Coherence Analysis of Ail-Night Sleep EEG. P. Achermann and A.A. Borbely (Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland). The interhemispheric and intrahemispheric coherence of the EEG may provide information on the functional connectivities between brain regions. The present study was designed to explore state-specific changes of EEG coherence during sleep. The nocturnal sleep EEG of 8 young healthy subjects was recorded. The power spectra (averages of five 4-s epochs) and coherence spectra (20-s epochs) between different bipolar derivations were calculated in the frequency range of 0.25-25 Hz. Intrahemispheric anterior-posterior coherences in nonREM sleep showed distinct peaks in the frequency range of sleep spindles, in the low delta band, and in the alpha band. Coherence was low throughout the entire frequency range in stage 1 and REM sleep. Interhemispheric coherences of corresponding sites showed an entirely different pattern. Coherence in nonREM sleep was high in the delta, theta and alpha range, and the distinct peaks of intrahemispheric coherence were also present. They were most prominent in the anterior derivations. The pattern in stage 1 and REM sleep was similar to that of nonREM sleep although the typical peaks were absent and the values in the low delta range were lower. Our results indicate that a state-specific high coherence is limited to distinct frequencies within the low delta, alpha and sigma band. Zurich, Switzerland). According to the triarchic model, P300 amplitude depends, at given levels of global probability, stimulus meaning and information transmission, on the specific sequence of preceding stimuli. Thus, in an oddball paradigm, P300 amplitude should depend on 1/ITI where ITI is the inter-target interval. Single potentials evoked by target tone bursts (p=0.10; N=31), were averaged according to their occurrence in the experiment, separately for 58 normal healthy subjects aged 20-29 years, and 41 normal healthy subjects aged 60-79 years. Latencies, amplitudes and electrical activity in the brain localized by means of "low resolution electromagnetic tomography (LORETA)" were evaluated. P300 latency was strongly related to 1/ITI both in young and elderly subjects, with short latencies for long ITIs (r=0.91 and r=0.89 in young and elder-lies, respectively). On the other hand, P300 amplitude at Pz was related to 1/ITI only in young subjects with high amplitudes for long ITIs (r=-0.75), but not in elderlies (r=-0.19). As shown previously, LORETA revealed frontal and parieto-occiptal P300 generators. In young subjects the parieto-occipital source was predominant for short ITI. With increasing ITI the parieto-occipital source decreased, while the frontal increased. In elderlies, however, frontal and parieto-occipital P300 sources were approximately equal in size and strength, independent of the ITI.

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.

Objective: The aim of this observational study was to evaluate the effects of duloxetine in the treatment of seasonal affective disorder (SAD).Patients and Methods: 26 SAD patients were treated with open-label duloxetine 60-120 mg per day over 8 weeks. Ratings included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD) and the Clinical Global Impression (CGI). To estimate treatment effects on social functioning in SAD we employed the Social Adaptation Self Evaluation Scale (SASS), the Sheehan Disability Scale (SDS), and assessments of days lost due to illness and days with reduction in productivity.Results: Duloxetine led to a significant improvement (p < 0.001) of SIGH-SAD, CGI severity, SASS, and SDS scores. Days lost due to illness and days with reduction in productivity were significantly diminished during treatment (p < 0.001). Treatment with duloxetine over 8 weeks yielded a response rate (SIGH-SAD < 50% of baseline value) of 80.8% and a remission rate (SIGH-SAD < 8) of 76.9% in the intention to treat sample. The drop-out rate due to side effects was 15.4%.Conclusions: Our preliminary results indicate that duloxetine might be effective and able to ameliorate the negative social consequences of SAD.

In a double-blind, placebo-controlled, multiple-ascending-dose study, the encephalotropic and psychotropic properties of ABIO-08/01, a new potentially anxiolytic and nootropic isoxazoline, were studied in 16 young healthy males. In a randomized nonbalanced phase 1 study, they received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (washout period 8 days). EEG mapping and psychometry were carried out at hours 0, 1, 6 of day 1 (acute effect) and day 5 (subacute and superimposed effects). MANOVA/ Hotelling T(2) test demonstrated significant central effects of ABIO-08/01 versus placebo after acute, subacute and superimposed administration of all doses in the resting, vigilance-controlled and eyes-open EEG. Univariate analysis revealed activating patterns in the resting EEG (40 mg > 20 mg > 10 mg), and sedative patterns in the eyes-open EEG (10 mg > 20 mg > 40 mg). In the vigilance-controlled EEG, 40 mg of ABIO-08/01 induced activating patterns, whereas 10 mg induced sedative patterns. Concerning psychometry, ABIO-08/01 improved concentration (40 mg > 20 mg > 10 mg; activating effect) and deteriorated well-being (10 mg > 20 mg > 40 mg; sedative effect). Ten milligrams also improved reaction time performance and psychomotor activity. ABIO-08/01 is well-tolerated and is of interest in anxiety disorders.

The influence of a combined estrogen-progestin regimen (Climodien, Lafamme) on auditory event-related potentials (ERPs) was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3=estradiol valerate 2 mg+the progestin dienogest 3 mg, EV=estradiol valerate 2 mg, and placebo), followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg+dienogest 2 mg). Both the double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone odd-ball paradigm in 49 patients aged between 46 and 67 yr with the diagnosis of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1). Climodien reduced standard N1 and target P300 latencies as compared to placebo, while EV did not affect N1 latency but similarly reduced P300 latency. Climodien increased N1, P2 and P300 amplitudes dose-dependently, predominantly at frontal leads. Estrogen alone had only minor effects on ERP amplitudes. The shortening of standard N1 latency and enhancement of N1 and P2 amplitudes indicates a positive effect of Climodien on perceptual processing, most likely due to vigilance improvements also observed in EEG mapping. Concerning target P300, it seems that estradiol is responsible for the improvement in stimulus evaluation time, as reflected by the shortening of the peak latency, while dienogest seems to account for the improvement in cognitive information processing capacity, whereby 3 mg induced a more pronounced augmentation of P300 amplitudes than 2 mg. Based on the spatial distribution of this increase, it can be speculated that Climodien mainly affects the more frontally distributed P3a subcomponent, which is associated with attention and orientation. Furthermore, the observed changes in ERP-components are consistent with recent studies showing significant positive effects of hormone replacement therapy on cholinergic functions. Thus, Climodien seems to be of interest in preventing cognitive decline and treating cognitive disorders in postmenopausal women. Indeed, there is increasing evidence of beneficial effects of estrogen in dementia. Our present findings suggest that the estrogen effects may be augmented by dienogest.

Cognitive event-related potentials were recorded from 17 EEG leads in an auditory two-tone paradigm in 43 patients aged 51–79 years with the diagnosis of age-associated memory impairment (AAMI), in age-and sex-matched normal controls and in a control group 10 years older than the AAMI patients. In addition to P300 latencies, amplitudes and topographies, three-dimensional current density distribution utilizing low-resolution brain electromagnetic tomography (LORETA) was computed. P300 latency was delayed and P300 amplitude was reduced in both AAMI and older subjects. Topographically this amplitude reduction was most pronounced frontally. LORETA revealed medial (frontal and parietal) and lateral (dorso- and ventrolateral prefrontal, middle/superior temporal, posterior superior temporal/inferior parietal) sources. Significant reductions in LORETA source strength in normal aging and in AAMI were found mainly medially frontally, right dorsolaterally prefrontally and right inferiorly parietally. Since these anatomically highly interconnected brain regions in the right hemisphere are part of a network associated with sustained attention, the results speak for a decline in attentional resource capacity in AAMI patients and elderly subjects.

In a double-blind, placebo-controlled cross-over study, the acute and subacute effects of S-adenosyl-L-methionine (SAMe), or ademetionine, on brain function and behavior of 10 elderly normal healthy volunteers (5 males and 5 females, aged 56-71 years, mean: 59.3 years) were investigated by means of EEG mapping and psychometry. In random order they received infusions of 800 mg SAMe and placebo, administered over 30 minutes for 7 days, with a wash-out period of 3 weeks in between. EEG recordings and psychometric tests were carried out 0, 1, 3 and 6 hours after drug administration on days 1 and 7. Multivariate analysis based on MANOVA/Hotelling T(2) tests demonstrated significant central effects of SAMe as compared with placebo after acute, subacute and superimposed drug administration. Acute SAMe-induced changes were characterized by a decrease in total power, an increase in absolute delta and a decrease in absolute alpha power, further by an increase in relative delta and a decrease in relative alpha power, a slowing of the delta/theta centroid as well as a slowing of the centroid of the total power spectrum. These changes are typical of classical antidepressants of the thymoleptic type such as imipramine and amitriptyline. After one week of daily infusions there was a marked increase in total power, reminiscent of nootropic drug effects. One additional superimposed dosage mitigated these effects in the direction of an antidepressant profile, with the inter-drug differences waning in the 6(th) hour. Our pharmaco-EEG findings suggest both inhibitory and excitatory drug effects underlying the antidepressant properties of SAMe well-documented in clinical trials. Psychometric tests concerning noopsychic and thymopsychic measures as well as critical flicker frequency generally demonstrated a lack of differences between SAMe and placebo, which again reflects a good tolerability of the drug in elderly subjects.

The effects of S-adenosyl-l-methionine (SAMe)—a naturally occurring molecule with antidepressant properties—on event-related potentials (ERPs) were investigated in normal healthy volunteers (10 young subjects aged 22–33 years and 10 elderly subjects aged 56–71 years). In random order, they received infusions of 800 mg SAMe in 250 ml of isotonic solution, and placebo, administered over 30 min for 7 days, with a wash-out period of 3 weeks in between. ERP recordings were carried out before and 1 h after drug administration on days one and seven in a two-tone odd-ball paradigm.

Noninvasive electrophysiological neuroimaging applied to cognitive components of event-related potentials (ERPs) may differentiate between structural and energetic processes related to information processing. The structural level, revealed by the location of the local maxima of the current source density distribution, describes the time-dependent network of activated brain areas. The magnitude of the source strength, a measure of the energetic component, describes the allocation of processing resources. ERPs were recorded in an odd-ball paradigm and low-resolution brain electromagnetic tomography (LORETA) was applied for standard and target ERP components. In a group of 60 menopausal depressed patients of 45-60 years of age, reduced P300 source strength was observed bilaterally, temporally and medially prefrontally reaching to rostal parts of the anterior cingulate, compared with 29 age-matched controls. In a double-blind, placebo-controlled study, 2 mg of the antidepressant citalopram induced a significant increase of P300 source strength in the (left) prefrontal cortex and precuneus compared with placebo, reaching to the posterior cingulate. Similar increases were observed after 800 mg S-adenosyl-L-methionine (SAMe) administered intravenously in ten young healthy subjects aged 22-33, and they were even more pronounced in ten elderly healthy subjects aged 56-71. Thus, ERP-tomography identified changes in energetic sources in brain areas predominantly involved in depression and in antidepressant action.

Middle latency and late components of event-related brain potential (ERPs) are closely related to perceptual and cognitive information processing, respectively. In a double-blind, placebo-controlled study, the acute effects of lorazepam (2 mg), haloperidol (3 mg), methylphenidate (20 mg) and citalopram (20 mg) on ERP latencies, amplitudes, topographies and tomographies were investigated in 20 healthy subjects of 23-34 years of age. After automatic artifact minimization and rejection, standard N1 and P2 and target N2 and P300 components were determined. The tranquilizer lorazepam prolonged P300 latency, which indicates an impairment of stimulus evaluation time. Low-resolution brain electromagnetic tomography (LORETA) revealed decreases in N1 and P300 source strength in those brain regions with relevant generators of these components, which reflects impairments of attentional and cognitive processing resources. The neuroleptic haloperidol decreased N1 and P300 source strength predominantly in those brain regions not involved in the generation of these components, suggesting a shift of resources. The psychostimulant methylphenidate increased P300 source strength in brain regions with major P3b generators, indicating increases in energetic resources associated with stimulus encoding. The antidepressant citalopram increased N1 and P3b source strength in multiple brain regions specifically in the left prefrontal cortex, a brain region in which reduced blood flow and metabolism was found in depressed patients.

ObjectiveThe aim of the field study was to objectify physicians’ vigilance, well-being, and cognitive performance in the course of 24-hr shifts with and without afternoon rest. Subjects, Setting, and DesignEleven residents (four women, seven men; age, 33.5 ± 4.7 yrs) were observed when doing two regular 24-hr shifts at the emergency department (randomized crossover design): one without rest, the other with a period of rest in the early afternoon (duration, 2:31 ± 1:04 hrs) and the opportunity of having a nap (duration, 1:07 ± 0:26 hrs, n = 6). Electroencephalography and psychometric tests were carried out at 8 am and at midnight. MeasurementsMeasurements included subjective perception of workload, stress, and sleeping behavior; computer-analyzed electroencephalography; adjective checklist (Eigenschaftswörterliste 60 S, a self-rating scale); complex reaction time test; Pauli test (number of calculations during 3 mins); and numerical memory test. ResultsElectroencephalographic analyses showed a significant decrease in alpha power and a significant increase in beta power in the evening as compared with the morning on both days. The nocturnal increase observed in delta activity was significantly less pronounced in duties with rest than in duties without rest. Physicians felt deactivated at night. The Eigenschaftswörterliste 60 S indicated deactivation at night and a rest-induced activation in the subgroup that had taken the opportunity to sleep in the afternoon. Psychometric tests did not show any significant differences, neither between performance in the morning and evening nor between results with and without rest. ConclusionAs expected, electroencephalographic recordings showed nocturnal deactivation and a vigilance-promoting effect of the afternoon rest. These objective findings were in accordance with the results derived from self-rating scales. On the other hand, in short-lasting psychometric tests, performance was found unchanged after 16 hrs of routine work. In further studies, a discrimination between resting periods with and without sleep will be important.

In a double-blind, placebo-controlled, cross-over study, the central effects of the natural molecule S-adenosyl-L-methionine (SAMe), or ademetionine (ADE), used in low doses as a nutraceutical and in higher doses as a pharmaceutical, were investigated by means of EEG mapping and psychometry. Ten young, normal healthy volunteers of both sexes, with a mean age of 25.2+3.9 yr received, in random order, infusions of 800 mg ADE in 250 ml of isotonic solution, and placebo consisting of 250 ml of isotonic solution administered over 30 min for 7 d, with a wash-out period of 3 wk in between. EEG recordings and psychometric tests were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 7. While there were no significant changes in psychometric findings, multivariate analyses of the EEG results based on MANOVA/Hotelling T 2 tests demonstrated significant encephalotropic effects of ADE compared to placebo. ADE-induced changes were characterized by a decrease in total power, an increase in absolute delta power and a decrease in absolute alpha and beta power, further by an increase in relative delta and beta power and a decrease in relative alpha power, a slowing of the delta/theta centroid, an acceleration of the alpha centroid as well as a slowing of the centroid of the total power spectrum. These changes are typical of classical antidepressants of the thymoleptic type such as imipramine and amitriptyline. Time-efficacy calculations demonstrated a significant central effect of ADE in the first hour after the first infusion, declining slowly until the third hour and thereafter steeply until the sixth hour; a further significant effect was after 1 wk of daily infusions and in the third hour after one superimposed infusion on day 7 of subacute treatment. Our pharmaco-EEG findings suggest both inhibitory and excitatory drug effects at the neurophysiological level, underlying the antidepressant properties well-documented in clinical trials.

The aim of the present study was to investigate the influence of the response criterion, the current well-being, and the speed of cognitive processing on fusion and flicker frequency measured by method of limits, in 65 healthy subjects, aged between 20 and 30 years. The findings demonstrated that the fusion and flicker frequency could not be measured exactly. Evaluation of the reliability of the obtained results was not possible, mainly because the necessary basic psychological variables could not be recorded using the method.

The aim of the present study was to investigate the influence of the response criterion, the current well-being, and the speed of cognitive processing on fusion and flicker frequency measured by method of limits, in 65 healthy subjects, aged between 20 and 30 years. The findings demonstrated that the fusion and flicker frequency could not be measured exactly. Evaluation of the reliability of the obtained results was not possible, mainly because the necessary basic psychological variables could not be recorded using the method.

The P300 event-related potential (ERP) is considered to be closely related to cognitive processes. In normal aging, P300 scalp latencies increase, parietal P300 scalp amplitudes decrease and the scalp potential field shifts to a relatively more frontal distribution. Based on ERPs recorded in 172 normal healthy subjects aged between 20 and 88 years in an auditory oddball paradigm, the effects of age on the electrical activity in the brain corresponding to N1 and P300 components were estimated by means of low resolution electromagnetic tomography (LORETA). This distributed approach directly computes a unique 3-dimensional electrical source distribution by assuming that neighbouring neurons are simultaneously and synchronously active. N1 LORETA generators, located predominantly in both auditory cortices and also symmetrically in prefrontal areas, increased with advancing age for standards but remained stable for targets. P300 LORETA generators, located symmetrically in the prefrontal cortex, in the parieto-occipital junction and in the inferior parietal cortex (supramarginal gyrus) and medially in the superior parietal cortex, were differentially affected by age. While age did not affect parieto-occipital sources, superior parietal and right prefrontal sources decreased pronouncedly. Thus, in normal aging, P300 current density decreased in regions were a fronto-parietal network for sustained attention was localized.

The P300 event-related potential (ERP) is considered to be closely related to cognitive processes. Previous reports regarding major generators contributing to the scalp-recorded P300 suggested widely distributed multiple sources. Based on ERPs recorded in 172 normal healthy subjects aged between 20 and 88 years in an auditory oddball paradigm, electrical activity in the brain corresponding to N1 and P300 components was localized by means of low resolution electromagnetic tomography (LORETA). The N1 LORETA generators, located in both auditory cortices, did not change over age. On the other hand, the P300 LORETA generators, located predominantly in the frontal neocortex and less pronounced in the posterior parietal cortex, decreased over age both in frontal and parietal source strength.