Summary characteristics of clinical studies using rTMS to treat AD
| Authors | Sample | Exclusion/ inclusion criteria | Methods | Stimulation site | Cognitive outcome variable | Assessment schedule | Summary results | Author conclusions |
|---|---|---|---|---|---|---|---|---|
| Cotelli et al., 2006 | 15 mild to moderate AD patients | Exclusion of patients with major depression | One session of 20 Hz rTMS during cognitive stimulation. No sham group | Unilateral dlPFC and sham region | Action naming and Object naming | Baseline and during stimulation | Patients improved action naming accuracy during stimulation with rTMS applied to either the right or left dlPFC. | High-frequency TMS could represent a potential treatment for language deficits in AD patients. |
| Cotelli et al., 2008 | 12 mild AD, 12 moderate to severe AD patients | Exclusion of patients with major depression | One session of 20 Hz rTMS during cognitive stimulus. No sham group | Unilateral dlPFC and sham region | Action naming and Object naming | Baseline and during stimulation | Mild AD improved action naming accuracy during stimulation with rTMS applied to either the right or left DLPFC. Moderate to severe AD improved action and object naming accuracy with rTMS applied to either the right or left DLPFC. | High-frequency TMS could represent a potential treatment for language deficits not only in the early phase of AD, but also in more advanced stages. |
| Cotelli et al., 2011 | 10 moderate AD patients | Exclusion of patients with major depression | Two groups: a 4 week stimulation group, and 2 week placebo treatment + 2 weeks of stimulation. 20 Hz rTMS, for 25 min/d, 5 d/week. No sham group | dlPFC (hemisphere not specified) | MMSE, ADL, IADL, Picture naming, SC-BADA, Aachen Aphasia Test, serial curve position, Cognitive estimation test | Baseline, 2, 4, and 12 weeks after stimulation onset | The 4 week stimulation group improved on SC-BADA after the first 2 weeks of stimulation. The placebo + real stimulation group only improved on SC-BADA after the 2 weeks of stimulation. Effects lasted for 8 weeks in both groups. | High-frequency TMS has long lasting effects on auditory sentence comprehension performance in moderate AD patients. |
| Drumond Marra et al., 2015 | 34 MCI subjects | Exclusion of patients with psychiatric disorders | Sham and stimulation groups. 10 Hz for 5 s, 25 s intertrain interval 20 min/d for 5 d/week for 2 weeks | Left dlPFC | IQCODE, B-ADL, MMSE, RBMT, Logical memory I and II, RAVLT, Letter-number sequencing test, Digit span, TMT A/B, Verbal fluency tests, Victoria Stroop Test | Baseline, end of treatment and 30 days after end of treatment | MCI improved RBMT scores after 10 Hz stimulation, lasting up for 30 d. MCI improved TMT-B 30 d after treatment. Sham improved Logical memory, letter-number sequencing and TMT-B after treatment. Effects on the Logical memory lasted up for 30 d. Sham improved verbal fluency 30 d after treatment. | High-frequency rTMS may represent an effective intervention for MCI and could delay further decline. |
| Bentwich et al., 2011 | 7 mild or moderate AD patients | Inclusion of 2 patients with depression and 4 patients with depression in remission | No sham groups. rTMS-COG. Intensive + maintenance phase (4.5 months of stimulation total). 10 Hz for 2s, 20 trains | Broca, right/left dlPFC, Wernicke, right/left pSAC | ADAS-cog, CGIC, MMSE, ADAS-ADL, HAMILTON, NPI | Baseline, after intensive phase, and after maintenance phase | Improved ADAS-cog scores after 6 weeks and 4.5 months of treatment. No significant changes on other tests. | High-frequency TMS combined with cognitive training may have a synergistic effect and improve cognition for up to 4.5 months. |
| Ahmed et al., 2012 | 32 mild to moderate AD, 13 severe AD patients | N/A | Sham, 20 Hz and 1 Hz groups. 20 Hz: 5s, 20 trains. 1 Hz: 2 trains of 1000 s, 30 s intertrain interval. 5 d | Bilateral dlPFC | MMSE, IADL, GDS | Baseline, end of treatment, 1 and 3 months after treatment | Mild to moderate AD improved in all tests after 20 Hz up to 3 months compared to 1 Hz and sham. Mild to moderate AD improved in IADL after 1 Hz compared to sham. There was no improvement in severe AD. | High-frequency TMS has long lasting effects in mild to moderate AD and is more effective than low-frequency stimulation. |
| Turriziani et al., 2012 | 100 healthy control subjects, 8 MCI subjects | Exclusion of MCI subjects with history of psychiatric disorders | Sham and stimulation groups. One session of 1 Hz and iTBS applied in controls, 1 Hz applied in MCI. iTBS: 20 trains, three 50 Hz pulses (a burst) repeated at 5 Hz for 2s. 1 Hz: 600 pulses | Unilateral dlPFC for healthy controls and bilateral dlPFC for MCI (interval of 3 weeks) | Recognition memory for faces, buildings and words. | Immediately after stimulation | Recognition memory improved in controls and MCI after 1 Hz stimulation over the right dlPFC. iTBS over right dlPFC impaired nonverbal recognition memory in healthy controls. iTBS over left dlPFC had no effect in healthy controls. | Low frequency TMS over the right dlPFC improves recognition memory when applied during encoding in MCI and healthy controls. |
| Rabey et al., 2013 | 15 mild to moderate AD patients | N/A | Sham and stimulation groups. rTMS-COG. Intensive phase + maintenance phase (4.5 months in total). 10 Hz, 20 trains, for 2 s. | Broca, right/left dlPFC, Wernicke, right/left pSAC | ADAS-cog, CGIC, NPI | Baseline, after intensive phase and after maintenance phase | AD patients improved on ADAS-cog and CGIC scores at the end of intensive phase. Effects lasted up for 4.5 months. | rTMS-COG treatment significantly improves cognition, is superior to currently available medications, and better than COG or TMS alone. |
| Eliasova et al., 2014 | 3 MCI and 7 mild AD patients | N/A | Sham-controlled study with a crossover design. 2 sessions of 10 Hz, 45 trains of 4.9 second duration with an interval of 25 s, resulting in 2250 pulses/session. One-day interval between each session | Right inferior frontal gyrus and right superior temporal gyrus (active rTMS), and vertex (sham rTMS) | TMT, Stroop test, complex visual scene encoding task test | Baseline and immediately after each stimulation | Stimulation over the inferior frontal gyrus induced significant improvement in the TMT A and B. No significant difference in the Stroop test or in the CVSET after the rTMS of the right inferior frontal gyrus. | Modulating the inferior frontal gyrus excitability with rTMS may lead to clinically relevant improvement in attentional task performance in early AD patients. |
| Rutherford et al., 2015 | Stage 1: 10 mild to moderate AD patients; Stage 2: 6 mild to moderate AD patients | Exclusion of patients with moderate or severe depression. Inclusion of one patient with mild depression | 4 week block of double-blind treatment with sham condition (Stage 1) followed by 2 weeks of open-label maintenance treatment repeated every 3 months (Stage 2). 20 Hz (40 pulses per burst) with 5-second inter-train intervals during cognitive task. 2000 pulses to each side | Both the left and right DLPFC per session | ADAS-cog, RMBC, MoCA | Stage 1: baseline and 4 weeks after the treatment. Stage 2: a few days after the treatment. MoCA was assessed every week in both stages | Stage 1: no statistically significant changes on ADAS-cog or RMBC scores comparing treated vs sham. Treated patients scored higher on MoCA in 2 and 3 weeks after start of treatment compared to baseline. Stage 2: with the exception of the ADAS-cog scores for 2 patients, all decline rates were better than the expected. | rTMS can be an effective tool for improving the cognitive abilities of patients with early to moderate stages of AD. However, the positive effects of rTMS may persist for only up to a few weeks. Specific skills being practiced during rTMS treatment may retain their improvement for longer periods. |
| Rabey and Dobronevsky, 2016 | 30 mild to moderate AD patients | N/A | No sham groups. rTMS-COG. Intensive phase only (6 weeks). 10 Hz, 20 trains for 2 s | Broca, right/left dlPFC, Wernicke, right/left pSAC | ADAS-cog, MMSE | Baseline and end of treatment | AD patients improved on ADAS-cog and MMSE scores at the end of treatment. | Repeated rTMS-COG treatment might be used to improve patients' cognitive status and maintain improvement over time. |
| Lee et al., 2016 | 19 mild AD, 7 moderate AD patients | Exclusion of patients who had taken psychoactive medications within a month of the study | Sham and stimulation groups. rTMS-COG. Intensive phase (6 weeks). 10 Hz, 20 trains for 2 s | Broca, right/left dlPFC, Wernicke, right/left pSAC | ADAS-cog, CGIC, MMSE, GDS | Baseline, end of treatment and 6 weeks after end of treatment | Mild AD patients improved in ADAS-cog after treatment and remained for 6 weeks, but no different than the sham group. The mild AD group also improved in MMSE 6 weeks after end of treatment. Sham group improved in GDS scores at the end of the treatment. | rTMS-COG is a useful adjuvant therapy with currently available medication for AD, especially during the mild stage of the disease. |
| Nguyen et al., 2017 | 2 MCI, 1 mild AD, and 4 moderate-to-severe AD patients | N/A | No sham group. rTMS-COG. Intensive phase + maintenance phase (4.5 months in total). 10 Hz, 20 trains, for 2 s | Broca, right/left dlPFC, Wernicke, right/left pSAC | ADAS-cog, MMSE, Dubois score, Frontal Assessment battery, Stroop color test, locomotor score, apathy score, caregiver burden interview and dependence score | Baseline, after intensive phase and 6 months after end of treatment | Patients improved on ADAS-cog, locomotor, apathy and dependence scores after intensive phase. Scores returned to baseline 6 months after treatment. | AD patients can benefit from rTMS-COG in terms of cognitive performance, apathy and independence. The duration of the benefit suggests that the repetition of a full course of stimulation every 6 months might be sufficient to produce a sustained clinical effect. |
| Zhao et al., 2017 | 30 mild to moderate AD patients | Exclusion of patients with a history of alcohol abuse or who had taken psychoactive medications within the past month | Sham and stimulation groups. 20 Hz, 20 s intermediate/train. 1 session/day, 5 d/week for 6 weeks | Parietal P3/P4 and posterior temporal T5/T6 according to electroence-phalogram system | ADAS-cog, MMSE, MoCA, WHO-UCLA AVLT | Baseline, end of treatment and 6 weeks after the end of treatment | Patients improved on ADAS-cog, MMSE, MoCA and WHO-UCLA AVLT after the treatment. 6 weeks following treatment, patients further improved on ADAS-cog and WHO-UCLA AVLT remained higher. The sham group also improved on ADAS-cog compared to pretreatment. | rTMS improves cognitive level, memory and language of AD patients, especially in the mild stage. Thus, rTMS can be recommended as a promising adjuvant therapy combined with cholinesterase inhibitors at the mild stage of AD patients. |
| Koch et al., 2018 | 14 mild AD | AD confirmed by CSF protein levels | Sham and stimulation groups (crossover design). Two weeks of 20 Hz stimulation (40 trains, for 2 s, 1600 pulses/d) | Precuneus | RAVLT, DSST, MMSE and FAB | Baseline and end of treatment | Patients improved on the Delayed Recall of RAVLT at the end of treatment. No significant effects after sham stimulation. | High-frequency rTMS is a promising treatment for memory impairment in patients at early stages of AD. |
ADAS-ADL, Alzheimer Disease Assessment Scale-Activities of Daily Living subscale; B-ADL, Bayer Activities of Daily Living Scale; DSST, Digit Symbol Substitution Test; FAB, Frontal Assessment Battery; HAMILTON, Hamilton Depression Scale; IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; pSAC, parietal somatosensory association cortex; RAVLT, Rey Auditory Verbal Learning Test; RMBC, Revised Memory and Behavior Checklist; RBMT, Rivermead Behavioral Memory Test; SC-BADA, Battery for Analysis of Aphasic Deficits; TMT A/B, Trail Making test A and B; WHO-UCLA AVLT, World Health Organization University of California-Los Angeles, Auditory Verbal Learning Test.