Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits

Accepted Manuscript Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits Myung Sik Lee, Myung Jun Lee, Antonella Conte, Alfredo Berardelli PII: DOI: Reference:

S1388-2457(17)31170-7 https://doi.org/10.1016/j.clinph.2017.11.022 CLINPH 2008355

To appear in:

Clinical Neurophysiology

Accepted Date:

21 November 2017

Please cite this article as: Lee, M.S., Lee, M.J., Conte, A., Berardelli, A., Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits, Clinical Neurophysiology (2017), doi: https://doi.org/10.1016/j.clinph.2017.11.022

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Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits Myung Sik Lee, MD, PhD1; Myung Jun Lee, MD2; Antonella Conte, MD, PhD3,4; Alfredo Berardelli, MD, PhD3,4

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Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea E-mail: [email protected]

2

Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Republic of Korea E-mail:[email protected]

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Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy 4 IRCCS Neuromed, Pozzilli (IS), Italy E-mail: Antonella Conte: [email protected] Alfredo Berardelli: [email protected] Correspondence to: Alfredo Berardelli, MD, PhD Department of Neurology and Psychiatry, Sapienza University of Rome, IRCCS Neuromed, Pozzilli (IS), Rome, Italy E-mail: [email protected].

Title character count:126 including spaces Word count of abstract:200 Word count of manuscript: 3449

Abstract 1

Objective: The somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval required for two tactile stimuli to be perceived as separate, is longer in patients with Parkinson’s disease (PD). In this review, we discuss STDT findings in healthy subjects and in PD patients and the relationship between altered STDT and motor disturbances. Methods: A search was conducted on PubMed for papers dealing with PD and temporal discrimination published from January 1990 to July 2017. Results: Abnormal STDT in PD correlates with disease duration, disease severity and degree of nigrostriatal dopamine loss, and responds to dopaminergic medication. In PD, a prolonged STDT does not correlate, or only marginally correlates, with clinically assessed bradykinesia of finger tapping. By contrast, a prolonged STDT correlates with the variability in amplitude and speed of finger tapping as assessed by means of neurophysiological techniques and may contribute to impaired finger dexterity in PD. Conclusions: We suggest that abnormal temporal processing of sensory information in PD generates incorrect signals for the execution and control of voluntary movements. Significance: This review sheds light on unsolved questions regarding the relationship between STDT alterations and motor disturbances in PD and proposes directions for future research on this topic.

Keywords: Parkinson’s disease, temporal discrimination threshold, finger dexterity, finger tapping

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Highlights 

Somatosensory temporal discrimination threshold (STDT) is abnormal in PD.

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Prolonged STDT in PD correlates with the degree of nigrostriatal dopamine loss.

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Prolonged STDT in PD generates incorrect signals for the execution and control of finger movements.

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1. Introduction Ever since it was first described in ‘An essay on the shaking palsy’(Parkinson, 1817), Parkinson’s disease (PD) has been considered to be a motor disorder characterized by bradykinesia, rigidity, tremor at rest and postural instability (Berardelli et al., 2013; Postuma et al., 2015; Rodriguez-Oroz et al., 2009).However, approximately half of patients with PD complain of various sensory symptoms, including heaviness, numbness, coldness, a burning feeling, tingling, aching and severe pain (Koller, 1984). Patients with PD also display abnormal higher order sensory functions, including position sense, kinesthetic sense and cutaneous discriminative sense, especially in the fingers (Abbruzzese and Berardelli, 2003; Conte et al., 2013; Demirci et al., 1997; Konczak et al., 2009; Schneider et al., 1987; Zia et al., 2000). PD patients are also affected by abnormal temporal processing of sensory information, as evidenced by prolonged auditory, visual or tactile temporal discrimination thresholds (Artieda et al., 1992; Conte et al., 2010; Fiorio et al., 2007a; Lee et al., 2010).In humans, temporal processing of sensory information plays a prominent role in the performance of accurate voluntary movements through a process known as sensorimotor integration (Avanzino et al., 2016; Brown et al. 2013; Chapman et al. 1987; Colder, 2015; Juravle et al. 2016). In this review, we first describe the physiological mechanisms involved in the somatosensory temporal discrimination threshold (STDT) in healthy subjects. We then discuss the pathophysiological mechanisms responsible for the abnormal STDT in PD and the possible role played by this alteration in the pathophysiology of motor disturbances in PD.

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A search was conducted on PubMed for full-text papers dealing with PD and temporal discrimination published in English from January 1990 to July 2017. The search terms were "sensory abnormalities and Parkinson's disease", "temporal discrimination and Parkinson's disease", “temporal discrimination and movement” and “sensorimotor integration and movement and Parkinson’s disease”.

2. Temporal discrimination threshold in healthy subjects The temporal discrimination threshold is defined as the shortest time interval required for two temporally separate sensory stimuli to be perceived as separate (Artieda et al., 1992). The STDT is measured by using paired electrical stimuli over the skin of a body region. When the volar surface of the distal phalanx of the index finger is tested, the hand lies on a table with the fingers at rest in order to avoid changes in proprioceptive incoming information. When this experimental setting is used, the mean STDT values in healthy individuals range from 27 to 78 ms (Table 1). On methodological grounds, the intensity of electrical stimulation for the STDT is about 1.2 to 2 times the threshold for sensory perception, but is lower than the threshold for pain (Conte et al., 2016a; Lee et al., 2016; Ramos et al., 2016; Leodori et al., 2017). Paired stimulations can be given to a single site of a digit, two sites of a digit, or two spatially separate sites of different digits (for example, on the index and third fingers) (Fiorio et al., 2008; Lee et al., 2005; Lyoo et al., 2007). However, as stimulation of two different points involves a spatial discrimination component, single-point stimulation is preferable. The time interval between paired stimuli can be increased stepwise until the subject reports two stimuli; alternatively, the time interval can be reduced stepwise from an interval that is longer than the STDT until 5

the subject reports a single stimulus. Ascending STDT values are higher than descending STDT values (Artieda et al., 1992; Lee et al., 2005; Lyoo et al., 2007) (Table 1). When the stepwise method is used, a single stimulus can be delivered randomly during the test (“catch trials”) to maintain the subject’s attention. Single stimuli for the catch trials are usually mixed with trials characterized by interstimulus intervals that are longer than those needed by subjects to recognize the paired stimuli as sequential in order to disclose perseverative responses and check attention levels (Conte et al., 2010; Conte et al., 2016a). In addition to adopting stepwise methods, some researchers have explored the possibility of using a randomized technique to assess the STDT (Rocchi et al., 2016; Mc Govern et al., 2017). Which method more reliably differentiates healthy subjects from patients remains a matter of debate. Previous studies on healthy subjects have shown that the STDT varies across different body regions (e.g. face and neck < finger
is therefore limited. Although it bypasses cutaneous receptors, the STDT is commonly believed to involve cortical and subcortical processing (Conte et al., 2012; Rocchi et al., 2016; Leodori et al., 2017). This hypothesis is supported by several studies on humans in whom the microneurography technique was used (Rowe, 2002 for review). Weak electrical stimuli delivered to the sensory nerve trunk elicit conscious perceptive consequences localizable to the skin area corresponding to the receptive field of the afferent fibers. Similarly, experiments with STDT and somatosensory evoked potentials (SEP) have also shown that paired electrical stimuli for the STDT activate inhibitory interneurons in S1 (Rocchi et al., 2016; Conte et al., 2012; Antelmi et al., 2017; Tamura et al., 2008). Investigations of cortical areas with transcranial magnetic stimulation (TMS)have demonstrated that TMS over the pre-supplementary motor area (pre-SMA) does not change STDT values but merely modifies the number of errors in the “catch trials” (Conte et al., 2012), thereby suggesting that the pre-SMA is only involved in focusing attention on the task (Conte et al., 2012).The role played by the primary somatosensory cortex (S1), dorsolateral prefrontal cortex and cerebellum in the STDT has also been investigated by means of TMS in healthy subjects. TMS applied over S1 increased STDT values (Bolognini and Ro, 2010; Conte et al., 2012; Conte et al., 2014; Hannula et al., 2008; Rocchi et al., 2016; Leodori et al., 2017). Indeed, when Tamura et al. (2008) studied the paired-pulse paradigm SEP, they found that higher STDT values are associated with lower P27 suppression within S1.The findings of both TMS and SEP studies suggest that S1 plays an important role in the STDT.The increased STDT correlated with changes in SEP amplitudes, paired SEP inhibition and highfrequency oscillations in S1 (Rocchi et al., 2016; Antelmi et al., 2017). Since high frequency 7

oscillations in S1 (Ozaki and Hashimoto, 2011), paired SEP and the STDT all share common mechanisms (i.e. inhibitory interneuron activity in S1), it is reasonable to assume that TMS delivered over S1 modifies STDT values by modulating the excitability of inhibitory interneurons (Leodori et al., 2017). In conclusion, data suggest that the STDT strongly depends on S1 inhibitory interneurons. In pathological conditions, focal lesions in the frontal cortex, parietal cortex, basal ganglia or medial thalamus may increase the STDT without causing primary sensory changes (Lacruz et al., 1991). In keeping with this hypothesis, a brain functional magnetic resonance imaging (fMRI) study showed that a STDT task activated the prefrontal cortex, pre-SMA, anterior cingulate cortex, post-central cortex, inferior parietal cortex, basal ganglia and cerebellum (Pastor et al., 2004).These findings suggest that various cortical as well assubcortial neuronal structures are involved in the STDT. The main subcortical structures that may be involved in temporal processing are the cerebellum and basal ganglia. Both of these neuronal structures function as ‘internal clocks’ for the precise timing of movement and sensory perception (Ivry, 1996; Ivry and Spencer, 2004).The cerebellum is known to beinvolved in the discrimination of temporal processing in the millisecond range, whereas nigrostriatal-prefrontal circuits are implicated in temporal processing in the second range (Ivry, 1996; Ivry and Keele, 1989). The cerebellum and basal ganglia are interconnected, their role in temporal discrimination tasks being determined not only by the time interval but also by the characteristics of the stimulus and task (Koch et al., 2009; Wu and Hallett, 2013). TMS over the cerebellum in healthy individuals was not found to modulate STDT values (Conte et al., 2012). In a study by Rammsayer (1997a), the administration of a selective cortical dopamine 8

receptor blocker (remoxipride) caused overestimation of temporal processing in the second, though not millisecond, range. By contrast, a non-selective dopamine receptor blocker (haloperidol) that acts on cortical and basal ganglia dopamine receptors was found to lead to an overestimation of temporal processing in both the millisecond and second ranges and to impair motor control (Rammsayer, 1997b). In keeping with the importance of the role played by the basal ganglia in temporal processing, Pastor et al. (2008) demonstrated, by means of fMRI, that the putamen is activated only when participants are positive that two stimuli have been perceived (Pastor et al., 2008). It has been suggested, on the basis of animal and human studies, that temporal discrimination also involves an alerting circuit mediated by dopaminergic transmission (Dean et al., 1989; Redgrave and Gurney, 2006; Redgrave et al., 2010; Overton et al., 2014). Lastly, a recent study on healthy subjects revealed that when the STDT is tested on the index finger during index finger abductions, STDT values increase upon movement onset and the increase fades away 200 ms later (Conte et al. 2016b). S1 modulation induced by TMS does not affect movement-induced STDT changes. In view of both these findings and of previous findings from animals showing that sensory gating at the basal ganglia level is induced by movement (Colder et al., 2015), movement-induced STDT modulation provides indirect evidence of a sensory gating process that may be mediated by basalganglia/thalamus connections to preserve motor output from irrelevant afferent input (Conte et al., 2016b).

Overall, the STDT appears to be encoded in S1 and to depend on a widespread network that also involves subcortical structures, including the basal ganglia.

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3.Temporal discrimination threshold changes in PD In their pioneering study, Artieda et al. (1992) found that the STDT of the finger was increased in patients with PD. Numerous other studies have since reported significantly higher STDT values following stimulation of the finger and toe in PD patients (mean values ranged from 90 to 130ms) than in healthy subjects (mean values ranged from 27 to 90ms) (Table 1). Several mechanisms may be responsible for the longer STDT in PD. A recent investigation based on quantitative sensory testing and skin biopsies in PD patients revealed a marked fiber distal axonopathy in PD (Nolano et al., 2017). This alteration was also observed in de novo PD patients. The suggestion that peripheral mechanisms underlie the increased STDT goes against recent findings based on 63 PD cases with varying disease severity and duration in whom STDT values were found to be in the normal range in de novo-/early stage PD patients and abnormal only in mild-moderate and severe PD patients (Conte et al., 2016a) (Table 1). Since STDT values in de novo/early stage PD are normal when skin biopsies already display large fiber distal involvement (Nolano et al., 2017), large fiber involvement is unlikely to be the main mechanism underlying altered STDT values. A number of observations point to a major role of the basal ganglia and dopaminergic neurotr ansmission in altered STDT values. Several studies have consistently shown that levodopa tre atment influences STDT values in PD. In a dopamine transporter (DAT) PET study ([18 F]-N -3-fluoropropyl-2-beta-carboxymethoxy-3-beta- (4-iodophenyl-nortropane) conducted on PD patients, Lyoo et al. (2012) reported that increased STDT values of the index finger correlated with the uptake of DAT in both the caudate (p=0.01) and putamen (p=0.004). A TMS study found that the effects of cerebellar stimulation on the STDT were 10

clearly detectable when patients were off levodopa therapy but were negligible when patients were on levodopa therapy (Di Biasio et al., 2015). The fact that dopaminergic therapy affects STDT values further supports the hypothesis that dopaminergic mechanisms mediate the STDT. However, the extent of the levodopa-induced improvement in STDT values of PD patients remains unclear. One study found that abnormally increased STDT values of the great toe returned to within the normal range following levodopa treatment (Lee et al., 2005), whereas other authors observed that although such treatment did have a significant effect, abnormally increased STDT values of the finger did not return to normal following levodopa intake (Artieda et al., 1992; Conte et al., 2010; Lyoo et al., 2012). In patients with a subthalamic nucleus deep brain stimulation (STN-DBS) implant, STDT values markedly improved in the levodopa ON condition but worsened in the OFF condition (Conte et al., 2010). In keeping with this observation, Bologna et al. (2016) recently showed that Ldopa/carbidopa intestinal gel infusion markedly improved, despite again failing to normalize, high STDT values in PD. There may be two explanations for the normal STDT in the early stages of PD (Conte et al., 2016a). The first is that the dopaminergic depletion threshold required to alter the STDT is higher than that required for the appearance of motor disturbances. The second is that subcortical dopaminergic depletion alters the cortical mechanisms involved in STDT processing. Whatever the exact mechanism is, the basal ganglia play a role in STDT whether it be directly or indirectly. It cannot, however, be ruled out that mechanisms other than those related to dopamine partly contribute to STDT alterations. The other issue that remains unclear is why STDT values are higher in clinically unaffected subjects with a heterozygous PINK1 mutation for parkinsonism (Fiorio et al., 11

2008). An [18F]-dopa PET study demonstrated that asymptomatic PINK1 mutation carriers display a 20 to 30% uniform reduction in striatal uptake, whereas PD patients display an anterior-posterior gradient in striatal uptake reduction (Khan et al., 2002). Such differences in the topographic distribution of striatal dopamine loss might be one explanation for the contradictory findings that have emerged. In conclusion, although STDT abnormalities in PD arise above all from nigrostriatal dopamine depletion, they may also reflect the failure of non-dopaminergic compensatory mechanisms in brain areas other than the basal ganglia.

4.Temporal discrimination threshold and motor deficits in PD Tactile afferent information can be gated or prioritized in healthy subjects according to the type of finger movement. Tactile information also competes with kinesthetic information during movement execution (Burke et al., 1982; Rowe et al., 2002; Costa et al., 2008; Colder et al., 2015). Temporal processing of tactile information is, therefore, a prerequisite for correct tactile-proprioceptive integration during ongoing movement. The increased STDT in PD may thus play a role in the alterations of finger movement execution. Several authors have investigated whether the extent of STDT alterations correlates with the severity of motor impairment in PD. However, such correlationbased experimental approaches have certain limitations because any correlation between the STDT and clinical scales does not necessarily reflect a direct role of altered STDT on the quality of movement performance. This is likely to explain the discrepant results yielded by these studies. Some studies have reported correlations between increased STDT values of the finger and the overall severity of PD as measured by King’s College 12

Hospital PD rating scale scores and UPDRS total motor scores (Artieda et al., 1992; Conte et al., 2016a) (Table 1). By contrast, other studies have found no, or only marginally significant, correlations between STDT values of the finger and UPDRS total motor or finger bradykinesia scores (Conte et al., 2010; Lee et al., 2010; Lee et al., 2016; Lyoo et al., 2012; Rocchi et al., 2013). One possible explanation for these contrasting results might be the inherent limitation of the UPDRS, which includes various parkinsonian motor deficits associated with independent pathophysiological mechanisms into a single score (Heldman et al., 2011; Rodriguez-Oroz et al., 2009). In order to shed more light on the relationship between the STDT and finger movement kinematic, some authors (Heldman et al., 2011; Lee et al., 2016) have investigated possible correlations between STDT values and quantitative measurements of finger movements. Inertial sensors attached to the fingers yield quantitative measurements of mean values, variability and decrements in the amplitude, speed and frequency of free amplitude finger tapping (Heldman et al., 2011; Lee et al., 2016). In PD, inertial sensor analyses of free amplitude maximum speed (FRAMS) finger tapping revealed reduced values and increased variability in the amplitude, speed and frequency of finger movements (Heldman et al., 2011; Lee et al., 2016). Although Lee et al. (2016) found no relationship between STDT changes and the amplitude and speed of movements, they did find that higher STDT values correlated with the increased variability in amplitude and speed, which may reflect altered sensorimotor integration due to the prolonged temporal processing of tactile information. This issue, however, deserves further investigation. The coin rotation task is a simple and validated method for the quantitative assessment of impaired finger dexterity (Hill et al., 2010; Mendoza et al., 2009). This task requires timely 13

generation, execution and feedback control of motor programs through continuous tactile sensory monitoring of fingers and a coin (Hanna-Pladdy et al., 2002). In PD, coin rotation performance abnormalities have been found to correlate with STDT values measured over the fingers (Lee et al.,2016). Abnormal tactile temporal discrimination may therefore be involved in impaired manual dexterity. Accordingly, recent findings from studies on sensory gating during movement execution in PD patients show that STDT-gating during movement is altered and that movement velocity concomitantly decreases (Conte et al., 2017). Overall, these observations point to a link between an altered STDT and finger movement abnormalities in PD patients.5. Conclusions In healthy subjects, the STDT is a useful and reliable measure for assessing temporal processing of sensory information. It is encoded in S1 but is also modulated by neuronal networks between the basal ganglia, cerebellum and various cortical areas (Conte et al., 2010; Conte et al., 2012; Di Biasio et al., 2015). Several studies have consistently shown that the STDT is abnormally increased in PD, which suggests that the ‘internal clock’ for temporal discrimination of sensory information runs slowly in PD (Artieda et al., 1992). STDT abnormalities in PD correlate with the degree of nigrostriatal dopamine loss as well as with the severity and duration of the disease (Conte et al., 2016a; Lyoo et al., 2012), and are improved by dopaminergic medication (Artieda et al., 1992; Conte et al., 2010; Lee et al., 2010). Hence, dopamine loss in the striatum seems to be the main pathophysiological mechanism responsible for the prolonged STDT in PD (Conte et al., 2010; Conte et al., 2013; Lyoo et al., 2012). In 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated monkeys, proprioceptive inputs arising from the limb induce excessive responses in the cortico-basal ganglia-thalamic 14

network (Boraud et al., 2000; Crutcher and DeLong, 1984; DeLong et al., 1985; Escola et al., 2002; Filion et al., 1988; Pessiglione et al., 2005). It is therefore conceivable that temporal dispersion of the noise in this neuronal network obscures phasic changes in neuronal bursts induced by temporally-separate paired sensory inputs and may prolong the STDT in PD (Escola et al., 2003; Conte et al., 2013). The observation that the STDT is normal at the onset of PD suggests that STDT abnormalities only appear when dopamine loss reaches a certain threshold (possibly higher than that for motor symptoms), though they may also be caused by non-dopaminergic mechanisms outside the basal ganglia (Conte et al., 2016a). An increased STDT may be considered as a marker of disease progression in PD (Conte et al., 2016a). However, the observation that the STDT is increased in clinically unaffected subjects with a heterozygous PINK1 mutation for parkinsonism suggests that an increased STDT is an endophenotypic biomarker of hereditary parkinsonism, just as it is of dystonia (Fiorio et al., 2007b; Bradley et al., 2009; Hutchinson et al., 2013; Tinazzi et al., 2013; Kimmich et al., 2014; Conte et al., 2016c). STDT abnormalities in PD may contribute to specific motor dysfunctions such as irregular amplitude and speed of fast repetitive movements and impaired manual dexterity. This hypothesis is supported by recent evidence showing that the STDT in PD is not properly gated during movement execution and that movement performances deteriorate concomitantly (Conte et al., 2017). Alternatively, STDT abnormalities and motor control deficits may be considered to represent two sides of the same coin, both of which are independent consequences of nigrostriatal dopamine loss. Further studies designed to

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manipulate the STDT and motor performance are likely to shed light on these unresolved issues. Conflict of interest None of the authors have any potential conflicts of interest to disclose.

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Table. Summary of previous studies on somatosensory temporal discrimination threshold (STDT) in degenerative parkinsonism Authors (year)

Body sites tested

Subjects (n)

Artieda et al. (1992)

Index finger

PD (44)

Stimulation point (side)

aSTDT

dSTDT

Findings

Same point (right)

118.0 ± 23.0

95.2 ± 24.0

STDT Correlated with,

Same point (left)

117 ± 24.7

90.3 ± 22.3

• King's College PD rating scores

Same point (right)

39.5 ± 14.3

28.8 ± 11.1

• Movement time of ballistic wrist extension

Same point (left)

37.4 ± 13.5

27.7 ± 10.1

• Speed of fixed amplitude finger tapping

Control (20)

Levodopa: reduced STDT

Lee et al. (2005)

Great toe & little toe

PD (22)

NM (both)

122.5 ± 47.4

102.1 ± 40.8

Control (11)

NM (both)

NM

NM

STDT correlated with FOG-Q STDT in PD with off gait freezing > without off gait freezing Levodopa: normalize STDT

Lyoo et al. (2007)

Great toe & little toe

Same point (both)

130.4 ± 29.5

91.9 ± 22.5

Different point (both)

119.5 ± 28.7

85.6 ± 22.2

Same point (both)

90.5 ± 5.9

77.8 ± 8.6

Different point (both)

81.0 ± 13.5

70.0 ± 14.4

PINK1 homo (7)

Different point (both)

120.4 ± 64.4

NE

PINK1 hetero (14)

Different point (both)

110.7 ± 59.7

NE

Control (14)

Different point (both)

62.2 ± 30.0

NE

Prolonged STDT (both in PINK1-homo & -hetero)

PD (13)

Same point (both)

NM

NE

STDT not correlate with UPDRS-TM

Control (13)

Same point (both)

NM

NE

MSA (30)

STDT correlated with UPDRS-TM & BR - independent with ICARS scores

Control (11)

Fiorio et al. (2008)

Conte et al. (2010)

Index & middle finger

Index finger, eye & neck

Prolonged STDT of MSA patients

STDT not correlated with UPDRS-TM (PINK1-homo)

Levodopa: reduced STDT DBS: increased STDT

Lee et al. (2010)

Lyoo et al. (2012)

PD (48)

Same point (right)

124.0 ± 44.8

NE

STDT correlated with CRT performance

Control (24)

Same point (right)

78.1 ± 26.2

NE

STDT not correlated with speed of fixed amplitude finger tapping

Same point (right)

111.3 ± 44.7

NE

Same point (left)

103.7 ± 39.4

NE

STDT correlated with.

Same point (both)

107.5 ± 38.8

NE

• UPDRS-AX (not with UPDRS-TM)

Same point (right)

70.7 ± 24.3

NE

• Striatal DAT uptake

Same point (left)

65.5 ± 18.5

NE

Levodopa: reduced STDT

Same point (both)

68.1 ± 20.5

NE

Index finger

Index finger

PD (30)

Control (29)

26

Rocchi et al. (2013)

MSA (20)

Same point (both)

NM

NE

STDT not correlated with,

PD (21)

Same point (both)

NM

NE

• UPDRS-TM both in PD & MSA

Control (18)

Same point (both)

NM

NE

Index finger

• MMSE & FAB scores STDT in MSA > PD Di Biasio et al. (2015)

Index finger

Conte et al. (2016a)†

Index finger & face

PD (15)

Same point (both)

NM

NE

c-TBS over cerebellum: reduced off-period STDT

Control (10)

Same point (both)

NM

NE

Levodopa: reduced STDT

PD (21), baseline

Same point (both)

94.9 ± 25.2

NE

STDT correlated with

PD (21), follow-up

Same point (both)

91.1 ± 19.5

NE

• UPDRS-TM

Control (51)

Same point (both)

NM

NE

• Disease duration Normal STDT at PD onset

Lee et al. (2016)

Index finger

PD (33)

Control (24)

Same point (right)

100.3 ± 37.5

NE

Same point (left)

97.3 ± 38.2

NE

STDT correlated with,

Same point (both)

98.8 ± 67.6

NE

• CRT performance‡

Same point (right)

53.8 ± 16.9

NE

• UPDRS finger BR‡

Same point (left)

53.8 ± 20.0

NE

• Variability in amplitude & speed of finger tapping

Same point (both)

53.8 ± 18.3

NE

Mean ± SD; aSTDT = ascending somatosensory temporal discrimination threshold; c-TBS = continuous theta-burst stimulation; CRT = coin rotation task; DAT = dopamine transporter; DBS= deep brain stimulation; dSTDT = descending somatosensory temporal discrimination threshold; FAB = frontal assessment battery; FOG-Q = freezing of gait questionnaire; ICARS = international cooperative ataxia rating scale; MMSE = mini-mental status examination; MSA = multiple system atrophy; NM= not mentioned; NE=not examined; PD = Parkinson’s disease; PINK1- hetero= heterozygous PINK1 mutation; PINK1-homo = homozygous PINK1 mutation; UPDRS-AX = UPDRS subscores for axial motor deficits; UPDRS-BR = UPDRS subscores for bradykinesia; UPDRS-TM = Unified Parkinson's Disease Rating Scale total motor scores; † = STDT values in 21 early phase PD were shown; ‡ = marginal statistical significance (p = 0.05) 27