Gongfeng Li

Supervisor

Khalid Daoudi

Speech analysis for the differential diagnosis between Parkinson's disease, progressive supranuclear palsy and multiple system atrophy

Acoustic speech analysis has been shown to have a good potential in dierentiation between Parkinson's disease and atypical Parkinsonian syndromes (APS) such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).

. However, accuracy between PSP and MSA still has a large space to be improved and the more important aim is to provide more explicit information for dierential diagnosis. In [7], 75% accuracy was achieved using support vector machine classier based on radial basis function kernel. This means it's dicult to interpret the relation between selected features and decision hyperplane. In this internship, for discrimination between PSP and MSA, 9% higher accuracy (i.e, 84% accuracy) was attained by using support vector machine classier based on radial basis function kernel and 80% accuracy was attained using linear dimension reduction methods and linear classier. More importantly, with this strategy, we obtain a better understanding of feature discriminative power. This can be indeed very useful in clinical application.

Introduction

Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS) are neurodegenerative diseases. In the early periods of the disease, the symptoms of PD and APS are very similar. The dierential diagnosis may be very dicult in the early stages of the diseases, while that certainty of early diagnosis is important for the patient due to divergent prognosis.

Speech disorders, commonly known as dysarthria, are an early symptom common to both diseases from dierent origins. Speech assessment is an inexpensive, quick and simple technique that could potentially used in evaluation of subjects even in early periods of diseases.

Most studies of speech disorder analysis focused on the description of the dysarthria prole, some of them are based on perceptual dysarthria assessment [START_REF] Ho | Speech impairment in large sample of patients with Parkinson's disease[END_REF][START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF][START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF], while in recent years several studies tend to perform objective acoustic analysis to provide the description of dysarthria [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF][START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF][START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF][START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. The dysarthria may provide important clues to the discrimination between these three diseases since [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] was already able to discriminate between PD and APS with 95% accuracy and between PSP and MSA with 75% accuracy.

The objective of this internship is to use dierent voice impairment measurements (features) to perform a preliminary experimental study on discriminating power of these dierent measurements. Our approach is to use impairment speech dimensions, obtained by digital processing of voice recordings of patients provided by [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF], as a means for discrimination between PD, PSP and MSA.

Our study is divided into two parts, the rst part is the comparison study with results obtained by [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] using only voicing (sustained vowels) and articulation (syllable repetitions) features. We can achieve 84% accuracy with compared to 75% in [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] only with voicing and articulation features. But we can't rely on this result since we may have overtting problem.

Moreover, with such nonlinear SVM classication, we can't get insight about the discriminating power of features. Given these observations, we carry out in Part 2. The goal of the second part is to get a deeper understanding of relationship among speech dimensions through exploration of linear dimension reduction methods which could aid in classication procedure. With linear dimension reduction, linear classier could provide decent accuracy which is also higher than [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF].

This lower complexity model will provide greater insight into the relationship between speech dimensions and dierential diagnosis result.

3 State of the art

Perceptual evaluation

Studies of speech disorder analysis before 2000 are mainly based on perceptual estimation of dysarthria type [START_REF] Ho | Speech impairment in large sample of patients with Parkinson's disease[END_REF][START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF][START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF].

Study [START_REF] Ho | Speech impairment in large sample of patients with Parkinson's disease[END_REF] recorded two-minute conversational speech samples of 200 PD patients and evaluated them in three dimensions (voice(e.g. harsh quality, reduced volume, disturbed intonation), articulation (undershooting of articulatory movement resulting in imprecise articulation), uency (e.g. motor initiation diculties, inappropriate pauses, syllable repetition, rushes of speech)) subjectively. It reported that the hypokinetic dysarthria exist in majority (74%) of PD patients.

Meanwhile, study [START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF][START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF] mainly focused on the characteristics of dysarthria of MSA and PSP. In general, APS patients typically develop mixed dysarthria with various combinations of hypokinetic, spastic and ataxic components.

To be more clear, here are some descriptions of these three types of dysarthrias:

Hypokinetic dysarthria can be described as the dysarthria associated with disorders of the extra pyramidal motor system resulting in reduction and rigidity of movement, causing monotony of pitch and loudness, reduced stress, and imprecise enunciation of consonants [START_REF]Medical Dictionary for the Health Professions and Nursing[END_REF]. Spastic can be described as the disturbance associated with upper motor neuron disorders causing excess tone and limited range in muscle movements, characterized by imprecise consonants, monotony of pitch and reduced stress, and a labored voice quality [START_REF]Medical Dictionary for the Health Professions and Nursing[END_REF]. Ataxic can be described as the dysarthria associated with damage to the cerebellar system, characterized by imprecise consonants, excess and equal stress, inconsistent articulatory errors, and monotony of pitch and volume [START_REF]Medical Dictionary for the Health Professions and Nursing[END_REF].

Study [START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF] investigated 44 PSP patients using oral examinations and oral agility assessment as well as perceptual speech analysis to identify the deviant speech dimensions and types of dysarthria in PSP. Perceptual speech analysis included identifying and rating severity of the deviant speech dimensions during the examination and from videotaped or audiotaped samples of spontaneous speech and oral reading of the Grandfather Passage. The denitions of deviant speech dimensions are given by Darley et al [START_REF] Darley | Motor Speech Disorders[END_REF]. And they used the University of Michigan classication of the deviant speech dimensions for ataxic and spastic, Mayo clinic hypokinetic list for hypokinetic(table 1).

Study [START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF] has reported that all PSP patients developed two or three types mixed dysarthrias, 50% of patients had prominent spastic dysarthria and hypokinetic dysarthria was greater than the the spastic and ataxic components for 34% of patients. In general, the spastic components were present in all cases and were the most severe components and the ataxic components were least severe.

Study [START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF] evaluated 46 MSA patients with oral motor function, oral agility and perceptual speech analysis. The perceptual speech analysis consisted of quantitative evaluation of spontaneous speech, expository speech and oral reading of The Grandfather passage. They used the denitions of deviant speech dimensions as given by Darley et al [START_REF] Darley | Motor Speech Disorders[END_REF] and the University of Michigan classication of ataxic, spastic, and hypokinetic dysarthrias(table 1).

For MSA patients in study [START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF], 48% of them had prominent hypokinetic components and 35% of patients had ataxic components that were greater than other two type dysarthrias. In the view of mean total score of severity, the hypokinetic components were the most severe (total score, 12.7/9.0, mean / SD) followed by ataxic (total score, 11.1/8.2, mean / SD) and spastic components (total score, 9.1/5.7, mean / SD).

In addition, study [START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF] have reported that the severity of some dysarthria components have relations with certain abnormalities found during the oral motor examination. The severity of hypokinetic components correlated signicantly with the severity of masked face(r = 0.57, p < 0.001) and was signicantly associated with the presence of lip tremors(t = 5.1; p = 0.001) and tongue tremors (t = 2.9; p = 0.005). A signicant inverse correlation was found between the severity of ataxic components and the severity of masked face(r = -0.44; p = 0.003). And ataxic components were signicantly less prominent in patients with lip tremors(t = 4.0; p = 0.003). From study [START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF] and [START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF], it can be concluded that spastic components were most severe in PSP and ataxic components were the least severe and only presented in 68% of patients(compared to 100% for spastic and 95% for hypokinetic). While for MSA patients, the spastic components were the least severe and ataxic components presented in 89% of MSA patients.

Considering individual speech aspects, stuttering occurred only in PSP.

For future study, especially for discrimination between MSA and PSP, speech dimensions of spastic and ataxic dysarthrias can be helpful since spastic components were the most severe in PSP and least severe in MSA and ataxic components were extremely less severe than the other two type dysarthrias (spastic : 10.7, hypokinetic : 9.6, ataxic: 2.6

) in PSP while were quite severe in MSA patients (hypokinetic: 12.7, ataxic: 11.1, spastic: 9.7). The maximum score for each type of dysarthria is 30 for PSP and is 40 for MSA. Thus it can be expected to get some discriminative speech dimensions from spastic and ataxic components.

For example, there are some speech dimensions that haven't been used in recent acoustic objective analysis: excessively nasal. Excessive amount of air is resonated by nasal cavities.

Ataxic: Irregular articulatory breakdown: Intermittent nonsystematic breakdown in accuracy of articulation. Alternating loudness variations: There are alternating changes in loudness. Audible inspiration: Audible, breathy inspiration.

However, a recent study claimed that there is no consistent and signicant dierences found when using perceptual evaluations for discrimination between PSP and MSA [START_REF] Miller | Utility and accuracy of perceptual voice and speech distinctions in the diagnosis of Parkinson's disease, PSP and MSA-P[END_REF]. Thus, we still mainly focus on acoustical measures.

Objective evaluation

In last ten years, several studies focused on an objective analysis of the dysarthria prole [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF][START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF][START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF][START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. Most of them provided some characteristics in speech dimensions compared between PD and APS. Generally, the impairment of some specic speech dimensions is more severe in APS than in PD.

Study [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF] investigated 22 PD patients, 18 PSP patients and 20 MSA patients to evaluate the presence and characteristics of dysarthria by quantitative assessment of three parameters: maximum phonation time (MPT), semantic uency and reading speed.

For MPT, patients were instructed to take a deep breath and then sustain phonation [a] for as long as possible. Three samples were obtained and the longest response was taken. Semantic uency was dened as the number of names of animals a person was able to spontaneously report in one minute. Reading speed was obtained by asking the patient to read aloud a standard paragraph in Hindi language. The number of words read by the subject in one minute was considered as his / her reading speed.

Signicant overall dierence was only seen for MPT (p = 0.015), the reading speed was aected most in PSP group but not signicant and the semantic uency is comparable between groups.

Study [START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF] focused on measuring quantitatively dierent speech parameters in PSP as compared with PD by acoustic analysis including mean F0, standard deviation of fundamental frequency, net speech rate (syllables per second related to net speech time), pause ratio (percentage of pause time related to total speech time), ratio of intraword pauses (percentage of pauses within polysyllabic words in relation to overall speech pauses) and Vowel articulation index. Twenty-six PSP patients and 30 age-and gender-matched PD patients were tested by performing a speech task consisting of a standard reading passage composed of four complex sentences.

In PSP group, the net speech rate was signicantly reduced (p = 0.001) in while pause ratio was signicantly increased (p = 0.017) and ratio of intraword pauses was reduced( p < 0.001 ). Vowel articulation index (VAI) is a gender dependent measure, in the male patients' subgroup, VAI was signicantly reduced (p = 0.002) whereas no such dierence seen in the female patients' subgroup. The intonation variability measured by F0 SD was lower in PSP group (p < 0.001) and no signicant dierence was seen for the mean fundamental frequency.

For study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF], speech samples were acquired from 29 PD patients and 26 MSA patients by performing speech tasks consisted of sustained vowel phonation and reading a syntactically balanced text composed of 9 sentences.

To assess the pitch and quality of voice, mean fundamental frequency (F0), jitter, shimmer and noise-to-harmonic ratio (NHR) were measured from a relatively stable 1.5-s period of sustained phonation. In addition, the total speech rate (syllables per second based on total speech time of sentence 1 or 9), articulatory acceleration (total speech rate of sentence 9 minus that of sentence 1), total pause duration(of sentence 1 or 9), pause ratio within polysyllabic words (dened as in study [START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF] and of sentence 1 or 9) were estimated.

For the comparison between MSA and PD, study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF] has reported that among male patients' subgroups, F0 was signicantly increased in MSA group(p = 0.017), total speech rate was markedly decreased (p = 0.048 for sentence 1 and p = 0.008 for sentence 9). In addition, total pause time for sentence 9 was longer in men with MSA than in those with PD (p = 0.047). None of speech variables showed signicant dierences between female patient groups.

Previous studies [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF][START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF][START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF] provided us some characteristics in speech dimensions related to PD, PSP and MSA rather than discriminate them with these characteristics. However, study [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] was able to discriminate between APS and PD with 95 % accuracy and between PSP and MSA with 75 % accuracy which is really interesting.

Speech samples were acquired from 77 subjects including 15 PD, 12 PSP, 13 MSA and 37 healthy controls. None of the patients received antipsychotic therapy. Each participant was instructed to perform sustained phonation of the vowel/a/per one breath as long and steadily as possible, fast /pa/-/ta/-/ka/syllable repetition at least seven times per one breath and monologue on a given topic for approximately 90s.

They evaluated sixteen dimensions in total, eight dimensions in hypokinetic dysarthria of PD, including airow insuciency,harsh voice, rapid AMR, inappropriate silences, reduceloudness, monopitch, imprecise vowels and dysuency.

While strained-strangled voice quality, slow AMR and slow rate were assessed as elements of spastic dysarthria. Meanwhile, excess pitch uctuations, vocal tremor, irregular AMR, prolonged phonemes and excess intensity variations were related to ataxic dysarthria.

A support vector machine with a Gaussian radial basis kernel was applied in a classication experiment to determine the best combination of acoustic features to dierentiate between PD, PSP and MSA groups. The combination of six acoustic features related to ve deviant speech dimensions including harsh voice (jitter),inappropriate silences (percent pause time and number of pauses), slow AMR (diadochokinetic rate), excess intensity variation (intensity variation) and excess pitch uctuation (pitch variation) were used to separate PD from APS 95% accuracy. Considering discrimination between PSP and MSA,the four deviant speech dimensions including harsh voice (harmonics-to-noise ratio), uency (percent dysuent word), slow rate (articulation rate) and vocal tremor (frequency tremor intensity index) were able to discriminate PSP from MSA with 75% accuracy.

Another study [START_REF] Muller | Progression of dysarthria and dysphagia in postmortem-conrmed Parkinsonian disorders[END_REF] focused on the dierent latencies of dysarthria and dysphagia for PD, PSP and MSA. Median dysarthria latencies were short in PSP and MSA (24 months each), and long in PD (84 months) [START_REF] Muller | Progression of dysarthria and dysphagia in postmortem-conrmed Parkinsonian disorders[END_REF]. Median dysphagia latencies were intermediate in PSP (42 months), MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for APS (specicity, 100%).

The most recent study investigated the patterns and degree of consonant articulation decits also focused on discrimination between PD, PSP and MSA [START_REF] Tykalova | Distinct patterns of imprecise consonant articulation between Parkinson's disease, progressive supranuclear palsy and multiple system atrophy[END_REF]. Speech samples were acquired from 16 PD, 16 PSP, 16 MSA and 16 healthy control speakers by completing a series of speaking tasks lasting approximately 20 min. During the task, the participants were instructed to read the words presented by the examiner on paper cards which are tokens designed as CVtka used for the assessment of consonant articulation, where C represented a consonant and V corresponded to a corner vowel.

Three acoustic variables including VOT (Voice onset time ), VOT ratio and vowel duration were investigated in this study where VOT was determined as the interval between the articulatory release of stop and the onset of vocal fold vibration. The acoustic variables were assessed for a subset of voiceless and voiced consonants separately.

For the subsets of voiceless plosives, the VOT is signicantly longer in both PSP and MSA compared to PD or HC(both p < 0.001). The HC group manifested signicantly smaller VOT ratio than all patient groups including PD (p < 0.05), PSP (p < 0.01) and MSA (p < 0.001).Meanwhile the vowel length is signicantly longer in PSP group compared to both HC (p < 0.05) and PD (p < 0.01). For the subsets of voiced plosives, MSA group manifested signicantly shorter negative VOT as compared to all groups including HC (p < 0.001), PD (p < 0.01) and PSP (p < 0.001).

Discussion

In general, quite a few studies investigated the relation between the characteristics of speech disorder especially in the aspect of dysarthria. The study [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] is the rst one who did the classication between PD, PSP and MSA using these dysarthria features and achieved high accuracy (95 %) in dierentiation between PD and APS patients. Meanwhile, the accuracy of discrimination between PSP and MSA is 75%, which may can be improved with considering VOT variable in the subsets of voiced plosives since the MSA group manifested signicantly shorter negative VOT comparing to PSP (p<0.001).

In addition, there is one point should be noticed is that the dierence of MPT was signicant between the PSP and MSA groups (p = 0.014) in study [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF] which is contrary to the result in [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF].

The ratio of intraword pauses in study [START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF] and study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF], which hasn't been used in study [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] can be helpful for discrimination between MSA and PSP. According to the study [START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF], the ratio of intraword pauses is signicantly decreased in PSP group compared to PD group while according to the study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF], the ratio of intraword pauses is not signicantly dierent between MSA group and PD group.

Study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF] compared the speech acoustic parameters between MSA and PD with gender separated. It concluded that some speech acoustic parameters were discriminative between MSA and PD, not for all the patients, but only for male or female subgroup. The disadvantage for this method is that the database would be even smaller. This idea will bring us more accurate results for our future study if there are enough patient samples.

Statistical analyses

Values used of speech dimensions for statistical analyses are measured as the average value of two voice samples for each patient except that for maximal phonation time we considered the maximum one of two recordings. To assess group dierences, each speech dimension was compared across all three groups using a Kruskal-Wallis test.

Airow insuciency

For Maximum phonation time, we count the maximum one of two voice records of each patients. The tendency is similar, this symptom is more widely exists in APS patients than PD patients. However, it isn't a speech dimension discriminative compared to others.

Harsh Voice (Jitter, Shimmer, HNR)

We can conclude that we get similar results for these three speech dimensions in absolute values and tendency, both results conrm that APS patients manifest harsh voice more severe than PD patients. These speech dimensions are quite discriminative and jitter is more discriminative between MSA and PSP compared to (1), which maybe useful for the classication procedure.

Rapid AMR

The results are similar with the paper, indicating that this speech dimension is the least discriminative one compared to others.

Strained-strangled voice

The strained-stragled voice was determined using the degree of voicelessness(DUV). We obtained similar results that conrm APS patients manifest the strained-strangled voice more severe than PD patients and this speech dimension is very discriminative between PSP and MSA patients. In addition, it's also a discriminative speech dimension between MSA and PSP.

Slow AMR

We obtained similar results and can conclude that this is a discriminative speech dimension between APS patients and PD patients, the slow AMR DDK rate exists more widely in APS patients than PD patients.

Excess pitch uctuations

The results obtained by us are quite dierent with the results in the paper, the scale of values are larger while the discrimination between MSA and PSP is disappear in our result.

Vocal Tremor

Our results conrm that the Vocal tremor is more severe in APS patients than PD patients which is similar to the paper, however, discrimination between PSP and MSA patients is less in our result compared to the paper.

Irregular AMR

Our result is a bit dierent compared to the results in paper, the discrimination is less for our result even though the tendency is similar that APS patients manifest the symptom of irregular AMR more severe than PD patients.

Estimation procedure

A free program called PRAAT for the analysis and reconstruction of acoustic speech signals is used to calculate these 10 speech dimensions. The calculation procedures of these 10 speech dimensions can be divided into 3 groups according to the scripts used. In this section we provide and compare results computed by ourselves using PRAAT and by Prof. Etienne SICARD using VOCALAB and results in the [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. Since each patient has two voice recordings, we computed each voice le and counting the average value for one patient except that we count the maximum value for MPT, while Prof. Etienne SICARD only computed the value of the rst le of each patient except that the maximum value for MPT.

The standards provide ranges that if the speech dimension value falls in this range, this patient is considered as manifesting this symptom.

Table

Preprocessing

Scaling the original data is highly recommended when applying a support vector machine since the support vector machine algorithms are not scale invariant and if a feature has a variance in much larger scale compared to others, it might dominate the objective function. Here the scaled data has zero mean and unit variance for each feature.

Feature selection and parameter tuning

During the cross-validation process, the automatic feature selection and the parameter tuning were performed at the same time. To determine the best combination of features, a naive method is to generate all the combinations of features for each cross-validation process. However, even our dataset is quite small, it still took much time since that parameter tuning was also necessary to be performed at the same time.

Thus, greedy search policy was implemented. Greedy search policy serves for searching in a large range of parameter tuning area, since it has much lower time complexity. Exhaustive search policy which means generate all the combinations of features used for searching in a relative small range of parameter tuning area and to decide the best combination of features.

Greedy search policy: In the beginning, all the two-features combinations were generated, and the one which has highest accuracy was chosen as the temporary optimal one. Then considering all the reset feature, each time one feature is added to the temporary optimal combination and then the combination which has the highest accuracy is chosen.

Continue this process until the accuracy is decreased or unchanged when a new feature is added. This approach has much lower time complexity than the exhaustive search and can get approximate accuracy which helps us perform the parameter tuning with much smaller step.

Exhaustive search policy: It generates all the subset combinations of features so that can get the optimal result but has very high time complexity.

With greedy search, parameter tuning was performed in a large range primitively, then we focused on the smaller range which has higher accuracy. This process was repeated until the range is relatively small. Then the exhaustive search is used to determine the best combination of features performing ne-tuning.

Result

There were two combinations of three acoustic features able to discriminate PSP from MSA with an accuracy of 84% which is better compared to the 75% the best accuracy obtained in [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. The combination of features change with the parameters of SVM model. When gamma = 0.8, 0.9 and 1.0, C = 10, the three acoustic features including shimmer, HNR and vocal tremor were able to achieve an accuracy of 84% for discrimination between PSP and MSA.

When gamma = 0.8, 0.9, 1.0 and 1.1, C ranges from 100 to 100000, the combination of three features including jitter, strained-strangled voice (DUV) and vocal tremor were also able to discriminate PSP from MSA with an accuracy of 84%.

In this model, C trades o the misclassication of training samples against the simplicity of the decision surface, a large C makes the model try to classify all the the training correctly rather than have a big margin. Thus, keeping C in small value means that the distance from sample points to the decision surface would be large.

Since there are too few samples(12 PSP patients and 13 patients), it's very dicult to avoid the overtting problem.

As consequence C was set to a low value(<10) to keep smoother decision hyperplane to avoid overtting problem as much as we can.

Thus, we focus on the C in low value range(from 1 to 10) as gure 2:

Fig. 2 It can be observed that even C is smaller than 10, in the white area of the gure, with the three acoustic features including shimmer, HNR and vocal tremor, the 84% accuracy still can be achieved which means a relative simple decision hyperplane can possibly be obtained.

Discussion

Figure 3 is a 3d visualization gure plotted to observe more clearly the relation between the classied label and the combination of features. The misclassied patients were marked in the gure. Each time there were 4 misclassied patients of these 5 patients, the misclassied patients change when applying dierent values of sigma and C. Fig. 3 From the gure 3, it's hard to nd a obvious decision surface but it can be noticed that the misclassied patient MSA17a is inside the PSP patients which is not normal and may have a great impact on decision surface. Thus MSA17a can be considered as a noise sample and a new classication process was implemented with the dataset excluding the MSA17a, the new 3d visualization gure is gure 4:

Fig. 4 The best accuracy for this new classication process is 87.5% which is normal since one misclassied sample was excluded and the combination of features to achieve this accuracy stays at the same and the range of C and gamma values is almost the same as before. Each time there were 3 misclassied patients of these marked 4 patients, the misclassied patients change when applying dierent values of sigma and C. Generally, the classied samples were more separate compared to the gure 3, however the expecting result is that much more accuracy improvement can be gained since msa17 was considered as a noisy sample. And it's still hard to nd a obvious decision surface since SVM may have a high dimension decision surface in high dimension feature space and there were too few patients so that any patient can't be ignored to get a rough decision surface.

As consequence, some linear analysis experiments were performed in the following to try to get a explicit linear decision boundary even the accuracy may not as high as 84%.

Part II

Deep analysis

In the previous experiment, only features from voicing and articulation recordings were used, here several new features were implemented based on monologue and reading recordings of database of paper [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. And the maximum phonation time was excluded thus there are 13 acoustic measurements in total as followings: In this part, we mainly focused on relations between features then try some dimension reduction methods as projection to observed data and linear classier to separate MSA and PSP patients thus the result could be much easier to interpret.

7 Prosody features

Intraword pause ratio

The intraword pause ratio was computed based on the reading recordings and dened as the ratio of total pause time within the polysllabic words relative to the total pause time for all speech. The denition of pauses is the silence period lasts more than 10ms [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF].

From the state of the art, the intraword pause ratio would be a discriminative feature between PSP and MSA, since according to the study [START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF], the ratio of intraword pauses is signicantly decreased in PSP group compared to PD group while according to the study [START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF], the ratio of intraword pauses is not signicantly dierent between MSA group and PD group.

To distinguish the inter-word pauses and intraword pauses, it's better to have a speech recognition system to detect word boundaries. However, it will go far away from our topic of internship and take too much time, I decided to distinguish the inter-word pauses and intraword pauses simply by the silence length since the study [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF][START_REF] Skodda | Acoustical analysis of speech in progressive supranuclear palsy[END_REF][START_REF] Huh | Dierences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease[END_REF] didn't provide specic information about it. The intraword pause is mainly the voice onset time(VOT), which is a feature of the production of stop consonants.

The typical length of VOT is less than 100ms in English, but may vary with dierent languages. Our voice recordings come from Czech native speakers, however no study really focused on the VOT for Czech. The threshold is set at 120ms which means the length of silence larger than 120ms is considered as the inter-word pause, otherwise the intraword pause.

Percentage of pause time and Number of pauses

These two features were examined using reading passage recordings. Percentage of pause time was dened as the ratio of total pause time of recordings relative to total speech time and number of pauses as the number of all pauses, where pauses are dened as silence longer than 60ms. According to the linearly uncorrelated property of rst and second principal component, it can be concluded that vowel features and the reset features are approximately linearly uncorrelated. Thus these 13 features can be divided into two parts: 1. Vowel features plus Monopitch. 2.Syllable features plus intraword pause ratio and number of pauses.

9 Linear discriminant analysis

Introduction

Linear discriminant analysis(LDA) is a feature reduction method used to nd a linear combination of features so that the variance within the group is minimal while the variance between the group is maximal. Unlike PCA, LDA is a supervised method, the linear combination can be seen as a linear classier or used for dimensionality reduction before later classication. The implementation of LDA experiment was based on LinearDiscriminantAnalysis function of scikitlearn library.

1d LDA projection

Firstly LDA was applied on three dierent categories of features (i.e., voicing, articulation and prosody) separately and on all features. Figure 9 represents the projection values of LDA using all 13 features, the result is almost prefect. However, the curse of dimensionality should be considered since there are only 25 samples.

Classication on 1d LDA projection values

Consequently, a classication experiment was performed taken the all features projection values as input using SVM with linear kernel in a leave one out cross validation scheme which is the same with the previous classication experiment in the section 5. The implementation of SVM was based on scikit-learn library with svm.svc() class. In the following several classication experiments in section 8 and 9, same classier and cross validation scheme were used and to expect a good generalization ability, C is always less than 10 in linear SVM.

As expected, overtting problem occurs and an accuracy of 72% was achieved when C =1, which decreased greatly compared to the Fig. 9.

2d LDA projection and classication

Inspired by the Fig. Similarly, a classication experiment(same conditions as the one in 1d LDA classication) was performed on 2d LDA projection values. An accuracy of 68% was attained which was even worse compared to classication on 1d LDA projection values. Since less features were used for each dimension in LDA projection process, a better generalization ability was expected, however, the accuracy was even worse.

A possible reason is that the margin is not large enough especially for MSA samples. As consequence, one more learning layer was added to make our model has more learning ability to push the samples far away from decision boundary. Comparing gure 9 and 12, it can be found that logistic regression layer 'push' the data into two sides which makes a better separation in probabilities compared to projection values. As described in upper path of gure 11, same classication process with section 8 was applied on 1d probability values. An accuracy of 72% was attained which is the same as the classication process on 1d projection values. For 1d(i.e., all features used ), the adding logistic regression didn't make a contribution during classication process even though it makes training data more separate. Following the lower path of gure 11, same classication process was applied on 2d probability values. Here, an interesting result was achieved. An accuracy of 80% was attained with SVM regularization term C = 1, which improves 8% compared to perform classication process directly on LDA 2d projection values.

2d Result

Discussion

Even though 80% accuracy is a little bit lower than the best accuracy 84% that achieved by using SVM based on rbf kernel, this structure only contains linear projection and linear classier which greatly reduces the complexity of model and makes the interpretation easier.

2D 3-layers model achieved good accuracy proving that the method dividing features into two parts is reasonable. Here is the weights of features for 2D LDA projection. For second dimension, weights of Slow AMR, Intraword pause ratio and NO.Pauses are larger than others.

Since combination of features found by LDA is a linear combination and logistic regression also is a linear projection, these combinations found in these two dimensions are more meaningful and can give much more information for the relations between features and diseases compared to the combination found by nonlinear SVM.

Conclusion

In rst part, this study performed a comparison study which basically conrmed the conclusion in [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] and gained an 9% accuracy improvement(84% accuracy) on discriminating between PSP and MSA. However, this 84% accuracy was obtained by using a support vector machine with a Gaussian radial basis kernel. Since only 25 patients were acquired for our study, which are too few for this high complexity model, it's dicult to avoid overtting problem. We thus seek obtaining an comparable accuracy with simpler classier, which is the motivation of second part. In second part, 80% accuracy was achieved which still better than [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] by only using linear dimension reduction and linear classier which proves a decent accuracy can be achieved by linear combination of certain features. Considering we never have too much data on this kind of problem, the second part shows a good path for future study. In addition, this result also provides us a deeper understanding of relationships among features. It proves that features can be divided into two approximately uncorrelated dimensions which is also an important conclusion for future objective acoustic study. The results of this internship will be submitted to IEEE-ICASSP'2018 (HTTP://2018.ieeeicassp.org/).

4. 3 . 1

 31 Airow insuciency, Jitter, Shimmer, HNR, Strained-strangled voice, Excess pitch uctuations These speech dimensions are calculated based on standard autocorrelation to get pitch with default parameters, then get pulses with command (pulses = To PointProcess (cc)). By selecting sound le, pitch and pulses, we get voice report with default parameters in PRAAT, then we extract values as following in voice report. Airow insuciency -MPT(Maximum phonation time): duration Jitter: Jitter (local) Shimmer: Shimmer (local) 5 Comparison of deviant speech dimensions characteristics 5.1 Introduction

Fig 1

 1 Fig 1 describes the relation between the accuracy and the parameters.

Fig. 1

 1 Fig.1

  , HNR, Unvoiced degree(DUV), F0 SD, Vocal Tremor articulation Slow AMR, Rapid AMR, Irregular AMR Prosody Intraword pause ratio, number of pauses(No.Pauses), Percentage of pause time (PPT), Monopitch

  Fig.5

Fig. 5

 5 Fig.5 presents the relations between features and the rst and second principal components. Dim 1 is the rst principal component which accounts 33.76% variability of data and Dim 2 is the second principal component which accounts 20.24%

Fig. 6

 6 Fig.6

Fig. 7

 7 Fig.7

Fig. 8 Figure 6 ,

 86 Fig.8

Fig. 9

 9 Fig.9

Fig. 10 A

 10 Fig.10

10. 2 Fig. 11 As

 211 Fig.11 As Fig.11 describes above, logistic regression learning process was added between the LDA projection and Linear SVM classication process. The output of logistic regression layer is the probability of MSA which should close to 0 for PSP group and close to 1 for MSA group. Here, logistic regression regularization term C was set to 1 which means a good generalization ability can be expected.

Fig. 13 Compared

 13 Fig.13

  9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 1d LDA projection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Classication on 1d LDA projection values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4 2d LDA projection and classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Logistic regression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 Model structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 1d Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4 2d Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

	10 3-layers model
	10.1 11 Conclusion
	12 References

Table 1 .

 1 Deviant Speech Dimensions for Hypokinetic, Ataxic, and Spastic Dysarthrias:

	University of Michigan Classication	Mayo Clinic
				classication
	Hypokinetic	Ataxic	Spastic	Hypokinetic
	Low volume, able to	Excess and equal	Strained-strangled	Monopitch
	increase on command	stress	sound
	Monopitch	Irregular articulation	Reduced stress	Reduced stress
		breakdown
	Loudness decay	Alternating loudness	Harsh voice,	Monoloudness
		variation	continuous
	Short rushes of speech	Fluctuating pitch	Slow rate	Imprecise consonants
		levels
	Increased speaking	Variable rate	Low pitch	Inappropriate silences
	rate over time
	Imprecise phonemes	Harsh voice, transient	Imprecise phoneme	Short rushes
	over time
	Decreased stress	Breathy voice,	Monoloudness	Harsh voice quality
		transient
	Repetition of sounds,	Altered nasality,	Hypernasality,	Breathy voice,
	words and phrases	transient	continuous	continuous
	Inappropriate silences,	Voice tremors	Monopitch	Pitch level
	diculty initiating
	phonation
	Breathy voice,	Audible inspiration	Prolonged phoneme	Variable rate
	continuous		and/or intervals

  5, features were divided into two groups to perform LDA projection separately:

	group	features
	1	Jitter, Shimmer, HNR, DUV, F0 SD, Vocal Tremor, Monopitch
	2	Slow AMR, Rapid AMR, Irregular AMR, Intraword pause ratio, No. Pauses
	The Percentage of pause time was excluded since the mode of this vector was small both in rst and second principal

component. Then these two group's projection values are represented as two axis of gure which are reasonable since features in rst group are approximately linearly uncorrelated with features in second group.

  Logistic regression is a regression model where the dependent variable is categorical. In our case, this binary logistic regression process was used to estimate the probability of MSA patient based on LDA projection values.

	10 3-layers model
	10.1 Logistic regression

  Rapid AMR, Irregular AMR, Intraword pause ratio, No.Pauses -0.68, 0.18, -0.27, 0.58, 0.78 For rst dimension, Shimmer, HNR, DUV and Vocal Tremor are more important than other features which partially conrm the PCA result and the optimal feature combination to achieve 84% accuracy that obtained by nonlinear SVM classier.

		2D LDA projection weights
	dimension	features	weights
	1	Jitter, Shimmer, HNR, DUV, F0 SD, Vocal Tremor, Monopitch	1.42, 4.72, 6.30, 2.84, -0.95, 2.13, -1.18
	2	Slow AMR,

Part I Comparison study on voicing and articulation features

This part mainly includes acoustic features extracting, comparison and analysis of obtained results and classication experiment. In this part, all experiments were performed based on the voicing and articulation recordings for [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. [START_REF] Sachin | Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy[END_REF]

Comparison of acoustic speech analyse results

A comparison study was performed based on the part of database of [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF], including the voicing and articulation recordings, aiming to reproduce the results in the [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] for 10 speech dimensions .

Acoustic features

We evaluated 10 deviant speech dimensions including airow insuciency, Harsh voice, strained-strangled voice, excess pitch uctuations, slow AMR, rapid AMR, irregular AMR and vocal tremor. See table as following for more comprehensive details. This table is provided by [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF]. In script,the tremor frequencies are determined by auto-correlating the contours. If the highest autocorrelation coecient that can be detected in the contour is smaller than the threshold (that can be set individually; standard value: 0.15), it is assumed that there is no tremor and therefore no tremor frequency nor intensity nor power and the output will be 'undened'. FTRI is computed by the average of local maximas and local minimas of contours after subtracting their linear t in order to compensate for natural declinations.

Deviant speech dimension

The algorithm and the attached script is provided in [START_REF] Brückl | Vocal Tremor Measurement Based on Autocorrelation of Contours[END_REF], but there are some modications since too many 'undened'

FTRI results if we use the default version, we change a little bit the parameters compared to default version for better results:

Minimal_pitch_(Hz) 60 -> 50

Voicing threshold 0.3 -> 0.25

Rapid AMR, Slow AMR, Irregular AMR

Rapid AMR was dened as the ratio for DDK rate of rst half of /pa/-ta/-/ka/ utterance compared to the DDK rate of second half of /pa/-ta/-/ka/ utterance. Slow AMR was dened as the DDK rate measured as the number of syllables per second based on the rst seven repetitions of the /pa/-/ta/-/ka/ syllables. Irregular AMR is based on the rst seven repetitions of /pa/-/ta/-/ka/ syllables and was dened as the standard deviation of distances between following local maxima, representing the greatest energy during the performed /pa/, /ta/, or /ka/ syllable.

To compute these values, the key is to identify the positions of syllables, once we have the positions of syllables, the remaining calculation procedures are simple, just following the denitions. The syllables are considered as the local maximas of intensity contours of sound les. While not all local maximas are considered as syllables, there are two mainly ltering conditions:

1. Dierences between two intensity peaks should be larger than 2dB.

2. The local maximas of intensity should be large enough to be considered as voicing part.

Then the positions of these ltered local intensity maximas are considered as the positions of syllables.

The algorithm and the script is modied based on [START_REF]Syllable Nuclei Copyright (C)[END_REF]

Analysis Airow insuciency

The result (2) and ( 3) are a bit dierent with (1) but could generally conrm that the airow insuciency is more severe for APS patients.

Harsh voice

We can't directly compare the results since we don't know the standards for paper but can conrm that the harsh voice is slightly more severe for PSP patients than MSA and much more severe than PD patients.

Rapid AMR

Results (2) and ( 3) are quite dierent with the result in paper, [START_REF] Kluin | Perceptual analysis of speech disorders in progressive supranuclear palsy[END_REF] shows even less dierence between APS and PD patients and PD patients even manifest more severe rapid AMR symptom than APS patients in result [START_REF] Kluin | Characteristics of the dysarthria in multiple system atrophy[END_REF]. In general, it's not a speech dimension discriminative for APS and PD patients.

Strained-strangled voice

The results show similar tendency with the paper. Result ( 2) and ( 3) are less discriminative between APS and PD patients but still conrm that the Strained-strangled voice exists only in APS patients. In addition, our result show the dierence between the MSA and PSP patients in this speech dimension.

Slow AMR

The results are quite similar and all conrm that slow AMR exists only in APS patients.

Excess pitch uctuations

Result( 2) is dierent with the (1) and (3), our result has higher values and lost the dierence between MSA and PSP patients. All results conrm that the APS patients manifest more severe excess pitch uctuations symptom than PD patients.

Vocal tremor

Both results conrm the tendency that APS patients manifest more severe Vocal tremor than PD patients but the dierence between MSA and PSP patient is less compared to the paper.

Irregular AMR

Results(1) and (2) conrm that APS patients manifest more severe Irregular AMR than PD patients but according to the paper, this speech dimension never exists in PD patients which is dierent with (2). However, result (3) lost the discrimination between APS and PD patients.

6 Classication

Introduction

In following sections, we focused on dierentiating between MSA and PSP since the accuracy obtained in [START_REF] Rusz | Speech disorders reect diering pathophysiology in Parkinson'sdisease, progressive supranuclear palsy and multiple system atrophy[END_REF] was 75% which could be improved. A classication experiment was performed using python with scikit-learn library to determine the best combination of acoustic features and the highest accuracy that can be achieved in dierentiating between MSA and PSP. A support vector machine with a Gaussian radial basis kernel was applied and a leave one out cross-validation scheme was used, where the original data was separated into a training set contains all subjects exclude 1 (24 subjects in our case) and the test set contains only one subject. This process was repeated 25 times and each time test set contains dierent subject. The average percentage of correctly classied subjects into correspond group was considered as the performance of the model.


Valentina Camomilla

Raphaël Dumas

Aurelio Cappozzo

Human movement analysis: the soft tissue artefact issue

This Special Issue of the Journal of Biomechanics reports an overview of the innovative research being conducted on a problem which every researcher reporting on the kinematics of humans and animals must cope with. The problem is rooted in our inability to directly observe the bones of our participants during the activities of interest and it represents a critical challenge since it is the motion of these underlying bones that is generally the nexus of our research.

We are most often forced to reconstruct the motion of bones using the recorded trajectories of markers placed on the skin, which, due to the interposed soft tissues, are not rigidly fixed to the underlying bones. The local mobility of these markers (now commonly referred to as soft tissue artefact, or STA) leads to errors that, in some cases, are of the same order of magnitude as the motions at the joints being investigated. This problem therefore puts at risk the validity of a significant body of research in the basic, clinical and applied sciences. It is also a problem that, until recently, has been neither fully understood nor considered, arguably overlooked, by many of us whose research is affected by it. With this Special Issue, we hope this scenario will change.

Up to the sixties of the last century, scientists reconstructed the movement of a stick model of the human locomotor system as projected on a 2-D space or, in rare cases, in the 3-D space.

These models were activated by the trajectories of markers located on the skin surface, most of the time on points approximating the joint centres and recorded using optical systems so that a sort of virtual exoskeleton in motion could be reconstructed. With these models they described body segment motions and no observation of any inner structure was attempted. This all changed with a study on human locomotion carried out from 1945 to 1947 at the University of California with the aim of designing advanced lower limb substitutes [START_REF] Eberhart | Fundamental studies of human locomotion and other information relating to design of artificial limbs[END_REF]. Relevant results reported on the rotation of the pelvis, femur, and tibia about their longitudinal axes during walking and, for the first time, we could legitimately talk of bone movement as opposed to body segment movement. To achieve this, however, cortical pins with markers affixed to them had to be inserted into the volunteer's bones, thus providing a rigid link between the object being recorded (the marker) and that of interest (the bone). In doing so Eberhart's team was acknowledging the fact that markers located on the skin surface were incapable of reliably tracking the small rotations of the underlying bones due to the interposed deformable tissues. Bresler and Frankel, who participated in that study, seemed, however, to underestimate the magnitude of this problem. In fact, they tracked skin-mounted markers in their historical work on joint kinetics during level walking [START_REF] Bresler | The forces and moments in the leg during level walking[END_REF], describing the movement of the skin over the bone as causing "some slight error in location of the target" (target now being commonly described as marker).

In the 1950s and 1960s, the development of endo-and arthro-prostheses, and of reconstructive orthopaedic surgery in general, made the acquisition of deeper knowledge concerning both the movement of bones and the mechanics of human joints paramount. John Paul, at the University of Glasgow, responded to this urgency by initiating his pioneering studies around 1965. He estimated bone movement during different locomotor tasks using skin mounted markers and cinecameras and was able to provide fundamental data concerning the muscular forces and hip loading [START_REF] Paul | The biomechanics of the hip-joint and its clinical relevance[END_REF][START_REF] Paul | Forces at the human hip joint[END_REF][START_REF] Paul | Loading on the head of the femur[END_REF]. This seminal research is a milestone in the history of biomechanics, and, once again, the problem of the skin movement over the bones was identified but given limited importance. For instance, errors in the reconstructed hip joint centre coordinates around 3 mm were hypothesized and assumed to "correspond to inaccuracies in measurement, movement of the skin marker (located over the greater trochanter) relative to the skeleton and distortions due to film processing or projector lens" [START_REF] Paul | Forces at the human hip joint[END_REF]. While [START_REF] Paul | Forces at the human hip joint[END_REF] concentrated on the distortion of the lenses and on high frequency errors and their effect on time derivatives of position data, we know now that, as reported by a number of papers in this Special Issue, STA errors caused by those skin mounted markers were much larger.

An often cited paper by [START_REF] Spoor | Rigid body motion calculated from spatial co-ordinates of markers[END_REF], reports on the first study aimed at optimising the estimate of the pose of a body using measured positions of point markers located on it. This important report provided a framework which is still used today for the analysis of movement using multiple skin markers per segment. Nevertheless, their statement "Methods based on light photogrammetry of markers associated to bone are usually relatively accurate as compared to electro-goniometry" [START_REF] Spoor | Rigid body motion calculated from spatial co-ordinates of markers[END_REF] gives the impression that the STA problem was, again, underestimated. At that time, however, there seemed to be already an awareness of the importance of improving current practice. For example, Cappozzo, in 1984, while elaborating on the sets of markers that should be mounted on the body segments, states that the "relative movement between markers and underlying bone due to soft tissue deformation" should be regarded as a measurement "artefact" [START_REF] Cappozzo | Gait analysis methodology[END_REF]. He then recommends that markers be positioned so that the abovementioned relative movement "should be minimal", without, however, quantifying the importance of the issue.

Awareness of what we today call soft tissue artefact (STA) was gained in the nineties. In [START_REF] Cappozzo | Three-dimensional analysis of human walking: Experimental methods and associated artifacts[END_REF], in a section entitled "Skin marker artefacts", we read: "A major source of error in the experimental procedures using optoelectronic systems is associated with the relative movement between skin markers and underlying bone. This displacement, which cannot be avoided, exhibits time histories with the same frequency content of those which describe the actual body segment movement". This paper, besides reinforcing the concept that, while estimating bone pose, the above-mentioned marker local movements should be regarded as measurement artefacts, also provides a measure of their effect on the estimate of the trajectory of the centre of the femoral head during walking.

From that time on, several groups have measured the magnitude of the STA and tackled the problem of the minimization of its propagation to bone pose estimate. By the end of the nineties, the measurement of STA was initiated first using markers mounted on cortical or periosteum pins [START_REF] Cappozzo | Position and orientation in space of bones during movement: experimental artefacts[END_REF][START_REF] Fuller | A comparison of lower-extremity skeletal kinematics measured using skin-and pin-mounted markers[END_REF][START_REF] Holden | Surface movement errors in shank kinematics and knee kinetics during gait[END_REF]Reinschmidt et al., 1997a;Reinschmidt et al., 1997b) and then using different medical imaging techniques [START_REF] Maslen | Radiographic study of skin displacement errors in the foot and ankle during standing[END_REF][START_REF] Sati | Quantitative assessment of skin-bone movement at the knee[END_REF][START_REF] Tranberg | The relative skin movement of the foot: a 2-D roentgen photogrammetry study[END_REF]. As for the STA compensation methods, several algorithms were developed addressing STA at single-body [START_REF] Andriacchi | A point cluster method for in vivo motion analysis: applied to a study of knee kinematics[END_REF][START_REF] Ball | Modeling of the pliant surfaces of the thigh and leg during gait[END_REF][START_REF] Cappello | Multiple anatomical landmark calibration for optimal bone pose estimation[END_REF][START_REF] Cheze | A solidification procedure to facilitate kinematic analyses based on video system data[END_REF] or multibody [START_REF] Lu | Bone position estimation from skin marker co-ordinates using global optimisation with joint constraints[END_REF] level.

More recently, further studies, comprehensively quoted and reviewed in the papers of this Special Issue, have been performed using the above-mentioned invasive methods, providing artefact-free bone movement and joint kinematics during a wider range of tasks, quantifying the STA effect on joint kinematics, determining its main characteristics, and creating models to help understand its nature. It is important to notice, however, that the resulting information is still incomplete and, until this Special Issue, not readily available to the community. In the last decade, more elaborate STA compensation methods, also quoted in this Special Issue, have been proposed, but, given the scarcity of artefact-free data, none of them could be comprehensively validated.

It is interesting to note that, in recent times, both the assessment of the STA and the development of compensation methods have moved from an individual marker displacement perspective towards considering the overall movement of the maker-cluster, by characterizing its geometrical transformation [START_REF] Benoit | Surface marker cluster translation, rotation, scaling and deformation: Their contribution to soft tissue artefact and impact on knee joint kinematics[END_REF][START_REF] Dumas | Generalized mathematical representation of the soft tissue artefact[END_REF][START_REF] Grimpampi | Metrics for Describing Soft-Tissue Artefact and Its Effect on Pose, Size, and Shape of Marker Clusters[END_REF], and focusing specifically on the rigid component (i.e., translation and rotation) of this transformation as the only artefact movement to be compensated for [START_REF] Bonci | Rigid and non-rigid geometrical transformations of a marker-cluster and their impact on bone-pose estimation[END_REF][START_REF] Dumas | What portion of the soft tissue artefact requires compensation when estimating joint kinematics[END_REF].

Despite the above-mentioned efforts, the problem is still regarded as having critical relevance for human movement analysis research: "Probably the last great challenge for optical systems is in using computational techniques to compensate for soft tissue measurements" [START_REF] Baker | Gait analysis methods in rehabilitation[END_REF]. "Despite the numerous solutions proposed, the objective of reliable estimation of 3D skeletal system kinematics using skin markers has not yet been satisfactorily achieved and greatly limits the contribution of human movement analysis to clinical practice and biomechanical research" [START_REF] Leardini | Human movement analysis using stereophotogrammetry: Part 3. Soft tissue artifact assessment and compensation[END_REF].

Presently, STA, along with other less critical factors, still limits the possibility to reach the desired accuracy in various applications. Only in a limited number of clinical applications (e.g., cerebral palsy, adult brain injuries), there is evidence that the use of motion analysis applied to gait and combined with an expert clinical evaluation can modify or reinforce the clinical decision, influence the planning of orthopaedic surgery, and/or rehabilitation programs [START_REF] Chang | Effectiveness of instrumented gait analysis in children with cerebral palsy -comparison of outcomes[END_REF][START_REF] Cook | Gait analysis alters decision making in cerebral palsy[END_REF][START_REF] Ferrarin | Does gait analysis change clinical decision-making in post-stroke patients? Results from a pragmatic prospective observational study[END_REF][START_REF] Lofterød | Preoperative gait analysis has a substantial effect on orthopedic decision making in children with cerebral palsy: comparison between clinical evaluation and gait analysis in 60 patients[END_REF][START_REF] Wren | Efficacy of clinical gait analysis: A systematic review[END_REF][START_REF] Wren | Outcomes of lower extremity orthopedic surgery[END_REF]. Similarly, STA has a negative impact when investigating injury mechanisms during dynamic motor tasks. For example, although studies using skin markers have provided clues that the combination of knee abduction and internal rotation is a potential risk for the anterior cruciate ligament [START_REF] Mclean | Knee joint kinematics during the sidestep cutting maneuver: potential for injury in women[END_REF][START_REF] Shimokochi | Mechanisms of Noncontact Anterior Cruciate Ligament Injury[END_REF] and, similarly, that excessive inversion and internal rotation of the rearfoot may constitute a potential risk for lateral ankle ligaments [START_REF] Hertel | Functional Anatomy, Pathomechanics, and Pathophysiology of Lateral Ankle Instability[END_REF][START_REF] Gehring | How to sprain your anklea biomechanical case report of an inversion trauma[END_REF], the accuracy with which such angles are currently estimated is still not adequate with respect to the entailed range of motion [START_REF] Benoit | Effect of skin movement artifact on knee kinematics during gait and cutting motions measured in vivo[END_REF]. Improving this accuracy would enable a re-evaluation and improved understanding of the underlying mechanisms. In summary, the generalisation and strengthening of the effective role of motion analysis in clinical practice and in other application areas requires the six degrees-of-freedom joint kinematics to be estimated with a much higher accuracy than is possible today.

During the Seventh World Congress of Biomechanics, held in Boston in 2014, a number of human movement analysts recognised the need to address this ongoing issue and established a working group aimed at its resolution (the Soft-Tissue-Artefact-Propagation-Attenuation Group; STAPAG). The founding idea was that such a challenging problem could only be solved through a solidarity pact among interested scientists willing to share competences and resources. This Special Issue of the Journal of Biomechanics is one of the products of this joint effort.

In the first part of this Special Issue, this solidarity is highlighted by a detailed report made possible by the contributions of the majority of the authors who have measured the STA using either pins inserted into bones or fluoroscopy. By providing their raw data, the characteristics of the STA at various joints are expounded upon since a detailed knowledge of the phenomenon is a prerequisite for the assessment of its negative effects and to devise methods that minimize these effects. Standardized metrics for the description of the STA are proposed and data samples for body segments of both the upper and lower extremities and for numerous motor tasks are provided [START_REF] Cereatti | Standardization proposal of soft tissue artefact description for data sharing in human motion measurements[END_REF]. These data samples also include artefact-free joint kinematics for the validation of STA compensation methods. In other studies, the amplitude of the STA, either assessed as displacements of individual markers or as the translation and rotation of a maker-cluster, are analysed at the pelvis level for different hip joint angles [START_REF] Camomilla | Soft tissue displacement over pelvic anatomical landmarks during 3-D hip movements[END_REF], at the thigh and shank levels during treadmill gait [START_REF] Barré | Assessment of the lower limb soft tissue artefact at marker-cluster level with a high-density marker set during walking[END_REF] and cycling [START_REF] Li | Soft tissue artefacts of skin markers on the lower limb during cycling: effects of joint angles and pedal resistance[END_REF], and at the clavicle, scapula and humerus levels during daily life and sports activities [START_REF] Blache | Main component of soft tissue artifact of the upper-limbs with respect to different functional, daily life and sports movements[END_REF]. The well-known relationship between STA and joint angles is observed for some of the marker-cluster geometrical transformations (not only rotations and translations but also homotheties and stretches) [START_REF] Barré | Assessment of the lower limb soft tissue artefact at marker-cluster level with a high-density marker set during walking[END_REF]. At the same time the role of factors other than joint angles, e.g. muscle activation, are investigated, suggesting that further development of STA compensation methods may have to include not only kinematic constraints but also internal forces, especially during activities with varying loading conditions [START_REF] Li | Soft tissue artefacts of skin markers on the lower limb during cycling: effects of joint angles and pedal resistance[END_REF]. In [START_REF] Dumas | Stiffness of wobbling mass models analysed by a smooth orthogonal decomposition of the skin movement relative to the underlying bone[END_REF] the local displacements of the skin markers are not analysed as artefacts to be compensated for, but are seen in their real nature and used to characterize the movement of the soft tissue masses relative to the bone (wobbling masses) and the relevant dynamic effects on the execution of a motor task. This contribution was included in the Special Issue in order to emphasize the double perspective through which the local movement of the skin markers may be seen.

In the second part of the Special Issue, the propagation of the STA to different outputs of motion analysis is investigated to highlight the importance and the consequences of the phenomenon. The effect of the STA on the estimate of the knee joint axes through functional calibration is analysed both experimentally [START_REF] Sangeux | Evaluation of knee functional calibration with and without the effect of soft tissue artefact[END_REF] and analytically [START_REF] De Rosario | Analytical study of the effects of soft tissue artefacts on functional techniques to define axes of rotation[END_REF]. Both studies confirm the effects of STA on knee angles for all functional calibration approaches, stating that no approach can be generally considered superior to others regarding the impact of STA. Different calibration approaches proved different sensitivities to the knee varus-valgus or internal-external rotation ranges of movement [START_REF] Sangeux | Evaluation of knee functional calibration with and without the effect of soft tissue artefact[END_REF] and to different characteristics of the artefacts [START_REF] De Rosario | Analytical study of the effects of soft tissue artefacts on functional techniques to define axes of rotation[END_REF], calling for strategies to limit the negative effects of STA that are specific to the selected approach. As regards the accuracy of the kinetic quantities estimated through musculoskeletal models driven by stereophotogrammetric recordings of skin-mounted marker trajectories, STA can cause variations in some cases higher than 30%, but without significantly altering the overall pattern of joint kinetics and contact forces [START_REF] Lamberto | To what extent is joint and muscle mechanics predicted by musculoskeletal models sensitive to soft tissue artefacts[END_REF].

The third part of the Special Issue revises the kinematic models of the lower limb [START_REF] Leardini | Kinematic models of lower limb joints for musculo-skeletal modeling and optimization in gait analysis[END_REF] and upper limb joints [START_REF] Duprey | Kinematic models of the upper limb joints for multibody kinematics optimisation: An overview[END_REF] used in multibody kinematics optimisation, a method which is becoming extensively used for STA compensation as expounded upon in the fourth part of the Issue. The evaluation of these methods is focused on the knee [START_REF] Richard | Comparative assessment of knee joint models used in multi-body kinematics optimisation for soft tissue artefact compensation[END_REF] and shoulder [START_REF] Naaim | Effect of various upper limb multibody models on soft tissue artefact correction: a case study[END_REF] joints, assessing the efficacy of different joint models in improving the kinematics estimates using the artefact-free kinematics made available in the first paper of this Special Issue [START_REF] Cereatti | Standardization proposal of soft tissue artefact description for data sharing in human motion measurements[END_REF].

Results in this third part lead to the conclusion that the joint models devised so far still do not represent a reliable solution to the STA issue, for none of the investigated joints. These models have shown to somehow help the reduction of the STA effects, but enhanced joint modelling approaches including personalisation and/or stochastic processes are required to take full advantage of the anatomical information.

While the previous parts of the Special Issue dealt with improving our understanding of STA through descriptive modelling approaches, the fourth part deals with the state of the art in STA compensation. Most of these methods were validated using the data provided in this Special Issue [START_REF] Cereatti | Standardization proposal of soft tissue artefact description for data sharing in human motion measurements[END_REF]. By exploiting the continuum mechanics theory of Cosserat and least squares methods and using a large in vivo database, [START_REF] Solav | Bone orientation and position estimation error using Cosserat point elements and least squares methods: Application to gait[END_REF] confirms the existence of time variant marker-clusters almost unaffected by STA and proposes criteria for the instantaneous non-invasive selection of them. Alternatively, the compensation entailed in using multibody kinematics optimisation is enhanced by the projection of the skin markers onto a selected axis of the local system of coordinates (i.e., the humerus longitudinal axis) to cancel the deleterious effect of STA on this degree-of-freedom, reducing by half the errors for humerus axial orientation [START_REF] Begon | Multibody kinematics optimization with marker projection improves the accuracy of the humerus rotational kinematics[END_REF]. Multibody kinematics optimisation is also used in the context of musculoskeletal modeling: adaptive kinematic constraints are introduced to limit the impact of STA and obtain a more physiologically valid representation of joint kinematics and intersegmental moments during gait [START_REF] Potvin | A practical solution to reduce soft tissue artifact error at the knee using adaptive kinematic constraints[END_REF]. Using these constraints, physiologically consistent representations of knee joint kinematics during motions commonly associated with non-contact knee injuries were obtained and injury mechanisms reconsidered [START_REF] Smale | Knee joint kinematics and kinetics during the hop and cut after soft tissue artifact suppression: time to reconsider ACL injury mechanisms[END_REF]. Methods are also reported that exploit the potential of extended Kalman filters, either simultaneously tracking maker trajectories and external forces (Bonnet et al., 2017a) or embedding an STA mathematical model in the filter (Bonnet et al., 2017b). The former approach, although tested only for sagittal symmetric motor tasks, may reduce up to one-third the STA effects on the reconstructed ground reaction forces and moments and, by inference, on intersegmental loads (Bonnet et al., 2017a). This approach also allows for a reduced error in joint kinematics, with the exception of degrees of freedom that undergo moderate displacements (Bonnet et al., 2017b).

And finally, the fifth part of the Special Issue addresses the emerging use of ultrasound techniques for the assessment and compensation of the STA [START_REF] Jia | CAT & MAUS: A novel system for true dynamic motion measurement of underlying bony structures with compensation for soft tissue movement[END_REF][START_REF] Masum | Multi-slice ultrasound image calibration of an intelligent skin-marker for soft tissue artefact compensation[END_REF].

Advanced optical motion capture systems have never been more affordable and accessible.

The obvious question, with this compilation of STA-related research is this, however: can we now reliably and validly represent bone and joint motions using markers placed on the skin?

The answer is that we are closer than fifteen years ago, but the light at the end of the tunnel cannot be seen yet. The papers in this Special Issue are nevertheless laying the tracks needed to reach this light. They bring together different approaches and points of view, facilitating a structured debate to devise future developments and provide knowledge, suggestions, and data that may accelerate the achievement of the ultimate goal of enhancing the accuracy of human and animal motion analysis performed using stereophotogrammetry and markers attached to the skin.

The guest editors would like to take this opportunity to thank the editors of the Journal of Biomechanics for hosting this Special Issue, especially Farshid Guilak for his precious support and advice. Last but not least, we would like to thank the reviewers for their valuable help in assessing and improving the contributions, and the authors for contributing their highquality studies. We are also grateful to the Editorial Office of the Journal of Biomechanics for the opportunity and assistance to publish all the papers within this Special Issue.

in ambulatory children with cerebral palsy with and without gait analysis: Results of a randomized controlled trial. Gait & Posture 38,[236][237][238][239][240][241]