Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique with potential to improve memory. Mild cognitive impairment (MCI), which still lacks a specific therapy, is a clinical syndrome associated with increased risk of dementia. This study aims to assess the effects of high-frequency repetitive TMS (HF rTMS) on everyday memory of the elderly with MCI. We conducted a double-blinded randomized sham-controlled trial using rTMS over the left dorsolateral prefrontal cortex (DLPFC). Thirty-four elderly outpatients meeting Petersen’s MCI criteria were randomly assigned to receive 10 sessions of either active TMS or sham, 10 Hz rTMS at 110% of motor threshold, 2,000 pulses per session. Neuropsychological assessment at baseline, after the last session (10th) and at one-month follow-up, was applied. ANOVA on the primary efficacy measure, the Rivermead Behavioural Memory Test, revealed a significant group-by-time interaction
Mild cognitive impairment (MCI) is an intermediary status between normal aging and very early dementia [
MCI is not necessarily a prodrome of Alzheimer’s disease (AD), although evidence suggests that patients with the amnesic subtype (a-MCI) are likely to progress to AD [
Even though some older adults perform as well as young adults [
Such cognitive deficits, even mild, cause great distress to the elderly with MCI, who feel that their autonomy, independence, and ability to lead high-quality lives are negatively affected. These impairments are often considered the most debilitating aspect of aging [
Transcranial magnetic stimulation (TMS) emerges as a therapeutic tool with clinical benefits in neurological and psychiatric diseases. The method is based on generating a rapidly variable magnetic field over the scalp in awake subjects, which induces a transitory electric current in the cortical surface and modulating neuronal function directly underneath the coil, and in connected brain regions [
Thereby, TMS fulfills an important contribution for studying mechanisms of cognitive function and behavioral plasticity in the human brain [
HF rTMS induces upregulation of N-methyl-D-aspartate (NMDA) receptor activity and increases gamma-aminobutyric acid (GABA) mediated inhibition [
With regard to TMS and memory studies, Turriziani et al. [
A recent article [
Manenti et al. [
Finally, [
In the present study, we used several neuropsychological measures, including a very sensitive measure of everyday memory (RBMT). We firstly aimed to investigate whether HF rTMS over the left DLPFC improve everyday memory of elderly patients with MCI and, secondly, to evaluate the effects of rTMS in executive functions. We have chosen the left DLPFC as the target area based on previous rTMS and functional neuroimaging studies of memory in healthy and in MCI patients. To date, there has been no randomized controlled double-blind study in this population.
Thirty-four elderly subjects, both sexes, age ranging between 60 and 74 years, with education level ≥ 4 years, meeting clinical/neuropsychological criteria for MCI for at least one year, were recruited from the community, through media advertisements, between October 2010 and June 2011.
The study protocol was approved by the Local Ethics Committee and all subjects signed informed-consent forms before enrolling in the trial and registering at Clinicaltrials.gov
In the first step of the screening (part I), we used the Montreal Cognitive Assessment test (MoCA test) [
Screening tests for MCI cut-off points.
Screening battery | Cut-off scores |
---|---|
MoCA Test1 | ≤24 |
CDR2 | =0 |
GDS-153 | <5 |
HAMD-174 | <7 |
HAMA-145 | <8 |
The second step of the screening (part II) included lab tests, cerebral MRI scan, and neuropsychological evaluation.
All the scores were adjusted according to age, gender, and education level, and the tests were administered in accordance with the standard procedures.
The exclusion criteria are listed as follows: psychiatric disorders (except remitted depression ≥ 12 months) and alcohol and/or drug abuse, according to SCID-P [
Participants were randomly assigned in a double-blind condition to receive either active or sham rTMS. Randomization was performed through a random number generator (
We used a high-speed magnetic stimulator (MagPro X100, MagVenture A/S, Farum, Denmark) with a figure-of-eight coil.
We used for the sham group a placebo coil, with a mechanical outline and sound level (click) identical to the active one. The placebo coil’s magnetic shield provides a field reduction of approximately 90% [
rTMS was applied over the left DLPFC at the point located approximately 5 cm in a parasagittal plane parallel to the point of maximum stimulation of the short abductor of the thumb, with the lowest possible intensity in five of ten stimuli.
Subjects assigned to the active group received 10 Hz rTMS at 110% of MT, each train lasting 5 seconds, with 25-second intervals (2,000 pulses/day) for 10 consecutive weekdays. The sham group received the same protocol using a placebo coil.
At the end of the study period, after blinding was removed, the sham patients were given the option of receiving active rTMS treatment.
Security and side effects scales were assessed through a questionnaire as well as clinical evaluation, based on the most frequent adverse effects of TMS by The Safety of TMS Consensus Group [
Patients and team raters were blinded to the assignment condition; however, for technical reasons, the clinicians who administered the rTMS were not. The rater was an experienced neuropsychologist, blinded to the treatment status and with no contact with the treatment team.
After completing the sessions, patients were asked what treatment they thought they received and why.
A lab researcher (C. G. M.) generated and concealed the random allocation sequence, and a secretary (S. L. F.) enrolled and assigned participants to interventions. The effectiveness of the blinding was assessed after the follow-up period.
The primary outcome variable was the RBMT, for assessing everyday memory.
The secondary efficacy outcome variables were other neuropsychological domains assessments.
Statistical analysis was performed by the SPSS v. 14 (Statistical Package for the Social Sciences, Chicago, IL, 2005). The Kolmogorov-Smirnov test was conducted to assess whether continuous variables followed a normal distribution. Statistical significance for all analyses was set to
Descriptive statistical analysis was performed for demographics: contingency tables for categorical variables (gender, comorbidity, marital status, and education level) and descriptive measures (mean and standard deviation) for continuous variables (age). The Fisher’s exact test was used to verify the association of categorical variables. A Student’s
Table
Study structure timing.
(T-2) = screening part I |
Clinical and demographic data |
MoCA test1, CDR2, and GDS-153 |
HAMD-174 and HAMA-145 |
Signed informed-consent forms |
|
(T-1) = screening part II |
IQCODE6 and B-ADL7 |
Lab blood sample analysis |
Brain MRI/Hachinsky Ischemic Score |
SCID DSM-IV8 |
Randomization |
|
(T0) = 1st cognitive assessment battery |
|
|
|
(T1) = 10th rTMS session |
|
|
|
(T2) = one month after T1 |
3rd cognitive assessment battery |
IQCODE and B-ADL |
Out of 109 screened subjects, 73 did not fulfill the enrollment criteria. Among the 36 subjects left, 17 were randomly assigned to the active group and 19 to the sham group. In the active group, two drop-out subjects, after the first session, were excluded due to inability to follow the protocol. Therefore, 34 subjects entered the treatment phase (Figure
Flow diagram of referred and enrolled patients.
Causes of exclusion are listed in Table
Causes of exclusion in the screening phase.
Excluded |
|
Percentage |
---|---|---|
MoCA1 > 26 | 7 | 9.59% |
Education level <4 years | 2 | 2.74% |
Depressive symptoms (GDS-152 > 5) | 25 | 34.25% |
Effective bipolar disorder (SCID-DSM IV3) | 7 | 9.59% |
Anxiety | 10 | 13.70% |
Alcoholism | 5 | 6.85% |
Chronic benzodiazepine use | 1 | 1.37% |
Sleep disorders | 4 | 5.48% |
Epilepsy | 4 | 5.48% |
History of traumatic brain injury | 2 | 2.74% |
Cerebral MRI4 disorders | 15 | 20.55% |
Normal pressure hydrocephalus | 2 | 2.74% |
Lacunar infarct/ischemic stroke | 8 | 10.96% |
Frontoparietal meningioma | 1 | 1.37% |
Cerebellar cyst | 1 | 1.37% |
Neurocysticercosis | 1 | 1.37% |
Frontal granuloma | 1 | 1.37% |
Hemorrhagic lesion | 1 | 1.37% |
Frontal lobe atrophy | 1 | 1.37% |
Mild AD5 | 3 | 4.11% |
Parkinson disease | 3 | 4.11% |
Frontotemporal dementia | 1 | 1.37% |
In the first step of the screening phase, no statistically significant difference was observed among the selected subjects (Table
Subjects screening: part I.
Test/scale | Active rTMS |
Sham |
|
---|---|---|---|
MoCA1 | 24.5 ± 1.8 | 24.2 ± 2.3 | 0.605 |
GDS-152 | 1.7 ± 1.7 | 1.4 ± 1.3 | 0.559 |
HAMD-173 | 1.7 ± 2.1 | 1.5 ± 2.1 | 0.781 |
HAMA-144 | 1.7 ± 1.1 | 1.4 ± 1.5 | 0.532 |
Clinical and demographic characteristics were also similar in both groups, as seen in Table
Demographic data.
Features | Active rTMS |
Sham |
|
---|---|---|---|
Age, years (mean ± SD) | 65.1 ± 3.5 | 65.2 ± 4.1 | 0.9541 |
Gender, |
0.7242 | ||
Male | 6 (40.0) | 6 (31.6) | |
Female | 9 (60.0) | 13 (68.4) | |
Education level, years |
15.1 ± 4.4 | 12.4 ± 4.7 | 0.0941 |
Marital status, |
0.9092 | ||
Married | 8 (53.3) | 8 (42.1) | |
Single | 2 (13.3) | 4 (21.1) | |
Widow | 3 (20.0) | 4 (21.1) | |
Divorced | 2 (13.3) | 3 (15.8) | |
Residence | 0.0532 | ||
Living alone, |
1 (67) | 7 (36.8) | |
Living with family, |
14 (93.3) | 12 (63.2) | |
Professional activities, |
0.2882 | ||
Not retired | 7 (46.7) | 5 (26.3) | |
Retired | 8 (53.3) | 14 (73.7) | |
Physical activity, |
9 (60.0) | 12 (63.2) | >0.9992 |
Comorbidities, |
|||
Hypertension | 9 (60.0) | 5 (26.3) | 0.0802 |
Diabetes mellitus | 2 (10.5) | 2 (13.3) | >0.9992 |
Dyslipidemia | 9 (60.0) | 9 (47.4) | 0.5102 |
Thyroid disease | 7 (46.7) | 4 (21.1) | 0.1512 |
Osteoporosis | 3 (20.0) | 5 (26.3) | >0.9992 |
Tobacco consumption | 1 (6.7) | 1 (5.3) | >0.9992 |
Neoplasia | 1 (6.7) | 2 (1.5) | >0.9992 |
SD: standard deviation; 1Student’s
An assessment of the effectiveness of the blinding revealed that most patients did not guess correctly, when asked to which group they believed they were assigned. The Kappa coefficient was equal to 0.190, which indicates a low correlation and blind integrity.
rTMS at 10 Hz with 110% of the MT was safe and well tolerated. A zero value presented in almost all cells of the side effects precludes any statistical analysis beyond a descriptive one. Side effects were mild and transient prevailing in the active group. However, a gradual reduction in side effects was observed throughout the sessions (see Table
Side effects after rTMS sessions.
# Sessions |
1 | 5 | 10 | |
---|---|---|---|---|
Side effects |
Group |
|
|
|
Headache | Active rTMS | 5 (33.3) | 4 (26.7) | 1 (5.3) |
Sham | 5 (33.3) | 0 (0) | 0 (0) | |
|
||||
Cervical pain | Active rTMS | 0 (0) | 0 (0) | 0 (0) |
Sham | 1 (5.3) | 0 (0) | 0 (0) | |
|
||||
Scalp pain | Active rTMS | 5 (33.3) | 2 (13.3) | 2 (13.3) |
Sham | 1 (5.3) | 1 (5.3) | 0 (0) | |
|
||||
Burning scalp | Active rTMS | 0 (0) | 0 (0) | 0 (0) |
Sham | 1 (5.3) | 0 (0) | 0 (0) | |
|
||||
Concentration difficulties | Active rTMS | 0 (0) | 0 (0) | 0 (0) |
Sham | 0 (0) | 0 (0) | 0 (0) |
Four neuropsychological tests showed heterogeneous statistical improvement along time (Table
Comparison of the statistically significant neuropsychological outcomes.
T0 | T1 | T2 |
| |||||||
---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | Mean | SD | Mean | SD | T0 × T1 | T1 × T2 | T0 × T2 | ||
RBMT | Active rTMS | 20.87 | 2.10 | 22.60 | 1.68 | 22.87 | 1.36 | |||
Sham | 21.58 | 1.77 | 22.16 | 1.57 | 22.11 | 1.29 | ||||
Group effect | 0.042 |
0.593 | 0.029 | |||||||
|
||||||||||
Logical memory II (delayed) | Active rTMS | 21.87 | 6.40 | 21.67 | 6.79 | 25.47 | 6.56 | |||
Sham | 17.58 | 7.50 | 22.68 | 6.44 | 26.89 | 6.81 | ||||
Group effect | 0.033 |
0.821 | 0.002 | |||||||
|
||||||||||
Letter-number sequencing test | Active rTMS | 10.20 | 2.08 | 9.80 | 1.74 | 10.87 | 2.36 | |||
Sham | 9.16 | 2.57 | 9.74 | 2.08 | 9.32 | 2.79 | ||||
Group effect | 0.130 | 0.039 |
0.489 | |||||||
|
||||||||||
Trail making test B | Active rTMS | 99.13 | 29.26 | 107.13 | 47.87 | 95.40 | 31.58 | |||
Sham | 110.89 | 49.31 | 93.79 | 30.84 | 107.32 | 46.45 | ||||
Group effect | 0.036 |
0.023 |
0.988 | |||||||
|
||||||||||
Verbal fluency/animal naming | Active rTMS | 18.47 | 4.49 | 18.00 | 5.66 | 18.80 | 5.65 | |||
Sham | 15.95 | 3.66 | 17.58 | 4.69 | 19.00 | 5.08 | ||||
Group effect | 0.095 | 0.613 | 0.029 |
The primary outcome variable RBMT was statistically higher in the active group after the 10th session and after one-month follow-up (Figure
Comparison of RBMT means scores in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing of procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive assessment. Student’s
Although final scores of the logical memory II were similar, initial values for the sham group indicate a significance favoring them (Figure
Comparison of logical memory II means scores in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing of procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive assessment. Student’s
Figure
Comparison of letter-number sequencing means scores in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing of procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive assessment. Student’s
In TMT-B, an initial improvement in the sham group was showed as well as, conversely, a later improvement in the active rTMS group (T1-T2). No definitive effect was shown in either group from basal to last evaluation (Figure
Comparison of Trail Making Test B means scores in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing of procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive assessment. Mann-Whitney-Wilcoxon test for comparison of rTMS versus sham basal means,
Transient improvement was observed in the sham group in verbal fluency/animal naming, at T2. However, the final scores were similar in both groups and quite heterogeneous in T0 (Figure
Comparison of semantic verbal fluency/animal naming means scores in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing of procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive assessment. Student’s
We report improvement in everyday memory after 10 sessions of HF rTMS, in a double-blind, randomized sham-controlled study. The duration of the improvement persisted at least for 30 days after the last rTMS session, assessed by the RBMT. This is the first randomized, controlled, double-blind study on early and late after-effects of rTMS on everyday memory of the elderly with MCI. This result suggests a sustained gain in episodic memory. The RBMT aids to identify compensatory strategies and to design specific neuropsychological rehabilitation programs. As the tasks mimic daily life situations, RMBT analyses individuals’ tasks performances and how memory impairment affects everyday activities [
Nevertheless, others memory tests, logical memory (LM) II and letter-number sequencing (LNS) exhibited different outcomes. Sham group improvement in LM II is probably due a tendency to different baseline scores between both groups. A gain in the score of the active group in T2 is noted and can suggest a lag practice effect compared to that which may occur in sham group. In LNS test, we have an improvement of sham group at T1 and impairment at T2. Conversely, active group performance suggested a temporary deterioration soon after rTMS protocol (T1), followed by lag amelioration at T2.
Concerning the two frontal tasks, TMT-B and the verbal fluency test animal naming, the results showed some discrepancies. In TMT-B, there was an initial impairment in the active TMS group, followed by a great improvement after a month. Conversely, in animal naming test, the sham group had a gain and then impairment at the last evaluation, but the improvement of sham group may be due a tendency to statistical difference between baseline scores, which should require a larger sample to better define the result.
Anyway, this raises the possibility that the rTMS could have, at least in a short term, some negative effect on some performances. Even if most of the TMS findings show considerable variability, genetic factors can be argued. The presence of BDNF-Val66Met polymorphism could influence the protein synthesis, affecting cortical reactivity with decreased experience-dependent plasticity induced by rTMS. Thereby, this genetic variation in the normal population can produce significant differences in the after-effects of rTMS protocols [
One of the strengths of our study is its ecological validity. The patients recruited actively sought healthcare for memory disturbance in the community, through the media (radio and newspapers) and ads in the subway and buses, even by referral of fellow physicians or participants themselves.
Some peculiarities about rTMS efficacy in elderly populations are consistent with our data. It is well described that there is a better response to higher frequencies and intensity pulses rTMS, which should be explained by the greater prefrontal atrophy in the elderly. Due to cerebral atrophy, the distance from the skull to the PFC increases with age in greater proportion than the motor cortex [
The duration of off-line rTMS after-effects in cognitive performance seems to indicate that longer trains induce longer-lasting and more robust effects, and rTMS parameters used in this study were consistent with those recommended on the induction of long-term cognitive effects (off-line paradigm) after more than one session of HF rTMS [
Besides distant activations via neural pathways projections from the target of stimulation, the length of action of rTMS also depends on the rTMS “dose,” that is, the intensity of stimulation [
Specific particularities influencing the interpretation of the results should be considered. First, due to the presence of a continuum of memory impairment from normal aging to MCI [
Interventional therapies studies for improving cognitive skills are of paramount importance and are likely to have a great impact on public health. The growing proportion of older people and the length of life increase through the world rapidly. Such issue requires the development of interventions to improve well-being, social engagement, and independence for ageing people [
There is a great interest in neuromodulation by rTMS due the persistence of after-effects induced by LTP mechanism [
Most studies on healthy aging are focused on prevention. rTMS can be viewed as a tool for cognitive enhancement of the elderly with MCI, reversing or compensating cognitive deficits [
In conclusion, this study suggests that 10 consecutive sessions or HF rTMS to the left DLPFC at 10 Hz in the elderly with MCI selectively improve everyday memory. The improvement was sustained for at least a month. rTMS may be a promising useful tool for interventional single (or combined) therapy for individuals with MCI or with memory decline. Further research is necessary to replicate these findings with larger sample size and also to investigate rTMS combined with other cognitive training therapies.
All authors reported no financial conflict of interests.
The authors thank Mrs. Julia Tizue Fukushima for precious paper suggestions, Mr. Bernardo dos Santos for statistical analysis, and Mrs. Sandra de Lima Falcon for the carefully working on recruitment of volunteers.