Phase-amplitude investigation of spontaneous low-frequency oscillations of cerebral hemodynamics with near-infrared spectroscopy: a sleep study in human subjects.

We have investigated the amplitude and phase of spontaneous low-frequency oscillations (LFOs) of the cerebral deoxy- and oxy-hemoglobin concentrations ([Hb] and [HbO]) in a human sleep study using near-infrared spectroscopy (NIRS). Amplitude and phase analysis was based on the analytic signal method, and phasor algebra was used to decompose measured [Hb] and [HbO] oscillations into cerebral blood volume (CBV) and flow velocity (CBFV) oscillations. We have found a greater phase lead of [Hb] vs. [HbO] LFOs during non-REM sleep with respect to the awake and REM sleep states (maximum increase in [Hb] phase lead: ~π/2). Furthermore, during non-REM sleep, the amplitudes of [Hb] and [HbO] LFOs are suppressed with respect to the awake and REM sleep states (maximum amplitude decrease: 87%). The associated cerebral blood volume and flow velocity oscillations are found to maintain their relative phase difference during sleep, whereas their amplitudes are attenuated during non-REM sleep. These results show the potential of phase-amplitude analysis of [Hb] and [HbO] oscillations measured by NIRS in the investigation of hemodynamics associated with cerebral physiology, activation, and pathological conditions.

Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity.

BACKGROUND: Genes are involved in the etiology of restless legs syndrome, a common sensorimotor disorder. OBJECTIVES: To replicate and to further characterize our previously reported chromosome 12q linkage results. DESIGN: Family linkage study. SETTING AND PARTICIPANTS: A total of 276 individuals from 19 families have been examined using a selection of markers spanning the identified candidate interval on chromosome 12q. RESULTS: Two-point analyses of individual pedigrees indicated that 5 kindreds were consistent with linkage to chromosome 12q. When considering these 5 pedigrees along with the family in which linkage was originally reported, we observed a maximum 2-point logarithm-of-odds score of 5.67 (at theta = 0.10; for marker D12S1636; autosomal recessive) and a maximum multipoint logarithm-of-odds score of 8.84 between the interval defined by markers D12S326 and D12S304. Furthermore, our results also suggest the presence of heterogeneity in restless legs syndrome as linkage was formally excluded across the region in 6 pedigrees. Interestingly, significantly higher periodic leg movements during sleep indices were observed for all probands with restless legs syndrome from linked families. CONCLUSIONS: These results support the presence of a major restless legs syndrome-susceptibility locus on chromosome 12q, which has been designated as RLS1, and also suggest that at least one additional locus may be involved in the origin of this prevalent condition.

Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers.

The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.

An algorithm for the management of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Kinetics and EEG effects of midazolam during and after 1-minute, 1-hour, and 3-hour intravenous infusions.

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid.

We aimed to compare the efficacy of valproic acid (VPA) on paresthesias and sleep in RLS to that of levodopa (LD). Twenty patients with idiopathic restless legs syndrome (RLS) were treated with 600 mg slow-release VPA and 200 mg slow-release LD+50mg benserazid in a randomized, placebo-controlled, cross-over, double-blind setting with polysomography (PSG) at the end of each 3-week treatment periods. There was no major difference between the efficacy of valproic acid or LD. Periodic leg movements in sleep (PLMS) and PLM arousal index (PLMAI) significantly decreased with LD (p < or= 0.005). However, LD, but not VPA, significantly increased arousals not associated with PLMS (p = 0.002). Decrease of intensity and duration of RLS symptoms were more pronounced with VPA (p < or= 0.022) than with LD (NS). We conclude that slow-release VPA provides a treatment alternative for RLS.

Bilateral near-infrared monitoring of the cerebral concentration and oxygen-saturation of hemoglobin during right unilateral electro-convulsive therapy.

Reductions in right prefrontal cerebral blood flow have been correlated with symptomatic improvement in depressed individuals receiving electroconvulsive therapy (ECT). Non-invasive near infrared spectroscopy has previously been shown to reliably measure changes in cerebral hemoglobin concentrations and oxygen saturation. In this study, we measured the concentration and oxygen saturation of hemoglobin on the right and left frontal brain regions of nine patients during right unilateral ECT. In all patients, we have found that the electrically induced seizure causes a stronger cerebral deoxygenation on the side ipsilateral to the electrical current (-21+/-5%) with respect to the contralateral side (-6+/-4%). On the brain side ipsilateral to the ECT electrical discharge, we have consistently observed a discharge-induced decrease in the total hemoglobin concentration, i.e. in the cerebral blood volume, by -7+/-3 microM, as opposed to an average increase by 6+/-3 microM on the contralateral side. The ipsilateral decrease in blood volume is assigned to a vascular constriction associated with the electrical discharge, as indicated by the observed decrease in cerebral oxy-hemoglobin concentration and minimal change in deoxy-hemoglobin concentration during the electrical discharge on the side of the discharge. These findings provide indications about the cerebral hemodynamic/metabolic mechanisms associated with ECT, and may lead to useful parameters to predict the individual clinical outcome of ECT.

Different sleep characteristics in restless legs syndrome and periodic limb movement disorder.

OBJECTIVE: Periodic limb movements in sleep (PLMS) may or may not be associated with restless legs syndrome (RLS). The number of PLMS is commonly used to assess the clinical severity and sleep quality of patients with RLS. It is still unclear whether the sleep disorder of periodic limb movement disorder (PLMD) is different from the sleep disorder in RLS. METHODS: We compared the polysomnograms (PSGs) of 27 prospectively recruited RLS patients and 26 retrospectively recruited age- and sex-matched PLMD patients without RLS symptoms. RESULTS: The PLM index and the index of arousal-associated PLMS (PLMAI) were significantly higher in PLMD, whereas the index of EEG arousals not associated with any sleep-related event was significantly higher in RLS. In PLMD patients, the PLMI correlated negatively with the percentage of PLMS associated with an arousal, whereas this correlation was positive in RLS patients. Further, RLS patients spent significantly more time in wake-after-sleep onset, had more rapid eye movement sleep (REM) and less sleep stage I. CONCLUSIONS: We conclude that the sleep disorder in RLS differs from that in PLMD. Spontaneous, not PLM associated EEG arousals should be included in the assessment of the sleep structure of patients with RLS, particularly in studies concerned with drug-efficacy.