High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer’s disease

  • Fengxia Zhang
  • Yuanyuan Qin
  • Lingfeng Xie
  • Caixia Zheng
  • Xiaolin HuangEmail author
  • Min ZhangEmail author
Neurology and Preclinical Neurological Studies - Original Article


Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer’s disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [1H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using 1H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer’s Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.


Repetitive transcranial magnetic stimulation–cognitive training Alzheimer’s disease N-Acetyl aspartate/creatine ratio 



The authors thank Professor Ping Yin (Department of Epidemiology and Biostatistics, School of Public Health Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for his statistical analysis advice. We also thank Fengfei Ding and Xiaofan Zhang (Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for their advice in this research.


This work was supported by grants from the National Natural Science Foundation of China (Beijing, China; Grant numbers 81873890, 81271406, 81702231).

Compliance with ethical standards

Conflict of interest

The authors in the present study disclose no conflict of interest.

Supplementary material

702_2019_2022_MOESM1_ESM.tif (9.4 mb)
Figure 1 Supplement 1. The images show the spectroscopic volume of interest in the left dorsolateral prefrontal cortex (a) and the left temporal lobe (b) (TIFF 9662 kb)
702_2019_2022_MOESM2_ESM.tif (9.8 mb)
Figure 1 Supplement 2. A representative image shows the spectrum of the left dorsolateral prefrontal cortex (DLPFC) and left temporal lobe (TL) before and immediately after treatment in the real repetitive transcranial magnetic stimulation–cognitive training (rTMS-CT) group (TIFF 10066 kb)
702_2019_2022_MOESM3_ESM.docx (21 kb)
Supplementary material 3 (DOCX 22 kb)
702_2019_2022_MOESM4_ESM.docx (17 kb)
Supplementary material 4 (DOCX 17 kb)


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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Rehabilitation, Medicine Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Radiology, Medicine Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.Department of Neurology, Medicine Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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