The effect of repetitive transcranial magnetic stimulation on cognitive impairment in Parkinson’s disease with dementia: Pilot study

Abstract

Background:

The exact mechanism of cognitive impairment in PD is not known. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for cognitive impairment and to treat the motor symptoms in Parkinson’s disease (PD) where its effects seem additive to those of dopaminergic medications.

Objective:

In this pilot study we investigated whether repeated sessions of rTMS have an effect on measures of cognitive impairment in patients with PD dementia.

Methods:

33 patients with PD dementia were randomly assigned sham or real rTMS (2000 pulses; 20 Hz; 90% RMT; 10 trains of 10 s with 25 s between each train) over the hand area of each motor cortex (5 min between hemispheres) for 10 days (5 days/week) followed by 5 booster sessions every month for 3 months. Assessments included the Unified Parkinson’s Disease Rating Scale part III (UPDRS), Montreal Cognitive Assessment (MoCA); Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR); Memory and Executive Screening (MES) and Instrumental activity of Daily Living (IADL). Event related potentials (P300) and cortical excitability were measured before treatment and after the last session.

Results:

There were no significant differences in the effects of rTMS between groups. Although rTMS improved motor function in the active group it had only a minor effect on two of the dementia rating scores (the MMSE and MoCA) but not the others (CDR and MES). There was also a reduction in the latency of the P300 in the active group.

Conclusions:

rTMS over M1 is useful for motor function and may have a small positive effect on cognition. However, better approaches for the latter are necessary, may be require multisite rTMS to target both motor and frontal cortical region.

Keywords

Parkinson’s disease cognitive impairment dementia repetitive transcranial magnetic stimulations Unified Parkinson’s Disease Rating Scale part III Montreal cognitive assessment Mini mental state examination Clinical Dementia Rating P300 cortical excitability parameters

1 Introduction

The non-motor symptoms of PD increase the cost of care by fourfold because of increased hospitalization and treatment costs and pose a major challenge to healthcare professionals (Hagell, Nordling, Reimer, Grabowski, & Persson, 2002). One of the most important non-motor symptoms is cognitive impairment. According to the Movement Disorder Society (MDS), an estimated 26.7% of PD patients have mild cognitive impairment (Litvan et al., 2011) whereas another 30% to 40% of patients have Parkinson’s disease dementia (PDD) (Goetz et al., 2008). The exact mechanism of cognitive impairment in PD is not known; widespread brain atrophy and brain cell death occurs in those with PDD.

Dopaminergic medications have mixed effects on cognition. They can improve or impair cognitive performance depending on the nature of the task and the basal level of dopamine function in the underlying corticostriatal circuitry. For example, task switching (which is dependent on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus) improves, but probabilistic reversal learning (which is dependent on orbitofrontal cortex– ventral striatal circuitry) deteriorates with use of dopaminergic medications (Cools, Barker, Sahakian, & Robbins, 2001).

Randomized controlled trials have shown modest benefits for the central acetylcholine esterase inhibitor (van Laar, Paul, Aarsland, Barone, & Galvin, 2011) (e.g. rivastigmine, donepezil) and memantine in PD dementia (Dag Aarsland et al., 2009; Emre et al., 2004; Emre et al., 2010; Ravina et al., 2005). There are currently no systematic clinical trials in PD with cognitive impairment. Behavioral treatment options (e.g. cognitive behavioral therapy, exercise) are under investigation (D. Aarsland, Bronnick, & Fladby, 2011).

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for cognitive impairment and dementia in Alzheimer’s disease (Ahmed, Darwish, Khedr, & Ali, 2012; Elder & Taylor, 2014; Eliasova, Anderkova, Marecek, & Rektorova, 2014; Hsu, Ku, Zanto, & Gazzaley, 2015; Eman M. Khedr, Al Fawal, Abdelwarith, Saber, & Rothwell, 2019; Rabey et al., 2013; Zhao et al., 2017) and has been used in several positive clinical trials to treat the motor symptoms in Parkinson’s disease, where its effects seem additive to those of dopaminergic medications. The question we ask here is whether rTMS treatment of motor symptoms in Parkinson’s disease might also have some benefit on cognitive impairment. This could occur because (a) improvement in being able to move around and function in the environment could itself improve cognition; and/or (b) M1 itself is involved in some aspects of cognition such as visual imagery of movement, language and working memory. In addition, M1 rTMS could also impact the premotor areas which also contribute to some aspects of cognition via its connections with more frontal areas of cortex. The P300 is an average positive-going EEG that occurs about 300 ms during task in which subjects differentiate between target and non-target stimuli. Its generator is unknown, although hippocampus, amygdala, thalamus and basal ganglia have been proposed (Yingling & Hosobuchi, 1984). The latency of the P300 has been considered to be a marker of cognitive processing speed (Egerh $\overset{´}{a}$ zi, Glaub, Balla, Berecz, & Degrell, 2008) and has been used as a measure of cognitive dysfunction that is particularly related to attention and short-term memory in mild cognitive dysfunction and dementia (Polich, Ehlers, Otis, Mandell, & Bloom, 1986).

In this preliminary investigation we tested whether 10 sessions of high frequency rTMS over M1 had any effect on measures of cognitive function in PD dementia. Outcomes were measured using clinical rating scales and event related EEG potentials (P300).

2 Methodology

We recruited 90 patients with PD according to UK bank criteria (Hughes, Daniel, Kilford, & Lees, 1992) from the neurology outpatient clinic in Assiut University.

2.1 Inclusion criteria

1- Age range from 50–75 years, and both sex were included. 2- MMSE Arabic version (Wrobel & Farrag, 2007) was used to select patients with cognitive impairment (≤23 point for educated patients or 21 for non-educated patients), 3- Subjective complaint of either gradual or sudden cognitive change by the patient.

2.2 Exclusion criteria

Other organic causes of dementia, depression and other psychiatric comorbidities or a history of repeated head injury, repeated cerebrovascular strokes or encephalitis. Patients with oculogyric crises or supranuclear gaze palsy were excluded as were patients who had previously taken antipsychotics or been exposed to MPTP. Other exclusion criteria were: early severe dementia, severe dysautonomia, cerebellar signs, Babiniski sign, strictly unilateral features after 3 years, sustained remission, hydrocephalus or intracranial lesion on neuroimaging and no response to levodopa.

2.3 Methods

All cases were assessed for motor and cognitive impairment.

Clinical rating scales: motor part of Unified Parkinson’s disease rating scale (UPDRS) (Martínez-Martín et al., 1994); Mini Mental State examination Arabic version (MMSE) (Wrobel & Farrag, 2007), Montreal Cognitive Assessment Arabic version (MoCA) (Rahman & El Gaafary, 2009); Memory and Executive screening Scale (MES) (Fang, Weihong, Chen, & Wang, 2015); Clinical Dementia Rating Scale (CDR) (Morris, 1997) and Instrumental Activities of Daily Living scale (IADL) (Morrow, 1999).

Neurophysiological tests: Event related potential (P300) (Picton, 1992); cortical excitability measures (resting and active motor threshold (rMT, and aMT) and short-interval intracortical inhibition (SICI) at intervals of 1, 2, 4 ms (see (Eman M Khedr, Ahmed, Ali, Badry, & Rothwell, 2015; Eman M Khedr et al., 2016) for methodological details).

2.4 Event-related potentials (P300)

Event-related potentials were elicited using an auditory discrimination task paradigm by presenting a series of binaural 2000 Hz (standard) vs. 1000 Hz (target) tones at 70 dB with a 10 ms rise/fall and 40 ms plateau time. Tones were presented at a rate of 1.1 per second, with target tones occurring randomly with a probability of 0.2. The interstimulus interval was 3 s. EEG recordings were made with a Nihon Kohden 9400 (Japan) using silver– silver chloride surface electrodes, applied at Fz and reference electrode in the ear. P300 latency was measured as the major positive peak after N200 within a range of 250–500 ms. P300 amplitude was measured peak to peak from the preceding negative component (N200) to the maximum positive peak. Details of methodology are reported in a previous study (Eman M Khedr et al., 2014).

2.5 Cortical excitability measures

Subjects sat in a comfortable chair. Electromyographic (EMG) recordings (Nihon Kohden 9400, Japan) from the abductor digiti minimi muscle (ADM) of right hand were acquired with silver— silver chloride surface electrodes, using a muscle belly— tendon setup with a 3 cm-diameter ground electrode placed on the wrist. The EMG parameters included a bandpass of 20 to 1000 Hz and a recording time window of 200 ms. TMS was performed with a 90 mm figure-of eight coil connected to Magstim (UK) super rapid magnetic stimulator. Motor thresholds were determined after localization of the motor “hot spot” for the right ADM on the left hemisphere. The EMG signals were monitored and recorded for 20 ms before stimulation. RMT was measured at complete rest; aMT, while subjects made a mild contraction of approximately 10% maximum. Both rMT and aMT were expressed as a percentage of the maximal stimulator output (equal to 100%). Short-interval intracortical inhibition (SICI) was assessed using a subthreshold conditioning stimulus set at 80% of rMT and a suprathreshold test stimulus (TS) which was adjusted to produce an average MEP of 0.5–1.5 mV peak-to-peak amplitude in the contralateral ADM (Kujirai, 1993).

Conditioning stimuli were applied to the motor cortex before the TS at one of three random inter-stimulus intervals (ISIs): 1, 2 and 4 ms. A total of 30 trials were performed, 10 for each condition. The changes in the TS MEP amplitude at each ISI were expressed as a fraction of the mean unconditioned MEP amplitude (Daskalakis et al., 2002).

2.6 Randomization (Parallel design)

Out of 90 PD patients, 36 patients had cognitive impairment and participated in the study (see Fig. 1: flow chart). Group allocations (real or sham with ratio 1 : 1) were placed in serially numbered opaque closed envelopes. Each patient was placed in the appropriate group after opening the corresponding sealed envelope.

Fig.1

Flow chart. Out of 90 cases of PD were recruited from Assiut University Hospital (AUH) only 36 have cognitive impairment and were participated in the study and classified randomly into 2 groups (each 18 patients). Three patients did’t complete the sessions.

2.7 Repetitive transcranial magnetic stimulation procedure

Real rTMS was applied for 10 sessions (5 days per week) using a figure-of-8 coil (9 cm diameter loop) with the center of the coil positioned over the motor area (M1). A session of stimulation consisted of sequential stimulation of each hemisphere (right then left hemisphere) with 10 trains of 20 Hz stimulation, each lasting for 10 seconds with an intertrain interval of 25 seconds. The intensity of stimulation was set at 90% of the rMT for the first dorsal interosseous of the contralateral hand with a total 2000 pules for each hemisphere. Given our previous experience in treating PD (Eman M Khedr, Rothwell, Shawky, Ahmed, & Hamdy, 2006) we decided to give 5 consecutive booster sessions at the end of every month for 3 months follow-up and reassessment of each rating scale after the end of sessions. Sham rTMS was applied using the same parameters, but with the coil held so that the edge was in contact with the head perpendicular to the scalp while the remainder was rotated 90° away from the scalp in the sagittal plane to reproduce the noise of the stimulation as this sham procedure has no effects on cortical excitability (A. Karim, Kammer, Cohen, & Birbaumer, 2004; A. A. Karim et al., 2003). Two patients didn’t complete even the 5th session and refused to complete it, the other didn’t complete the 7th session ... .because they came from city away from the hospital so we exclude these cases from the analysis.

2.8 Follow-up

At the end of the therapy, patients were asked whether they thought they had received active or sham rTMS. We followed up the patients clinically after the end of the 10th session and at 1, 2 and 3 months later, after the end of booster sessions using the cognitive rating scales (MMSE, MoCA) as well as P300 latency changes as primary outcome. Other outcome measures were changes in UPDRS and cortical excitability as secondary outcomes. Three patients withdrew from the study because they experienced no improvement after 10 sessions. See flow chart Fig. 1.

Assessment of the different scales, the P300 and cortical excitability parameters was performed by an assessor who was unaware of the type of stimulation. Likewise, the patients did not know which type of stimulation they had received.

We also asked patients specifically whether they experienced any of the common side effects of rTMS. Three patients of the active group refused to complete the sessions: one developed headache and insomnia and the other two failed to remain in the hospital.

3 Ethics

Informed consent was obtained from all subjects and the methodology was approval by the faculty of medicine ethical committee.

4 Statistical analysis

All data were analyzed with the aid of the SPSS ver.16. The results were expressed as mean±SD. Since measures of age, onset and duration of illness were not distributed normally at baseline, non-parametric Mann-Whitney tests were used for comparison between groups. Statistical analysis of the scores in each of the cognitive and physiological tests was performed with repeated measures analysis of variance (ANOVA) with TIME, as the within-subject factor, and treatment condition (active, and sham rTMS) as the between subject measure. Greenhouse– Geisser degree of freedom corrections were applied to correct for the non-sphericity of the data. P < 0.05 was considered significant for all statistical analysis. Spearman correlation between the changes in the total rating scales (UPDRS III, MoCA, MMSE, CDR, and IDLA (Pre-Post 10th sessions and post three months) and P300 and cortical excitability changes (Pre-Post 10th sessions) was performed.

5 Results

5.1 Baseline data

Demographic and clinical characteristics are summarised in Table 1. There were no significant differences between the real and sham groups in age, sex, educational level, UPDRS III score, IADL, MMSE, MoCA, CDR, MES and IADL.

Table 1
Base line parameters in active and sham groups

Active (N = 18) Sham (N = 15) P-Value^*

Sex

Male 14 (77.8%) 10 (66.7%) 0.475

Female 4 (22.2%) 5 (33.3%)

Educational Level

Illiterate 10 (55%) 8 (53.3%) 0.619

Primary school 2 (11.1%) 3 (20%)

High school 5 (27.8%) 2 (13.3%)

College 1 (5.6%) 2 (13.3%)

Age years 65.56±8.73 59.33±10.27 0.073

Age of onset years 59.67±11.20 53.83±10.81 0.143

Duration of illness years 5.89±5.37 5.50±3.85 0.884

UPDRS part III 61.00±16.4 58.00±21.3 0.656

MMSE 19.82±2.71 20.86±2.97 0.957

MoCA 16.33±4.23 14.93±5.15 0.401

CDR 7.14±3.36 7.07±3.34 0.957

MES 52.44±13.13 53.40±12.97 0.901

IADL 13.78±3.83 16.27±5.62 0.15

P300 Latency (ms) 391.07±37.38 373.76±41.96 0.225

	Active (N = 18)	Sham (N = 15)	P-Value^*
Sex
Male	14 (77.8%)	10 (66.7%)	0.475
Female	4 (22.2%)	5 (33.3%)
Educational Level
Illiterate	10 (55%)	8 (53.3%)	0.619
Primary school	2 (11.1%)	3 (20%)
High school	5 (27.8%)	2 (13.3%)
College	1 (5.6%)	2 (13.3%)
Age years	65.56±8.73	59.33±10.27	0.073
Age of onset years	59.67±11.20	53.83±10.81	0.143
Duration of illness years	5.89±5.37	5.50±3.85	0.884
UPDRS part III	61.00±16.4	58.00±21.3	0.656
MMSE	19.82±2.71	20.86±2.97	0.957
MoCA	16.33±4.23	14.93±5.15	0.401
CDR	7.14±3.36	7.07±3.34	0.957
MES	52.44±13.13	53.40±12.97	0.901
IADL	13.78±3.83	16.27±5.62	0.15
P300 Latency (ms)	391.07±37.38	373.76±41.96	0.225

^*P-value of categorical data by Pearson Chi Square Test; P-value of numerical data by Mann-Whitney U Test. UPDRS; Unified Parkinson’s Disease Rating Scale, MMSE; Mini mental state examination, MoCA; Montreal cognitive assessment scale, CDR; Clinical Dementia Rating, MES; Memory Executive Screening.

5.2 Clinical rating scales

Table 2 shows the scores for each rating scale at baseline and up to 3 months after the end of treatment. As reported previously, active rTMS produced a sustained improvement in motor function as reflected in a 13-point reduction in the UPDRS rating compared with no change in the sham group. The active group also improved in the MoCA, MMSE and IADL scores, but the effect was relatively small. There was no effect on the CDR nor the MES test.

Table 2
Clinical assessment scales repeated measure analysis (Group x Time)

Pre Post 0 Post 1 m Post 2 m Post 3 m Repeated measure analysis (One-way ANOVA) each group separately Repeated measure analysis (Two-way ANOVA) Time X group

Mean ± SD Mean ± SD Mean ± SD Mean±SD Mean±SD

Unified Parkinson’s Disease Rating Scale III (UPDR)

Active Group 61.0±16.4 46.0±14.0 47.6±14.2 48.5±14.0 48.4±14.0 Df = 2.2, F = 21.7, P = 0.0001 Df = 2.1, F = 10.7, Sig. = 0.0001

Sham Group 58.0±21.3 56.3±22.4 56.8±22.7 57.5±20.8 58.1±21.2 Df = 1.9, F = 0.5, P = 0.62

P-value 0.612 0.082 0.193 0.133 0.127

Montreal cognitive assessment scale (MoCA)

Active Group 16.33±4.23 19.11±4.30 17.17±4.19 17.00±4.20 17.50±3.93 Df = 1.7, F = 18.4, P = 0.0001 Df = 1, F = 4.5, Sig. = 0.041

Sham Group 14.93±5.15 15.67±5.16 15.67±5.19 15.73±5.30 15.73±5.30 Df = 1.9, F = 2.2, P = 0.13

P-value 0.394 0.040 0.354 0.455 0.329

Mini mental state examination (MMSE)

Active Group 19.82±2.71 24.64±2.50 21.55±2.70 20.82±3.09 20.73±3.17 Df = 2, F = 25.9 P = 0.0001 Df = 1, F = 13.2, Sig. = 0.0001

Sham Group 20.86±2.97 21.43±2.44 21.71±2.29 21.71±2.29 21.86±2.12 Df = 1, F = 2.3, P = 0.177

P-value 0.885 0.002 0.467 0.549 0.404

Clinical Dementia Rating (CDR)

Active Group 7.11±3.28 6.31±2.95 6.94±2.96 7.22±3.13 6.63±3.14 Df = 1.5, F = 1.5, P = 0.23 Df = 1, F = 0.1, Sig. = 0.733

Sham Group 7.07±3.34 7.33±3.51 7.33±3.51 7.53±3.79 7.60±3.70 Df = 1.9, F = 2.7, P = 0.32

P-value 0.957 0.319 0.758 0.870 0.593

Memory Executive Screening (MES)

Active Group 52.44±13.13 57.94±10.39 56.39±9.92 55.39±9.94 55.56±9.32 Df=1.6, F = 1.9, P = 0.17 Df = 1 F = 0.0001 Sig.=0.98

Sham Group 53.40±12.97 55.47±13.53 55.00±14.14 54.20±14.58 54.07±14.73 Df=1.6, F = 1.1, P = 0.33

P-value 0.899 0.550 0.704 0.814 0.859

Instrumental Daily activity living (IADL)

Active Group 13.78±3.83 17.39±4.98 16.44±4.82 16.44±4.94 17.13±4.43 Df=1.7, F = 13.8, P = 0.0001 Df = 1 F = 6.5 Sig.=0.01

Sham Group 16.27±5.62 17.13±5.64 16.80±5.92 16.80±5.82 16.80±5.82 Df=2.4, F = 2.4, P = 0.09

P-value 0.194 0.717 0.870 0.899 0.766

	Pre	Post 0	Post 1 m	Post 2 m	Post 3 m	Repeated measure analysis (One-way ANOVA) each group separately	Repeated measure analysis (Two-way ANOVA) Time X group
Unified Parkinson’s Disease Rating Scale III (UPDR)
Active Group	61.0±16.4	46.0±14.0	47.6±14.2	48.5±14.0	48.4±14.0	Df = 2.2, F = 21.7, P = 0.0001	Df = 2.1, F = 10.7, Sig. = 0.0001
Sham Group	58.0±21.3	56.3±22.4	56.8±22.7	57.5±20.8	58.1±21.2	Df = 1.9, F = 0.5, P = 0.62
P-value	0.612	0.082	0.193	0.133	0.127
Montreal cognitive assessment scale (MoCA)
Active Group	16.33±4.23	19.11±4.30	17.17±4.19	17.00±4.20	17.50±3.93	Df = 1.7, F = 18.4, P = 0.0001	Df = 1, F = 4.5, Sig. = 0.041
Sham Group	14.93±5.15	15.67±5.16	15.67±5.19	15.73±5.30	15.73±5.30	Df = 1.9, F = 2.2, P = 0.13
P-value	0.394	0.040	0.354	0.455	0.329
Mini mental state examination (MMSE)
Active Group	19.82±2.71	24.64±2.50	21.55±2.70	20.82±3.09	20.73±3.17	Df = 2, F = 25.9 P = 0.0001	Df = 1, F = 13.2, Sig. = 0.0001
Sham Group	20.86±2.97	21.43±2.44	21.71±2.29	21.71±2.29	21.86±2.12	Df = 1, F = 2.3, P = 0.177
P-value	0.885	0.002	0.467	0.549	0.404
Clinical Dementia Rating (CDR)
Active Group	7.11±3.28	6.31±2.95	6.94±2.96	7.22±3.13	6.63±3.14	Df = 1.5, F = 1.5, P = 0.23	Df = 1, F = 0.1, Sig. = 0.733
Sham Group	7.07±3.34	7.33±3.51	7.33±3.51	7.53±3.79	7.60±3.70	Df = 1.9, F = 2.7, P = 0.32
P-value	0.957	0.319	0.758	0.870	0.593
Memory Executive Screening (MES)
Active Group	52.44±13.13	57.94±10.39	56.39±9.92	55.39±9.94	55.56±9.32	Df=1.6, F = 1.9, P = 0.17	Df = 1 F = 0.0001 Sig.=0.98
Sham Group	53.40±12.97	55.47±13.53	55.00±14.14	54.20±14.58	54.07±14.73	Df=1.6, F = 1.1, P = 0.33
P-value	0.899	0.550	0.704	0.814	0.859
Instrumental Daily activity living (IADL)
Active Group	13.78±3.83	17.39±4.98	16.44±4.82	16.44±4.94	17.13±4.43	Df=1.7, F = 13.8, P = 0.0001	Df = 1 F = 6.5 Sig.=0.01
Sham Group	16.27±5.62	17.13±5.64	16.80±5.92	16.80±5.82	16.80±5.82	Df=2.4, F = 2.4, P = 0.09
P-value	0.194	0.717	0.870	0.899	0.766

Statistical analysis using a two-way ANOVA with TIME (baseline, post treatment, one, two and three months later) and CONDITION (real and sham) as main factors revealed a significant interaction for UPDRS III, MoCA, MMSE and IADL (P value = 0.001; 0.0001, 0.041; 0.016 respectively) with improvement in all scores being more pronounced in active group. This was confirmed in follow up one-way ANOVAs with TIME as the main factor which showed significant improvement in UPDRS, MoCA, MMSE, and IADL in the active (P = 0.0001 for each) but not in the sham group. There were no significant changes in other rating scales. (Table 2, and Fig. 2). Post hoc testing suggested that the improvement in MoCA and MMSE that were observed immediately at the end of treatment were not maintained at follow-up (see Table 2). For the UPDRS, there were no individual time points after treatment when the clinical improvement in the active group was different to sham. In both cases, it is likely that this lack of post hoc significance is due to the small group sizes.

Fig.2

Time course of changes in UPDRS III (a), MMSE (b), MoCA (c), and IADL (d) scores from before, immediately after 10 day’s rTMS and 1,2, and 3 month later. A significant effect of time (pre-treatment, post-treatment and 1, 2, and 3 months later) for all illustrated scales in the active group while no such changes were observed in the sham group. A significant interaction effect (Time×Group) for UPDRS III (0.001), MMSE (0.0001), MoCA (0.041), and IADL (0.016). *P < <0.05, **P < 0.001 significant between groups at each point of assessment using Mann Whitney test. Points are the mean±SD. Statistical details are given in Table 2.

5.3 Electrophysiological tests

Table 3 and Fig. 3 give details of the results of the electrophysiological tests for P300, rMT, and aMT. The only difference between groups was seen in the P300 latency where a two-way ANOVA revealed a significant GROUP (active v sham) &times TIME (pre- v post-10 days of treatment) interaction (P = 0.0001) that was due to a significantly greater reduction in P300 latency in the active group compared to sham. There was also a significant increase in P300 amplitude in both groups without significant interaction between groups. There was a significant reduction of aMT in the active group but with no significant interaction between groups suggesting that the effect did not differ from that in the sham group.

Fig.3

P300 Latency and Active motor threshold in active and sham group. There is a significant shorting in P300 latency post 10 rTMS sessions in both groups with significant interaction between groups (P = 0.0001) indicating the shorting of p300 is more pronounced in active group (Fig, 3a). There is a significant reduction of active motor threshold post 10 rTMS sessions in active group with no significant interaction between groups. (Fig. 3b).

Table 3

Event Related Potentials and cortical excitability changes among studied groups

	Pre	Post	P-Value	Repeated measure analysis
	Mean ± SD	Mean ± SD	(Paired T-test)	(Two-way ANOVA Time x group)
P 300 Latency (ms)
Active	391.07±37.38	342.56±37.61	0.0001	df = 1 F = 19.062 Sig. = 0.0001
Sham	373.76±41.96	362.82±43.50	0.014
P 300 Amplitude (mv)
Active	9.56±5.03	13.76±6.79	0.007	df = 1 F = 2.625 Sig. = 0.115
Sham	10.09±6.72	11.73±6.73	0.015
Resting Motor Threshold (RMT) (mv)
Active	38.33±3.98	35.16±4.75	0.069	df = 1 F = 1.250 Sig. = 0.272
Sham	37.93±4.77	37.13±2.72	0.530
Active Motor Threshold (AMT) (mv)
Active	28.50±7.48	25.22±6.39	0.039	df = 1 F = 3.780 Sig. = 0.061
Sham	27.00±4.64	27.07±4.18	0.922

Table 4 details the effect of treatment on SICI. A three-way ANOVA revealed a significant GROUP (real v sham)×TIME (pre v post 10 days treatment) ×ISI (1, 2, 4 ms) interaction (P = 0.005) that was due to the fact that active treatment increased SICI whereas there was no effect in the sham group. This was confirmed using separate two-way ANOVAs to explore separately the effects of active and sham treatment. There was a significant ISI×TIME interaction in the active group (P = 0.001) but no effect in the sham group.

Table 4

Short interval intracortical Inhibition changes Pre and Post 10 sessions among studied groups

	Pre (Mean ±SD)				Post (Mean ±SD)				Two-way ANOVA*	Three-way ANOVA**
SICI (ms)	Single pulse 130%	ISI 1ms	ISI 2MS	ISI 4MS	Single pulse 130%	ISI 1ms	ISI 2MS	ISI 4MS
Active	1.35±0.381	0.47±0.12	0.53±0.17	0.64±0.30	1.64±0.34	0.40±0.23	0.54±0.26	0.58±0.31	df = 2.208	df = 2.116
									F = 15.203	F = 5.585
									Sig. = 0.0001	Sig. = 0.005
Sham	1.41±0.35	0.32±0.15	0.30±0.13	0.57±0.34	1.49±0.29	0.32±0.16	0.34±0.12	0.58±0.25	df = 1.678
									F = 0.927
									Sig. = 0.394

SICI; Short interval intracortical inhibition, ISI; inter-stimulus interval, ^*Greenhouse-Geisser test (time (pre and post sessions) x interstimulus interval 1,2,4 ms). ^**Greenhouse-Geisser test (time (pre and post sessions) × interstimulus interval (ISI) 1, 2, 4 ms x group active versus sham).

Figure 4 shows significant positive correlation between changes in MoCA (pre-post 10 sessions) and changes in UPDRS (pre-post 10 sessions). A significant negative correlation between change in CDR and UPDRS (pre-post 10 sessions) was recorded. No other significant correlations between different scales (the changes in cognitive scores and the changes in cortical excitability) were found.

Fig.4

Correlation between the changes in MoCA (pre-post 10 session and UPDRS (pre-post 10 sessions) and CDR; Clinical Dementia Rating (pre-post 10 sessions), and UPDRS (pre-post 10 sessions). There are significant correlation between both scores (MoCA and CDR) with the UPDRS.

6 Discussion

Cognitive impairment in PD is heterogeneous in its severity, rate of progression, and affected cognitive domains (Goldman, Williams-Gray, Barker, Duda, & Galvin, 2014); it varies from subtle cognitive decline, to mild cognitive impairment (MCI), to dementia (PDD). MCI in PD increases the risk of conversion to dementia, 80% of patients with PD-MCI develops PDD (Hoogland et al., 2017). The primary motor cortex (M1) is traditionally implicated in voluntary movement control. However, many studies suggested that M1 not only plays a role in stimulus-response compatibility, plasticity, motor sequence learning and learning of sensorimotor associations but also is engaged in motor imagery and spatial transformations (Pascual-Leone, Ganis, Keenan, & Kosslyn, 2000; Schieber, 2000; B. Tomasino, Borroni, Isaja, & Rumiati, 2005; B. Tomasino, Fink, Sparing, Dafotakis, & Weiss, 2008).

In the present study the main result was the significant improvement in UPDRS, MoCA, MMSE, and IADL in the active group (P = 0.0001, for each), while there were no such changes in the sham group. The significant interaction effect between groups for UPDRS III, MoCA, MMSE, and IADL suggests that these scores were differentially affected by rTMS, and they support the effect of high frequency rTMS on both motor dysfunction and some measures of cognitive impairment. The results were supported by the significant shortening in P300 latencies, (Pre- post 10 sessions) in active group in comparison to sham group.

As the improvement in cognitive impairment (MoCA and CDR) was significantly correlated with improvement the UPDRS, it is possible that improvement of motor dysfunctions in PD may also lead to improvement in cognitive impairment.

The motor, premotor and prefrontal regions are connected through the frontal longitudinal system (FLS) (Thiebaut de Schotten, Dell’Acqua, Valabregue, & Catani, 2012) and it is possible that this plays a role in integrating the activity of the different local networks of the frontal lobe, such as coordinating movement planning and execution (carried out by the motor and premotor networks) with an overall goal directed strategy supervised by the frontal pole (FP) networks (Grafman, 2002; Stuss, Floden, Alexander, Levine, & Katz, 2001). Thus, the improvement in some cognitive measures after repetitive sessions of high frequency rTMS could be caused by enhanced connectivity within the network, particularly since we used bilateral rTMS to improve the effect size of brain stimulation as previously reported by (Nguyen et al., 2008).

It is known that M1 can be divided into area 4a and Area 4p. Area 4a receives more cortico-cortical projections from premotor area and it is activated by externally triggered movements. It is responsible for maintaining the execution of a motor program, irrespective of the amount of attention paid to it. Area 4p is connected with somatosensory areas and activated by movements guided by somatosensory information and its activation is modulated by attention to action (Binkofski et al., 2002; Geyer et al., 1996). More recently Nobis et al (2017) assessed affective and cognitive theory of Mind (ToM) in twenty-four with left and twenty with right dominant motor symptoms of PD patients. Affective ToM was found to be associated with motor symptom severity and cognitive ToM predominantly with executive function but not with symptom lateralization. They suggested that deficits in social cognition occur as a sequel of the general corticobasal pathology in PD. So, activation of the M1 after rTMS may enhance the cortico-cortical projection to the premotor area and indirectly enhance cognitive function. Functional studies had reported M1 activation in relation to six cognitive functional categories (Barbara Tomasino & Gremese, 2016). Area 4a and 4p were activated bilaterally in motor imagery, working memory and language processing tasks (Crepaldi et al., 2013; Kaas, Van Mier, & Goebel, 2006). The left area 4a was activated in mental rotation, auditory processing and social/emotion/empathy tasks (Brown & Martinez, 2007; Kosslyn, L. Thompson, Wraga, & Alpert, 2001; Lamm, Nusbaum, Meltzoff, & Decety, 2007). M1 activation by high frequency rTMS could activate cognitive processing and could be related to mental simulation processing. Rowe and colleagues (Rowe et al., 2002) observed increased SMA activity in PD patients. rTMS over M1 showed a significant reduction in activity in SMA when performing a complex motor task. This decreased activation was associated with a stronger effective connectivity to the medial prefrontal cortex ‘’attention-to-action” circuit (Miller, 1999) and an improvement in attention could contribute to the improvement of cognitive function in PD patients with cognitive impairment after high frequency rTMS over motor area in the presentstudy.

There are a few studies on the effect of low and high frequencies rTMS on cognitive impairment in PD over dorsolateral prefrontal areas but there have been no previous studies on the effect of high frequency rTMS over the motor area on cognitive function on PD. Low-frequency rTMS over bilateral dorsolateral prefrontal areas in Parkinson’s disease improved executive function and motor function which may produce trans-synaptic effects on the fronto-striatal circuit, particularly the prefrontal circuit (Furukawa, Shin-Ichi, Toyokura, & Masakado, 2009). On the contrary, another study had shown that high frequency rTMS over the left DLPFC was shown to improved cognitive function in PD patients through increased regional cerebral blood flow in the prefrontal lobe as documented by increased in blood oxygen-level dependent (BOLD) signal (Boggio et al., 2005).

7 Limitations

Small sample size limits the power of this study and a larger sample size is recommended for future investigations. In addition, obtaining an adequate sham for rTMS is tricky. However, given that our participants had not received any TMS previously we do not think they would have perceived they were being given sham treatment. A possible solution in future trials might be to consider active stimulation at a non-relevant scalp site.

8 Conclusion

rTMS over M1 is useful for motor function and may have a small positive effect on cognition. However, better approaches for the latter are necessary, perhaps by using multisite rTMS to target both motor and frontal cortical regions.

Footnotes

Acknowledgments

The authors would like to thank Prof John Rothwell for useful discussion and editing during the preparation of this article.

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