- Email: [email protected]
Somatosensory temporal discrimination threshold in Parkinson’s disease parallels disease severity and duration
Clinical Neurophysiology 127 (2016) 2985–2989
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Somatosensory temporal discrimination threshold in Parkinson’s disease parallels disease severity and duration Antonella Conte a, Giorgio Leodori b, Gina Ferrazzano a, Maria I. De Bartolo b, Nicoletta Manzo b, Giovanni Fabbrini a,b, Alfredo Berardelli a,b,⇑ a b
IRCCS Neuromed, Pozzilli (IS), Italy Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
a r t i c l e
i n f o
Article history: Accepted 29 June 2016 Available online 5 July 2016 Keywords: Somatosensory temporal discrimination Parkinson’s disease Early-phase Disease progression
h i g h l i g h t s STDT (somatosensory temporal discrimination threshold) does not differ between PD at clinical onset
and healthy subjects. STDT abnormalities correlate with the duration and severity of PD. Abnormal STDT appears when compensatory mechanisms fail to compensate altered basal ganglia
activity.
a b s t r a c t Objective: To investigate whether the somatosensory temporal discrimination threshold (STDT) is already altered at the clinical onset of Parkinson’s disease (PD) and whether STDT abnormalities correlate with disease progression we tested STDT values in patients with different severity of disease. Methods: We prospectively and consecutively enrolled 63 PD patients: 26 drug-naive PD patients with symptom onset no longer than two years prior to inclusion in the study (early-phase), 37 PD patients with varying degrees of disease severity and 51 age-matched healthy subjects. The STDT was tested on the index finger of both hands, and on both sides of the face. Twelve out of 26 early phase PD patients were re-tested two years after the initial diagnosis. Results: PD patients as a whole displayed higher STDT values than healthy subjects. STDT values did not significantly differ between early-phase PD patients and healthy subjects, whereas they were significantly higher in patients with mild/moderate and advanced PD. In early-phase PD patients STDT values at the two years-follow up assessment did not statistically differ from those obtained at baseline. Considering the whole group of PD patients STDT abnormalities significantly correlated with duration and severity of the disease. Conclusions: STDT increases as disease progresses. In early-phase PD patients STDT values are still statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. Significance: Our study gives new insight into the sensory abnormalities in PD. Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The somatosensory temporal discrimination threshold (STDT) is defined as the shortest interval at which an individual recognizes a ⇑ Corresponding author at: Department of Neurology and Psychiatry, ‘‘Sapienza” University of Rome, Viale dell’Università 30, 00185 Rome, Italy. Fax: +39 0649914700. E-mail address: [email protected] (A. Berardelli).
pair of stimuli as separate in time (Lacruz et al., 1991). It relies on a purely sensory process that allows the brain to ‘‘filter” the relevant sensory information from external sources (Costa et al., 2008). Previous studies on healthy subjects have suggested that the STDT depends on the integrity of a complex cortico-subcortical network in which S1 plays an encoding role and basal ganglia determine a time-related interaction between cortical and subcortical structures (Conte et al., 2012; Harrington et al., 1998a,b; Ivry, 1996).
http://dx.doi.org/10.1016/j.clinph.2016.06.026 1388-2457/Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2986
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
Some studies have demonstrated that the STDT is altered in Parkinson’s disease (PD) (Abbruzzese and Berardelli, 2003; Artieda et al., 1992; Conte et al., 2010, 2013; Lyoo et al., 2012; Patel et al., 2014). Whether the STDT is already altered at the clinical onset of PD symptoms is however unknown. The results of previous studies on the relationship between STDT values and disease severity are contrasting (Conte et al., 2010; Lee et al., 2010; Lyoo et al., 2012; Rocchi et al., 2013). Studies that did find a significant association between STDT values and motor deficit scores reported that the STDT only correlated with the Unified Parkinson’s Disease Rating Scale (UPDRS) subscores for axial motor deficits (Lyoo et al., 2012). A better knowledge of these issues would provide further insight into sensory disturbances in PD. In particular, if STDT abnormalities are already present at the onset of motor symptoms, the STDT may be a valuable hallmark of the disease and consequently be considered a disease trait. Alternatively, if STDT abnormalities appear during the course of the disease, STDT may be a feature which reflects disease progression in PD thus giving new insight into the pathophysiology of altered STDT. The aim of our study was to investigate whether STDT is already altered at the clinical onset of Parkinson’s disease (PD) or whether STDT abnormalities develop only in the late-phase of the disease. We therefore studied STDT values in 63 PD patients in different disease stages, including patients with early-phase PD, and compared the results with those obtained from a group of 51 healthy subjects. We then investigated whether there were any correlations between the STDT values and the clinical and demographic features of the PD patients.
Since the temporal sensory processing data yielded by STDT testing are only reliable if cognitive functions are normal, patients with a MMSE score lower than 26, a FAB score lower than 15 or a MOCA score lower than 24 were excluded. We also excluded patients with a HMRD score higher than 10. All participants were screened for peripheral sensory neuropathy by medical history and bed-side clinical examination. Any patients or healthy subjects who had a clinically-diagnosed peripheral sensory neuropathy or which presented major risk factor for neuropathy (e.g. diabetes, chronic metabolic diseases, autoimmune diseases, etc.) were not included in the study. No patient had a history of central nervous system disease different from PD, neither was taking drugs with actions on the central nervous system other than dopaminergic treatment. Healthy subjects had no history of any neuropsychiatric disorders and were not taking drugs with actions on the central nervous system at the time of the experiments. We included patients in different stages of disease: 26 earlyphase drug-naïve PD patients with onset of symptoms no longer than two years prior to inclusion in the study (early phase: H&Y = 1–2.5), 37 PD patients with a disease duration longer than two years and varying degrees of disease severity (28 mild/moderate: H&Y = 1–3; 9 advanced: H&Y = 4–5) who were on chronic dopaminergic treatment. PD patients on chronic dopaminergic treatment were tested OFF dopaminergic therapy (12 h after the last dose of dopaminergic medication). A subgroup of 12 of the 26 drug-naive PD patients who started dopaminergic therapy after the first assessment were tested again two years later in the OFF therapy condition.
2.2. STD procedure 2. Methods 2.1. Study participants and clinical assessment We enrolled a total of 63 PD patients (mean age 63.6 ± 8.1 years) diagnosed according to published criteria (Berardelli et al., 2013) and 51 age-matched healthy subjects recruited among caregivers and spouses of PD patients (mean age 63.1 ± 8.7 years). All participants were right-handed. Patients were consecutively and prospectively recruited from the movement disorder outpatient clinic of the Department of Neurology and Psychiatry at Sapienza University of Rome from June to December 2013. Written informed consent was obtained from all the patients and healthy subjects. The experimental procedure was approved by the institutional review board at Sapienza University of Rome and conducted in accordance with the Declaration of Helsinki. Information regarding the demographic characteristics, family history and disease course were collected during a face-to-face interview. Parkinsonian motor symptoms were assessed using the Hoehn and Yahr Scale (H&Y) and the UPDRS part III (Table 1). All the patients underwent the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MOCA) and Hamilton Rating Scale for Depression (HMRD).
The STD was investigated by delivering paired stimuli starting with an interstimulus interval (ISI) of 0 ms (simultaneous pair), and progressively increasing the ISI in 10 ms steps, according to the experimental procedures used in previous studies (Conte et al., 2012; Scontrini et al., 2009). Paired tactile stimuli consisted of 100-ls square-wave electrical pulses delivered with a constant current stimulator (Digitimer DS7AH) through surface skin electrodes with the anode located 0.5 cm distally to the cathode, which was applied to the volar surface of the index finger of the left and right hands, and to the left and right sides of the face. The stimulation intensity was defined for each subject by delivering a series of stimuli at an increasing intensity starting from 2 mA in 0.5 mA steps; the intensity used for the STD was the minimal intensity perceived by the subject in 10 out of 10 consecutive stimuli. The first of three consecutive ISIs at which participants recognized the stimuli as temporally separate was considered the STDT value. To keep the subjects’ attention level constant during the test and minimize possible perseverative responses, we included ‘‘catch” trials consisting of a single stimulus delivered randomly. Paired stimuli were delivered at intervals of between 3 and 5 s. Patients were asked to report, as soon as possible, whether they perceived a single stimulus or two temporally separated stimuli by saying ‘‘one” or ‘‘two” after each stimulation in the interval preceding the next paired stimuli. Each session comprised four separate
Table 1 Clinical and demographic features of patients.
Early-phase PD Mild/Moderate PD Advanced PD Kruskal–Wallis’ test p
Subjects
Age (years)
Disease duration (months)
Hoehn & Yahr
UPDRS III
MMSE
MOCA
FAB
Hamilton
26 28 9 –
64.4 ± 8.6 64.6 ± 8.7 61.4 ± 6.1 0.62
13.23 ± 7.9 108.9 ± 66.9 164.0 ± 31.2 <0.000001
1.5 ± 0.6 2.2 ± 1.1 4.1 ± 1.1 <0.000001
13.3 ± 5.5 25.9 ± 11.7 39.7 ± 10.1 <0.000001
28.7 ± 1 28.6 ± 1 27.9 ± 1 0.5
26.8 ± 2 26.6 ± 2 27.8 ± 1 0.2
17.2 ± 1 16.9 ± 1 16.0 ± 1 0.13
5.1 ± 2 5.0 ± 3 6.0 ± 3 0.4
UPDRS III: Unified Parkinson’s Disease Rating Scale (UPDRS) part III. PD: Parkinson’s disease. Data are expressed as mean ± SD.
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
2987
blocks. The STDT was defined as the average of four STDT values, i.e. one for each block, and was entered in the data analysis. 2.3. Statistical analysis Kruskal–Wallis’ test was used to compare clinical scores among the PD subgroups. To analyze STDT values we first used a between-group ANOVA to evaluate any differences in STDT values between the whole PD patient group (n = 63) and healthy subjects (n = 51). We then performed a between-group ANOVA with factor group (early-phase PD, mild/moderate PD, advanced PD and healthy subjects), factor side (right and left) and factor body part (hand and face). The Tukey test was applied for the post hoc analysis. To assess the diagnostic accuracy (sensitivity and specificity) of STDT testing in differentiating patients with PD from healthy subjects, we used a receiver operating characteristic (ROC) curve analysis. The ROC analysis was performed on the STDT values of the healthy group and the whole group of PD patients. The ROC curve allows to identify the optimal threshold value (the so-called best cut-off), that is, the test value- corresponding to the highest diagnostic accuracythat maximizes the difference between the true positive (i.e. the proportion of individuals who have an altered value of the test among all those actually affected by the disease) and false positives (i.e. the proportion of individuals that despite having an altered value of the test are not suffering from the disease of interest). To estimate the diagnostic accuracy of STDT testing, we then calculated the area under the curve (AUC) value. In the group of earlyphase PD patients, we applied the ‘cut-off value’ to discriminate between patients with normal STDT and those with impaired STDT, and then ran a Mann–Whitney U test to investigate any differences in clinical features between the two subgroups. To analyze changes in STDT values in early-phase PD at the baseline and at the two-year follow-up assessment, we used a repeated measures ANOVA with factor time (2 levels: baseline and one-year follow-up assessment), side (right and left) and body part (hand and face). Holm’s test for multiple comparisons was applied. Data were tested for non-sphericity. Greenhouse–Geisser’s correction was applied when needed. Spearman’s correlation coefficient was used to identify any correlations between the clinical scale scores and STDT values. p < 0.05 was considered to indicate statistical significance. 3. Results Demographic and clinical data are reported in Table 1. The between-group ANOVA revealed a significant factor group (F(1,112) = 33.45; p < 0.0000001) though no significant factor side, body part or interactions. STDT values were higher in PD patients (whole sample) than in healthy subjects regardless of the body part or body side assessed. Between-group ANOVA, which was performed to detect any differences in STDT values between the three groups of PD patients stratified according to disease severity (early-phase, mild/moderate and advanced) and healthy subjects, revealed a significant factor group (F(1,110 = 18.22; p < 0.0000001) though no significant factor side, body part or interactions. Posthoc analysis showed that STDT values in early-phase PD patients did not differ from those in healthy subjects (p = 0.09), whereas STDT values in mild/moderate and advanced PD patients were significantly higher than in healthy subjects (mild/moderate PD vs. healthy subjects: p < 0.000001; advanced PD patients vs. healthy subjects: p < 0.0000001) (Fig. 1). The ROC curve analysis for the STDT mean values in both the PD patients and healthy subjects yielded a 68.25% sensitivity and 76.48% specificity, with a cut-off STDT value of 93.95 ms. The esti-
Fig. 1. Somatosensory temporal discrimination threshold (STDT) tested in healthy subjects and in patients with Parkinson’s disease (PD) (early-phase, mild/moderate and advanced PD). STDT was tested on the right and left hands, and on the right and left sides of the face as indicated on the X axis. Y axis: STDT values expressed in milliseconds.
mate of the AUC value (0.826) showed that the STDT yielded accurate scores. According to the cut-off STDT value determined by the ROC analysis, 12 of the 26 early-phase PD had a normal STDT, whereas the remaining 14 patients had a mildly increased STDT. The Mann– Whitney U test showed, however, that age (p = 0.94), disease duration (p = 0.93), H&Y (p = 0.54) and UPDRS part III (p = 0.78) did not significantly differ between early-phase PD patients with normal STDT values and those with increased STDT values. Repeated measures ANOVA performed to detect any changes in STDT values in early-phase PD patients between the baseline (mean value 94.9 ± 25.2) and the two-year follow-up assessment (mean value 91.1 ± 19.5) did not reveal any statistical significance of factor time (F(1,11) = 0.73; p = 0.41), side (F(1,11) = 0.27; p = 0.6) or body part (F(1,11) = 0.30; p = 0.59). Spearman’s correlation coefficient showed that STDT values significantly correlated with scores in the H&Y (p = 0.003), UPDRS part III total (p = 0.005) (Fig. 2) and disease duration (p = 0.006) (Fig. 3). 4. Discussion In this study, we show that STDT values did not statistically differ between early-phase PD patients and normal subjects, but were significantly higher in patients with mild/moderate and advanced PD. With a 2-years-follow-up in a subgroup of 12 out of 26 early-phase PD patients we also show that STDT values did not change significantly two years after the initial diagnosis. Lastly,
Fig. 2. Correlation between somatosensory temporal discrimination threshold (STDT) and UPDRS score in patients with Parkinson’s disease (PD) (STDT value corresponds to the mean STDT in the individual subject). X axis: STDT values expressed in milliseconds; Y axis: UPDRS score.
2988
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
Fig. 3. Correlation between somatosensory temporal discrimination threshold (STDT) and disease duration in patients with Parkinson’s disease (PD) (STDT value corresponds to the mean STDT in the individual subject). X axis: STDT values expressed in milliseconds; Y axis: disease duration in months.
we found that STDT abnormalities significantly correlated with the duration and severity of the disease. We took numerous precautions to ensure that the results regarding the STDT study were reliable. We excluded peripheral nerve abnormalities in all the patients who had altered STDT values by means of conventional nerve conduction studies. Subjects with a MMSE score lower than 26, FAB lower than 15 or MOCA lower than 24 were also excluded to avoid a confounding effect on the reliability of the STDT due to cognitive impairment. To detect any potential response bias related to changes in attention levels or perseverative responses, our experimental protocol also included catch trials consisting of a single stimulus (Scontrini et al., 2009). In order to avoid possible false negative results due to the positive effects of dopaminergic therapy on the STDT, we only included drug-naive patients in the group of early-phase PD patients and tested all the patients with mild/moderate and advanced PD in the OFF therapy condition (Artieda et al., 1992; Conte et al., 2010, 2013; Rocchi et al., 2013). The strength of this study, unlike previous reports based on limited numbers of patients, is that we enrolled a cohort of 63 patients in varying disease stages and performed a follow-up assessment after two years in the patients with early-phase PD. The novel finding of the present paper is that in early-phase PD patients the STDT did not significantly differ from that of healthy subjects, whereas in mild/moderate and advanced PD patients it did. Differences in STDT values between early-phase PD patients and healthy subjects did not reach statistical significance, though when we applied the cut-off value determined by the ROC curve analysis we found that about half of the early-phase PD patients had unequivocally normal STDT values whereas the other half had mildly increased STDT values. No differences were detected in the clinical and demographic features between these two early-phase subgroups. The observation that STDT is unequivocally normal in at least half of patients with early-phase PD suggests that STDT abnormalities cannot be considered a disease trait. The finding that values were higher in advanced than in mild/moderate PD suggests that the abnormalities in the STDT reflect disease severity. This hypothesis is supported by the correlation we found between higher STDT values and higher UPDRS Part III scores. Unlike other studies, which did not find any correlation between STDT values and global UPDRS scores, a correlation did emerge in our study, in which we enrolled a large sample of PD patients with a wide-ranging disease severity. Since patients with greater motor symptom severity also had the longest disease duration, abnormalities in STDT values also depend on disease duration. One possible explanation for STDT abnormalities in PD is based on the theory of background noise. Studies on animal models of PD have suggested that altered dopaminergic projections reduce func-
tional segregation and expansion of the somatosensory receptive fields in the striatum, thus increasing the background noise related to sensory input (Filion et al., 1988). Dopamine may play a key role as a pacemaker in the internal clock model of interval timing (Meck, 1983; Rammsayer, 1993). A recent [18F]-N-3-fluoropro pyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) positron emission tomography study on PD patients found a correlation between STDT values and a dopaminergic deficit in the striatum (Lyoo et al., 2012). These findings, combined with our observation that the STDT deteriorates as the disease worsens, suggest that the mechanisms underlying the increase in STDT values in PD are linked to dopaminergic denervation. In keeping with this hypothesis, several authors have demonstrated that STDT values are improved, though not fully normalized, by dopaminergic therapy (Artieda et al., 1992; Conte et al., 2010, 2013; Rocchi et al., 2013). The hypothesis that dopaminergic denervation is responsible for STDT abnormalities does not, however, explain why all early-phase PD patients, who already suffer from degeneration of the dopaminergic neuron system above a critical threshold and therefore display motor symptoms, have normal STDT values. Several recent reports have identified dopamine- and non-dopamine-mediated compensatory mechanisms implemented by structures outside the basal ganglia, including several cortical areas and the cerebellum (AppelCresswell et al., 2010; Lee et al., 2000; Obeso et al., 2004; Sabatini et al., 2000; van Nuenen et al., 2009; Zigmond, 1997). Since STDT abnormalities in PD patients appear when motor symptoms become more severe, we may speculate that alterations of basal ganglia output alone do not lead to STDT abnormalities, which only appear when the compensatory activity of structures including the cortex fails to compensate for abnormal basal ganglia activity. Changes in several neurotransmitters are indeed known to occur as the disease progresses (Barone, 2010; Giza et al., 2012; Langston, 2006). Our observation that patients with early-phase PD have normal STDT values is apparently in contrast to that made in unaffected PINK1 (PARK6) heterozygous carriers (Fiorio et al., 2008). Fiorio et al. suggested that deficits in temporal processing might be considered a subclinical alteration, at least in PINK1-related parkinsonism. Functional neuroimaging studies have demonstrated that PARK6 and idiopathic PD patients matched for disease duration and clinical disease severity display different nigrostriatal dopaminergic dysfunction patterns (Khan et al., 2002). Differences in the STDT between idiopathic and unaffected PINK1 heterozygous carriers may thus reflect differences in the pathophysiological mechanisms underlying these two conditions. We acknowledge that our study has some limitations. The suggestion that STDT reflects disease progression is based on a transverse observation in patients with different stages of PD, and we did not test early-phase PD with a follow-up design longer than two years or until the appearance of STDT alterations. The other limitation we recognize is that the number of early phase-PD patients who completed the 2-years follow up assessment was not particularly numerous to definitively conclude that STDT did not statistically differ after the first few years of disease. We also acknowledge that 12 h might be insufficient to obtain a definite OFF therapy state after the last dose of dopaminergic medication, which means we cannot exclude that the STDT abnormalities we observed in the mild/moderate and advanced PD groups were underestimated. STDT values obtained in early-phase PD patients at the follow-up assessment might also have been underestimated. However, if this were the case, the extent of the STDT alterations would increase, but the observation that the STDT increases as disease worsens would still stand. Our results that in PD patients early-phase STDT did not significantly differ from that of healthy subjects while the STDT values correlates with the disease severity and duration may seem contradictory. On the basis of our results
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
we conclude that the correlation between STDT values and duration of disease possibly arises only pooling together the whole sample of PD patients characterized by a wide range of disease duration. A recent study reported that hysteresis, which stabilizes a percept across successive stimuli with different properties, influences threshold assessments in a spatial discriminative task (Thiel et al., 2014). Similarly, we may hypothesize that our STDT protocol might have been affected by hysteresis. However the hysteresis effect described by Thiel et al. relates to a different sensory modality (spatial discrimination) from that we tested with STDT. In addition, the hysteresis seems to reflect a decision-making process rather than a perceptual process. In our study patients were specifically asked to report what they perceived for each trial as it was presented and the decision was not based on previous perceptive experience. Recent findings suggest that the temporal processing involving short ISIs is a task requiring highly perceptual discrimination not accessible to cognitive control (Koch et al., 2009; Conte et al., 2012). We therefore believe that with the ascending method we used there is little impact of internal prior knowledge (i.e. hysteresis) in STDT processing. Finally, if hysteresis affects STDT processing this would more likely affect the descending staircase method than the ascending method (Thiel et al., 2014; Kleinschmidt et al., 2002). In conclusion, our study demonstrates that STDT changes in PD reflect disease progression. In early-phase PD patients, who already have motor symptoms, STDT values are statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. Conflict of interest Dr. Conte, Dr. Leodori, Dr. Ferrazzano, Dr. De Bartolo, and Dr. Manzo report no competing interests. Dr. Fabbrini received research support from Allergan, Lundbeck and Novartis. Dr. Berardelli received research support from Allergan, Lundbeck and Merz. Funding No funding received. References Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231–40. Appel-Cresswell S, de la Fuente-Fernandez R, Galley S, McKeown MJ. Imaging of compensatory mechanisms in Parkinson’s disease. Curr Opin Neurol 2010;23:407–12. Artieda J, Pastor MA, Lacruz F, Obeso JA. Temporal discrimination is abnormal in Parkinson’s disease. Brain 1992;115:199–210. Barone P. Neurotransmission in Parkinson’s disease: beyond dopamine. Eur J Neurol 2010;17:364–76. Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, et al. EFNS/ MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013;20:16–34. Conte A, Modugno N, Lena F, Dispenza S, Gandolfi B, Iezzi E, et al. Subthalamic nucleus stimulation and somatosensory temporal discrimination in Parkinson’s disease. Brain 2010;133:2656–63. Conte A, Rocchi L, Nardella A, Dispenza S, Scontrini A, Khan N, et al. Theta-burst stimulation-induced plasticity over primary somatosensory cortex changes
2989
somatosensory temporal discrimination in healthy humans. PLoS One 2012;7: e32979. Conte A, Khan N, Defazio G, Rothwell JC, Berardelli A. Pathophysiology of somatosensory abnormalities in Parkinson disease. Nat Rev Neurol 2013;9:687–97. Costa J, Valls-Solé J, Valldeoriola F, Rumià J. Subcortical interactions between somatosensory stimuli of different modalities and their temporal profile. J Neurophysiol 2008 Sep;100:1610–21. Filion M, Tremblay L, Bédard PJ. Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. Brain Res 1988;444:165–76. Fiorio M, Valente EM, Gambarin M, Bentivoglio AR, Ialongo T, Albanese A, et al. Subclinical sensory abnormalities in unaffected PINK1 heterozygotes. J Neurol 2008 Sep;255:1372–7. Giza E, Gotzamani-Psarrakou A, Bostantjopoulou S. Imaging beyond the striatonigral dopaminergic system in Parkinson’s disease. Hell J Nucl Med 2012;15:224–32. Harrington DL, Haaland KY, Hermanowicz N. Temporal processing in the basal ganglia. Neuropsychology 1998a;12:3–12. Harrington DL, Haaland KY, Knight RT. Cortical networks underlying mechanisms of time perception. J Neurosci 1998b;18:1085–95. Ivry RB. The representation of temporal information in perception and motor control. Curr Opin Neurobiol 1996;6:851–7. Khan NL, Valente EM, Bentivoglio AR, Wood NW, Albanese A, Brooks DJ, et al. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol 2002;52:849–53. Kleinschmidt A, Büchel C, Hutton C, Friston KJ, Frackowiak RS. The neural structures expressing perceptual hysteresis in visual letter recognition. Neuron 2002;34:659–66. Koch G, Oliveri M, Caltagirone C. Neural networks engaged in milliseconds and seconds time processing: evidence from transcranial magnetic stimulation and patients with cortical or subcortical dysfunction. Philos Trans R Soc Lond B Biol Sci 2009;364:1907–18. Lacruz F, Artieda J, Pastor MA, Obeso JA. The anatomical basis of somaesthetic temporal discrimination in humans. J Neurol Neurosurg Psychiatry 1991;54:1077–81. Langston JW. The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 2006;59:591–6. Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47:493–503. Lee MS, Lyoo CH, Lee MJ, Sim J, Cho H, Choi YH. Impaired finger dexterity in patients with Parkinson’s disease correlates with discriminative cutaneous sensory dysfunction. Mov Disord 2010;25:2531–5. Lyoo CH, Ryu YH, Lee MJ, Lee MS. Striatal dopamine loss and discriminative sensory dysfunction in Parkinson’s disease. Acta Neurol Scand 2012;126:344–9. Meck WH. Selective adjustment of the speed of internal clock and memory processes. J Exp Psychol Anim Behav Process 1983;9:171–201. Obeso JA, Rodriguez-Oroz MC, Lanciego JL, Rodriguez Diaz M. How does Parkinson’s disease begin? The role of compensatory mechanisms. Trends Neurosci 2004;27:125–7. Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014;13:100–12. Rammsayer TH. On dopaminergic modulation of temporal information processing. Biol Psychol 1993;36:209–22. Rocchi L, Conte A, Nardella A, Li Voti P, Di Biasio F, Leodori G, et al. Somatosensory temporal discrimination threshold may help to differentiate patients with multiple system atrophy from patients with Parkinson’s disease. Eur J Neurol 2013;20:714–9. Sabatini U, Boulanouar K, Fabre N, Martin F, Carel C, Colonnese C, et al. Cortical motor reorganization in akinetic patients with Parkinson’s disease: a functional MRI study. Brain 2000;123:394–403. Scontrini A, Conte A, Defazio G, Fiorio M, Fabbrini G, Suppa A, et al. Somatosensory temporal discrimination in patients with primary focal dystonia. J Neurol Neurosurg Psychiatry 2009;80:1315–9. Thiel SD, Bitzer S, Nierhaus T, Kalberlah C, Preusser S, Neumann J, et al. Hysteresis as an implicit prior in tactile spatial decision making. PLoS One 2014;9:e89802. van Nuenen BFL, van Eimeren T, van der Vegt JPM, Buhmann C, Klein C, Bloem BR, et al. Mapping preclinical compensation in Parkinson’s disease: an imaging genomics approach. Mov Disord 2009;24:S703–10. Zigmond MJ. Do compensatory processes underlie the preclinical phase of neurodegenerative disease? Insights from an animal model of parkinsonism. Neurobiol Dis 1997;4:247–53.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Somatosensory temporal discrimination threshold in Parkinson’s disease parallels disease severity and duration Antonella Conte a, Giorgio Leodori b, Gina Ferrazzano a, Maria I. De Bartolo b, Nicoletta Manzo b, Giovanni Fabbrini a,b, Alfredo Berardelli a,b,⇑ a b
IRCCS Neuromed, Pozzilli (IS), Italy Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
a r t i c l e
i n f o
Article history: Accepted 29 June 2016 Available online 5 July 2016 Keywords: Somatosensory temporal discrimination Parkinson’s disease Early-phase Disease progression
h i g h l i g h t s STDT (somatosensory temporal discrimination threshold) does not differ between PD at clinical onset
and healthy subjects. STDT abnormalities correlate with the duration and severity of PD. Abnormal STDT appears when compensatory mechanisms fail to compensate altered basal ganglia
activity.
a b s t r a c t Objective: To investigate whether the somatosensory temporal discrimination threshold (STDT) is already altered at the clinical onset of Parkinson’s disease (PD) and whether STDT abnormalities correlate with disease progression we tested STDT values in patients with different severity of disease. Methods: We prospectively and consecutively enrolled 63 PD patients: 26 drug-naive PD patients with symptom onset no longer than two years prior to inclusion in the study (early-phase), 37 PD patients with varying degrees of disease severity and 51 age-matched healthy subjects. The STDT was tested on the index finger of both hands, and on both sides of the face. Twelve out of 26 early phase PD patients were re-tested two years after the initial diagnosis. Results: PD patients as a whole displayed higher STDT values than healthy subjects. STDT values did not significantly differ between early-phase PD patients and healthy subjects, whereas they were significantly higher in patients with mild/moderate and advanced PD. In early-phase PD patients STDT values at the two years-follow up assessment did not statistically differ from those obtained at baseline. Considering the whole group of PD patients STDT abnormalities significantly correlated with duration and severity of the disease. Conclusions: STDT increases as disease progresses. In early-phase PD patients STDT values are still statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. Significance: Our study gives new insight into the sensory abnormalities in PD. Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The somatosensory temporal discrimination threshold (STDT) is defined as the shortest interval at which an individual recognizes a ⇑ Corresponding author at: Department of Neurology and Psychiatry, ‘‘Sapienza” University of Rome, Viale dell’Università 30, 00185 Rome, Italy. Fax: +39 0649914700. E-mail address: [email protected] (A. Berardelli).
pair of stimuli as separate in time (Lacruz et al., 1991). It relies on a purely sensory process that allows the brain to ‘‘filter” the relevant sensory information from external sources (Costa et al., 2008). Previous studies on healthy subjects have suggested that the STDT depends on the integrity of a complex cortico-subcortical network in which S1 plays an encoding role and basal ganglia determine a time-related interaction between cortical and subcortical structures (Conte et al., 2012; Harrington et al., 1998a,b; Ivry, 1996).
http://dx.doi.org/10.1016/j.clinph.2016.06.026 1388-2457/Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2986
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
Some studies have demonstrated that the STDT is altered in Parkinson’s disease (PD) (Abbruzzese and Berardelli, 2003; Artieda et al., 1992; Conte et al., 2010, 2013; Lyoo et al., 2012; Patel et al., 2014). Whether the STDT is already altered at the clinical onset of PD symptoms is however unknown. The results of previous studies on the relationship between STDT values and disease severity are contrasting (Conte et al., 2010; Lee et al., 2010; Lyoo et al., 2012; Rocchi et al., 2013). Studies that did find a significant association between STDT values and motor deficit scores reported that the STDT only correlated with the Unified Parkinson’s Disease Rating Scale (UPDRS) subscores for axial motor deficits (Lyoo et al., 2012). A better knowledge of these issues would provide further insight into sensory disturbances in PD. In particular, if STDT abnormalities are already present at the onset of motor symptoms, the STDT may be a valuable hallmark of the disease and consequently be considered a disease trait. Alternatively, if STDT abnormalities appear during the course of the disease, STDT may be a feature which reflects disease progression in PD thus giving new insight into the pathophysiology of altered STDT. The aim of our study was to investigate whether STDT is already altered at the clinical onset of Parkinson’s disease (PD) or whether STDT abnormalities develop only in the late-phase of the disease. We therefore studied STDT values in 63 PD patients in different disease stages, including patients with early-phase PD, and compared the results with those obtained from a group of 51 healthy subjects. We then investigated whether there were any correlations between the STDT values and the clinical and demographic features of the PD patients.
Since the temporal sensory processing data yielded by STDT testing are only reliable if cognitive functions are normal, patients with a MMSE score lower than 26, a FAB score lower than 15 or a MOCA score lower than 24 were excluded. We also excluded patients with a HMRD score higher than 10. All participants were screened for peripheral sensory neuropathy by medical history and bed-side clinical examination. Any patients or healthy subjects who had a clinically-diagnosed peripheral sensory neuropathy or which presented major risk factor for neuropathy (e.g. diabetes, chronic metabolic diseases, autoimmune diseases, etc.) were not included in the study. No patient had a history of central nervous system disease different from PD, neither was taking drugs with actions on the central nervous system other than dopaminergic treatment. Healthy subjects had no history of any neuropsychiatric disorders and were not taking drugs with actions on the central nervous system at the time of the experiments. We included patients in different stages of disease: 26 earlyphase drug-naïve PD patients with onset of symptoms no longer than two years prior to inclusion in the study (early phase: H&Y = 1–2.5), 37 PD patients with a disease duration longer than two years and varying degrees of disease severity (28 mild/moderate: H&Y = 1–3; 9 advanced: H&Y = 4–5) who were on chronic dopaminergic treatment. PD patients on chronic dopaminergic treatment were tested OFF dopaminergic therapy (12 h after the last dose of dopaminergic medication). A subgroup of 12 of the 26 drug-naive PD patients who started dopaminergic therapy after the first assessment were tested again two years later in the OFF therapy condition.
2.2. STD procedure 2. Methods 2.1. Study participants and clinical assessment We enrolled a total of 63 PD patients (mean age 63.6 ± 8.1 years) diagnosed according to published criteria (Berardelli et al., 2013) and 51 age-matched healthy subjects recruited among caregivers and spouses of PD patients (mean age 63.1 ± 8.7 years). All participants were right-handed. Patients were consecutively and prospectively recruited from the movement disorder outpatient clinic of the Department of Neurology and Psychiatry at Sapienza University of Rome from June to December 2013. Written informed consent was obtained from all the patients and healthy subjects. The experimental procedure was approved by the institutional review board at Sapienza University of Rome and conducted in accordance with the Declaration of Helsinki. Information regarding the demographic characteristics, family history and disease course were collected during a face-to-face interview. Parkinsonian motor symptoms were assessed using the Hoehn and Yahr Scale (H&Y) and the UPDRS part III (Table 1). All the patients underwent the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MOCA) and Hamilton Rating Scale for Depression (HMRD).
The STD was investigated by delivering paired stimuli starting with an interstimulus interval (ISI) of 0 ms (simultaneous pair), and progressively increasing the ISI in 10 ms steps, according to the experimental procedures used in previous studies (Conte et al., 2012; Scontrini et al., 2009). Paired tactile stimuli consisted of 100-ls square-wave electrical pulses delivered with a constant current stimulator (Digitimer DS7AH) through surface skin electrodes with the anode located 0.5 cm distally to the cathode, which was applied to the volar surface of the index finger of the left and right hands, and to the left and right sides of the face. The stimulation intensity was defined for each subject by delivering a series of stimuli at an increasing intensity starting from 2 mA in 0.5 mA steps; the intensity used for the STD was the minimal intensity perceived by the subject in 10 out of 10 consecutive stimuli. The first of three consecutive ISIs at which participants recognized the stimuli as temporally separate was considered the STDT value. To keep the subjects’ attention level constant during the test and minimize possible perseverative responses, we included ‘‘catch” trials consisting of a single stimulus delivered randomly. Paired stimuli were delivered at intervals of between 3 and 5 s. Patients were asked to report, as soon as possible, whether they perceived a single stimulus or two temporally separated stimuli by saying ‘‘one” or ‘‘two” after each stimulation in the interval preceding the next paired stimuli. Each session comprised four separate
Table 1 Clinical and demographic features of patients.
Early-phase PD Mild/Moderate PD Advanced PD Kruskal–Wallis’ test p
Subjects
Age (years)
Disease duration (months)
Hoehn & Yahr
UPDRS III
MMSE
MOCA
FAB
Hamilton
26 28 9 –
64.4 ± 8.6 64.6 ± 8.7 61.4 ± 6.1 0.62
13.23 ± 7.9 108.9 ± 66.9 164.0 ± 31.2 <0.000001
1.5 ± 0.6 2.2 ± 1.1 4.1 ± 1.1 <0.000001
13.3 ± 5.5 25.9 ± 11.7 39.7 ± 10.1 <0.000001
28.7 ± 1 28.6 ± 1 27.9 ± 1 0.5
26.8 ± 2 26.6 ± 2 27.8 ± 1 0.2
17.2 ± 1 16.9 ± 1 16.0 ± 1 0.13
5.1 ± 2 5.0 ± 3 6.0 ± 3 0.4
UPDRS III: Unified Parkinson’s Disease Rating Scale (UPDRS) part III. PD: Parkinson’s disease. Data are expressed as mean ± SD.
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
2987
blocks. The STDT was defined as the average of four STDT values, i.e. one for each block, and was entered in the data analysis. 2.3. Statistical analysis Kruskal–Wallis’ test was used to compare clinical scores among the PD subgroups. To analyze STDT values we first used a between-group ANOVA to evaluate any differences in STDT values between the whole PD patient group (n = 63) and healthy subjects (n = 51). We then performed a between-group ANOVA with factor group (early-phase PD, mild/moderate PD, advanced PD and healthy subjects), factor side (right and left) and factor body part (hand and face). The Tukey test was applied for the post hoc analysis. To assess the diagnostic accuracy (sensitivity and specificity) of STDT testing in differentiating patients with PD from healthy subjects, we used a receiver operating characteristic (ROC) curve analysis. The ROC analysis was performed on the STDT values of the healthy group and the whole group of PD patients. The ROC curve allows to identify the optimal threshold value (the so-called best cut-off), that is, the test value- corresponding to the highest diagnostic accuracythat maximizes the difference between the true positive (i.e. the proportion of individuals who have an altered value of the test among all those actually affected by the disease) and false positives (i.e. the proportion of individuals that despite having an altered value of the test are not suffering from the disease of interest). To estimate the diagnostic accuracy of STDT testing, we then calculated the area under the curve (AUC) value. In the group of earlyphase PD patients, we applied the ‘cut-off value’ to discriminate between patients with normal STDT and those with impaired STDT, and then ran a Mann–Whitney U test to investigate any differences in clinical features between the two subgroups. To analyze changes in STDT values in early-phase PD at the baseline and at the two-year follow-up assessment, we used a repeated measures ANOVA with factor time (2 levels: baseline and one-year follow-up assessment), side (right and left) and body part (hand and face). Holm’s test for multiple comparisons was applied. Data were tested for non-sphericity. Greenhouse–Geisser’s correction was applied when needed. Spearman’s correlation coefficient was used to identify any correlations between the clinical scale scores and STDT values. p < 0.05 was considered to indicate statistical significance. 3. Results Demographic and clinical data are reported in Table 1. The between-group ANOVA revealed a significant factor group (F(1,112) = 33.45; p < 0.0000001) though no significant factor side, body part or interactions. STDT values were higher in PD patients (whole sample) than in healthy subjects regardless of the body part or body side assessed. Between-group ANOVA, which was performed to detect any differences in STDT values between the three groups of PD patients stratified according to disease severity (early-phase, mild/moderate and advanced) and healthy subjects, revealed a significant factor group (F(1,110 = 18.22; p < 0.0000001) though no significant factor side, body part or interactions. Posthoc analysis showed that STDT values in early-phase PD patients did not differ from those in healthy subjects (p = 0.09), whereas STDT values in mild/moderate and advanced PD patients were significantly higher than in healthy subjects (mild/moderate PD vs. healthy subjects: p < 0.000001; advanced PD patients vs. healthy subjects: p < 0.0000001) (Fig. 1). The ROC curve analysis for the STDT mean values in both the PD patients and healthy subjects yielded a 68.25% sensitivity and 76.48% specificity, with a cut-off STDT value of 93.95 ms. The esti-
Fig. 1. Somatosensory temporal discrimination threshold (STDT) tested in healthy subjects and in patients with Parkinson’s disease (PD) (early-phase, mild/moderate and advanced PD). STDT was tested on the right and left hands, and on the right and left sides of the face as indicated on the X axis. Y axis: STDT values expressed in milliseconds.
mate of the AUC value (0.826) showed that the STDT yielded accurate scores. According to the cut-off STDT value determined by the ROC analysis, 12 of the 26 early-phase PD had a normal STDT, whereas the remaining 14 patients had a mildly increased STDT. The Mann– Whitney U test showed, however, that age (p = 0.94), disease duration (p = 0.93), H&Y (p = 0.54) and UPDRS part III (p = 0.78) did not significantly differ between early-phase PD patients with normal STDT values and those with increased STDT values. Repeated measures ANOVA performed to detect any changes in STDT values in early-phase PD patients between the baseline (mean value 94.9 ± 25.2) and the two-year follow-up assessment (mean value 91.1 ± 19.5) did not reveal any statistical significance of factor time (F(1,11) = 0.73; p = 0.41), side (F(1,11) = 0.27; p = 0.6) or body part (F(1,11) = 0.30; p = 0.59). Spearman’s correlation coefficient showed that STDT values significantly correlated with scores in the H&Y (p = 0.003), UPDRS part III total (p = 0.005) (Fig. 2) and disease duration (p = 0.006) (Fig. 3). 4. Discussion In this study, we show that STDT values did not statistically differ between early-phase PD patients and normal subjects, but were significantly higher in patients with mild/moderate and advanced PD. With a 2-years-follow-up in a subgroup of 12 out of 26 early-phase PD patients we also show that STDT values did not change significantly two years after the initial diagnosis. Lastly,
Fig. 2. Correlation between somatosensory temporal discrimination threshold (STDT) and UPDRS score in patients with Parkinson’s disease (PD) (STDT value corresponds to the mean STDT in the individual subject). X axis: STDT values expressed in milliseconds; Y axis: UPDRS score.
2988
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
Fig. 3. Correlation between somatosensory temporal discrimination threshold (STDT) and disease duration in patients with Parkinson’s disease (PD) (STDT value corresponds to the mean STDT in the individual subject). X axis: STDT values expressed in milliseconds; Y axis: disease duration in months.
we found that STDT abnormalities significantly correlated with the duration and severity of the disease. We took numerous precautions to ensure that the results regarding the STDT study were reliable. We excluded peripheral nerve abnormalities in all the patients who had altered STDT values by means of conventional nerve conduction studies. Subjects with a MMSE score lower than 26, FAB lower than 15 or MOCA lower than 24 were also excluded to avoid a confounding effect on the reliability of the STDT due to cognitive impairment. To detect any potential response bias related to changes in attention levels or perseverative responses, our experimental protocol also included catch trials consisting of a single stimulus (Scontrini et al., 2009). In order to avoid possible false negative results due to the positive effects of dopaminergic therapy on the STDT, we only included drug-naive patients in the group of early-phase PD patients and tested all the patients with mild/moderate and advanced PD in the OFF therapy condition (Artieda et al., 1992; Conte et al., 2010, 2013; Rocchi et al., 2013). The strength of this study, unlike previous reports based on limited numbers of patients, is that we enrolled a cohort of 63 patients in varying disease stages and performed a follow-up assessment after two years in the patients with early-phase PD. The novel finding of the present paper is that in early-phase PD patients the STDT did not significantly differ from that of healthy subjects, whereas in mild/moderate and advanced PD patients it did. Differences in STDT values between early-phase PD patients and healthy subjects did not reach statistical significance, though when we applied the cut-off value determined by the ROC curve analysis we found that about half of the early-phase PD patients had unequivocally normal STDT values whereas the other half had mildly increased STDT values. No differences were detected in the clinical and demographic features between these two early-phase subgroups. The observation that STDT is unequivocally normal in at least half of patients with early-phase PD suggests that STDT abnormalities cannot be considered a disease trait. The finding that values were higher in advanced than in mild/moderate PD suggests that the abnormalities in the STDT reflect disease severity. This hypothesis is supported by the correlation we found between higher STDT values and higher UPDRS Part III scores. Unlike other studies, which did not find any correlation between STDT values and global UPDRS scores, a correlation did emerge in our study, in which we enrolled a large sample of PD patients with a wide-ranging disease severity. Since patients with greater motor symptom severity also had the longest disease duration, abnormalities in STDT values also depend on disease duration. One possible explanation for STDT abnormalities in PD is based on the theory of background noise. Studies on animal models of PD have suggested that altered dopaminergic projections reduce func-
tional segregation and expansion of the somatosensory receptive fields in the striatum, thus increasing the background noise related to sensory input (Filion et al., 1988). Dopamine may play a key role as a pacemaker in the internal clock model of interval timing (Meck, 1983; Rammsayer, 1993). A recent [18F]-N-3-fluoropro pyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) positron emission tomography study on PD patients found a correlation between STDT values and a dopaminergic deficit in the striatum (Lyoo et al., 2012). These findings, combined with our observation that the STDT deteriorates as the disease worsens, suggest that the mechanisms underlying the increase in STDT values in PD are linked to dopaminergic denervation. In keeping with this hypothesis, several authors have demonstrated that STDT values are improved, though not fully normalized, by dopaminergic therapy (Artieda et al., 1992; Conte et al., 2010, 2013; Rocchi et al., 2013). The hypothesis that dopaminergic denervation is responsible for STDT abnormalities does not, however, explain why all early-phase PD patients, who already suffer from degeneration of the dopaminergic neuron system above a critical threshold and therefore display motor symptoms, have normal STDT values. Several recent reports have identified dopamine- and non-dopamine-mediated compensatory mechanisms implemented by structures outside the basal ganglia, including several cortical areas and the cerebellum (AppelCresswell et al., 2010; Lee et al., 2000; Obeso et al., 2004; Sabatini et al., 2000; van Nuenen et al., 2009; Zigmond, 1997). Since STDT abnormalities in PD patients appear when motor symptoms become more severe, we may speculate that alterations of basal ganglia output alone do not lead to STDT abnormalities, which only appear when the compensatory activity of structures including the cortex fails to compensate for abnormal basal ganglia activity. Changes in several neurotransmitters are indeed known to occur as the disease progresses (Barone, 2010; Giza et al., 2012; Langston, 2006). Our observation that patients with early-phase PD have normal STDT values is apparently in contrast to that made in unaffected PINK1 (PARK6) heterozygous carriers (Fiorio et al., 2008). Fiorio et al. suggested that deficits in temporal processing might be considered a subclinical alteration, at least in PINK1-related parkinsonism. Functional neuroimaging studies have demonstrated that PARK6 and idiopathic PD patients matched for disease duration and clinical disease severity display different nigrostriatal dopaminergic dysfunction patterns (Khan et al., 2002). Differences in the STDT between idiopathic and unaffected PINK1 heterozygous carriers may thus reflect differences in the pathophysiological mechanisms underlying these two conditions. We acknowledge that our study has some limitations. The suggestion that STDT reflects disease progression is based on a transverse observation in patients with different stages of PD, and we did not test early-phase PD with a follow-up design longer than two years or until the appearance of STDT alterations. The other limitation we recognize is that the number of early phase-PD patients who completed the 2-years follow up assessment was not particularly numerous to definitively conclude that STDT did not statistically differ after the first few years of disease. We also acknowledge that 12 h might be insufficient to obtain a definite OFF therapy state after the last dose of dopaminergic medication, which means we cannot exclude that the STDT abnormalities we observed in the mild/moderate and advanced PD groups were underestimated. STDT values obtained in early-phase PD patients at the follow-up assessment might also have been underestimated. However, if this were the case, the extent of the STDT alterations would increase, but the observation that the STDT increases as disease worsens would still stand. Our results that in PD patients early-phase STDT did not significantly differ from that of healthy subjects while the STDT values correlates with the disease severity and duration may seem contradictory. On the basis of our results
A. Conte et al. / Clinical Neurophysiology 127 (2016) 2985–2989
we conclude that the correlation between STDT values and duration of disease possibly arises only pooling together the whole sample of PD patients characterized by a wide range of disease duration. A recent study reported that hysteresis, which stabilizes a percept across successive stimuli with different properties, influences threshold assessments in a spatial discriminative task (Thiel et al., 2014). Similarly, we may hypothesize that our STDT protocol might have been affected by hysteresis. However the hysteresis effect described by Thiel et al. relates to a different sensory modality (spatial discrimination) from that we tested with STDT. In addition, the hysteresis seems to reflect a decision-making process rather than a perceptual process. In our study patients were specifically asked to report what they perceived for each trial as it was presented and the decision was not based on previous perceptive experience. Recent findings suggest that the temporal processing involving short ISIs is a task requiring highly perceptual discrimination not accessible to cognitive control (Koch et al., 2009; Conte et al., 2012). We therefore believe that with the ascending method we used there is little impact of internal prior knowledge (i.e. hysteresis) in STDT processing. Finally, if hysteresis affects STDT processing this would more likely affect the descending staircase method than the ascending method (Thiel et al., 2014; Kleinschmidt et al., 2002). In conclusion, our study demonstrates that STDT changes in PD reflect disease progression. In early-phase PD patients, who already have motor symptoms, STDT values are statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. Conflict of interest Dr. Conte, Dr. Leodori, Dr. Ferrazzano, Dr. De Bartolo, and Dr. Manzo report no competing interests. Dr. Fabbrini received research support from Allergan, Lundbeck and Novartis. Dr. Berardelli received research support from Allergan, Lundbeck and Merz. Funding No funding received. References Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231–40. Appel-Cresswell S, de la Fuente-Fernandez R, Galley S, McKeown MJ. Imaging of compensatory mechanisms in Parkinson’s disease. Curr Opin Neurol 2010;23:407–12. Artieda J, Pastor MA, Lacruz F, Obeso JA. Temporal discrimination is abnormal in Parkinson’s disease. Brain 1992;115:199–210. Barone P. Neurotransmission in Parkinson’s disease: beyond dopamine. Eur J Neurol 2010;17:364–76. Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, et al. EFNS/ MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013;20:16–34. Conte A, Modugno N, Lena F, Dispenza S, Gandolfi B, Iezzi E, et al. Subthalamic nucleus stimulation and somatosensory temporal discrimination in Parkinson’s disease. Brain 2010;133:2656–63. Conte A, Rocchi L, Nardella A, Dispenza S, Scontrini A, Khan N, et al. Theta-burst stimulation-induced plasticity over primary somatosensory cortex changes
2989
somatosensory temporal discrimination in healthy humans. PLoS One 2012;7: e32979. Conte A, Khan N, Defazio G, Rothwell JC, Berardelli A. Pathophysiology of somatosensory abnormalities in Parkinson disease. Nat Rev Neurol 2013;9:687–97. Costa J, Valls-Solé J, Valldeoriola F, Rumià J. Subcortical interactions between somatosensory stimuli of different modalities and their temporal profile. J Neurophysiol 2008 Sep;100:1610–21. Filion M, Tremblay L, Bédard PJ. Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. Brain Res 1988;444:165–76. Fiorio M, Valente EM, Gambarin M, Bentivoglio AR, Ialongo T, Albanese A, et al. Subclinical sensory abnormalities in unaffected PINK1 heterozygotes. J Neurol 2008 Sep;255:1372–7. Giza E, Gotzamani-Psarrakou A, Bostantjopoulou S. Imaging beyond the striatonigral dopaminergic system in Parkinson’s disease. Hell J Nucl Med 2012;15:224–32. Harrington DL, Haaland KY, Hermanowicz N. Temporal processing in the basal ganglia. Neuropsychology 1998a;12:3–12. Harrington DL, Haaland KY, Knight RT. Cortical networks underlying mechanisms of time perception. J Neurosci 1998b;18:1085–95. Ivry RB. The representation of temporal information in perception and motor control. Curr Opin Neurobiol 1996;6:851–7. Khan NL, Valente EM, Bentivoglio AR, Wood NW, Albanese A, Brooks DJ, et al. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol 2002;52:849–53. Kleinschmidt A, Büchel C, Hutton C, Friston KJ, Frackowiak RS. The neural structures expressing perceptual hysteresis in visual letter recognition. Neuron 2002;34:659–66. Koch G, Oliveri M, Caltagirone C. Neural networks engaged in milliseconds and seconds time processing: evidence from transcranial magnetic stimulation and patients with cortical or subcortical dysfunction. Philos Trans R Soc Lond B Biol Sci 2009;364:1907–18. Lacruz F, Artieda J, Pastor MA, Obeso JA. The anatomical basis of somaesthetic temporal discrimination in humans. J Neurol Neurosurg Psychiatry 1991;54:1077–81. Langston JW. The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 2006;59:591–6. Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47:493–503. Lee MS, Lyoo CH, Lee MJ, Sim J, Cho H, Choi YH. Impaired finger dexterity in patients with Parkinson’s disease correlates with discriminative cutaneous sensory dysfunction. Mov Disord 2010;25:2531–5. Lyoo CH, Ryu YH, Lee MJ, Lee MS. Striatal dopamine loss and discriminative sensory dysfunction in Parkinson’s disease. Acta Neurol Scand 2012;126:344–9. Meck WH. Selective adjustment of the speed of internal clock and memory processes. J Exp Psychol Anim Behav Process 1983;9:171–201. Obeso JA, Rodriguez-Oroz MC, Lanciego JL, Rodriguez Diaz M. How does Parkinson’s disease begin? The role of compensatory mechanisms. Trends Neurosci 2004;27:125–7. Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014;13:100–12. Rammsayer TH. On dopaminergic modulation of temporal information processing. Biol Psychol 1993;36:209–22. Rocchi L, Conte A, Nardella A, Li Voti P, Di Biasio F, Leodori G, et al. Somatosensory temporal discrimination threshold may help to differentiate patients with multiple system atrophy from patients with Parkinson’s disease. Eur J Neurol 2013;20:714–9. Sabatini U, Boulanouar K, Fabre N, Martin F, Carel C, Colonnese C, et al. Cortical motor reorganization in akinetic patients with Parkinson’s disease: a functional MRI study. Brain 2000;123:394–403. Scontrini A, Conte A, Defazio G, Fiorio M, Fabbrini G, Suppa A, et al. Somatosensory temporal discrimination in patients with primary focal dystonia. J Neurol Neurosurg Psychiatry 2009;80:1315–9. Thiel SD, Bitzer S, Nierhaus T, Kalberlah C, Preusser S, Neumann J, et al. Hysteresis as an implicit prior in tactile spatial decision making. PLoS One 2014;9:e89802. van Nuenen BFL, van Eimeren T, van der Vegt JPM, Buhmann C, Klein C, Bloem BR, et al. Mapping preclinical compensation in Parkinson’s disease: an imaging genomics approach. Mov Disord 2009;24:S703–10. Zigmond MJ. Do compensatory processes underlie the preclinical phase of neurodegenerative disease? Insights from an animal model of parkinsonism. Neurobiol Dis 1997;4:247–53.