Deep brain stimulation for treatment of severe Alzheimer's disease: Study protocol for a prospective, self-controlled, phase I trial (case observation)
Zhi-qi Mao M.D., Ph.D. 1, Xin-guang Yu1, Zhi-pei Ling1, Jian-jun Jia2, Long-sheng Pan1, Xin Xu1, Zhi-qiang Cui1, Ying Han3, Shan-shan Wang2, Shu-li Liang1
1 Department of Neurosurgery, Chinese General PLA Hospital, Beijing, China
2 Department of Neurology, Chinese General PLA Hospital, Beijing, China
3 Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
|Date of Web Publication||28-Apr-2017|
Department of Neurosurgery, Chinese General PLA Hospital, Beijing
Source of Support: This study was supported by Beijing Science and Technology Plan Project Fund of China., Conflict of Interest: None
Background: With the aging of the global population, an increasing number of people are at risk of developing Alzheimer's disease. There is currently no effective treatment to hinder or postpone the progression of Alzheimer's disease. Cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist Memantine are the commonly prescribed drugs for this disease, but their therapeutic effects are still unsatisfactory. Therefore, there is an urgent need to investigate novel treatment methods. Many animal experiments have suggested that deep brain stimulation benefits Alzheimer's disease, but clinical trials investigating this are still in their infancy. This study aims to investigate the safety and effectiveness of deep brain stimulation in the treatment of severe Alzheimer's disease.
Methods/Design: This study is a prospective, self-controlled, phase I trial (case observation), which will be performed in the Department of Neurosurgery, Chinese PLA General Hospital (Beijing, China). Six patients with severe Alzheimer's disease will be enrolled to receive continuous bilateral deep brain stimulation of the fornix. Evaluations will be performed at baseline (prior to surgery) and at 1, 6, and 12 months after surgery. The primary outcome measures are disability and mortality rates during the 12-month deep brain stimulation trial period. Secondary outcome measures include the incidence of complications and Clinical Dementia Rating scale, Zarit Caregiver Burden Interview, Mini-Mental State Examination, and Barthel Index of Activities of Daily Living Scale scores. Patient recruitment will begin in August 2017, the analysis of primary outcome measures will be completed in October 2018, and the study will finish in June 2019.
Discussion: The results of this study will help to determine the safety of deep brain stimulation for the treatment of severe Alzheimer's disease. We will also assess whether deep brain stimulation can improve the cognition, symptoms, and activities of daily living of patients with Alzheimer's disease. If the study succeeds, a novel option for patients with Alzheimer's disease who respond poorly to current treatments may be provided.
Trial registration: The study protocol is registered with ClinicalTrials.gov (identifier: NCT03115814).
Ethics: The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital (approval No. S2015-013-02) and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association in 2013.
Informed consent: Written informed consent will be obtained from each patient's legal representative.
Keywords: deep brain stimulation; severe Alzheimer′s disease; cognitive deficits; quality of life; self-control trial
|How to cite this article:|
Mao Zq, Yu Xg, Ling Zp, Jia Jj, Pan Ls, Xu X, Cui Zq, Han Y, Wang Ss, Liang Sl. Deep brain stimulation for treatment of severe Alzheimer's disease: Study protocol for a prospective, self-controlled, phase I trial (case observation). Asia Pac J Clin Trials Nerv Syst Dis 2017;2:66-71
|How to cite this URL:|
Mao Zq, Yu Xg, Ling Zp, Jia Jj, Pan Ls, Xu X, Cui Zq, Han Y, Wang Ss, Liang Sl. Deep brain stimulation for treatment of severe Alzheimer's disease: Study protocol for a prospective, self-controlled, phase I trial (case observation). Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2017 Jun 27];2:66-71. Available from: http://www.actnjournal.com/text.asp?2017/2/2/66/205196
| Introduction|| |
With the prolongation of life expectancy throughout the world, Alzheimer's disease (AD) has become one of the major diseases influencing the quality of life of the aging population. The latest data show that there are currently approximately 24 million AD sufferers and this number doubles every 20 years (Mayeux and Stern, 2012). Therefore, there is an increasing number of people at risk of AD (Mayeux and Stern, 2012). Epidemiological studies in China have shown that the incidence of AD increases with aging, being ~5% in people aged over 65 years and ~20% in people aged over 85 years. AD greatly affects patients' quality of life (Jia et al., 2013); however, there is currently no effective method to hinder, postpone, or treat AD. Cholinesterase inhibitors (Donepezil, Galantamine, and Rivastigmine) (Huong et al., 2006; Liu et al., 2016) and the N-methyl-D-aspartate receptor antagonist Memantine (Sklyarova et al., 2013) are the commonly used medications, although their therapeutic effects are still unsatisfactory. Therefore, there is an urgent need to investigate novel treatments for AD.
Deep brain stimulation is an established treatment used to relieve the symptoms of AD. There is clinical evidence that it can effectively postpone, hinder, and even reverse the progression of AD (Laxton et al., 2010; Smith et al., 2012). Clinical data shows that selective atrophy of cholinergic neurons in the nucleus basalis of Meynert (NBM) is one of characteristics of AD. In 1985, Turnbull et al. were the first to report the effects of deep brain stimulation of the NBM in AD patients. They assessed cortical glucose metabolic activity in AD patients using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and found it decreased by 21%, 24%, 10%, and 7.5% in the frontal, temporal, parietal, and occipital lobes of the unstimulated right hemisphere, but only decreased by 12%, 4%, 0, and −1.5%, respectively, in the stimulated left hemisphere. Although there were no improvements in clinical symptoms, this study's findings suggest that deep brain stimulation of the NBM is safe and leads to strong pathophysiologic response. Laxton et al. (2010) administered deep brain stimulation to the hypothalamus and fornix of six patients with mild AD. At 6 and 12 months after deep brain stimulation, Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) evaluations showed that the patients' cognition improved. In the same case cohort, Smith et al. (2012) investigated cerebral glucose metabolism and found that deep brain stimulation increased cerebral glucose metabolism mainly through two orthogonal networks: a frontal-temporal-parietal-striatal-thalamic network and a frontal-temporal-parietal-occipital-hippocampal network. Fontaine et al. (2013) performed deep brain stimulation in one AD patient presenting with mild cognitive disorder. Twelve months later, cerebral glucose metabolism was slightly increased in the cerebrum, particularly in the bilateral middle temporal gyri. In addition, cognitive function was improved according to MMSE and ADAS-Cog evaluations. Lozano et al. (2016) evaluated the phase II study of fornix DBS in mild AD, they found that DBS for AD was safe and could increase cerebral glucose metabolism, and it could not change the cognitive outcomes, but participants aged ≥ 65 years may benefit.
Internationally, deep brain stimulation for the treatment of AD is in its infancy. Only clinical trials or case report involving mild or moderate AD patients have been reported, with none from China. Globally, doctors are eager to understand the exact effects, and possible complications and risks of deep brain stimulation in the treatment of severe AD. AD patients also anticipate the effectiveness of this therapy as a means of reducing their suffering.
The objectives of this study are to investigate in patients with severe AD: (1) the safety of deep brain stimulation as a treatment, (2) the effectiveness of deep brain stimulation by evaluating cognitive function and changes in dementia grading, and (3) the effects of deep brain stimulation on cerebral glucose metabolism.
| Methods/Design|| |
A prospective, self-controlled, phase I trial (case observation).
Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China.
After screening against inclusion and exclusion criteria and obtaining written informed consent, each patient's baseline evaluation will be performed. Six eligible patients with severe AD will then receive continuous deep brain stimulation for 12 months. All outcomes will be evaluated at baseline (prior to surgery) and 1, 6, and 12 months after surgery. After discharge, outpatient follow-up will be performed by physicians from the Treatment Team of Alzheimer's Disease, Department of Neurology, Chinese PLA General Hospital of China. Flow chart of the trial protocol is shown in [Figure 1].
|Figure 1: Flow chart of the trial protocol |
Note: AD: Alzheimer's disease; CDR: Clinical Dementia Rating; ZBI: Zarit Caregiver Burden Interview; MMSE: Mini-Mental State Examination; ADL: Activities of Daily Living.
Click here to view
Participants and recruitment
Six patients with severe AD scheduled to receive deep brain stimulation will be recruited from the clinics and wards of the Department of Neurosurgery, Chinese PLA General Hospital of China.
The objectives and procedures of the study and the possible adverse events of deep brain stimulation will be fully explained to each patient's legal representative. If the patient chooses to participate in the study, written informed consent will be obtained. Patients will be informed that they are free to withdraw at any time during the study.
Patients presenting with all the following conditions will be considered for inclusion in this study:
- Meeting the diagnosis criteria of AD formulated by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984)
- MMSE score 0–10 points (Winblad et al., 2016)
- Age 40–80 years
- Provision of signed informed consent
Patients presenting with any of the following conditions will be excluded from the study:
- Abnormal brain structure prior to surgery (tumor, cerebral infarction, or intracranial hematoma)
- Any other neurological system disorder, such as multiple sclerosis or epilepsy
- Psychiatric disorders, such as anxiety, depression, or drug-induced psychosis
- Severe internal diseases requiring respiratory system drugs, cardiovascular drugs, anticonvulsants, or psychotropic drugs
- Inability to tolerate surgery
- Severe auditory or visual disorders
Patients will be withdrawn from the study if one or more of the following conditions occur:
- Upon the request of researchers for safety reasons
- Patient's withdrawal of consent and declining of continued treatment
- Lost to follow-up
As a preliminary clinical trial, we will recruit six patients with severe AD.
After the patients' providing written informed consent, baseline evaluations will be performed prior to deep brain stimulation in six patients with severe AD.
Baseline evaluations include: demographic characteristics (sex, age, ethnicity, marital status, and educational attainment), disease history (cerebral infarction, transient ischemic attack, carotid artery stenosis, intracranial artery stenosis, cerebral hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, diabetes mellitus, atrial fibrillation, hypertension, coronary heart disease, hyperlipidemia, valvular heart disease, and lower extremity arterial disease), drug history (cholinesterase inhibitor donepezil, statins, anticoagulants, antihypertensive drugs, and hypoglycemic agents), smoking history, drinking history, physical examination, neurological examination, laboratory examination, magnetic resonance imaging examination (to screen against severe brain disease), 18FDG-PET (to measure cerebral glucose metabolism), and evaluation of the Zarit Caregiver Burden Interview (ZBI), MMSE, Clinical Dementia Rating (CDR), and Barthel Index of Activities of Daily Living (ADL) Scale scores.
Under general anesthesia, a Leksell® Coordinate Frame G (Elekta Instruments AB, Stockholm, Sweden) will be applied to the patient's head. MRI of the brain will be used to scan the fornix bilaterally. The electrode target will be 2 mm anterior and parallel to the vertical portion of the fornix in the hypothalamus. The ventral-most contact will be 2 mm above the dorsal surface of the optic tract, approximately 5 mm from the midline.
Deep brain stimulation electrodes (PINS L302, PINS Inc., Beijing, China) will be implanted into the fornix bilaterally while the patient is in general anesthesia. The stimulator is composed of an electrode connected to a pulse generator by an extension wire. Deep brain stimulation will be initiated after the electrodes are positioned. Adverse events such as sweating and high blood pressure will be simultaneously recorded. Under general anesthesia, the pulse generator will be implanted in the subcutaneous layer of the patient's chest.
On the day following surgery, electrode placement will be confirmed by MRI. At postoperative days 1–3, deep brain stimulation will be started and patients will be discharged if necessary.
All outcome measures will be evaluated at baseline (prior to surgery) and at 1, 6, and 12 months after surgery. Outcome evaluations will be performed by an independent, experienced, blinded evaluator.
Primary outcome measures
- Deep brain stimulation-related disability and mortality rates
Secondary outcome measures
- Incidence of deep brain stimulation-related complications.
- CDR score: The CDR is 5-point scale used to characterize six domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) of the cognitive and functional performance of the aged (AD patients in particular). The information is obtained through semi-structured interviews of the patient and a reliable informant or collateral source (e.g., family member). Patients are rated for dementia severity: 0 = normal, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, and 3 = severe dementia (Morris, 1993).
- ZBI score: The ZBI (Zarit et al., 1980), a popular caregiver self-report measure, contains 22 items covering two dimensions of burden to caregivers (role and personal burden). Each item on the interview is a statement which the caregiver is asked to endorse using a 5-point scale. Response options range from 0 (never) to 4 (nearly always). The range of possible total points is 0–88, with higher total points reflecting greater level of burden.
- MMSE score: The MMSE is one of the most influential cognitive screening tools worldwide. It consists of five dimensions including orientation (10 points), registration (3 points), attention and calculation (5 points), recall (3 points), and language and praxis (9 points). The MMSE is a 30-point scale, with a score of 27–30 indicating normal cognitive function and a score of < 27 suggesting cognitive disorder. The severity of dementia is graded as per MMSE score: mild (≥ 21 points), moderate (27–30 points) and severe (≤ 9 points).
- Barthel Index of ADL: The Barthel Index of ADL consists of 10 items including feeding, bathing, grooming, dressing, bowels, bladder, toilet use, transfers (bed to chair), and mobility on level surfaces and stairs. There are a possible 10 points for each item, giving a maximum of 100 points. The ADL can be classified into three grades: Grade I (61–100 points), living independently, with mild dysfunction and basic self-care; grade II (41–60 points), moderate dysfunction and needs assistance in daily living; grade III (≤ 40 points), severe dysfunction and is totally dependent on help in daily living (Bucks et al., 1996).
- Cerebral glucose metabolism: 18FDG-PET will be performed to measure cerebral glucose metabolism.
All outcome measures are shown in [Table 1].
At 6 months after surgery, radiological examination of the implants will be performed to determine that the stimulation system is not impaired. After the commencement of deep brain stimulation, follow-up evaluations will be performed once every 6 months. Deep brain stimulation-related complications, such as dyskinesia, dysarthria, gait disorder, eye apraxia, depression, apathy, and hypomania, will be recorded and relevant treatment methods administered. These will be reported to the principal investigator and Institutional Review Board within 24 hours.
According to the trial design, a table will be formulated for data collection. Collected data will be input into an electronic database by professional staff using a double-data entry strategy. Information accuracy will be checked when all recruited patients are followed up. The database will be locked by the researcher in charge and will not be altered. All information relating to this trial will be preserved by Department of Neurosurgery, Chinese PLA General Hospital of China. The electronic database will be fully disclosed to a professional statistician for statistical analysis.
All data will be analyzed by a statistician, blinded to randomization, using SPSS 18.0 software (SPSS, Chicago, IL, USA). Normally distributed variables will be expressed as the mean ± SD, and non-normally distributed variables will be expressed as medians and quartiles. Classification variables will be expressed as counts and percentages.
Paired t-tests or Wilcoxon matched-pairs signed-rank tests will be used to compare continuous variables of the primary and secondary outcome measures at each time point. Chi-square tests or Fisher's exact tests will be used to compare classification variables. A P-value of < 0.05 will be accepted as statistically significant.
This study protocol was approved by Ethics Committee of Chinese PLA General Hospital (approval No. S2015-013-02) and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association in 2013. Manuscript writing and modification comply with the Guidance for Protocols of Clinical Trials (SPIRIT checklist) (Additional file 1 [Additional file 1]). After fully understanding the objectives and content of the study, each patient's legal representative will sign the informed consent form.
| Trial Status|| |
Recruitment of patients will be initiated in August 2017. Analysis of outcome measures will be completed in October 2018. The whole study will be finished in June 2019.
| Discussion|| |
Deep brain stimulation for the treatment of AD is an area of increasing research globally. The results of animal experiments have confirmed that deep brain stimulation is effective for the treatment of AD (Zheng et al., 2011; Hescham et al., 2012; Gondard et al., 2015; Zhang et al., 2015). However, there are no reports of deep brain stimulation for the clinical treatment of AD in more than 60 patients with complete clinical records (Turnbull et al., 1985; Laxton et al., 2010; Smith et al., 2012; Kuhn et al., 2015; Lozano et al., 2016). Although other reports have shown that deep brain stimulation for AD achieves certain therapeutic effects, there are no reports of its benefits in the treatment of severe AD in the world. Therefore, we will perform this self-controlled, clinical trial, hoping to provide such clinical evidence.
Two international teams are engaged in investigations into deep brain stimulation for the treatment of AD: One is a Canadian team led by Professor Andres M. Lozano who, in 2010, began to study deep brain stimulation for treatment of AD (Laxton et al., 2010). They used the fornix and hypothalamus as the targets and reported the outcomes of six patients with AD. In 2012, they investigated cerebral glucose metabolism in the same case cohort and found that deep brain stimulation influenced two orthogonal networks (Smith et al., 2012). However, both studies involved patients with mild AD. The other is a team led by Turnbull. They reported deep brain stimulation of the NBM for the treatment of AD in seven patients (Turnbull et al., 1985; Kuhn et al., 2015). Based on their experience, equipment, and theoretical basis, as well as their study findings, and because of our greater number of cases, they cooperated with us to investigate bilateral deep brain stimulation of the fornix for treatment of severe AD to allow more patients to reduce sufferings and acquire treatments as early as possible. The preliminary outcomes from these two teams suggest the feasibility of our current study protocol, but no results of severe cases. Therefore, it remains to be seen whether deep brain stimulation can be a candidate for the future treatment of severe AD in patients that do not respond to current medications.
Our preliminary trial will investigate patients' disability and mortality rates, the incidence of complications, cognitive functioning, quality of living, and cerebral glucose metabolism. This will provide important objective clinical evidence regarding the safety and effectiveness, as well as the possible risks and complications, of deep brain stimulation for the clinical treatment of severe AD.
Additional file 1: SPIRIT checklist (PDF 48.0 kb). 
| References|| |
Birks J (2006) Cholinesterase Inhibitors for Alzheimer's Disease. Cochrane Database Syst Rev (1):cd005593.
Bucks Rs, Ashworth Dl, Wilcock Gk, Siegfried K (1996) Assessment of Activities of Daily Living in Dementia: Development of the Bristol Activities of Daily Living Scale. Age Ageing 25:113-120.
Conti E, Tremolizzo L, Santarone Me, Tironi M, Radice I, Zoia Cp, Aliprandi A, Salmaggi A, Dominici R, Casati M, Appollonio I, Ferrarese C (2016) Donepezil Modulates the Endogenous Immune Response: Implications for Alzheimer's Disease. Hum Psychopharmacol 31:296-303.
Fontaine D, Deudon A, Lemaire Jj, Razzouk M, Viau P, Darcourt J, Robert P
(2013) Symptomatic Treatment of Memory Decline in Alzheimer's Disease by Deep Brain Stimulation: a Feasibility Study. J Alzheimers Dis 34:315-323.
Geldmacher Ds (2004) Donepezil (Aricept) for Treatment of Alzheimer's Disease and Other Dementing Conditions. Expert Rev Neurother 4:5-16.
Gondard E, Chau Hn, Mann A, Tierney Ts, Hamani C, Kalia Sk, Lozano Am (2015) Rapid Modulation of Protein Expression in the Rat Hippocampus Following Deep Brain Stimulation of the Fornix. Brain Stimul 8:1058-1064.
Hescham S, Lim Lw, Jahanshahi A, Steinbusch Hw, Prickaerts J, Blokland A, Temel Y (2012) Deep Brain Stimulation of the Forniceal Area Enhances Memory Functions in Experimental Dementia: the Role of Stimulation Parameters. Brain Stimul 6:72-77.
Huong X, Zhang Zx, Wang Ln, Shao Fy, Xiao Sf, Wang Yh, Qian Cy, Shu L, Chen Sd, Xu Xh (2006) a Randomized Study Comparing the Effect and Safety of Galantanfine and Donepezil in Patients With Mild to Moderate Alzheimer's Disease. Chin J Neurol 39:379-382. (In Chinese)
Jian Jp, Tang Y, Wang F
(2013) Attention to Alzheimer's Disease Before Dementia. Chin J Neurol 46:2-4.
Kuhn J, Hardenacke K, Lenartz D, Gruendler T, Ullsperger M, Bartsch C, Mai Jk, Zilles K, Bauer A, Matusch A, Schulz Rj, Noreik M, Bührle Cp, Maintz D, Woopen C, Häussermann P, Hellmich M, Klosterkütter J, Wiltfang J, Maarouf M, et al. (2015) Deep Brain Stimulation of the Nucleus Basalis of Meynert in Alzheimer's Dementia. Mol Psychiatry 20:353-360.
Laxton Aw, Tang-Wai Df, Mcandrews Mp, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith Gs, Lozano Am (2010) a Phase I Trial of Deep Brain Stimulation of Memory Circuits in Alzheimer's Disease. Ann Neurol 68:521-534.
Li F, Wang Zm, Wu Jj, Wang J, Xie Ss, Lan Js, Xu W, Kong Ly, Wang Xb (2016) Synthesis and Pharmacological Evaluation of Donepezil-Based Agents as New Cholinesterase/monoamine Oxidase Inhibitors for the Potential Application Against Alzheimer's Disease. J Enzyme Inhib Med Chem 31(Sup3):41-53.
Liu W, Lang M, Youdim Mb, Amit T, Sun Y, Zhang Z, Wang Y, Weinreb O (2016) Design, Synthesis and Evaluation of Novel Dual Monoamine-Cholinesterase Inhibitors as Potential Treatment for Alzheimer's Disease. Neuropharmacology Doi: 10.1016/j.neuropharm.2016.06.013.
Lozano Am, Fosdick L, Chakravarty Mm, Leoutsakos Jm, Munro C, Oh E, Drake Ke, Lyman Ch, Rosenberg Pb, Anderson Ws, Tang-Wai Df, Pendergrass Jc, Salloway S, Asaad Wf, Ponce Fa, Burke A, Sabbagh M, Wolk Da, Baltuch G, Okun Ms, et al. (2016) a Phase Ii Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. J Alzheimers Dis 54:777-787.
Mayeux R, Stern Y (2012) Epidemiology of Alzheimer Disease. Cold Spring Harb Perspect Med. 2(8). Pii: A006239.
Mckhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan Em (1984) Clinical Diagnosis of Alzheimer's Disease: Report of the Nincds-Adrda Work Group under the Auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939-944.
Morris Jc (1993) the Clinical Dementia Rating(Cdr): Current Version and Scoring Rules. Neurology 43:2412-2414.
Rogers Sl, Friedhoff Lt (1996) the Efficacy and Safety of Donepezil in Patients With Alzheimer's Disease: Results of a Us Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. the Donepezil Study Group. Dementia 7:293-303.
Rosen Wg, Mohs Rc, Davis Kl (1984) a New Rating Scale for Alzheimer's Disease. Am J Psychiatry 141:1356-1364.
Sklyarova As, Rodionov Vn, Parsons Cg, Quack G, Schreiner Pr, Fokin Aa (2013) Preparation and Testing of Homocubyl Amines as Therapeutic Nmda Receptor Antagonists. Med Chem Res 22:360-366.
Smith Gs, Laxton Aw, Tang-Wai Df, Mcandrews Mp, Diaconescu Ao, Workman Ci, Lozano Am (2012) Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease. Arch Neurol 69:1141-1148.
Turnbull Im, Mcgeer Pl, Beattie L, Calne D, Pate B (1985) Stimulation of the Basal Nucleus of Meynert in Senile Dementia of Alzheimer's Type: a Preliminary Report. Appl Neurophysiol 48:216-221.
Vidovich Mr, Lautenschlager Nt, Flicker L, Clare L, Almeida Op (2009) the Pace Study: a Randomised Clinical Trial of Cognitive Activity (Ca) for Older Adults With Mild Cognitive Impairment (Mci). Trials 10:114.
Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm Al, Jansson-Blixt C, Haglund A; Severe Alzheimer's Disease Study Group (2006) Donepezil in Patients With Severe Alzheimer's Disease: Double-Blind, Parallel-Group, Placebo-Controlled Study. Lancet 367:1057-1065.
Zarit Sh, Reever Ke, Bach-Peterson J (1980) Relatives of the Impaired Elderly: Correlated of Feelings of Burden. Gerontologist 20:649-655.
Zhang C, Hu Wh, Wu Dl, Zhang K, Zhang Jg (2015) Behavioral Effects of Deep Brain Stimulation of the Anterior Nucleus of Thalamus, Entorhinal Cortex and Fornix in a Rat Model of Alzheimer's Disease. Chin Med J (Engl) 128:1190-1195.
Zheng F, Lammert K, Nixdorf-Bergweiler Be, Steigerwald F, Volkmann J, Alzheimer C (2011) Axonal Failure during High Frequency Stimulation of Rat Subthalamic Nucleus. J Physiol 589(Pt 11):2781-2793.
Declaration of patient consent
The authors certify that they will obtain all appropriate patientconsent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
Conception and design of study protocol: ZQM and XGY. Recruitment of patients: LSP, ZQC, YH, SSW, SLL, ZPL and JJJ. Surgery: ZQM and ZPL. Data collection and processing: XX and ZQM. All authors approved the final version of the manuscript for publication.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.