Strengthened theta-burst transcranial magnetic stimulation as an adjunctive treatment for Alzheimer’s disease: An open-label pilot study

Alzheimer’s disease (AD) is a globally prevalent debilitating neurodegenerative disorder with significant socioeconomic implications. Presently, successful neuroprotective or curative treatments for AD are lacking [[1]McDade E. Bateman R.J. Stop Alzheimer’s before it starts.Nature. 2017; 547: 153-155Crossref PubMed Scopus (121) Google Scholar]. However, one promising alternative therapy is repetitive Transcranial Magnetic Stimulation (rTMS) [[2]Vacas SM Stella F Loureiro JC do Couto FS Oliveira-Maia AJ Forlenza OV Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: a systematic review and meta-analysis.Int J Geriatr Psychiatry. 2019; 34: 1336-1344https://doi.org/10.1002/gps.5003Crossref PubMed Scopus (10) Google Scholar]. Most studies have chosen the dorsolateral prefrontal cortex (DLPFC) as the stimulus target because of its neuroplasticity and important role in cognitive functions (such as association memory) [[3]Lara A.H. Wallis J.D. The role of prefrontal cortex in working memory: a Mini review.Front Syst Neurosci. 2015; 9: 173Crossref PubMed Scopus (150) Google Scholar]. Moreover, application of excitatory stimuli to either the left or both DLPFC demonstrated improvements in general cognitive performance and multi-domain cognition [[4]Haffen E. Chopard G. Pretalli J.B. Magnin E. Nicolier M. Monnin J. et al.A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease.Brain Stimul. 2012; 5: 264-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. Intermittent theta burst stimulation (iTBS) is a novel, optimized stimulation paradigm which enables increased cortical excitability more rapidly than conventional rTMS [[5]Huang Y.Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar]. However, no study has previously reported the use of this protocol to improve the clinical symptoms of patients with AD. The primary aim of this open-label trial was to investigate the clinical efficacy of optimized iTBS in patients with AD. We assessed the efficacy of iTBS protocol to improve association memory (AM), general and multi-domain cognitions, daily functional and neuropsychiatric symptoms, and explored the underlying mechanisms using resting-state functional connectivity (RSFC) analysis. We predicted that a 2-week intervention with iTBS (total 14 sessions) that stimulates the DLPFC would be sufficient to improve the clinical symptoms of AD. Participants with AD were recruited according to predefined inclusion and exclusion criteria (details provided in the supplementary material) from the memory clinic of the First Affiliated Hospital of Anhui Medical University, China, and underwent a standardized evaluation. The study was approved by the Research Ethics Committee of Anhui Medical University. All subjects provided written informed consent and the study was conducted in accordance with the Declaration of Helsinki. In this study, participants received 14 treatment sessions daily over a two-week period. A MagStim Rapid2 stimulator (MagStim Company Ltd.) with a 70-mm air-cooled figure-of-eight coil was used to deliver the iTBS treatment [[5]Huang Y.Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar]. All stimulations were guided by participants’ anatomical image (1 × 1 × 1 mm3) and a frameless neuro-navigation system (Brainsight; Rogue Research, Montreal, QC, Canada). The stimulation was delivered on the left DLPFC proper using Montreal Neurological Institute (MNI) coordinates (−38, 44, 26) with an intensity equivalent to 70% of the resting motor threshold. A total of 1800 pulse stimulations were delivered 3 times daily in 600-pulse increments with two 15-min breaks between sessions. Participants underwent a complete neuropsychological battery of tests (see details in the supplementary materials) as well as a multimodal magnetic resonance imaging (MRI) scanning before the iTBS treatment (pre-treatment) and one day after the last stimulation session (post-treatment). Four men and nine women with AD were enrolled to receive the treatment. The MRI images of two patients were excluded from analysis because of excessive head-motion artifacts. The treatment was well-tolerated and no severe adverse events were reported (2 patients reported painful scalp sensations, which disappeared after completion of the stimulation). iTBS induced significant improvement in AM both in free recall (from 0.81 ± 1.47 at pre-treatment to 2.00 ± 2.18 at post-treatment; t = −3.19; p = 0.008) and in recognition (from 4.42 ± 2.65 at pre-treatment to 6.35 ± 2.81 at post-treatment; t = −5.67; p < 0.001). Cognitive enhancement also was found in memory, attention, executive, and language functions (Fig. 1A–C). Furthermore, the behavioral and psychiatric symptoms ameliorated with treatment. The DLPFC is involved in memory retrieval functions during free recall and its hypoactivity has been suggested to be a key substrate of behavioral and psychiatric symptoms in AD [[6]Foster C.M. Addis D.R. Ford J.H. Kaufer D.I. Burke J.R. Browndyke J.N. et al.Prefrontal contributions to relational encoding in amnestic mild cognitive impairment.Neuroimage Clin. 2016; 11: 158-166Crossref PubMed Scopus (3) Google Scholar]. iTBS, as an excitatory protocol, may increase the activity of DLPFC and facilitate improvement in memory. Robust synaptic plasticity is critical for cognitive processes, such as learning and memory [[7]Nardone R. Tezzon F. Holler Y. Golaszewski S. Trinka E. Brigo F. Transcranial magnetic stimulation (TMS)/repetitive TMS in mild cognitive impairment and Alzheimer’s disease.Acta Neurol Scand. 2014; 129: 351-366Crossref PubMed Scopus (63) Google Scholar]. Liao and Sara et al. demonstrated the efficacy of rTMS on cognitive function and behavioral psychiatric symptoms of AD [[2]Vacas SM Stella F Loureiro JC do Couto FS Oliveira-Maia AJ Forlenza OV Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: a systematic review and meta-analysis.Int J Geriatr Psychiatry. 2019; 34: 1336-1344https://doi.org/10.1002/gps.5003Crossref PubMed Scopus (10) Google Scholar,[8]Liao X. Li G. Wang A. Liu T. Feng S. Guo Z. et al.Repetitive transcranial magnetic stimulation as an alternative therapy for cognitive impairment in Alzheimer’s disease: a meta-analysis.J Alzheimer’s Dis. 2015; 48: 463-472Crossref PubMed Scopus (45) Google Scholar]. In addition, the correlation analysis in our study demonstrated improvement in cognition assessment in addition to the improvement in depression symptoms (p > 0.05; see supplemental material). Moreover, RSFC of seed-to-whole-brain analysis revealed that the connection between the target and right precuneus cortex (voxel = 79; peak MNI coordinate, 9, −72, 51) showed a dramatic decrease after treatment (RSFC change [post-pre], −0.2 ± 0.08; t = 8.77; p < 0.05; Fig. 1 E). The change correlated significantly with improvement in the verbal fluency test-semantic (r = −0.694; p = 0.018; Fig. 1 D). iTBS to the left DLPFC may enhance both its cortical excitability and function. Moreover, the abnormally elevated connectivity between the DLPFC and precuneus may ameliorate after iTBS [[9]Zhou J. Greicius M.D. Gennatas E.D. Growdon M.E. Jang J.Y. Rabinovici G.D. et al.Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease.Brain. 2010; 133: 1352-1367Crossref PubMed Scopus (646) Google Scholar]. This change has also been reported by previous rTMS studies [[10]Hallett M. Di Iorio R. Rossini P.M. Park J.E. Chen R. Celnik P. et al.Contribution of transcranial magnetic stimulation to assessment of brain connectivity and networks.Clin Neurophysiol. 2017; 128: 2125-2139Crossref PubMed Scopus (69) Google Scholar]. The present study had an open-label design; its main limitation is the lack of a control group. However, open-label clinical trials often provide a basis for the development and optimization of a subsequent randomized controlled trial. Other limitations include the small sample size of recruited patients and the limited number of patients who tolerated the functional imaging. This pilot study provides direct evidence that iTBS of the left DLPFC improves association memory as well as the clinical symptoms and cognitive performance of patients with AD. We also observed a negative correlation between improvement in cognitive function and connectivity of the DLPFC and right precuneus. Finally, our study showed that iTBS is well-tolerated in patients with AD. These results provide the first evidence for the potential utility of iTBS to improve cognitive function in patients with AD. There are no conflicts of interest to declare. We thank the study participants for their cooperation in this study. This work was supported by the National Key R&D Program of China (grant nos. 2016YFC1306400 , 2016YFC1305904 , 2018YFC1314504 and 2018YFC1314200 ) and the Province Natural Science Foundation Project of Anhui (grant no. 1608085MH169 ). The following are the Supplementary data to this article: Download .docx (.02 MB) Help with docx files Multimedia component 1 Download .docx (.85 MB) Help with docx files Multimedia component 2

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