Application of a novel actigraphy algorithm to detect movement and sleep/wake patterns in children with autism spectrum disorder.

OBJECTIVE: Actigraphy is a non-intrusive method of recording rest/activity cycles as well as a surrogate for sleep/wake activity. Standard actigraphy analysis is limited in ascribing discrete movement events to wake status during sleep. We applied a novel algorithm to overnight actigraphy data recorded simultaneously with video polysomnography-electroencephalography (video PSG-EEG) to determine its ability to define movement and sleep/wake patterns in children with autism spectrum disorder (ASD) and age-comparable typically developing (TD) controls. METHODS: A previously published novel algorithm uses mathematical endpoints to analyze actigraphy data without assumptions about sleep/wake status, and smooths data using moving windows of increasing length. Nighttime activity level "S" events (S1-S5) determined by this algorithm (n = 273) were identified in 15 children ages 3-10 years (nine with ASD and six TD) who wore an AW2 Spectrum Actiwatch (Philips Respironics) while undergoing simultaneous video PSG-EEG. Data were analyzed to identify the time each activity level "S" event occurred, video movement events (movements captured by video and scored based on level of severity), and sleep/wake status defined by PSG-EEG. The relationships among activity level "S" events, video movement events, and sleep/wake status were analyzed statistically. RESULTS: Activity level "S" events, the presence and severity of video movement events, and sleep-wake status, were significantly associated. These associations were present in both participants with ASD and those who were typically developing. CONCLUSION: This actigraphy algorithm shows promise for detecting nighttime movements and sleep/wake status and warrants further study in larger datasets of neurotypical children and those with neurodevelopmental disorders.

A novel actigraphy data analysis tool and its application to identifying the optimal threshold value in three subject populations.

Most actigraphy devices use different analysis methods and a non-standardized threshold value to estimate sleep/wake status and identify rest intervals. To address limitations of these approaches, a new algorithm was developed that makes no assumptions about sleep/wake status, objectively selects an optimal threshold for different populations, and provides mathematical endpoints to more fully describe the activity patterns of subjects. The optimal threshold (cts min(-1)) is defined as the value that maximizes the duration of the rest period while minimizing the inclusion of epochs from the active period. This value is identified as the beginning of a plateau region of a rest duration versus threshold value graph. Application of this new algorithm to data from 56 healthy adults, 6 healthy children, and 14 children with autism spectrum disorder (ASD) showed that the three groups had different optimal threshold values (35, 40, and 45 cts min(-1) for adults, children and ASD respectively). The rest periods of healthy children was longer than that of adults (8.5 ± 0.5 versus 6.3 ± 0.9 h, p < 0.001). Healthy children also had less activity during the rest periods than adults (10.5 ± 1.8 versus 15.1 ± 11.8 cts min(-1)) and ASD children (12.0 ± 2.2 cts min(-1)) but these differences were not statistically significant. However, the distributions of their activity values during rest periods as measured by skewness and kurtosis were significantly greater than that of healthy adults (skewness: 7.3 ± 0.9 versus 6.2 ± 0.9, p < 0.01, kurtosis: 83.3 ± 16.5 versus 52.8 ± 14.4, p < 0.001) and of ASD children (skewness: 6.4 ± 0.6. p < 0.05, kurtosis: 57.7 ± 12.8, p < 0.001). These findings are consistent with more restful sleep patterns which would have mostly low levels of activity with few large values. The new analysis tool may be helpful in standardizing actigraphy data analyses while providing new insights into activity patterns.

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another. While this fact does not invalidate results, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. The present guidelines are intended to assist investigators, who are using pharmaco-sleep measures in clinical research, in an effort to provide clear and concise recommendations and thereby to standardise methodology and facilitate comparability of data across laboratories.

Validity of activity monitors in health and chronic disease: a systematic review.

The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n=118), with few carried out in patients with chronic diseases (n=16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (-12.07 (95%CI; -18.28 to -5.85) %) compared to triaxial (-6.85 (95%CI; -18.20 to 4.49) %, p=0.37) and were statistically significantly less accurate than multisensor devices (-3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome. Triaxial and multisensor devices tend to be more valid monitors. Since activity monitors are less accurate at slow walking speeds and information about validated activity monitors in chronic disease populations is lacking, proper validation studies in these populations are needed prior to their inclusion in clinical trials.

Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical research unit.

OBJECTIVE: This study sought to compare devices that use actigraphy for measuring sleep endpoints in the clinical research unit (CRU) and home environment. The abilities of polysomnography (PSG) and actigraphy monitors to detect drug effects in a CRU were also investigated. METHODS: Eleven healthy subjects were recruited and monitored with PSG for four consecutive nights in a CRU after receiving no treatment (night 1, N1), and then placebo or 5 mg day(-1) or 10 mg day(-1) zolpidem in a randomised, cross-over design. Subjects wore two devices that use actigraphy (a Respironics® Actiwatch® on the wrist and a BodyMedia® Sensewear® Armband on the upper-arm) on the non-dominant arm for five nights at home and four nights in the CRU during PSG. RESULTS: Wake after sleep onset (WASO) and total sleep time (TST) measured by PSG and estimates of WASO by the Actiwatch decreased significantly with 5mg but not 10mg of zolpidem versus placebo. Direct activity (counts/min) with the Actiwatch decreased in response to zolpidem (both 5 and 10 mg day(-1)) versus placebo. Armband recordings of direct activity were similar to the Actiwatch but not significantly different versus placebo. Both actigraphy device estimates of TST were approximately 1h longer in CRU versus home. Agreement between actigraphy estimates of TST and WASO and PSG values of TST and WASO were closer during nights with zolpidem treatment. CONCLUSIONS: PSG can detect the effects of zolpidem on sleep in a CRU setting. Actigraphy can provide useful assessment of sleep, but direct activity endpoints may be more effective than estimates of TST and WASO.

A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome.

OBJECTIVE: This study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS). METHODS: This six-arm, double-blind, placebo-controlled, dose-response study randomized patients (N=137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose-response was characterized using an exponential decay model, which estimates the maximal effect (E(max)) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety. RESULTS: The separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED(50)) and 90% (ED(90)) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related. CONCLUSIONS: In this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.

Noncontrast dynamic magnetic resonance imaging for quantitative assessment of female sexual arousal.

PURPOSE: We evaluated a noncontrast, dynamic magnetic resonance imaging (MRI) technique for quantitative evaluation of the female sexual arousal response and compared these results with those of a previously described, contrast enhanced MRI technique. MATERIALS AND METHODS: Eight normal, healthy volunteer women underwent 2 separate MRI sessions, during which they were shown audiovisual material consisting of interleaved neutral and audiovisual sexual stimulation segments. Serial high resolution MRI of the genital structures was done at 3-minute intervals during a 45-minute period. Images were analyzed in blinded fashion and measurements of clitoral volume with time were obtained for each subject. Measured clitoral volumes together with the percent change in clitoral volume during audiovisual sexual stimulation for MRI sessions 1 and 2 were compared within subjects. Results were also compared to those of prior contrast enhanced MRI studies in the same subjects. RESULTS: There was excellent intrasubject reproducibility between sessions 1 and 2 using the noncontrast MRI technique (r = 0.99). There was also excellent agreement between the current noncontrast study and prior contrast enhanced studies with a correlation coefficient of 0.89. CONCLUSIONS: Dynamic, noncontrast MRI of the female genitalia appears to be a reproducible, nonintrusive and objective way to assess quantitatively the sexual arousal response in women without sexual difficulties.

Serial MR imaging with MS-325 for evaluating female sexual arousal response: determination of intrasubject reproducibility.

PURPOSE: To determine if a similar sexual arousal response in normal, healthy women could be obtained and monitored by serial magnetic resonance (MR) imaging at two separate sessions. MATERIALS AND METHODS: Serial imaging of the external genitalia was performed on nine healthy, sexually functional women at two separate MR sessions after administration of the contrast agent, MS-325. Images were obtained every three minutes during a 45-minute study period during each MR session. The second MR session began approximately 45 minutes after the end of the first MR session. While undergoing imaging, subjects viewed videotapes that contained neutral and sexually-explicit material through an audiovisual system. Analysis performed at each time point consisted of visual evaluation of the images, clitoral and femoral vein signal intensity measurements, relative regional blood volume calculations, and clitoral volume measurements. Statistical analysis of the results consisted of calculating correlation coefficients of the two MR sessions by using the least square fit method. RESULTS: All nine subjects reported sexual arousal on subjective questionnaires at each MR session. Post-contrast MS-325 MR images showed strong enhancement of the external genitalia at each session. There was excellent correlation between the two sessions for the clitoral volume measurements of all nine subjects. The correlation coefficient, r(2), was 0.95. CONCLUSION: The sexual arousal response in normal, healthy women can be monitored by serial imaging combined with the use of the contrast agent, MS-325, and similar results can be reproduced at two different MR sessions. This method holds promise for future studies of women with female sexual arousal dysfunction.

Dynamic MR imaging of the sexual arousal response in women.

The purpose of our studies was to evaluate whether MR imaging could be used to noninvasively observe and measure the sexual arousal response in normal women. We tested the feasibility as well as the reproducibility of rapid, dynamic, serial high-resolution MR imaging of the genital structures during presentation of neutral and sexually stimulating video material. Results show that these MRI techniques can visualize significant changes in clitoral volume during the stimulus segment of the video presentation. Quantitative measurements made of these changes were robust and reproducible. These studies suggest that MRI techniques may be a useful tool to improve our understanding of the physiology involved with the sexual arousal response in women. These MRI techniques may also prove useful as a surrogate end point marker for testing efficacy of future new treatments for women with sexual arousal disorder.

Female genitalia: dynamic MR imaging with use of MS-325 initial experiences evaluating female sexual response.

PURPOSE: To determine whether magnetic resonance (MR) imaging with MS-325, a recently developed blood pool contrast agent, can depict sexual arousal response in healthy women. MATERIALS AND METHODS: Serial MR imaging of the external genitalia was performed in 12 healthy sexually functional women before and after administration of MS-325. MR images were obtained every 3 minutes during a 45-minute examination. During the examination, the subjects viewed neutral and erotic video material while they were in the magnet bore. MR image analysis at each interval consisted of vaginal wall, vaginal mucosa, and clitoris assessments; femoral vein signal intensity measurements; relative regional blood volume (rRBV) calculations; and clitoral volume measurements. Statistical analysis of the results was performed with a t test. RESULTS: On subjective questionnaires, all subjects in the test group reported being sexually aroused. MS-325-enhanced MR images showed strong contrast enhancement of the external genitalia. The rRBV in the glans clitoris of seven of 10 subjects and in the clitoral body of eight of these subjects increased significantly (P <.05) during erotic visual stimulation. All 10 subjects had a significant (P <.05) increase in clitoral size. There were no significant differences in any measures between the pre- and postmenopausal study groups. CONCLUSION: The sexual arousal response in healthy women can be monitored at serial MR imaging with MS-325. This examination holds promise for future studies of sexual arousal dysfunction in women.