Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease
Highlights
► First study to test plasticity of motor cortex in de novo PD. ► First study to show severe loss of LTP and LTD in the less affected hemisphere in early PD. ► Provides evidence that loss of M1 plasticity is not related to motor signs of PD and might affect motor learning in early stages of PD.
Introduction
Animal models of Parkinson’s disease (PD), both toxic and genetic, have shown impairment in the ability of striatal neurons to express Long Term Potentiation (LTP) and Long Term Depression (LTD) (Calabresi et al., 2007). Such an impairment paralleled dopamine (DA) depletion in these models (Calabresi et al., 2007) and treatment with L-DOPA restored the expression of LTP in the 6-OHDA experimental model of PD (Picconi et al., 2003). Impaired ability of neurons in the basal ganglia circuits to undergo synaptic plasticity is now considered to play a potential key role in the neural network disturbances that occur in PD (Calabresi, 2009). Dopamine in the motor cortex (M1) promotes motor learning and synaptic plasticity of M1. This was demonstrated both in animal models (Molina-Luna et al., 2009) and in studies on healthy human volunteers (Flöel et al., 2005). In human subjects, LTP and LTD-like plasticity of M1 can be studied non-invasively using repetitive transcranial magnetic stimulation (rTMS) (Berardelli et al., 1998, Maeda et al., 2000), theta burst stimulation (TBS) (Huang et al., 2005), paired associative stimulation (PAS) (Ridding and Taylor, 2001, Stefan et al., 2000), and transcranial direct current stimulation (tDCS) (Nitsche et al., 2008). In healthy humans, exogenous DA or dopamine agonists exert a powerful effect on plasticity of M1 induced by rTMS (Lang et al., 2008), PAS (Kuo et al., 2008) and tDCS (Kuo et al., 2008). In PD patients, both LTP and LTD-like plasticity of M1 were found reduced using PAS (Ueki et al., 2006, Morgante et al., 2006), rTMS (Gilio et al., 2002) and TBS (Eggers et al., 2010, Suppa et al., 2010). These patients were on chronic treatment with multiple drugs and tested after 12 to 24 h of drug withdrawal. These studies, however, do not provide a clear insight into how DA might influence deficient M1 plasticity for the following reasons. (i) Effects of an acute stimulation of DA receptors was mixed with the effects of their chronic stimulation. (ii) Results of the studies depended on the plasticity-induction protocol used or (iii) on the clinical characteristics of the patients. In one study (Ueki et al., 2006) PAS-induced plasticity was restored in PD patients after intake of their morning dose of multiple medications, while in the other study (Morgante et al., 2006) the positive effect of L-DOPA was preserved only in non-dyskinetic patients and was absent in patients with L-DOPA-induced dyskinesias. When TBS was used instead of PAS, M1 plasticity was not restored by dopaminergic drugs (Suppa et al., 2010). The authors argued that such differences between the findings obtained with PAS and TBS may depend on the different mechanisms mediating the effects of TBS (homotopic NMDA-dependent plasticity involving exclusively M1) and PAS (spike timing-dependent plasticity involving somatosensory cortex and M1). A beneficial effect of DA on the abnormal sensori-motor coupling in PD reported by Sailer and colleagues (Sailer et al., 2003) might explain the beneficial effect of DA on PAS-induced plasticity without necessarily having any effect on plasticity of M1 per se.
We therefore re-investigated the ability of PD patients to respond to TBS plasticity-induction protocol of the M1 cortex. We chose the technique of TBS to induce plasticity of M1 since it does not involve sensori-motor coupling as in PAS which can be independently influenced by dopamine (Sailer et al., 2003) and therefore would be better to identify the specific abnormality in M1 plasticity. We tested both excitatory and inhibitory plasticity by using intermittent (iTBS) and continuous (cTBS) TBS in different groups of patients. To separate the effects of disease from those possibly related to the chronic dopaminergic replacement therapy, we enrolled only de novo patients. To further differentiate the abnormal cortical plasticity secondary to the severe motor signs, we selected patients who reported only unilateral symptoms. We compared the TBS-induced plasticity in the clinically asymptomatic or less affected hemisphere with the clinically symptomatic and more affected hemisphere. We also tested the TBS-induced plasticity after a single uniform dose of 100 mg of L-DOPA to examine the effect of exogenous DA on restoring deficient plasticity. We chose the 100 mg dose because such a dose was shown to enhance PAS- induced plasticity (Kuo et al., 2008) and also improve learning in humans (Flöel et al., 2005).
Section snippets
Materials and methods
Twenty-one, early cases of PD who satisfied the inclusion and exclusion features of the UK Brain Bank Criteria (Hughes et al., 1992), had strictly unilateral symptoms and were treatment-naïve (de novo) with no prior exposure to L-DOPA, were included in the study. They were randomly allocated to two groups to undergo either iTBS (n = 10) or cTBS (n = 11). Two groups of 10 age-matched healthy volunteers (HV) served as controls. None of the subjects were depressed, on antidepressants, cognitively
Experimental set up
Patients were randomly placed in one of two groups in a parallel study design. One group underwent iTBS, the other one cTBS. Each patient in each group (iTBS or cTBS) came for 4 sessions. They were tested on both hemispheres twice, in the untreated and ON states, i.e. 1 h after a dose of 100/25 mg of L-DOPA/C-DOPA after confirming the clinical response of PD signs. The sessions were randomized into untreated or ON states and for the more or less affected hemisphere, maintaining a one week gap
Transcranial magnetic stimulation
TMS was conducted with an air-cooled 7 cm inner diameter, figure-of-eight coil connected to a Magstim Rapid2 stimulator (The Magstim Company, UK). The coil was held with the handle pointing backwards and laterally at 45° (Brasil-Neto et al., 1992) over the optimal position for eliciting MEPs in the first dorsal interosseus (FDI) muscle. Induced current pulses were biphasic. Recordings and measurements were done using a Nicolet Viking IV NCV/EMG machine.
TBS intervention
TBS was given as trains of three pulses
Experimental design for both groups
At baseline (S1), the resting (RMT) and active (AMT) motor thresholds were calculated. The RMT was the minimum stimulator intensity that produced MEPs of ⩾50 μV in at least 5 of 10 trials. The AMT was the minimum stimulator intensity that produced MEPs ⩾200 μV in 5 of 10 trials while subjects performed a voluntary contraction of FDI of approximately 20 to 30% of maximum.
At S1, 15 individual MEPs were averaged adjusting the intensity of the magnetic stimulus to 120% of RMT. Patients then received
Clinical features
Ten de novo patients (age: 51.4 ± 9.9 years) were compared with 10 healthy subjects (mean age 45.6 ± 7.8) (p = 0.2). All subjects, both HV and controls were right handed. The left side (right hemisphere) was the less affected side in 5 patients, while it was the more affected side in the remaining 5 patients. Clinical characteristics of patients are presented in Table 1.
Patients had a good response to L-DOPA as they improved in the UPDRS score by around 50% (see Table 1) after a uniform dose of 100/25
Discussion
We found that LTP and LTD-like plasticity induced by excitatory and inhibitory TBS protocols respectively were severely impaired in M1 of both hemispheres of patients with de novo PD when compared to age and hemisphere-matched healthy volunteers. The severity of impairment of plasticity was not different between the less and more affected hemispheres, even though patients had no or only very mild signs on one side. A single dose of L-DOPA did not restore both types of plasticity in either the
Conclusion
The new findings in this study are: (i) the previously-described lack of TBS-induced plasticity in treated PD patients is also present in de novo patients (ii) lack of plasticity is present to a same extent in both hemispheres in early disease itself, regardless of the asymmetry of the clinical signs and (iii) acute dopamine replacement fails to restore both abnormal iTBS- and cTBS-induced plasticity in PD. We propose that the contrasting L-DOPA response of motor signs and M1 plasticity could
Funding
The study was supported by Sree Chitra Tirunal Institute for Medical Sciences and Technology, India (project 5040). Dr. Meunier is supported by a “contrat d’ interface” from AP-HP.
Acknowledgments
We thank Gangadhara Sarma for coordinating the study and all the subjects who kindly participated in the study.
References (49)
- et al.
Dopamine-mediated regulation of corticostriatal synaptic plasticity
Trends Neurosci
(2007) - et al.
Cortical inhibition in Parkinson’s disease: new insights from early, untreated patients
Neuroscience
(2007) - et al.
Functional and Dysfunctional Synaptic Plasticity in Prefrontal Cortex: Roles in Psychiatric Disorders
Biol Psychiatry
(2010) - et al.
Theta burst stimulation of the human motor cortex
Neuron
(2005) - et al.
The after-effect of human theta burst stimulation is NMDA receptor dependent
Clin Neurophysiol
(2007) - et al.
Serial reaction time learning and Parkinson’s disease: evidence for a procedural learning deficit
Neuropsychologia
(1995) - et al.
Dopaminergic potentiation of rTMS-induced motor cortex inhibition
Biol Psychiatry
(2008) Motor cortex dysfunction revealed by cortical excitability studies in Parkinson’s disease: influence of antiparkinsonian treatment and cortical stimulation
Clin Neurophysiol
(2005)- et al.
Dopaminergic signals in primary motor cortex
Int J Dev Neurosci
(2009) - et al.
Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation
Clin Neurophysiol
(2000)