and psychometric studies under hypoxia.

In a double-blind, placebo-controlled study, the antihypoxidotic properties of the novel neuroprotective agent, riluzole, were investigated utilizing blood gas analysis, EEG mapping and psychometry under a transient, reversible, hypoxic hypoxidosis. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found at 6000 m altitude), which was inhaled for 23 min under normobaric conditions by 20 healthy, young volunteers. They randomly received, after an adaptation session, single oral doses of placebo, and 50, 100 and 200 mg riluzole. Evaluation of blood gases, EEG mapping and psychometry were carried out 0, 2, 4, 6 and 8 h postdrug, each time under the 23-min hypoxia. Blood gas analysis demonstrated a drop in PO2 from 106 to 37 and 36 mmHg, in PCO2 from 35 to 31 and 31 mmHg at 14 and 23 min of inhalation, respectively, while pH increased from 7.43 to 7.48 and 7.48. Base excess and standard bicarbonate remained stable. EEG mapping exhibited under hypoxia a marked increase of delta/theta, decrease of alpha and an increase of superimposed beta activity, as well as a slowing of the centroid of the total activity, which reflects deterioration of vigilance. Riluzole in lower doses and at early hours after higher doses did not attenuate this hypoxia-induced vigilance decrement, while with higher doses (100-200 mg) in later recording periods (6-8 h) brain protection occurred. As compared with placebo, delta/theta power increased at 2-8 h after 50 mg riluzole and up to 4 h after 100 mg riluzole, while a decrease occurred at 4 and 8 h after 100 mg and at 6-8 h after 200 mg. Alpha power showed no changes after 50 mg, an increase at 2 and 8 h after 100 mg and a decrease at 4 h after 200 mg, with no changes thereafter. Beta power decreased at various times after all three doses. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noopsyche, which was not mitigated by riluzole. In regard to the thymopsyche, there was even a slight deterioration after all three doses, as compared with placebo.

Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled study, the encephalotropic and psychotropic effects of tianeptine (TIA)--a new tricyclic antidepressant, enhancing serotonin reuptake--were investigated as compared with the serotonin reuptake inhibiting antidepressant, fluvoxamine (FLU), utilizing EEG mapping, psychometric and psychophysiological measures. 16 healthy volunteers (8 males, 8 females) aged 21-35 (man 27) years received randomized and at weekly intervals single oral doses of placebo, 12.5 and 25 mg TIA and 50 mg FLU. EEG recordings, psychometric and psychophysiological tests and evaluation of pulse, blood pressure and side effects were carried out at 0, 2, 4, 6 and 8 hours; blood sampling, in addition, at hour 1. TIA plasma levels rose fast to peaks at 1-2 hours and declined rapidly as well, while the MC5 metabolite peaked in the 4th hour and declined more slowly. EEG mapping demonstrated that both TIA and FLU induced significant changes in brain function between the 1st and 8th hour, which, however, differed in their time course. 12.5 mg TIA exhibited, as compared with placebo, slight activating properties in the EEG (decrease of delta and theta, increase of alpha and beta, acceleration of the centroid), parallelled by thymopsychic improvement (mood elevation). 25 mg TIA showed EEG activation up to the 4th hour, later EEG sedation, accompanied by an initial thymopsychic improvement and differential changes thereafter (improved mood, decreased vigility), with the noopsyche improving at all times (attention, Pauli test). 50 mg FLU induced initially sedation and thereafter activation, accompanied by thymopsychic deterioration and subsequent improvement, the latter also being observed in the noopsyche (attention, memory). In pupillary and skin conductance measures, generally a slight activation occurred after placebo, which was attenuated by 25 mg TIA. Correlation maps between plasma levels and EEG changes demonstrated: the higher the TIA plasma levels, the more absolute and relative beta power, the less alpha power and the faster the centroid of the total power spectrum, reflecting CNS-activation. Topographically, the correlations were mostly seen over both fronto-temporal regions. In the latter, dominant frequency signalled desactivation in the right and activation in the left hemiphere after both antidepressants which, thereby induced changes in brain function opposite to those observed in depression. Both drugs were well tolerated.

Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression.

In a double-blind, placebo-controlled study, the antidepressant and vigilance-promoting properties of transdermal oestrogen in post-menopausal depression were investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty-nine menopausal women, aged 45-60 years without previous hormonal replacement therapy, diagnosed as major depression without psychotic or suicidal symptoms (DSM-III-R criteria), were randomly assigned to a 3-month treatment with transdermal oestradiol [Estraderm TTS (ETTS) 50 micrograms, applied twice weekly] or placebo. No other psychoactive medication was allowed. After removal of protocol violators, 32 patients were evaluable in each group, which did not differ in age, height or weight. As five patients discontinued prematurely in both groups and in one placebo patient a post-drug EEG could not be obtained, 27 patients remained in the ETTS and 26 in the placebo group for efficacy analysis. While in the placebo group, oestradiol (E2) and follicle stimulating hormone (FSH) remained unchanged, E2 increased and FSH decreased significantly in the ETTS group. Syndromal evaluation showed a significant improvement in the Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both groups, with no inter-group difference. However, EEG mapping demonstrated significant inter-drug differences in brain function, mostly over the left temporal region. While ETTS patients showed an increase of alpha and alpha-adjacent theta activity and a decrease of beta activity, as well as an acceleration of the delta/theta centroid and a slowing of the alpha, beta and total power centroid, no changes occurred in the placebo-treated patients. These neurophysiological findings suggest improvement of vigilance by oestrogen, previously referred to as "mental tonic" effect. There were no changes, however, in the frontal alpha asymmetry index, reflecting left frontal hypo- and right frontal hyperactivation. Thus, this neurophysiological variable represents a state-independent marker for depression. The tolerability of ETTS was very good.

[A new method for testing the psychopharmacologic pupil oscillation hypothesis following administration of a nootropic substance]. / Eine neue Methode zur Uberprüfung der psychopharmakologischen Pupillenoszillations-Hypothese nach Verabreichung einer nootropen Substanz.

Recently a new, precise and economical method for measuring central nervous activation in psychopathological groups was presented. By means of this procedure, the ¿psychopharmacological pupillary oscillations hypothesis¿ after administration of the nootropic compound bifemelane (CAS 90293-01-9) was examined in oder to assess pharmacologically induced changes in central activation. Before calculating the Fourier analysis, blinks have to be identified and eliminated by means of a new technique, which is called ¿smoothing¿. After application of bifemelane, a marked improvement of symptoms caused by cerebro-vascular disorders was reported. 18 subjects (7 females and 11 males), aged between 60 and 80 years, with a neurological and psychic age-adequate state, from whom a written, informed consent was obtained, participated voluntarily in the study. A placebo-controlled and double-blind design were administered in an interval of 8 days in cross-over design. The study, which also included measurement of noopsychic and thymopsychic changes, was carried out before and in the 2nd, 4th, 6th and 8th hour after application of the substances. In the slow frequency band, after application of bifemelane, an increase of activation (higher amplitudes) could be observed, which lasted from the 2nd to the 4th hour. However, differences between bifemelane and placebo did not reach the level of statistical significance. In faster frequencies, a reduction of the height of the amplitudes was found. Regarding the total spectrum, in the 2nd hour a moderate increase of activation could be demonstrated.

Improvement of decreased critical flicker frequency (CFF) in headache patients with drug abuse after successful withdrawal.

A considerable proportion of headache patients fulfill the criteria of "drug abuse" (definition according to the International Headache Society [IHS] criteria). These patients exhibit markedly reduced vigilance and continuous performance, as shown by the results of critical flicker frequency (CFF) analysis. The present study deals with the question whether this impairment of vigilance and continuous performance is reversible. Forty-eight headache patients with drug abuse were investigated three times by means of CFF analysis: immediately before (A), immediately after (B), and 3 weeks after having finished (C) inpatient drug withdrawal. Immediately after withdrawal, a significant decrease of headache intensity was observed. The CFF values, however, remained unchanged at a depressed level, probably due to withdrawal medication and the initial sedative side effects of thymoleptic agents (given as prophylaxis). Three weeks after withdrawal, however, the CFF values were significantly improved, and were now within a range not far from the normal values known from a healthy general population. Thus, even after many years of drug abuse, headache patients have a good chance to improve their vigilance and continuous performance and to reach normal or close to normal levels.