Effects of cranial electrical stimulation on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with alzheimer's disease

Applied Nursing Research 22 (2009) 119 – 125 Effects of cranial electrical stimulation on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with Alzheimer's disease☆ Karen M. Rose, PhDa,⁎, Ann Gill Taylor, MS, EdDa,b, Cheryl Bourguignon, PhDa,b aSchool of Nursing, University of Virginia, Charlottesville, VA 22908-0782, USA bCenter for the Study of Complementary and Alternative Therapies, The Blake Center, Charlottesville, VA 22908-0905, USA Received 26 February 2007; revised 7 June 2007; accepted 7 June 2007 Purpose: The purpose of this work was to investigate the effects of cranial electrical stimulation(CES) on sleep disturbances, depressive symptoms, and caregiving appraisal.
Methods: Thirty-eight participants were randomly assigned to receive active CES or sham CES for4 weeks.
Results: Both intervention groups demonstrated improvement in study measures from baselinescores. A trend toward statistically significant differences in daily sleep disturbances was foundbetween the groups. No differences in depressive symptoms and caregiving appraisal were foundbetween the groups.
Conclusions: These findings did not fully support the efficacy of the short-term use of active CESversus sham CES to improve sleep disturbances, depressive symptoms, or caregiving appraisal.
2009 Elsevier Inc. All rights reserved.
Sleep disturbances, depressive symptoms, and negative appraisal of a caregiving situation pose threats to elderly Family caregivers are the mainstay of caregiving support caregivers of persons with AD in terms of the caregivers' to persons with Alzheimer's disease (AD). More than 30% of own physical and psychological well-being and their ability caregivers for older people are, themselves, aged ≥ 65 years to provide adequate care to the care recipient. Although pharmacological therapies are most often used to relieve physical and psychological consequences of providing care sleep disturbances and depressive symptoms, these medica- to a person with AD may be detrimental to the caregiver, tions often have poorly tolerated side effects on older people.
particularly if the caregiver is elderly, has a negative For many elderly persons, hypnotic medications prescribed appraisal of one's caregiving situation, and is the spouse of to relieve sleep disturbances may, in fact, pose serious threats the care recipient. The negative health outcomes for to their own safety and to the safety of those who are in their caregivers, compared to those for noncaregiving persons care. Thus, nonpharmacological interventions, such as matched for age, include higher rates of sleep disturbances cranial electrical stimulation (CES), may offer viable and depressive symptoms, poorer self-ratings of overall alternatives to ameliorating sleep disturbances and depres- health status, and a 63% higher mortality rate ( sive symptoms in caregivers, while reducing the side effects encountered with conventional pharmacological regimens.
CES involves the use of a small battery-operated device that delivers low levels of alternating electrical current to the ☆ The contents of this work are solely the responsibility of the authors head via clips attached to the earlobes (CES and do not necessarily represent the official views of the National Center for therapy has had positive effects on the treatment of sleep Complementary and Alternative Medicine, National Institutes of Health.
disturbances, depressive symptoms, perceived stress, and Corresponding author. Tel.: +1 434 924 5627; fax: +1 434 982 1809.
other disorders in a variety of patient populations, including 0897-1897/$ – see front matter 2009 Elsevier Inc. All rights reserved.
K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 persons with fibromyalgia, depressive symptoms, anxiety, The means and standard deviations from a study on the effects of nonpharmacological intervention on sleep dis- precise mechanism of action of CES in unknown, it is turbances in elderly caregivers of persons with AD believed that CES stimulates the vagus nerve, causing parasympathetic response and resultant relaxation. Addi- for the proposed study. Given the means and standard tionally, increases in blood and cerebrospinal fluid levels of deviations from the McCurry et al. study, a sample size of 38 specific neurotransmitters, including serotonin, norepine- (19 per group) would yield 80% power to detect differences phrine, dopamine, and β-endorphin, have been reported between active and sham intervention groups over time in when CES was used for both 1 and 2 weeks (Shealey et al., 1998). However, no studies to date have specifically testedthe efficacy of CES in either an elderly population or a caregiver population. Therefore, the purpose of this study Participants were recruited from primary care providers was to investigate the short-term use of the AlphaStim CES and caregiver support groups in a rural setting in the device in sleep disturbances, depressive symptoms, and northeastern United States. Forty-four participants provided subjective appraisal in elderly persons who are the primary informed consent to participate in the study. Inclusion caregivers for their spouses with AD.
criteria were as follows: (1) primary caregiver for a spouse with AD or multi-infarct dementia in the home environment;(2) age of ≥ 60 years; (3) cognitive ability to complete Psychoneuroimmunology (PNI) serves as the framework questionnaires; (4) a Geriatric Depression Scale (GDS) score for this study. PNI focuses on the influence of thoughts on of ≥ 10 indicating the presence of depressive symptoms behavior; on interactions between the central nervous system, the endocrine system, and the immune system; and AlphaStim device for 60 minutes/day in the course of on the subsequent impact of these interrelationships on 4 weeks. Potential participants were excluded if they were overall health. The PNI framework provides a model using an antidepressant medication or a botanical agent with depicting the potential influence of the negative appraisal antidepressant properties (e.g., Ginkgo biloba, St. John's of the stressor (caregiving) on the development of sleep wort), or if they had an implantable device, such as a disturbances and depressive symptoms, and how these pacemaker or an internal defibrillator. After screening, 39 of symptoms, in turn, may contribute to the development of 44 persons were found to be eligible based on the inclusion other disease states stemming from neuroendocrine and and exclusion criteria. Of the five individuals excluded from participation, two persons were taking antidepressant The concurrent development of depressive symptoms and medications and three persons scored b10 on the GDS, sleep disturbances is thought to occur as a result of the indicating no depressive symptoms. Thirty-eight of the dysregulation of the hypothalamic–pituitary–adrenalcorti- 39 eligible participants completed the trial (active CES coid (HPA) and sympathetic–adrenal–medullary (SAM) group, n = 19; sham CES group, n = 19). One person axes in chronic stressful situations such as caregiving.
withdrew from the study after completing baseline measures, Long-term activation of the HPA and SAM axes leads to but prior to beginning CES intervention, due to health dysregulation of neurotransmitters and neurotransmitter concerns related to recent hospitalization.
receptors. The levels and functions of neurotransmitters Participants' and care recipients' demographic data are such as serotonin, norepinephrine, and dopamine have been presented in . The intervention groups did not differ shown to be affected by HPA and SAM axes dysregulation, in any demographic variable except age (t = −2.081, p b with resultant disturbances in sleep and mood.
.05), with the caregivers in the sham CES group being older(76.2 years; SD = 5.60) than those in the active CES group (71.9 years; SD = 7.78). There was N95% adherence to thestudy protocol by participants in both intervention groups, as documented by the participants' completion of a daily log ofCES use.
This study was a randomized, double-blind, controlled pilot study that used repeated measures throughout the 4-week intervention. Study participants were randomlyassigned to one of two groups: active AlphaStim CES or The CES device used in this study was the Alpha-Stim sham CES. The study protocol was approved by the Cranial Electrotherapy Stimulator device (Electromedical Institutional Review Board at the University of Virginia.
Products International, Mineral Wells, TX). This battery- Written informed consent was obtained from all participants.
operated device is relatively small and compact (3.9 in. long, Power analysis was performed based on the variable of 3 in. wide, and 0.9 in. thick). A single cable attaches the sleep disturbance as measured by the Pittsburgh Sleep device to two ear clips worn by the participant. The device Quality Index (PSQI) using nQuery power analysis software.
was preset at an electrical stimulation intensity of 100 μA; the K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 Table 1Demographic characteristics of the study sample Length of time in caregiving role (months) [M (SD)] Average hours of care provided by caregiver (weekly) [M (SD)] Length of time of memory changes (months) [M (SD)] Global Deterioration Scale score (cognitive decline) timer was preset at 60 minutes; and the pulse rate was preset at experienced by the caregivers during the past month. The 0.05 pulse/second, as recommended by the manufacturer.
component scores yield a global score in a range of 0–21 These preset parameters have been shown to attain the points, where 0 = no difficulty and 21 = severe difficulties in appropriate waveform configuration to achieve physiological all areas. A cutoff score of ≥ 5 identifies persons with poor changes in neurotransmitters. An electrical stimulation of sleep. Test–retest reliability, as well as a sensitivity of 89.6% 100 μA is generally an imperceptible amount of electrical and a specificity of 86.5%, has been established for this current to most persons; this is important as this setting per- scale. Scores on the PSQI were also analyzed with a three- mitted the blinding of the study participants. The sham device was identical in appearance to the active device, with the only The General Sleep Disturbance Scale (GSDS) was used to difference being that no electrical current was delivered.
measure caregivers' reports of sleep disturbances at baselineand at 2 and 4 weeks. The GSDS is a 21-item questionnaire that rates aspects of sleep quality and quantity during the pastweek ). This instrument The primary investigator gave both verbal and written uses an 8-point frequency scale, with responses ranging from instructions on the proper use of the AlphaStim CES device.
0 = never to 7 = every day. Higher scores indicate more sleep Participants in both intervention groups (active and sham) disturbances. A mean total GSDS score, or any mean on the received a device at the time of randomization and were three subscales (sleep quality, daytime function, and sleep given a demonstration of the use of the device. Participants medication), of ≥3 is equivalent to the Diagnostic and also gave a return demonstration of the use of the AlphaStim Statistical Manual of Mental Disorders, Fourth Edition device to ensure that they understood its use. Participants criteria for insomnia or sleeping difficulty. The GSDS has were instructed to wear the CES device for 60 minutes/day established internal consistency and reliability, with Cron- for the 4-week intervention period and to complete a daily bach's alpha values ranging from .80 to .88 ( log of CES usage. Study outcome measures were obtained at Participants also responded to a set of sleep diary questions pertaining to the previous night's sleep, including the time the participant went to bed, the time taken to fallasleep (sleep onset latency; in minutes), the number of nighttime awakenings, and the time the participant got out of was used to measure self-reported sleep disturbances K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 Depressive symptoms in the study participants were measured using the GDS at baseline and at 2 and Mean scores on study outcomes between intervention groups at the end ofthe study (Week 4) 4 weeks. Total scores range from 0 to 30, with 0–9 = nodepressive symptoms; 10–19 = mild depressive symptoms; and 20–30 = severe depressive symptoms ( ). The Cronbach's alpha for the scale was reported as .95, a with test–retest reliability of 0.85 ( Sleep onset latency (minutes; sleep diary) c 27.42 Caregiving appraisal in the study participants was measured using the Philadelphia Geriatric Center Caregiving designed to measure the impact of caring for disabled older people by family caregivers, comprises 28 questions b Trend toward statistical significance.
representing 4 subscales (burden, satisfaction, mastery, and impact). The Cronbach's alpha for the entire scale wasreported as .92 in a sample of community-dwelling spousecaregivers of persons with dementia ( Test–retest reliability ranged between .75 and .78 in103 caregivers of institutionalized demented persons There were no significant differences in overall scores on For this study, the researcher analyzed each sleep disturbances or sleep quality between the intervention of the four subscales of the PGCCAS.
groups over time. A trend toward statistical significance (p =.09) in the daily disturbances subscale of the PSQI was found between the intervention groups, with participants in the The Statistical Package for the Social Sciences, version active CES intervention group reporting a greater decrease in 12.0 (SPSS, Chicago, IL), was used to enter, clean, and mean scores than those participants in the sham CES group.
verify the data. Because this research was an exploratory No statistically significant results in sleep onset latency were study, the level of significance was set at .05 for all tests, and found between the two groups at baseline (p = .727) and at 4 weeks (p = .274), although clinically important differences Descriptive statistics were calculated for all demographic were found. The active CES group reported a 9-minute and study variables. Differences in the demographic decrease in sleep onset latency as compared to a 1-minute characteristics of the intervention groups were compared increase reported by participants in the sham CES group at using chi-square analysis for categorical variables and using independent t tests for continuous variables. Baseline differences in study outcome measures of interest (scoreson the PSQI, GSDS, GDS, and PGCCAS) between the two There were no significant differences in reports of intervention groups were examined using independent depressive symptoms between the intervention groups over time (F = 9.022, p = .224). Participants in both intervention Comparative analyses of the outcome variables of sleep groups did show a decrease in reports of depressive disturbances, depressive symptoms, and subjective appraisal symptoms in the 4-week study period, with final depressive in the 4-week trial period were conducted via one-way scores in both groups falling below baseline scores.
analysis of covariance (ANCOVA) models for sleep outcomes using the PSQI, or via repeated measuresANCOVA models for all other analyses. The between- No significant differences in the appraisal of caregiving subjects factor was treatment group, with two levels (active situation were seen between the intervention groups over CES and sham CES), and the within-subjects factor was time, as indicated by scores on the four subscales of burden, time, with two levels (Weeks 2 and 4). Baseline scores of mastery, impact, or satisfaction with caregiving situation.
dependent variables (sleep disturbances, depressive symp-toms, and subjective appraisal) were used as covariates inthese analyses.
Prior studies have provided evidence that use of the Study outcome findings at the end of the 4-week AlphaStim CES device at identical settings in 3 weeks improved subjective reports of sleep in persons with K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 these studies of adults with fibromyalgia, stress was measured with a three-choice ordinal self-rating of quality of sleep, using the POMS instrument. POMS provides subscale scores with response options of little or no sleep, moderate sleep, for anxiety, depression, anger, vigor, fatigue, and cognitive or good very restful sleep. These studies also demonstrated function, and a total mood disturbance score (Educational and reduction in pain and tender points, which are classic Industrial Testing Service, San Diego, CA). In all three symptoms of fibromyalgia. Thus, it is plausible that the studies, positive results for stress alleviation were achieved in reduction in pain and tender points found in these studies the active CES groups, whereas these measures of stress may have influenced the participants' reports of quality of showed mixed results in persons in the sham CES group.
sleep. These studies also reported improvement in fatigue as The results of this current pilot study do not support the measured by the Profile of Mood States (POMS). Other results of CES on the reduction of stress or caregiving studies of sleep disorders in persons with fibromyalgia have appraisal found in other studies. However, the concepts found that increased pain sensitivity and reports of fatigue in measured by the PGCCAS may be different in nature from persons with this disorder are associated with increases in those measured in the aforementioned studies that used POMS as a measure of stress. Thus, it is difficult to make Reports of sleep disturbances related to fatigue and daytime sleepiness are consistent with documented changesin sleep structure in older people. In this study, slight trends toward statistically significant differences in participants' Enrolling only spousal caregivers of persons with AD is a reports of daily disturbances were found, whereas global strength of this study. The literature supports the view that scores of sleep quality did not show these differences.
spousal caregivers experience the caregiving situation These findings suggest that the CES intervention may have differently than do persons in other familial roles who are been affecting other related indicators of sleep, such as fatigue and daytime sleepiness, that were not directly report that spousal caregivers exhibit more depressive measured. The addition of instruments to measure related symptoms and have other coping difficulties compared to indicators of sleep, such as fatigue and daytime sleepiness, other family members who are engaged in the caregiving role.
would strengthen the design of future studies of CES in By limiting enrollment exclusively to spousal caregivers, the effects of the intervention were not confounded by the caregiver's familial role in relation to the care recipient.
In this study, mean baseline scores on the GDS were Lengthy study protocols for intervention studies have minimal in both groups (12.84 in the active group and 13.10 been identified as a reason for the high attrition rates of in the sham group). Although these scores are consistent with caregivers. The length of time for this study protocol was the presence of mild depressive symptoms, the internal 4 weeks, as this amount of time has shown beneficial results consistency of the GDS in this study was low (Cronbach's in studies using CES. In this study, the attrition rate was low, α = .340). In further support of this low coefficient score, with only one caregiver dropping out from the study prior to numerous participants verbalized having difficulty complet- the 4-week study conclusion time. Participants in this study ing the GDS because of the format and the wording of some were able to complete all aspects of the study protocol in of the scale items. For example, several participants their home environments. This is a particular strength of the expressed turmoil with completing Item 10 (“Do you often study protocol as this feature permitted participants to feel helpless?”), Item 18 (“Do you frequently worry about the continue with their daily home routines without the need for past?”), and Item 19 (“Do you find life very exciting?”) on the contracting for respite care provisions for the care recipients.
GDS. Participants stated that the adverbs in these items Numerous study participants verbalized that the ability to (often, frequently, and very) and in other items made these stay in their homes and the absence of a need to travel to items confusing for them and that they were not confident in participate in this study were strong incentives for their their responses. Because obtaining a minimal score of 10 on participation in the study. The study participants demon- the GDS was required for inclusion into the study, it is strated a N95% adherence rate with the study protocol, possible that some of the participants who did not truly lending further support to the ease of use of the CES device.
exhibit depressive symptoms were enrolled into the study.
No prior published studies of CES and its effect on Several limitations of this study relate to design. First, caregiving appraisal were identified. There are, however, there were only subjective measurements of sleep outcomes studies of CES and its effects on perceptions of stress—a used in the study. There is ongoing research regarding concept that is conceptually close to that of caregiving correlations between subjective and objective measurements appraisal. Two of these studies used the AlphaStim device, of sleep. It has been repeatedly demonstrated that “non- with settings identical to the settings used in this study complaining” older men and women manifest significantly K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 disturbed sleep. It is suggested that healthy “noncomplain- were inactive during this time. Consistent with the literature ing” older adults appear to adapt their perceptions of what is regarding the health effects of high adherence to treatment, “acceptable” sleep and, therefore, do not necessarily whether active or placebo, the participants in both groups may have reported improvements in sleep disturbances, 74% of the study participants rated their baseline overall depressive symptoms, and caregiving appraisal as a result of health as excellent or very good, and reported minimal, if the perception of actively working to improve these study any, sleep disturbances at baseline. Thus, it is possible that although subjective measurements of sleep did not reveal sible, as participants in this study reported a 95% adherence sleep disturbances in this sample, objective measurements rate to the daily use of the CES device.
may have revealed these difficulties. In future studies, anobjective measurement of sleep, in addition to subjective measures and sleep-related outcomes (e.g., fatigue anddaytime sleepiness), should be used.
This study was a randomized, double-blind, clinical trial The small study sample did not allow for adequate power exploring whether short-term use of CES improved sleep for study outcome measures. The power analysis for this disturbances, depressive symptoms, and caregiving appraisal study was based upon the results of a previous study in elderly caregivers to spouses with AD. A trend toward statistically significant differences in reports of daily were obtained at baseline, with subsequent higher variability disturbances of sleep was found, with participants in the in scores than were found in this current study. In future active CES group demonstrating improvement in this area.
studies of CES in caregiving populations, the results from Clinically meaningful decreases in sleep latency were found this current study should be used to perform a more precise in the active CES group, with a reduction of 9 minutes in the active group as compared to an increase of 1 minute in the Additionally, the study design did not control for any sham group. Depressive symptoms in both intervention effects the study participants may have experienced from groups decreased to levels that indicated the absence of their interactions with the study coordinator or from the use depressive symptoms. However, these changes were not of a device as intervention in this study. Participants in both statistically significant. The limitations of the study may intervention groups received weekly telephone calls from the have obscured any effects of CES that may have been investigator regarding study-related issues (adherence to prevalent. Thus, a larger sample size, a more precise power protocol, change in medications). Although most of these analysis based upon the results of this study, a longer telephone calls were brief (b5 minutes), several participants' intervention period of CES, the addition of an attention- telephone calls lasted N10 minutes. One participant, who was control group, measurement of other indices of sleep randomized to the sham group, was blind and, consequently, (daytime sleepiness, fatigue), and objective measures of was unable to change the battery in his device every week.
sleep disturbances should be used in future studies of CES in For this participant, the investigator made weekly visits to his residence to change the device battery. During theseweekly visits, it was not uncommon for the participant and his care recipient to invite the investigator to eat snacks or toengage in conversation beyond the purpose of battery This publication was made possible by grant nos. 5-T32- change. Thus, it is plausible that this participant, specifically, AT000052 and 5-K30-AT000060 from the National Center and all participants, in general, perceived a supportive for Complementary and Alternative Medicine.
interaction between themselves and the investigator and that This publication was supported, in part, by a scholarship this interaction improved their ratings of depressive provided by the John A. Hartford Foundation's Building symptoms and caregiving appraisal. Additionally, investiga- Academic Geriatric Nursing Capacity Scholarship Program.
tions using medical devices, such as the CES device used inthis study, are proposed to have high “placebo effects”().
Participants in both intervention groups anecdotally reported “taking more time for themselves” as a result of Buysse, D. J., Reynolds III, C. F., Monk, T. H., Berman, S. R., & Kupfer, D. J.
(1989). The Pittsburgh Sleep Quality Index: A new instrument for being participants in this study. Although this study was not psychiatric practice and research. Psychiatry Research 28(2), 193–213.
designed to obtain qualitative measures of study outcomes, Cole, J., Motivala, S., Buysse, D., Oxman, M., Levin, M., & Irwin, M.
numerous study participants made remarks to the investi- (2006). Validation of a 3-factor scoring model for the Pittsburgh Sleep gator that on the hour each day during which they had used Quality Index. Sleep 29(1), 112–116.
the CES device, they had, concurrently, chosen to read a DiBartolo, M. K., & Soeken, K. L. (2003). Appraisal, coping, hardiness, and self-perceived health in community-dwelling spouse caregivers of book or to relax at home. Although the study protocol did not persons with dementia. Research in Nursing & Health 26(6), 445–458.
mandate that the participants be sedentary during their daily Granger, B., Swedberg, K., Ekman, I., Granger, C., Olofsson, B., use of the CES device, many participants reported that they McMurray, J., et al (2005). Adherence to candesartan and placebo and K.M. Rose et al. / Applied Nursing Research 22 (2009) 119–125 outcomes in chronic heart failure in the CHARM programme: Double- Ory, M., Yee, J., Tennstedt, S., & Schulz, R. (2000). The extent and impact blind, randomized, controlled clinical trial. The Lancet 366, 2005–2011.
of dementia care: Unique challenges experienced by family caregivers.
Irwin, M. (2002). Psychoneuroimmunology of depression: Clinical In: R. Schulz (Ed.). Handbook on dementia caregiving (pp. 1–32).
implications. Brain, Behavior, and Immunity 16, 1–16.
Kaptchuk, T. J., Goldman, P., Stone, D. A., & Stason, W. B. (2000). Do Shealy, C. N., Cady, R. K., & Wilkie, R. G., et al. (1998). Cerebral spinal medical devices have enhanced placebo effects. Journal of Clinical fluid and plasma neurochemicals: Response to cranial electrotherapy stimulation. J Neurol Ortho Med Surg 18, 94–97.
Kirsch, D. (2002). The science behind cranial electrotherapy stimulation.
Schulz, R., & Beach, S. R. (1999). Caregiving as a risk factor for mortality: The caregiver health effects study. JAMA : The Journal of the American Lawton, M. P., Kleban, M. H., Moss, M., Rovine, M., & Glicksman, A.
Medical Association 282(23), 2215–2219.
(1989). Measuring caregiving appraisal. Journal of Gerontology 44(3), Tyers, S., & Smith, R. (2001). A comparison of cranial electrotherapy stimulation alone or with chiropractic therapies in the treatment of Lee, K. A., Portillo, C. J., & Miramontes, H. (1998). The fatigue experience fibromyalgia. The American Chiropractor 23(2), 39–41.
for women with human immunodeficiency virus. Journal of Obstetric, Tyers, S., & Smith, R. (2001). Treatment of fibromyalgia with cranial Gynecologic, and Neonatal Nursing: JOGNN/NAACOG 28(2), electrotherapy stimulation. Original Internist 8(3), 15–17.
U.S. Department of Health and Human Services. (2001). The characteristics Lichtbroun, A., Raicer, M., & Smith, R. (2001). The treatment of of long-term care users. Rockville: Agency for Healthcare Research and fibromyalgia with cranial electrotherapy stimulation. Journal of Clinical Vitiello, M. V., Larsen, L. H., & Moe, K. E. (2004). Age-related sleep McCurry, S. M., Logsdon, R. G., Vitiello, M. V., & Teri, L. (1998).
change: Gender and estrogen effects on the subjective–objective sleep Successful behavioral treatment for reported sleep problems in elderly quality relationships of healthy, noncomplaining older men and women.
caregivers of dementia patients: A controlled study. The Journals of Journal of Psychosomatic Research 56(5), 503–510.
Gerontology Series B, Psychological Sciences and Social Sciences 53 Yesavage, J. A., Brink, T. L., Rose, T. L., Lum, O., Huang, V., Adey, M., et al. (1983). Development and validation of a geriatric depression McEwen, B. (2002). Sex, stress and the hippocampus: Allostasis, allostatic screening scale: A preliminary report. Journal of Psychiatric Research load and the aging process. Neurobiology of Aging 23, 921–939.

Source: http://www.elexoma.co.za/wp-content/uploads/2012/05/2009-App-Nurs-CES-Sleep-deprivation-Alzheimers.pdf

Interim administration of kosovo

Republika e Kosovës / Republika Kosovo / Republic of Kosovo Prokurori i Shtetit / Državni Tužilac / State Prosecutor Prokuroria Themelore Mitrovicë Më dt.02.05.2013. Shyqyri Syla, kryeprokuror -Raport i punës së Prokurorisë Themelore në Mitrovicë për periudhën kohore 1 janar – 31 mars 2013 - Çështjet e burimeve njerëzore Në Prokurorin Themelore të Mitrovicës

Doi:10.1016/j.juro.2006.11.083

Economic Evaluation of Treatment Strategies for Benign Prostatic Hyperplasia—Is Medical Therapy More Costly in the Long Run? Christopher S. Saigal,* Mehran Movassaghi, Jennifer Pace, Geoffrey Joyce and the Urologic Diseases in America Project From the Department of Urology, University of California-Los Angeles Medical Center, Los Angeles, California Purpose: Although medical therapy fo

Copyright ©2010-2018 Medical Science