Current treatments minimally impact Parkinson’s disease’s (PD) cognitive decline (1). Repetitive transcranial magnetic stimulation (rTMS) is a potential therapy for PD mild cognitive impairment (PD-MCI) that can improve cognitive functioning in healthy older adults and PD patients with normal cognition (2). The dorsolateral prefrontal cortex (DLPFC) is a key node in cognitive networks affected by PD (3) and is a common therapeutic target for neuromodulation. We thus studied the potential benefits of bilateral DLPFC 20 Hz rTMS for two weeks in a randomized sham-controlled clinical trial in 46 PD-MCI patients (real: 22, sham: 24; see supplementary material for Consolidated Standards of Reporting Trials (CONSORT) figure, Clinical and Demographic Characteristics and detailed Methods).
No significant group difference was found for our primary outcome: change from baseline to post-TMS on the total score of the Dementia Rating Scale-2 (DRS-2) (4) (Table 1). There was no significant difference between groups on the Clinical Global Impression of Improvement (χ2, p = 0.83) with 45% of rTMS and 58% of sham-treated participants reporting at least minimal improvement, and 23% of rTMS and 29% of sham-treated participants reporting “much” or “very much” improvement. Regarding secondary outcomes, there was a significant group difference on the initiation/perseveration subscore of the DRS-2 and the Symbol Digit Modalities Test (SDMT) favoring the sham group. While there were no other significant group differences, the real rTMS group significantly worsened on the total and conceptualization subscore of the DRS-2 and significantly improved on the Delis-Kaplan Executive Function System (DKEFS) Color-Word Interference and SDMT tasks while the sham group significantly increased their scores in the Trails making test, part B, and Boston Naming Test. There were no group differences in the perception of received treatment (χ2, p = 0.31), HADS depression, PDQ-39 or PDSS scores (p > .10). There were no significant adverse events (Supplementary Table 2).
Table 1.
Outcome measures at baseline and post ten-session intervention and between group differences.
| rTMS Mean ± SD Baseline |
rTMS Mean ± SD Visit 10 |
rTMS Change P Value |
Sham Mean ± SD Baseline |
Sham Mean ± SD Visit 10 |
Sham Change P Value |
Estimate | Standard Error |
Degrees Freedom |
P Value From MMR |
95% CI | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DRS-2 Total | 135.7 ± 3.5 | 134.3 ± 5.6 | 0.02 | 136.2 ± 5.4 | 136.2 ± 5.7 | 0.91 | −2.07 | 1.23 | 46 | 0.1 | −4.56 | 0.42 |
| ATT | 35.0 ± 1.6 | 35.6 ± 2.1 | 0.2 | 35.1 ± 1.6 | 35.2 ± 1.9 | 0.67 | 0.48 | 0.61 | 45.3 | 0.44 | −0.76 | 1.71 |
| I/P | 35.5 ± 2.0 | 34.8 ± 3.6 | 0.14 | 35.5 ± 2.6 | 36.6 ± 0.9 | 0.068 | −1.91 | 0.79 | 48.8 | 0.019 | −3.5 | −0.32 |
| CONCEPT | 36.7 ± 2.0 | 35.8 ± 1.9 | 0.026 | 36.3 ± 3.0 | 35.8 ± 3.0 | 0.3 | −0.54 | 0.63 | 50 | 0.4 | −1.81 | 0.73 |
| MEM | 22.5 ± 1.6 | 22.0 ± 1.7 | 0.15 | 23.3 ± 1.6 | 22.6 ± 2.3 | 0.14 | 0.19 | 0.54 | 44.9 | 0.72 | −0.9 | 1.29 |
| SDMT Oral | 41.7 ± 12.5 | 42.7 ± 13.8 | 0.44 | 38.8 ± 13.1 | 47.0 ± 10.7 | 0.0009 | −7.52 | 2.59 | 39.9 | 0.006 | −12.76 | −2.28 |
| SDMT Written | 35.0 ± 11.1 | 36.7 ± 12.1 | 0.002 | 36.2 ± 10.4 | 39.0 ± 9.8 | 0.0001 | −1.26 | 0.98 | 46.7 | 0.2 | −3.22 | 0.7 |
| Color-Word Interference | 77.0 ± 25.0 | 67.9 ± 12.1 | 0.042 | 72.3 ± 17.2 | 69.4 ± 20.5 | 0.15 | −6.17 | 4.66 | 35.8 | 0.19 | −15.61 | 3.27 |
| Color-Word with Switching | 85.5 ± 24.7 | 80.3 ± 20.3 | 0.27 | 90.6 ± 34.1 | 90.0 ± 30.9 | 0.96 | −5.38 | 8.28 | 38.1 | 0.52 | −22.15 | 11.39 |
| BTA | 14.0 ± 3.5 | 13.9 ± 4.4 | 0.9957 | 13.7 ± 4.0 | 14.3 ± 4.3 | 0.21 | −0.74 | 0.82 | 48 | 0.37 | −2.39 | 0.91 |
| Letter Fluency | 35.0 ± 11.7 | 35.3 ± 11.0 | 0.62 | 39.3 ± 15.1 | 40.3 ± 16.3 | 0.34 | −0.38 | 2.28 | 43.5 | 0.87 | −4.98 | 4.22 |
| PDQ-39 | 37.3 ± 21.4 | 35.4 ± 21.4 | 0.64 | 37.0 ± 16.1 | 34.1 ± 21.6 | 0.24 | −1.26 | 6.41 | 43 | 0.85 | −14.2 | 11.69 |
| PDSS | 109.2 ± 21.3 | 112.3 ± 20.6 | 0.81 | 101.6 ± 18.4 | 104.6 ± 26.9 | 0.36 | −7.78 | 7.33 | 42 | 0.29 | −22.58 | 7.01 |
| HADS Depression | 5.6 ± 3.1 | 5.6 ± 3.5 | 1 | 4.6 ± 2.7 | 4.4 ± 3.2 | 0.59 | 0.19 | 0.62 | 42 | 0.76 | −1.07 | 1.44 |
| Trails B | 121.2 ± 45.0 | 123.8 ± 70.3 | 0.89 | 139.2 ± 68.7 | 123.2 ± 58.6 | 0.02 | 19.58 | 12.7 | 41 | 0.13 | −6.07 | 45.23 |
| BNT | 55.3 ± 5.0 | 55.5 ± 6.9 | 0.97 | 56.9 ± 2.4 | 58.3 ± 2.1 | < 0.0001 | −1.25 | 1.38 | 24.2 | 0.38 | −4.1 | 1.6 |
| CVLT Trial 5 Total | 9.6 ± 2.9 | 9.0 ± 3.0 | 0.35 | 9.7 ± 2.8 | 8.2 ± 2.9 | 0.005 | 0.83 | 0.7 | 46.9 | 0.24 | −0.57 | 2.23 |
| CVLT Short Delay Cued Recall | 9.0 ± 2.1 | 8.7 ± 3.3 | 0.55 | 8.1 ± 3.3 | 8.6 ± 3.4 | 0.21 | −0.9 | 0.68 | 46.1 | 0.2 | −2.27 | 0.48 |
| CVLT Short Delay Free Recall | 7.5 ± 3.1 | 6.3 ± 3.8 | 0.13 | 6.5 ± 3.3 | 6.3 ± 3.3 | 0.48 | −0.62 | 0.71 | 41.6 | 0.39 | −2.05 | 0.81 |
| CVLT Long Delay Cued Recall | 8.9 ± 2.7 | 8.6 ± 3.3 | 0.67 | 8.1 ± 3.6 | 8.3 ± 3.6 | 0.79 | −0.42 | 0.83 | 44.4 | 0.62 | −2.1 | 1.26 |
| CVLT Long Delay Free Recall | 7.5 ± 3.5 | 7.3 ± 4.2 | 0.87 | 7.2 ± 3.9 | 6.4 ± 4.1 | 0.22 | 0.91 | 0.91 | 46.8 | 0.32 | −0.92 | 2.73 |
| JLO | 25.8 ± 4.9 | 26.7 ± 4.5 | 0.28 | 26.5 ± 4.5 | 27.5 ± 3.9 | 0.1 | −0.44 | 0.96 | 49.7 | 0.65 | −2.37 | 1.48 |
See manuscript for list of abbreviations. MMR: Mixed-model regression analysis. CI: confidence intervals. No significant group difference in baseline testing was found.
Contrary to our hypothesis, bilateral DLPFC high-frequency rTMS did not improve cognitive functioning in PD-MCI, at least with the rTMS parameters chosen. It is possible that the beneficial effects of rTMS rely only on intact executive networks, as seen in PD with normal cognition (2) but not in PD-MCI where those networks demonstrate both structural and functional disruption (5). Alternatively, other cognitive targets such as the ventrolateral prefrontal cortex or frontoparietal networks may be more suitable due to their involvement in cognition and their dysfunction in PD (6). Lastly, if mood improvement is an important mediator of rTMS cognitive benefits, especially in the context of PD (7), our cognitive findings may be explained by our lack of rTMS benefit on mood and exclusion of depressed participants. Recommended outcome measures for PD dementia may not be translatable to PD-MCI trials (e1). It is possible that our primary outcome, the DRS-2, may have suffered from ceiling effects as average PD-MCI cut-points are over 90% of the maximum score (e2). While lack of change in other neuropsychological tests provides reassurance that our negative results were not entirely due to test selection, future studies may consider using outcomes specifically validated in PD-MCI populations (e3).
Supplementary Material
Acknowledgments
Funding: All phases of this study were supported by an NIH grant, 1K02NS080885-01A1 (PI: Kluger)
List of abbreviations
- MCI
mild cognitive impairment
- rTMS
repetitive transcranial magnetic stimulation
- RMT
resting motor threshold
- DLPFC
dorsolateral prefrontal cortex
- DRS-2
Dementia Rating Scale-2
- ATT
attention subscale of DRS-2
- I/P
initiation/perseveration subscale of DRS-2
- CONCEPT
conceptualization subscale of DRS-2
- MEM
memory subscale of DRS-2
- SDMT
symbol digit modalities test
- BTA
brief test of attention.
- MoCA
Monteral cognitive assessment
- BNT
Boston Naming Test
- UPDRS
Unified Parkinson’s disease rating scale
- MFIS
Modified fatigue impact scale
- PDQ
Parkinson’s disease questionnaire
- HADS
Hospital anxiety and depression scale
- PDSS
Parkinson’s disease sleep scale
- CDR
clinical dementia rating
- MMR
mixed model regression
Footnotes
The authors have no conflicts of interest to disclose.
Authors' Roles: I. Buard conducted the study, reviewed and revised the manuscript; D.M. Sciacca drafted and reviewed the manuscript; C.S. Martin conducted the study and reviewed the manuscript; S.H. Sillau performed the statistical analyses; S. Rogers conducted the study; M.R. Greher reviewed the manuscript and assisted with study design; R. Chen revised the manuscript and assisted with study design; B.M. Kluger conceptualized the study, conducted the study, reviewed and revised the manuscript. All authors have reviewed the final version of the manuscript.
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