Abstract
Although the cerebellum is not among the most renowned brain structures affected in Alzheimer`s disease (AD), recent evidence suggest that it undergoes degenerative changes during the course of the disease. A main neurophysiological feature of AD patients is the remarkable impairment of long term potentiation (LTP)-like cortical plasticity assessed in the primary motor cortex (M1) using theta burst stimulation (TBS) protocols. In healthy conditions, continuous (cTBS) and intermittent TBS (iTBS) of the cerebellum induce respectively long term depression (LTD)-like and LTP-like after effects in the contralateral M1. Here we aimed at examining the effects of cerebellar TBS on contralateral M1 excitability in a sample of 15 AD patients and 12 healthy age matched controls (HS). Motor evoked potentials (MEPs) were obtained in the contralateral M1 before and after cerebellar cTBS and iTBS protocols. As compared to HS, AD patients showed an impairment of LTP-like cortical plasticity mechanisms following cerebellar iTBS. No difference was observed for the cTBS protocol, in which both populations exhibited the expected LTD-like after effect. This study shows that mechanisms of cerebellar-cortical plasticity are impaired in AD. Given its role in high order cognitive functions, new potential therapeutic strategies could be built up in the future to modulate neural activity in the cerebellum in AD.
References
Bonnì S, Lupo F, Lo Gerfo E et al (2013) Altered parietal-motor connections in Alzheimer’s disease patients. J Alzheimers Dis 33:525–533
Brusa L, Ponzo V, Mastropasqua C et al (2014) Theta burst stimulation modulates cerebellar–cortical connectivity in patients with progressive supranuclear palsy. Brain Stimul 7:29–35
Casula EP, Pellicciari MC, Ponzo V et al (2016) Cerebellar theta burst stimulation modulates the neural activity of interconnected parietal and motor areas. Sci Rep 6:36191
Daskalakis ZJ, Paradiso GO, Christensen BK, Fitzgerald PB, Gunraj C, Chen (2004) Exploring the connectivity between the cerebellum and motor cortex in humans. J Physiol 557:689–700
Delbeuck X, Van der Linden M, Collette F (2003) Alzheimer’s disease as a disconnection syndrome? Neuropsychol Rev 13:79–92
Del Olmo MF, Cheeran B, Koch G, Rothwell JC (2007) Role of the cerebellum in externally paced rhythmic finger movements. J Neurophysiol 9:145–152
Di Lorenzo F, Martorana A, Ponzo V et al (2013) Cerebellar theta burst stimulation modulates short latency afferent inhibition in Alzheimer’s disease patients. Front Aging Neurosci 5:2. https://doi.org/10.3389/fnagi.2013.00002
Di Lorenzo F, Ponzo V, Bonnì S et al (2016) Long-term potentiation-like cortical plasticity is disrupted in Alzheimer’s disease patients independently from age of onset. Ann Neurol 80:202–210
Di Lorenzo F, Ponzo V, Motta C et al (2018) Impaired spike timing dependent cortico-cortical plasticity in Alzheimer’s disease patients. J Alzheimers Dis 66:983–991
Evans GJ (2007) Synaptic signalling in cerebellar plasticity. Biol Cell 99:363–378
Fried PJ, Jannati A, Davila-Pérez P, Pascual-Leone A (2017) Reproducibility of single-pulse, paired-pulse, and intermittent theta-burst TMS measures in healthy aging, type-2 diabetes, and Alzheimer’s disease. Front Aging Neurosci 21:263
Fried PJ, Pascual-Leone A, Bolo NR (2019) Diabetes and the link between neuroplasticity and glutamate in the aging human motor cortex. Clin Neurophysiol 130:1502–1510
Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC (2013) The role of interneuron networks in driving human motor cortical plasticity. Cereb Cortex 7:1593–1605
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206
Koch G, Bonnì S, Casula EP et al (2019) Effect of cerebellar stimulation on gait and balance recovery in patients with hemiparetic stroke: a randomized clinical trial. JAMA Neurol 76:170–178
Koch G, Bonnì S, Pellicciari MC, Casula EP et al (2018) Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. Neuroimage 169:302–311
Koch G, Di Lorenzo F, Bonnì S, Ponzo V, Caltagirone C, Martorana A (2012) Impaired LTP- but not LTD-like cortical plasticity in Alzheimer’s disease patients. J Alzheimers Dis 31:593–599
Koch G, Di Lorenzo F, Del Olmo MF et al (2016) Reversal of LTP-like cortical plasticity in alzheimer’s disease patients with Tau-related faster clinical progression. J Alzheimers Dis 50:605–616
Koch G, Di Lorenzo F, Loizzo S et al (2017) CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer’s disease. Sci Rep 7:13728
Koch G, Esposito Z, Kusayanagi H et al (2011) CSF tau levels influence cortical plasticity in Alzheimer’s disease patients. J Alzheimers Dis 26:181–186
Koch G, Martorana A, Caltagirone C (2020) Transcranial magnetic stimulation: emerging biomarkers and novel therapeutics in Alzheimer’s disease. Neurosci Lett 719:134355
Koch G, Mori F, Marconi B et al (2008) Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum. Clin Neurophysiol 119:2559–2569
Koch G, Porcacchia P, Ponzo V et al (2014) Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients. Brain Stimul 7:564–572
Martorana A, Esposito Z, Di Lorenzo F et al (2012) Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients. J Neural Transm (Vienna) 119:771–778
Mavroudis IA, Manani MG, Petrides F et al (2013) Dendritic and spinal pathology of the Purkinje cells from the human cerebellar vermis in Alzheimer’s disease. Psychiatr Danub 25:221–226
Olivito G, Serra L, Marra C et al (2020) Cerebellar dentate nucleus functional connectivity with cerebral cortex in Alzheimer’s disease and memory: a seed-based approach. Neurobiol Aging. https://doi.org/10.1016/j.neurobiolaging.2019.10.026
Schmahmann JD (2016) Cerebellum in Alzheimer’s disease and frontotemporal dementia: not a silent bystander. Brain 139:1314–1318
Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791
Toniolo S, Serra L, Olivito G et al (2020) Cerebellar white matter disruption in alzheimer’s disease patients: a diffusion tensor imaging study. J Alzheimers Dis. https://doi.org/10.3233/JAD-191125
Toniolo S, Serra L, Olivito G, Marra C, Bozzali M, Cercignani M (2018) Patterns of cerebellar gray matter atrophy across Alzheimer’s disease progression. Front Cell Neurosci 12:430
Tabatabaei-Jafari H, Walsh E, Shaw ME, Cherbuin N, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2017 Jun) The cerebellum shrinks faster than normal ageing in Alzheimer’s disease but not in mild cognitive impairment. Hum Brain Mapp 38(6):3141–3150
Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I (1995) Magnetic stimulation over the cerebellum in humans. Ann Neurol 37:703–13
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Handling Editor: Christoph M. Michel
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Di Lorenzo, F., Bonnì, S., Picazio, S. et al. Effects of Cerebellar Theta Burst Stimulation on Contralateral Motor Cortex Excitability in Patients with Alzheimer’s Disease. Brain Topogr 33, 613–617 (2020). https://doi.org/10.1007/s10548-020-00781-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10548-020-00781-6