Acupuncture In The Treatment Of Alzheimer Disease Complicated By Agitation: A Randomized Controlled Pilot Study Paul J. Millea, MD Barbara R.

Reed, PhD Abstract Background In addition to destroying cognitive function, Alzheimer disease (AD) often causes symptoms of agitation, frequently the reason for institutionalization. Behavioral and pharmacological therapies are not always reliable; therefore, an effective complementary modality such as acupuncture could be helpful. Objective To evaluate the effect of acupuncture in reducing symptoms of agitation in patients diagnosed with probable or possible AD. Design, Setting, and Patients Randomized, single-blind controlled trial of patients with probable or possible AD based on the criteria of the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) and the Alzheimer and Related Disorders Association (ADRDA). Caregivers had to have spent an average of 5 hours of contact daily with the patient over the preceding month, with the same amount of contact planned for the duration of the study. Of 13 interested patientcaregiver pairs, 10 were enrolled. Seven patients resided in assisted living, in which the caregiver informant was not a family member, and 3 lived at home with the spouse as informant. Interventions Group 1 patients received standard care plus 20-minute discussion sessions twice weekly for 2 weeks. Group 2 patients received standard care plus acupuncture, achieving De Qi at designated points (Ear Shenmen, Governor Vessel 20, Pericardium 6, Heart 7, and Yin Tang), with needles taped in place for 20 minutes twice weekly for 2 weeks. Group 3 patients received standard care plus placebo acupuncture using a blunt acupuncture needle taped in place over the designated points for 20 minutes twice weekly for 2 weeks. Main Outcome Measures Baseline vs postintervention (collected 48-72 hours after the final intervention session) scores on the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), both validated questionnaires assessing cognitive impairment and behavioral disposition. Results Of the 10 pairs enrolled, 9 pairs completed the study: 4 were randomized to the acupuncture group, 2 to the placebo acupuncture group, and 3 to control treatment. The median total baseline score on the MMSE was 10 (range, 0-24); the possible range (from low to high cognitive ability) was from 0-30. The median severity score on the NPI at baseline was 41 (range, 24-71); the possible range (from lowest to highest frequency x severity of symptoms) was from 0-144. Among the 9 pairs, differences between placebo and control observations were all modest, ranging from 6 to -5 (median, 0: no change in symptoms). Score differences for acupuncture recipients were much larger, ranging from -6 to -31 (median between -18 and -23). An exact x2 test was made on a 2-x-2 table of acupuncture vs other treatments by score differences greater than vs less than or equal to the median of all 9 score differences. This yielded a 2-sided P=.047. Conclusions The improvement in agitation in the acupuncture group was consistent with the known effects of acupuncture on the central nervous system. A larger randomized trial is needed to generalize any of these findings to the clinical arena. KEY WORDS Acupuncture, Alzheimer Disease, Agitation, Randomized Controlled Trial, MMSE, NPI INTRODUCTION An epidemic of Alzheimer disease (AD) appears to be accompanying the aging of the US population. It is the most common cause of dementia, affecting approximately 10% of the population older than 65 years with prevalence rates doubling every 5 years thereafter. 1 In addition to destroying cognitive function, AD eventually causes symptoms of agitation in most, if not all, afflicted persons. These symptoms include irritability, restlessness, physical and verbal aggressiveness, anxiety, pacing, wandering, hallucinations, delusions, apathy, and depression. Symptoms of agitation become more pronounced as cognitive function declines, and both patients and families experience distress in their inability to manage these symptoms.2 Although patients and families usually prefer home care, agitation is frequently the reason for institutionalization. In 1996, annual home care costs averaged $11,000 per patient; skilled nursing care averaged $45,600.3 Furthermore, the powerful medications used to treat these symptoms have

adverse effects that are particularly prominent in this population and have at best modest efficacy.4 One investigator poignantly summarized this dilemma: "This lack of medication efficacy has implications for clinical care...other treatments for agitation in dementia need to be considered and evaluated."5 The need for additional therapeutic options in treating agitation in AD led us to design a randomized, single-blind placebo-controlled pilot study to test these hypotheses: AD patients with agitation will have a reduction in symptoms when treated with acupuncture at points traditionally indicated for these symptoms; and placebo acupuncture will be effective in creating the nonspecific effects associated with acupuncture. Other goals for the study were to minimize risk to participants and to obtain the maximum information regarding the technical difficulties that might be encountered in a larger trial. Standard Therapies for Agitation in AD Agitation responds to both pharmacological and behavioral therapies. Behavioral therapies seek to modify the behavior of both the caregiver and the patient.6 Despite their widespread use, the effectiveness of behavioral interventions as well as multidisciplinary ones has not been established. 7 Pharmacological therapy to control agitation uses antidepressants, neuroleptics, benzodiazepines, and anticonvulsants. Current evidence suggests that these agents provide modest efficacy at best, with some well-devised studies failing to find any benefit over placebo.5,8,9 Adverse effects of these medications are oversedation, increased falling risk, and possible acceleration of cognitive decline. Older neuroleptics such as haloperidol also carry the risk of tardive dyskinesia.10 The popular atypical neuroleptic, risperidone, recently has been found to double the risk of cerebrovascular accident. 11 The benefit of pharmacological therapies for agitation in AD has not been documented by clinical trials and is further hampered by adverse effects, induction of cognitive dysfunction, and sedation. 12 Complementary Therapies for Improving Deficits in AD Several newer approaches examining sensory stimulation for managing agitation have been tried but their effectiveness has not been extensively studied. Short-term evening bright light therapy has been shown to improve Mini-Mental State Examination (MMSE) scores when tested against evening dim light therapy.13 Bright light therapy has also shown benefit in improving sleep disturbance and circadian rhythm.14 Morning bright light therapy improved agitation in sleep-disturbed institutionalized AD patients, but it did not improve agitation in AD patients without sleep disturbance.15 Several small studies suggested that certain scents assist in the reduction of behavioral symptoms. A review of 43 studies determined that evidence for aromatherapy is not conclusive.7 A later study of use of adjunctive aromatherapy during medication administration, a typically stressful event for dementia patients, showed no effect on agitation.16 Several lines of evidence suggest that peripheral nerve stimulation can improve affective, cognitive, and circadian disorders in humans. In a 3-arm trial of acupressure, sham acupressure, and control on sleep disturbance in institutionalized adults, Chen et al17 found significant differences (P<.01) in sleep quality before and after receiving acupressure at 5 acupuncture points daily for 1 month. Motivated by animal studies showing that peripheral nerve stimulation activates the hippocampus and hypothalamus, Scherder et al18 studied AD patients and found that both transcutaneous electrical nerve stimulation (TENS) and tactile stimulation were effective when applied 30 minutes daily for 6 weeks. In a separate study of TENS, Scherder et al19 reported significant improvement in the restactivity rhythm in mid-stage AD. While these approaches demonstrate levels of positive effects, the intensity of the required treatment, equipment expense, and necessary staff time suggest that adopting acupressure, TENS, and massage as clinical tools in the management of AD patients may not be possible. Acupuncture for Improving Deficits in AD Research on the use of acupuncture and herbs together to treat agitation has not been reported. However, research into its mechanism shows that acupuncture alone modulates nervous system activity in ways that should reduce the intensity of agitation in AD.20 Research into acupuncture as a possible therapy for AD is just beginning. Two studies reported at the

World Alzheimer's Conference in 2000 found that acupuncture decreased anxiety and depression in AD patients21 and resulted in significant overall clinical improvement.22 Acupuncture has also been found to reduce anxiety in non-AD patients.23 Another small study in patients with acutely psychotic schizophrenia reported that acupuncture has the potential to ameliorate aggressive or agitated behavior in patients considered difficult to manage. 24 Because of the small sample sizes, these studies are inconclusive. Nevertheless, these results support the hypothesis that acupuncture is a viable therapy for use in AD. Although multiple neurotransmitters decline in concentration in AD, loss of acetylcholine and serotonin has been implicated as primary to the development of memory loss and in the case of serotinin, agitated and aggressive behavior. Both of these neurotransmitters are augmented by acupuncture.25 Acupuncture may decrease overall sympathetic tone and raise the agitation threshold. 26 Through this mechanism, acupuncture would be expected to support cognitive function through enhanced vagal stimulation, thus delaying further cognitive decline and increase in agitation. 27 Acupuncture may also increase cerebrovascular blood flow.28 The analgesic effect of acupuncture could also reduce agitation-related pain. The potential for multiple complementary mechanisms to improve agitation in AD makes acupuncture a logical choice for further investigation. Placebo Acupuncture Placebo acupuncture is defined as a technique that mimics acupuncture without penetrating the skin or otherwise strongly stimulating the acupuncture point. When properly performed, placebo acupuncture answers the question, "Does acupuncture have a specific or only a nonspecific effect on the condition being studied?" A number of placebo methods have been effective at blinding staff and/or patients to group assignment.29-31 These variations have in common the use of tactile pressure to simulate acupuncture needle insertion and withdrawal. METHODS The study was approved by both the Medical College of Wisconsin (HRRC#159-02) and Froedtert Memorial Lutheran Hospital institutional review boards (FMLH#02-088). All caregivers and decisional patients completed informed consent. Caregivers of non-decisional patients held health care power of attorney, and non-decisional patients completed assent prior to being enrolled in the study. 32 Hypotheses We tested the following hypotheses: (1) AD patients with agitation would have a reduction in symptoms when treated with acupuncture at points traditionally indicated for these symptoms; and (2) placebo acupuncture would be effective in creating the nonspecific effects associated with acupuncture. Our specific aims were to (1) identify and enroll 10 AD patients with agitation who met study inclusion criteria, and their caregivers. (It is difficult but critical to recruit both patients and caregivers to obtain data from caregivers and to best mimic the environment where therapy will occur.) (2) Evaluate baseline and postintervention cognitive and behavioral symptoms of AD patients using the MMSE 33 and the Neuropsychiatric Inventory (NPI).34,35 (3) Randomize pairs into 1 of 3 treatments: Group 1 to standard treatment plus supportive counseling regarding management of agitation Group 2 to standard treatment plus acupuncture Group 3 to standard treatment plus placebo acupuncture Acupuncture Point Selection AD patients can experience distress instantly and many safeguards were used to avoid adverse events. Due to concern that AD patients might resist removal of clothing to receive acupuncture or placebo acupuncture treatment, the first author and an experienced acupuncturist agreed on a protocol that would involve a few accessible acupuncture points but be sufficiently robust that, if effective, agitation would be treated. These points were selected on the basis of the convenience of their location and their traditional indication for agitation, mania, or anxiety. Acupuncture Protocol The acupuncture ear point location description and indication are based on the report by Xinnong, 36

and the reference for needle orientation and insertion depth appears in Helms.37 Ear Shenmen is located in the lateral aspect of the triangular fossa of the auricle and has traditional indications for stress. This point was located using a Pointer Plus point locator. Orientation was perpendicular and insertion depth was 2 mm. The acupuncture point, traditional indications, and insertion depths below are excerpted or paraphrased from Deadman et al:38 Governor Vessel 20 traditional indications include agitation, disorientation, poor memory, and mania. Orientation was transverse, oblique, and depth was 0.5 cun. Pericardium 6 traditional indications include mania, poor memory, apprehension, fear, and fright. Orientation was oblique, proximate, and depth was 0.5 cun. Heart 7 traditional indications include insomnia, mania, depression, and dementia. Orientation was oblique, proximal, and depth was 0.75 cun. Yin Tang point has a prominent traditional indication for agitation, restlessness, and insomnia among other indications. Orientation was transverse, inferior, and depth 0.75 cun. Acupuncture Method One Seirin L (0.030 x 50 mm) needle (Seirin Corp, Shizuoka, Japan) was inserted at each point and twirled clockwise until De Qi was achieved. The needle was then secured with a strip of narrow adhesive paper tape perpendicularly and left in place for 20 minutes. Placebo Acupuncture Method The first author removed the tips of Hwato (0.030 x 50 mm) needles (Hwato, Medical Appliance Factory, Fuzhou, China) with a wire cutter, tested them for bluntness, and wiped each with alcohol. The needles were then returned to their original package and sealed using a glue stick. Two-inch strips of narrow paper adhesive tape were prepared and attached to an index card. When the patient was ready, a needle was retrieved and the blunt end used to lightly stimulate the point. The tape was then placed onto the needle perpendicularly, attached over the point with minimal pressure, and left in place for 20 minutes. No skin penetration occurred using this technique. (The first author administered all treatments.) Apart from acupuncture, the patients received no other therapeutic influences such as heat lamp, moxa, aromatherapy, or special lighting. Subjects The study was advertised in 2 Froedtert and Medical College primary care clinics, and the pilot sample was obtained from this source. All patients were receiving regular medical care. To be eligible, patients had to be diagnosed with probable or possible AD based on the criteria of the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's and Related Disorders Association (ADRDA).1 Their caregivers had to have an average of 5 hours of contact daily with the patient over the preceding month, with the same amount of contact planned for the duration of the study. Caregivers reporting positive patient responses to the NPI domains of agitation, anxiety, and irritability, and at least weekly symptoms rated as creating moderate to severe distress yielding a total score of 12, were eligible if the patient had an MMSE score of 24 or lower. In association with screening, all volunteers wishing to participate received the booklet Tips for Caregivers of People with Alzheimer Disease.39 Patients were not enrolled if they had been diagnosed with a neurologic (e.g., stroke, delirium, hypoxia) or systemic illness or if they had been diagnosed with a major psychiatric disorder within the past 2 years. Other exclusions included current alcohol or other drug abuse, emergency treatment for agitation, or previous treatment with acupuncture (either patient or caregiver). Also excluded were patients allergic to adhesive tape. Of 13 interested pairs, 10 were enrolled. Seven patients received assisted living, in which the caregiver informant was not a family member, and 3 lived at home with the spouse as informant. In the preceding month, spouse contact averaged 22 hours daily and employee contact just over 7 hours per day, afternoon or night shift. Efficacy Measures

Following informed consent and assent, caregivers received the complete NPI to ascertain the severity of the patient's symptoms and the effect of these symptoms on the caregiver. Patients received a physical examination to rule out other causes of agitation and the MMSE to quantify cognitive impairment. Neuropsychiatric Inventory The NPI is a validated questionnaire given to the caregiver of patients with AD. It has 12 domains that cover the following areas: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, nighttime behavior, and appetite and eating abnormalities. A screening question is asked first, followed by subquestions if the answer to the screening question indicates the possibility that the AD patient experiences behavior within that domain. If the behavior is confirmed, the caregiver rates the frequency and severity of the behavior on separate scales. These scores multiplied together become the frequency x severity score. The final scale asks the caregiver to rate the distress associated with the behavior. The NPI has good sensitivity to changes in agitation. Intervention Assignment Study packets in blocks of 15 were prepared, enclosed in unmarked sealed envelopes, and stored in the study file cabinet. Caregiver-patient pairs were roomed separately for baseline assessment. Following the patient assessment, the first author drew the next envelope in sequence, opened it, and enacted the indicated protocol. Group 1 patients received standard care plus 20-minute discussion sessions with the first author twice weekly for 2 weeks. If verbal, discussion covered their agitation; if nonverbal, discussion covered their daily activities. Group 2 patients received standard care plus acupuncture, achieving De Qi at designated points, with needles taped in place for 20 minutes twice weekly for 2 weeks. Group 3 patients received standard care plus placebo acupuncture using a blunt acupuncture needle taped in place over the designated points for 20 minutes twice weekly for 2 weeks. Blinding and Follow-up Assessment All groups received a 2-question blinding assessment after each visit. The blinding data and all caregiver assessments and session notes were kept separately from the patient treatment record. The linking data were entered into a password-protected computer file. Follow-up NPI and MMSE scores were collected 48-72 hours after the final intervention session. Unblinding occurred after all study activities were complete and data were transferred for entry and analysis. Statistical Tests Exact statistical tests were applied to the 9 observations using StatXact 5 (CYTEL Software Corporation, Cambridge, Mass). To have enough data to make statements about the real acupuncture data, placebo and control observations were combined. The main null hypothesis tested is that results from acupuncture observations do not differ from other combined observations, and that all results come from the same population. The results compared are the differences in the products of frequency x severity scores before and after patient treatment, as measured by interviewing caregivers with the NPI. RESULTS Of the10 pairs enrolled, 9 pairs completed the study. Of these 9 pairs, 4 were randomized to the acupuncture group, 2 to the placebo acupuncture group, and 3 received a control treatment. Five of the patients were older than 80 years; all of them were older than 75 years. Five patients shared 2 hired caregivers younger than 25 years, 1 had a hired caregiver in the late 40's, and 3 received care from their spouses. Two spouses were older than 75 years and 1 was in the early 50's. The median total baseline score on the MMSE was 10, with the middle 5 patients in the range from 718. The lowest recorded score was 0 and the highest was 24, where the possible range (from low to high cognitive ability) was from 0-30. The median severity score on the NPI at baseline was 41, with the middle 5 patients in the range from 32-47. The lowest recorded score was 24, the highest 71. The possible range (from lowest to highest frequency x severity of symptoms) was from 0-144.

Preintervention and Postintervention Differences Among the 9 pairs, differences between placebo and control observations were all modest, ranging from 6 to -5 (increased to decreased frequency x severity of symptoms) and centered around a median of 0 (no change in symptoms). Score differences for acupuncture recipients were much larger, ranging from -6 to -31 (larger and larger decreases in frequency x severity of symptoms), with the median between -18 and -23. The median test, which makes no assumption of similar distribution shape, was applied. An exact x2 test was made on a 2-x-2 table of acupuncture vs other treatments by score differences greater-than vs less-than or equal-to the median of all 9 score differences. This yielded a 2-sided P=.047 for the true distribution to have a x2 greater than or equal to a Pearson statistic of 5.760. A second null hypothesis was that patients sensing skin penetration by acupuncture needles, as reported by caregivers, do not differ from those not sensing penetration in that they all come from the same population. In fact, none of the 9 patients were reported to have sensed penetration, although 4 received acupuncture and 2 received placebo. Patient Needs Numerous insights into accommodating AD patients occurred during the pilot study, resulting in revision of logistics and procedures. To gauge the unique needs of each patient, we proceeded more slowly than would occur in a typical medical visit, and there were no adverse occurrences. Quite notably, patients did not refuse to be separated from their caregiver in the study setting. None of the patients refused the cognitive assessment or physical examination. One patient in assisted living randomized to receive acupuncture refused the needling, and 1 acupuncture patient in assisted living refused the needle at ear Shenmen. Other patients randomized to the acupuncture or placebo conditions accepted the needles and their being taped in place. Acupuncture and placebo patients typically closed their eyes and remained still during the treatment. In the standard control, nonverbal patients maintained eye contact and accepted handshakes from the first author. Verbal patients talked freely during and after their intervention. Caregiver Needs During discussion of the Caregiver Guide,39 caregivers elaborated on their approach to achieving quality of life for the household. Beyond the "tips" given, caregivers asked for additional resources and these needs were incorporated into a curriculum. All caregivers reported receiving at least minimal social support and some had completed formal training in adapting to the patient. Placebo Acupuncture Use What constitutes an acceptable and adequate control for studies of acupuncture remains controversial. The method we used had the advantage of being easy to apply while avoiding the cost and difficulty of using a specially designed placebo needle. The disadvantage of the technique is that in lightly stimulating the point with the blunt needle, it is possible that the entire specific effect of acupuncture may not be measured. In our study, 1 patient in the placebo group had improvement in NPI scores that may be attributable to placebo acupuncture. Another possibility for controlling the placebo effect would be to use nonacupuncture points as the placebo needling sites. This method might increase the ability of the study to measure more completely the specific effects of acupuncture but has the disadvantage of not fully replicating the treatment to the fullest extent possible. We prefer a method that may slightly decrease the power of the study to detect acupuncture effects than to use a method that might not fully control for the placebo effect. DISCUSSION Participants came from 2 unique populations whose setting may not be equivalent: 7 assisted living and 3 home living pairs. Also, the MMSE score was used for inclusion and not for stratification of the sample, resulting in unequal distribution by cognitive score, which is important because agitation tends to increase as cognition declines. Our acupuncture protocol involved no clothing removal and contained the least number of points expected to decrease symptoms agitation. Use of more points might have produced different effects

in the acupuncture and placebo acupuncture groups. Our single follow-up assessment does not capture the longer-term outcomes necessary to learn how acupuncture might benefit AD patients. Our intention was to enroll 15 patients to demonstrate the feasibility of using acupuncture in AD patients. However, in view of the symptom improvement in the acupuncture group and the distress experienced by AD patients and caregivers, we stopped enrollment after 10 patients had completed. We felt compelled to amend our protocol to include a more refined measure for cognitive function, a more robust acupuncture treatment protocol, and a 1-month follow-up to gauge the durability of the acupuncture effects. CONCLUSION Although the results of this study should be interpreted with caution because of the small sample size, our hypotheses were supported. AD patients with agitation can have a reduction in symptoms when treated with acupuncture at points traditionally indicated for these symptoms. Placebo acupuncture may be effective in creating the nonspecific effects associated with acupuncture. The improvement in agitation in the experimental group is consistent with the known effects of acupuncture on the central nervous system. A larger randomized trial is needed to generalize any of these findings to the clinical arena. Funding/Support This work was supported by Medical College of Wisconsin Grant 604100-103-3302429. ACKNOWLEDGEMENTS We thank Theodore Kotchen, MD, and Jane Morley Kotchen, MD, MPH, for mentoring within the Clinical Research Scholars, Cohort II at the Medical College of Wisconsin. We acknowledge Xiping Zhou, MDOM, LAc, President of the East-West Healing Arts Institute, Madison, Wisconsin, for assistance in developing the acupuncture protocol. We thank Walt Saveland, MA, biostatistician, Department of Family and Community Medicine, Medical College of Wisconsin, for data entry and statistical analysis. REFERENCES

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AUTHORS' INFORMATION Dr Paul J. Millea is Assistant Professor in the Department of Family and Community Medicine, Medical College of Wisconsin in Milwaukee, WI, and has an active acupuncture practice delivering over 600 acupuncture treatments per year. Paul J. Millea, MD, MA* Department of Family and Community Medicine Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, WI 53226 Phone: 414-456-5726 Fax: 414-327-7639 E-mail: barbara@mcw.edu Barbara R. Reed, PhD, is Research Assistant Professor in the Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin in Milwaukee, WI. Barbara R. Reed, PhD Department of Psychiatry and Behavioral Medicine Medical College of Wisconsin 2071 No Summit Ave Milwaukee, WI 53202 Phone: 414-456-7773 Fax: 414-287-4206 E-mail: brh@mcw.edu