Automated sleep staging in people with intellectual disabilities using heart rate and respiration variability.

BACKGROUND: People with intellectual disabilities (ID) have a higher risk of sleep disorders. Polysomnography (PSG) remains the diagnostic gold standard in sleep medicine. However, PSG in people with ID can be challenging, as sensors can be burdensome and have a negative influence on sleep. Alternative methods of assessing sleep have been proposed that could potentially transfer to less obtrusive monitoring devices. The goal of this study was to investigate whether analysis of heart rate variability and respiration variability is suitable for the automatic scoring of sleep stages in sleep-disordered people with ID. METHODS: Manually scored sleep stages in PSGs of 73 people with ID (borderline to profound) were compared with the scoring of sleep stages by the CardioRespiratory Sleep Staging (CReSS) algorithm. CReSS uses cardiac and/or respiratory input to score the different sleep stages. Performance of the algorithm was analysed using input from electrocardiogram (ECG), respiratory effort and a combination of both. Agreement was determined by means of epoch-per-epoch Cohen's kappa coefficient. The influence of demographics, comorbidities and potential manual scoring difficulties (based on comments in the PSG report) was explored. RESULTS: The use of CReSS with combination of both ECG and respiratory effort provided the best agreement in scoring sleep and wake when compared with manually scored PSG (PSG versus ECG = kappa 0.56, PSG versus respiratory effort = kappa 0.53 and PSG versus both = kappa 0.62). Presence of epilepsy or difficulties in manually scoring sleep stages negatively influenced agreement significantly, but nevertheless, performance remained acceptable. In people with ID without epilepsy, the average kappa approximated that of the general population with sleep disorders. CONCLUSIONS: Using analysis of heart rate and respiration variability, sleep stages can be estimated in people with ID. This could in the future lead to less obtrusive measurements of sleep using, for example, wearables, more suitable to this population.

Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects.

BACKGROUND: ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer's disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. OBJECTIVES: To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. DESIGN: This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). SETTING: The study was conducted at a First-in-Human unit in Sweden. PARTICIPANTS: Twenty-four healthy male and female subjects. INTERVENTION: The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. MEASUREMENTS: Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. RESULTS: Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio. CONCLUSIONS: ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.

Sleep habits and sleep complaints in Austria: current self-reported data on sleep behaviour, sleep disturbances and their treatment.

OBJECTIVES: To acquire current information on sleep habits, disturbances and treatment options in the adult population of Austria and compare results with previously collected data. MATERIALS AND METHODS: A representative sample of the Austrian population (women: n = 522, men: n = 478). RESULTS: Seventy-five percent reported daily sleep-duration between 6 and 8 h. In 76%, sleep latency was <30 min, 15% described difficulties in sleep maintenance. Longer sleep on weekends was prevalent in 54%, 23% took a nap. Concerning sleep environment, 31% reported sleeping alone; the rest had a constant or occasional bed partner. Sleep disturbances such as sleep disruption or prolonged sleep latency were reported by 18%. Predominant symptoms included snoring/apneas (22%), nightmares (22%) and restless legs (21%). Daytime tiredness was reported by 17% and sleepiness by 20%. Twenty-four percent did not take treatment. Only 7% asked for medical help: 96% consulted their physician; 47% tried to change their way of living. Sleep promoting drugs were taken by 7%. Sleep improving measures were: sleep promoters (45%), general measures (20%), consultation of general practitioner (20%), psychotherapy (6%), and technical tools (3%). Comparison with a dataset of 1993 revealed only a slight increase in short sleepers and a slight decrease in long sleepers. CONCLUSIONS: Subjectively reported sleep disorders proved to be relatively stable between 1993 and 2007.

Direct application of an ECG-based sleep staging algorithm on reflective photoplethysmography data decreases performance.

OBJECTIVE: The maturation of neural network-based techniques in combination with the availability of large sleep datasets has increased the interest in alternative methods of sleep monitoring. For unobtrusive sleep staging, the most promising algorithms are based on heart rate variability computed from inter-beat intervals (IBIs) derived from ECG-data. The practical application of these algorithms is even more promising when alternative ways of obtaining IBIs, such as wrist-worn photoplethysmography (PPG) can be used. However, studies validating sleep staging algorithms directly on PPG-based data are limited. RESULTS: We applied an automatic sleep staging algorithm trained and validated on ECG-data directly on inter-beat intervals derived from a wrist-worn PPG sensor, in 389 polysomnographic recordings of patients with a variety of sleep disorders. While the algorithm reached moderate agreement with gold standard polysomnography, the performance was significantly lower when applied on PPG- versus ECG-derived heart rate variability data (kappa 0.56 versus 0.60, p < 0.001; accuracy 73.0% versus 75.9% p < 0.001). These results show that direct application of an algorithm on a different source of data may negatively affect performance. Algorithms need to be validated using each data source and re-training should be considered whenever possible.

Effects of a mandibular repositioning appliance on sleep structure, morning behavior and clinical symptomatology in patients with snoring and sleep-disordered breathing.

BACKGROUND: Mandibular repositioning appliances (MRAs) have become an established treatment for snoring and sleep-disordered breathing - though most studies only focused on the evaluation of respiratory variables. METHODS: This single-blind, placebo-controlled case-series study investigated the effects of an individually adjustable MRA on psychopathology, macro-/microstructure of sleep, periodic leg movements, morning performance, mood/affect and psychophysiology. Fifty patients (37 males) aged 59.7 +/- 10.3 years, suffering from primary snoring (7), mild (22), moderate (15) and severe apnea (6), spent 4 nights in the sleep laboratory (adaptation, placebo, drug and MRA night). The drug night is not subject of the present paper. RESULTS: Confirmatory statistics showed an improvement of the snoring index by 72%. Descriptively, the apnea index and the apnea-hypopnea index normalized. A clinical improvement was seen in the Pittsburgh Sleep Quality Index, the Zung Anxiety/Depression Scales and the Epworth Sleepiness Scale. The restless legs syndrome also improved. Polysomnographically, sleep stages REM and 4 as well as REM latency increased, stage 3, movement time, stage shifts and periodic leg movements decreased, as did all arousal measures. Subjectively, morning well-being, drive, affectivity and wakefulness improved. Objectively, attention, motor and reaction time performance, critical flicker frequency as well as muscular strength increased, diastolic blood pressure and the pulse rate decreased. CONCLUSION: Apart from its good therapeutic effects on snoring and respiratory variables (snoring showed complete or partial response in 68%, the apnea-hypopnea index in 67% of the apnea patients), the MRA also improved psychopathology, objective and subjective sleep and awakening quality.

Identifying target regions for vigilance improvement under hormone replacement therapy in postmenopausal syndrome patients by means of electroencephalographic tomography (LORETA).

RATIONALE: Daytime fatigue, which at the neurophysiological level is due to vigilance decrements, is a frequent complaint in postmenopausal women. OBJECTIVES: In a three-arm, 2-month, parallel group-design study, vigilance-promoting effects of a novel continuous combination (=Climodien 2/3) of estradiol valerate (EV; 2 mg) and dienogest (DNG; 3 mg) were compared with the effects of both EV alone and placebo in 55 insomniac, postmenopausal syndrome patients. METHODS: Low-resolution brain electromagnetic tomography (LORETA) was undertaken to identify the cerebral target regions of hormone replacement therapy. RESULTS: An omnibus significance test revealed Climodien to increase activity in 882 of 2,394 voxels in the alpha-2 band, followed by 733, 706, and 664 voxels in the beta-2, beta-1, and beta-3 bands, and 509 voxels in the delta band, whereas 2 mg EV alone did not produce a significant suprathreshold activity. Current density increased predominantly in the right hemisphere, which had already been described in the literature as the center of the vigilance system. In the fast alpha range, which plays a major role in the context of vigilance, increased activity was found in the right prefrontal, temporal, and superior parietal cortices, i.e., those brain areas of the right-sided fronto-parietal neuronal network that are responsible for sustained attention. A further activity increase was seen in the anterior cingulate gyrus associated with attentional control and conflict monitoring. The right temporal lobe showed increased current density in all frequency bands. CONCLUSIONS: Electroencephalographic tomography (LORETA) identified the right-hemispheric vigilance system as the target region of Climodien.

Double-blind, placebo-controlled pharmacodynamic studies with a nutraceutical and a pharmaceutical dose of ademetionine (SAMe) in elderly subjects, utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled crossover study, the effects of S-adenosyl-l-methionine (SAMe) on brain function measures of 12 normal elderly volunteers (6 m/6 f, aged 57-73 years, mean: 61 years) were investigated by means of EEG mapping and psychometry. In random order, the subjects were orally administered a pharmaceutical dose of 1600 mg SAMe, a nutraceutical dose of 400 mg SAMe and placebo, each over a period of 15 days, with wash-out periods of 2 weeks in between. EEG recordings, psychometric tests and evaluations of tolerability and side effects were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 15. Multivariate analysis based on MANOVA/Hotelling T2 tests of quantitative EEG data demonstrated significant central effects of SAMe as compared with placebo after acute, subacute and superimposed drug administration of both the nutraceutical and the pharmaceutical dose. EEG changes induced by SAMe were characterized by an increase in total power, a decrease in absolute and relative power in the delta/theta and slow alpha frequencies, an increase in absolute and relative power in the alpha-2 and beta frequencies as well as an acceleration of the alpha centroid and the centroid of the total power spectrum. The delta/theta and the beta centroid showed variable changes over time. The dominant alpha frequency was accelerated, the absolute and relative power in the dominant alpha frequency attenuated after SAMe as compared with placebo. These acute and subacute pharmaco-EEG findings in elderly subjects are typical of activating antidepressants. Time-efficacy calculations showed that acute oral administration of SAMe in both the nutraceutical and the pharmaceutical dose induced the pharmacodynamic peak effect in the first hour with a subsequent decline. The 3rd and 6th hours still showed a significant encephalotropic effect after the 1600 mg dose. The maximum EEG effect was noted after 2 weeks of oral administration of both 1600 mg/die and 400 mg/die. The superimposed dose induced significant encephalotropic effects in the 3rd hour after 400 mg and in the 3rd and 6th hours after 1600 mg as compared with pre-treatment. Dose-efficacy calculations showed that the pharmaceutical dose of 1600 mg had a more pronounced effect on the CNS than the nutraceutical dose of 400 mg, with both doses being superior to placebo. Psychometric tests concerning noopsychic and thymopsychic measures as well as critical flicker fusion frequency generally demonstrated a lack of differences between SAMe and placebo, which reflects a good tolerability of the drug in elderly subjects. This was corroborated by the findings on side effects, pulse and blood pressure.

EEG mapping and psychopharmacological studies with denbufylline in SDAT and MID.

Computed tomography (CT), electroencephalograms (EEG), clinical and psychometric data were obtained in 96 mildly to moderately demented patients (72 women, 24 men), aged 61-96 years (mean 82), diagnosed according to DSM-III criteria. Patients were off drugs for at least 2 weeks and subdiagnosed according to the modified Marshall-Hachinski ischemic score and CT in 45 senile dementia of the Alzheimer type (SDAT) and 51 multiinfarct dementia (MID) patients. Evaluations were carried out before and 12 weeks after treatment with either 100 mg denbufylline BID or placebo and included EEG mapping, the Sandoz Clinical Assessment Geriatric (SCAG) score/factors, the Clinical Global Impression (CGI), the Digit Symbol Substitution Test (DSST), the Trail-Making Test (TMT) and the Digit Span Test (DS). Descriptive data analysis including confirmatory statements found delta/theta activity enhanced, alpha and beta activity reduced, total power augmented, and the centroid slowed down over various brain regions in patients as compared with controls. The two subtypes of dementia could be differentiated in some conventional EEG variables but mostly by means of power asymmetry indices. Denbufylline induced a statistically significant and clinically relevant improvement in both SDAT and MID patients, whereas after placebo this was not the case in CGI, the TMT, and the DS, with interdrug differences being significant in all primary target variables such as the CGI, MMS, SCAG, and DSST. Thus, both the degenerative and vascular type of dementia exhibited a therapeutic benefit that could be objectified at the neurophysiological level by EEG mapping in an improvement of vigilance.

Non-invasive localization of P300 sources in normal aging and age-associated memory impairment.

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.

Low-resolution brain electromagnetic tomography revealed simultaneously active frontal and parietal sleep spindle sources in the human cortex.

Analyses of scalp-recorded sleep spindles have demonstrated topographically distinct slow and fast spindle waves. In the present paper, the electrical activity in the brain corresponding to different types of sleep spindles was estimated by means of low-resolution electromagnetic tomography. In its new implementation, this method is based on realistic head geometry and solution space is restricted to the cortical gray matter and hippocampus. In multichannel all-night electroencephalographic recordings, 10-20 artifact-free 1.25-s epochs with frontally, parietally and approximately equally distributed spindles were marked visually in 10 normal healthy subjects aged 20-35years. As a control condition, artifact-free non-spindle epochs 1-3s before or after the corresponding spindle episodes were marked. Low-resolution electromagnetic tomography demonstrated, independent of the scalp distribution, a distributed spindle source in the prefrontal cortex (Brodmann areas 9 and 10), oscillating with a frequency below 13Hz, and in the precuneus (Brodmann area 7), oscillating with a frequency above 13Hz. In extremely rare cases only the prefrontal or the parietal source was active. Brodmann areas 9 and 10 have principal connections to the dorsomedial thalamic nucleus; Brodmann area 7 is connected to the lateroposterior, laterodorsal and rostral intralaminar centrolateral thalamic nuclei. Thus, the localized cortical brain regions are directly connected with adjacent parts of the dorsal thalamus, where sleep spindles are generated. The results demonstrated simultaneously active cortical spindle sources which differed in frequency by approximately 2Hz and were located in brain regions known to be critically involved in the processing of sensory input, which is in line with the assumed functional role of sleep spindles.

Sleep laboratory studies on the single-dose effects of serotonin reuptake inhibitors paroxetine and fluoxetine on human sleep and awakening qualities.

Paroxetine is a novel antidepressant drug with selective serotonin (5-HT) reuptake inhibitory properties. In a double-blind placebo-controlled crossover sleep laboratory study the single-dose effects on objective and subjective sleep and awakening qualities were investigated after paroxetine 20, 30 and 40 mg morning doses (PX 20, 30, 40), paroxetine 30 mg evening dose, fluoxetine 40 mg morning dose (FX 40) and placebo in 18 healthy young volunteers. The drugs were orally administered in 2-wk intervals. In addition to each drug night, the adaptation night and washout night were recorded. Polysomnographic investigations (10:30 p.m. to 6:00 a.m.) showed a delayed sleep onset only after the morning intake of paroxetine, PX 40 being statistically different from placebo. Total sleep time and sleep efficiency deteriorated under morning PX 30, PX 40 and evening PX 30 as compared to placebo. The nocturnal wake time and sleep stage 1 increased under the paroxetine. Rapid eye movement (REM) reduction (min and %) occurred dose dependently after all paroxetine doses, but the REM latency was lengthened only after the morning intake. The suppressant effect on REM sleep is characteristic for antidepressants and was still significant in the washout nights following PX 40 and evening PX 30. The only statistically relevant finding under 40 mg fluoxetine referred to the increase of REM latency in both drug and washout nights. In contrast to objective results, subjective sleep quality remained generally unchanged. Attention, concentration and reaction performance improved under paroxetine as compared to baseline. The deterioration of well-being under PX 40 might be related to the appearance of drowsiness and nausea. Blood pressure and pulse rate were unaffected.

First-night-effects on generalized anxiety disorder (GAD)-based insomnia: laboratory versus home sleep recordings.

First-night effects (FNE) were comparatively investigated in patients with disorders in initiating and maintaining sleep (DIMS) associated with generalized anxiety disorder (GAD) in laboratory (n = 22) and home sleep polysomnography (n = 21). Patients had to be drug-free for at least 2 weeks prior to the first recording. Evaluation measures included 1) objective data on sleep initiation and maintenance; 2) sleep architecture based on polysomnographic recordings, analyzed visually according to the criteria of Rechtschaffen and Kales; 3) subjectively estimated sleep and awakening quality, assessed by a self-rating scale and visual analogue scales; 4) objective awakening quality as measured by a psychometric test battery; and 5) psychophysiological data, including critical flicker frequency, muscle strength, pulse, and blood pressure. Statistical analysis using multivariate analysis of variance (MANOVA) demonstrated multiple FNE in both groups regarding sleep efficiency, total sleep time, percentage of time in stage 2 sleep, percentage of time in stage 3/4 sleep, minutes of rapid eye movement (REM) sleep, and REM sleep latency. There was a group-by-night effect in the number of awakenings. There were no significant FNE regarding subjective sleep and awakening quality in either group. Differential adaptation effects were observed in attention and fine motor activity, with improvement in laboratory-recorded patients and deterioration in home-recorded patients. Differential findings also occurred in regard to evening blood pressure, with laboratory-recorded patients showing more adaptation.

Severe hypoglycaemia unawareness is associated with an early decrease in vigilance during hypoglycaemia.

To elucidate neurophysiological characteristics in hypoglycaemia unawareness, we investigated the relationship between electroencephalography (EEG) parameters of vigilance and awareness of various symptom categories early in response to hypoglycaemia in intensively treated diabetic patients with different degrees of hypoglycaemia unawareness. Hypoglycaemia (venous plasma glucose below 2.2 mmol/1) was induced with an intravenous insulin bolus in seven patients with insulin-dependent diabetes mellitus (IDDM) with a history of hypoglycaemia unawareness and repeated severe hypoglycaemia, as well as in a group of seven IDDM patients with good awareness of hypoglycaemia. Both groups were comparable in age, treatment strategy, glycaemic control and level of late complications. Basic cognitive performance and other symptom categories were estimated serially during a period of 2 h following the insulin bolus. A vigilance-controlled EEG was recorded continuously; its automatic analysis included the evaluation of vigilance indices. In the baseline prehypoglycaemic state, hypoglycaemia unaware patients showed higher initial vigilance (p = .05) than the aware group. Unaware patients reported fewer neurogenic (p = .002, mainly cholinergic, p = .009) hypoglycaemia symptoms during hypoglycaemia, and developed an impairment in cognitive performance over time (p = .002). EEG analysis indicated a more rapid decrease in vigilance after the hypoglycaemic stimulus for unaware patients than for aware patients. The lowering of plasma glucose to 3.06-3.89 mmol/l already induced a significant increase in delta and theta, as well as a decrease in alpha relative power only in the unaware group. Differences between groups with regards to the degree of deceleration were most pronounced early, during only slight hypoglycaemia, and topographically spread over central and parietal brain regions. Further lowering of plasma glucose induced an even more pronounced, abrupt increase in slow waves in unaware patients at higher plasma glucose levels than in hypoglycaemia aware subjects (for delta waves at 2.41 +/- 0.16 vs. 1.96 +/- 0.1 mmol/l, p = .04). This preceded the worsening of cognitive performance during hypoglycaemia in unaware patients by 19 +/- 3 min. Hypoglycaemia unawareness associated with previous unconsciousness is associated with- and may be the result of-an early hypoglycaemia-induced reduction in vigilance and an early EEG deceleration, which seems to be a teleologically effective measure for delaying eventual cerebral energy failure in hypoglycaemia.

Decrease of vigilance assessed by EEG-mapping in type I diabetic patients with history of recurrent severe hypoglycaemia.

In Type I diabetic patients with history of recurrent severe hypoglycaemia, a more rapid decrease in vigilance (slowing of brain function) during hypoglycaemia in comparison to patients without history of such events was found. Our aims were: (1) to study EEG parameters of vigilance in non-hypoglycaemic state in representative groups of Type I diabetic patients with and without previous recurrent severe hypoglycaemia; and (2) to compare them with non-diabetic controls. A vigilance-controlled EEG mapping (10-20 system, significance probability maps) was performed in a non-hypoglycaemic state (blood glucose 4.0-10.0 mmol/l) in a group of 13 Type I diabetic patients with a history of recurrent severe hypoglycaemia and compared to that of 14 Type I diabetic patients without history of severe hypoglycaemia, matched for HbA1c, age and gender, and to age- and gender-matched non-diabetic controls. When compared to non-diabetic controls, hypoglycaemia patients demonstrated a reduction in absolute power in beta band (13-35 Hz) and slowing of centroid frequencies of beta and total frequency bands (1.3-35 Hz) (up to P < 0.01), whereas patients without history of severe hypoglycaemia showed only a borderline reduction of absolute power in delta (1.3-3.5 Hz) band. Deceleration in hypoglycaemia patients versus those without recurrent hypoglycaemia was most remarkable (P < .01) in centroid frequency of total frequency band. Patients with history of recurrent severe hypoglycaemia demonstrated in non-hypoglycaemic state significantly reduced vigilance when compared to the group without hypoglycaemia history and to the controls, as well. Lower vigilance may be at least in part responsible for impaired hypoglycaemia perception in these patients, but, as it resembles EEG patterns seen in pathologic ageing, it might also represent a consequence of recurrent episodes of severe hypoglycaemia.

Dose-response studies with co-dergocrine mesylate under hypoxia utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled trial, human brain function and mental performance were studied under two different degrees of hypoxia after administration of two different doses (6 mg and 9 mg) of co-dergocrine mesylate (CDM) utilizing blood gas analysis, EEG mapping and psychometry. Hypoxic hypoxidosis (i.e. impairment of cerebral metabolism due to hypoxia) was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found in 6000 m altitude), and of 8.6% O2, 91.4% N2 (found in 7000 m altitude), which was inhaled for 23 min under normobaric conditions by 18 healthy volunteers. They received randomized after an adaptation session placebo, 6 mg and 9 mg co-dergocrine mesylate (CDM). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 h after oral drug administration. Blood gas analysis demonstrated a drop in PO2 to 42 and 32 mm Hg 23 min after inhalation of the 9.8% and 8.6% gas mixture, respectively, PCO2 decreased to 32 and 31 mm Hg, pH increased to 7.46 and 7.47 and base excess increased to 0.50 and 0.90 nmol/l, respectively. EEG mapping demonstrated an increase in delta and decrease of alpha power and a slowing of the centroid over almost the whole brain. 6 mg and slightly less so 9 mg CDM attenuated this deterioration of vigilance (i.e. dynamic state of the neuronal network determining adaptive behavior). At the behavioral level, moderate hypoxia induced a deterioration of noopsychic performance, which was mitigated by 6 mg, but not by 9 mg CDM. A deepening of the hypoxia resulted in a loss of these brain protective effects of both doses. Decrement of the thymopsyche increased after both doses in the moderate hypoxic condition, while under marked hypoxia 6 mg CDM attenuated and 9 mg aggravated this deterioration. Time-wise, brain protective effects reached the level of statistical difference between the 2nd and the 6th hour. Somatic complaints like feeling dazed, giddiness and headache were mitigated dose dependently by CDM in the moderate, but not in the marked hypoxic hypoxidosis.

Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study.

In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM III-R criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multiinfarct dementia (MID), based on computed tomography and Hachinski scores (< or = 49 SDAT, > or = 7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 x 30 mg nicergoline (NIC) or 2 x 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC. SDAT/PLAC, MID/NIC, MID/PLAC; 4 x 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable-the Clinical Global Impression (CGI)-a significant superiority of Global Impression (CGI)-a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (chi 2 = 4.1, P = 0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (chi 2 = 7.96, P < 0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment, while opposite changes occurred in PLAC-treated SDAT and MID patients. The differences between PLAC and NIC reached the level of statistical significance. Event-related potential (ERP) recordings demonstrated a significantly shortened P300 latency under NIC treatment in both SDAT and MID patients, while there was a trend towards lengthening under PLAC. Thus, nicergoline improved vigilance and information processing at the neurophysiological level, which leads at the behavioural level to clinical improvement both in degenerative and vascular dementia.

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.

Impaired conditional discrimination learning in schizophrenia.

Learning deficits have repeatedly been found in patients with schizophrenia. Eyelid conditional discrimination learning (ECDL) is a test of discriminative aversive conditioning and places minimal demands on motivation. An ECDL task was used to examine residual and paranoid type individuals with schizophrenia and age- and gender-equivalent healthy controls. In the experiment two differently colored light stimuli were randomly presented. Only one of the stimuli (in reinforced trials) was followed by an aversive airpuff to the cornea, as opposed to unreinforced trials where the stimulus was not followed by an aversive airpuff. Conditioned responses develop to both trial types during the course of the experiment. These conditioned responses consist of reflectory eyelid closures already upon light presentation. The patients showed significantly impaired conditional discrimination learning abilities. There was no significant difference between the results in the two schizophrenia subtypes. Patients failed to increase response frequencies on reinforced trials during the course of the experiment, while controls showed appropriate conditional discrimination ability. Thus the results show an impairment of adequate behavior modification in an aversive conditioning task in individuals with schizophrenia. It is concluded that ECDL might be a trait marker for schizophrenia.

EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls.

OBJECTIVES: Investigation of daytime brain function, psychopathology, and objective and subjective sleep and awakening quality in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). METHODS: Thirty-three RLS and 26 PLMD patients free of psychotropic drugs were studied as compared with age- and sex-matched normal controls, utilizing electroencephalographic (EEG) mapping and clinical evaluations by the Zung Self-Rating Depression (SDS) and Anxiety Scale (SAS), the Quality of Life Index, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale. In a subsample of 12 RLS patients, 12 PLMD patients, and 12 controls, objective and subjective sleep and awakening quality were evaluated in two sleep laboratory nights (adaptation and baseline night). RESULTS: Scores of the PSQI, SDS, and SAS were found increased in both patient groups; RLS patients showed reduced quality of life, while in the PLMD group daytime sleepiness was increased. EEG mapping demonstrated findings characteristic of major depression in RLS patients and of generalized anxiety disorder in PLMD patients. Polysomnography showed a significant deterioration of sleep efficiency only for RLS patients, while nocturnal awakenings were increased in both patient groups. Concerning sleep architecture, both groups exhibited increased S1 and stage shifts and decreased S2, while only PLMD patients showed an increase in S4. The PLM/(h TST), the PLM/(h wake) and the PLMS-arousal index were significantly increased in both patient groups as compared with controls. Subjective sleep and awakening quality and thymopsychic measures were deteriorated in RLS. Morning mental performance and fine motor activity were deteriorated in both groups, reaction time only in RLS, numerical memory and attention variability only in PLMD. CONCLUSION: EEG mapping revealed neurophysiological correlates of depression and anxiety in RLS and PLMD, respectively, which were confirmed by self-ratings of symptoms.

EEG-tomographic studies with LORETA on vigilance differences between narcolepsy patients and controls and subsequent double-blind, placebo-controlled studies with modafinil.

The aim of the present study was to identify brain regions associated with vigilance in untreated and modafinil-treated narcoleptic patients by means of low-resolution brain electromagnetic tomography (LORETA). 16 drug-free narcoleptics and 16 normal controls were included in the baseline investigation. Subsequently patients participated in a double-blind, placebo-controlled crossover study receiving a three-week fixed titration of modafinil (200, 300, 400 mg) and placebo. Measurements comprised LORETA, the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) obtained before and after three weeks' therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant inter-group differences in the resting (R-EEG), but not in the vigilance-controlled recordings (V-EEG). Subsequent univariate analysis revealed a decrease in alpha-2 and beta 1-3 power in prefrontal, temporal and parietal cortices, with the right hemisphere slightly more involved in this vigilance decrement. Modafinil 400 mg/d as compared with placebo induced changes opposite to the aforementioned baseline differences (key-lock principle) with a preponderance in the left hemisphere. This increase in vigilance resulted in an improvement in the MSLT and the ESS. LORETA provided evidence of a functional deterioration of the fronto-temporo-parietal network of the right-hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil on the left hemisphere, which is less affected by the disease.