Transcranial Magnetic Stimulation (TMS)Original ArticleTMS Enhances Retention of a Motor Skill in Parkinson's Disease
Introduction
Although acquisition of new motor skills is generally preserved in Parkinson's Disease (PD), short- and long-term skill retention is impaired in both drug-naïve and pharmacologically treated patients. This conclusion is based on the results of earlier studies from ours and other groups using an implicit learning task in which subjects adapted their movements to rotated visual displays [1], [2], [3], [4]. Adaptation in this task requires the formation of new visuo-motor relationships and, thus, the creation of new memories or ‘internal models’ [5]. In this thoroughly characterized task [6], [7], [8], [9], learning is evident as a constant decrease of directional error that occurs without subjects' awareness; retention is sleep-dependent and is reflected in after-effects, a trace of the achieved adaptation, and in faster rate of re-adaptation at successive exposures. Importantly, learning depends on the activity of right posterior parietal areas as demonstrated by imaging and electrophysiological studies [6], [10], [11], [12]. Indeed, this area, which is involved in the integration of proprioceptive, visual and vestibular inputs, plays an important role in forming and maintaining new internal models used for movement planning. In particular, the binding of multisensory information as well as the development of memories or models such as those required for moving under new visuo-motor coordinates is reflected by activity changes occurring over this area [12], [13], [14], [15]. Importantly, the degree of skill retention highly correlates with the magnitude of EEG changes during learning over the right posterior parietal area, as well as with the occurrence of slow wave activity in subsequent sleep over that same spot [10].
Adaptation to a 30° rotation occurs similarly in patients with PD and age-matched controls: at the end of training, adaptation levels are similar in both groups [1], [2], [3]. However, re-adaptation, tested either immediately after training or one-two days later, is faster than in the first exposure only in normal controls [1], [2], [3]. A possible explanation is that formation of internal models and their retention is hampered in PD because of impaired induction of long-term potentiation (LTP)-related phenomena [3]. In fact, many studies in PD have now demonstrated deficits of LTP-like phenomena in the primary motor cortex [16], [17], [18], [19], [20]. A way to enhance LTP-like phenomena in vivo is the use of 5 Hz-repetitive transcranial magnetic stimulation (5Hz-rTMS): in normal subjects, 5Hz-rTMS increases the amplitude of muscle and cortical responses and produces local increases of slow wave activity in subsequent sleep [21], [22], [23], [24]. More direct evidence of LTP induction comes from our animal study showing that 5Hz-rTMS increases expression of brain-derived neurotrophic factor, tyrosine-receptor-kinase-B and N-methyl-d-aspartate receptor that induce dendritic translation [25]. It is then plausible that, if LTP is impaired in PD, 5Hz-rTMS applied to an area involved in learning might enhance memory formation and retention in these patients. Therefore, in this study, a group of patients with PD adapted to one of two rotation types in two separate sessions. After training, 5Hz-rTMS or sham-rTMS was applied to the right posterior parietal area. While adaptation at the end of training was comparable in the two sessions, retention on the following day was abnormal after sham-TMS but not after 5Hz-rTMS.
Section snippets
Subjects
We tested 19 patients with PD (14 men, age: 60.9 ± 5.4 yrs) and 19 age-matched (10 men, age 58.9 ± 8.7 yrs) controls. As shown in Table 1, all patients had mild to moderate PD and were treated with dopaminergic drugs. None of the patients and controls had severe medical illness or had recently received chronic treatment for sleep complaints. During all the experiments, all the patients were in ON state, in their regular medication schedule. All subjects were right-handed and were naïve to the
Results
No subject experienced adverse effects of the rTMS procedure. Importantly, the amount of sleep was the same across groups and sessions: in the night before re-adaptation, patients slept an average of 6.25 ± 1.5 h in the placebo session and 6.30 ± 1.2 h in the treatment session (paired t-test: P = 0.88), not differently from controls (6.66 ± 1.0 h, unpaired t-test: P = 0.4).
In all the experimental sessions, movements were essentially straight with a bell-shaped velocity profile in both patients
Discussion
The main result of this study is that application of 5Hz-rTMS to the right posterior parietal area after adaptation to a visuo-motor rotation enhances indices of skill retention in patients with PD. Importantly, this effect was confined to the retention of new visuo-motor coordinates without affecting the kinematic characteristics.
Twenty-four hours after the initial training, skill retention measured with both after-effects and re-adaptation gains were lower in patients during the placebo
Acknowledgments
This work was supported by grants from the McDonnell Foundation to MFG, the National Parkinson Foundation to MFG & ADR, the National Institute of Health (NS-054864 to MFG). We thank ETT s.r.l (Genova, Italy) for providing the software used for the motor task. We thank Jamika Singleton-Garvin for help in patient selection.
References (32)
- et al.
Learning and consolidation of visuo-motor adaptation in Parkinson's disease
Parkinsonism Relat Disord
(2009) - et al.
Parkinson's disease differentially affects adaptation to gradual as compared to sudden visuomotor distortions
Hum Mov Sci
(2011) Internal models for motor control and trajectory planning
Curr Opin Neurobiol
(1999)- et al.
Patterns of regional brain activation associated with different forms of motor learning
Brain Res
(2000) - et al.
Electrophysiological traces of visuomotor learning and their renormalization after sleep
Clin Neurophysiol
(2011) The planning and control of reaching movements
Curr Opin Neurobiol
(2000)- et al.
Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson's disease
Clin Neurophysiol
(2012) - et al.
Lack of LTP-like plasticity in primary motor cortex in Parkinson's disease
Exp Neurol
(2011) - et al.
A direct demonstration of cortical LTP in humans: a combined TMS/EEG study
Brain Res Bull
(2006) - et al.
Visual feedback has differential effects on reaching movements in Parkinson's and Alzheimer's disease
Brain Res
(2000)
Continuous transcranial magnetic stimulation during positron emission tomography: a suitable tool for imaging regional excitability of the human cortex
Neuroimage
Basal ganglia-dependent processes in recalling learned visual-motor adaptations
Exp Brain Res
Dopaminergic striatal innervation predicts interlimb transfer of a visuomotor skill
J Neurosci
Adaptation to visuomotor transformations: consolidation, interference, and forgetting
J Neurosci
Independent learning of internal models for kinematic and dynamic control of reaching
Nat Neurosci
Learning of visuomotor transformations for vectorial planning of reaching trajectories
J Neurosci
Cited by (25)
EEG as a marker of brain plasticity in clinical applications
2022, Handbook of Clinical NeurologyA systems biology approach for studying neurodegenerative diseases
2020, Drug Discovery TodayCitation Excerpt :In addition, similarly to AD therapies, it is ineffective in reversing damage caused by neurodegeneration and patients display variable levels in their response to it [13]. Alternatively, transcranial magnetic stimulation (TMS) has been used as a non-invasive nonpharmaceutical intervention for AD and PD, with positive effects reported [14,15]; however, controversy remains with regards to the safety of some TMS modes [16]. For the most severe PD cases, invasive deep brain stimulation (DBS) therapy is an option.
Improving visuo-motor learning with cerebellar theta burst stimulation: Behavioral and neurophysiological evidence
2020, NeuroImageCitation Excerpt :Moreover, in this case the performance is also influenced by the ability of quickly selecting the appropriate internal model. In fact, during successive experiences with the same perturbation, the previously acquired internal models need to be retrieved proficiently in order to achieve faster re-adaptation, resulting in precise movement planning and small directional errors (Kitago et al., 2013; Moisello et al., 2015). Finally, when subjects are reintroduced to a condition where the visual transformation is removed, an error in the opposite direction to the perturbation is observed with this fading over subsequent trials (de-adaptation phase).
A cortical substrate for the long-term memory of saccadic eye movements calibration
2018, NeuroImageCitation Excerpt :Robinson et al. (2006) additionally stressed that long-term adaptation induced by repeating daily adaptation sessions relies on mechanisms distinct from those underlying short-term adaptation induced in a single session. Contrary to evidence in the skeletal-motor system that cerebral or cerebellar neurostimulation can facilitate the consolidation of adaptation independently of its acquisition (Galea et al., 2011; Moisello et al., 2015; Wessel et al., 2016; O'Shea et al., 2017), the present findings are the first to support the existence of consolidation mechanisms for saccadic adaptation and of their possible neural substrate. The hypothesis that TMS stimulation of the rTPJ has boosted consolidation processes supposes an activating effect of TMS.
The many facets of motor learning and their relevance for Parkinson's disease
2017, Clinical NeurophysiologyCitation Excerpt :However, both the timing and the location of the stimulation are crucial to obtain the desired result: the effect is present only for stimulation of the contralateral M1 applied just after the task. Enhancement of retention can also be obtained using high frequency rTMS (Moisello et al., 2015a) and by anodal tDCS applied over the motor cortex (Cantarero et al., 2013; Leow et al., 2014). Another important aspect that affects retention of motor skills is sleep.