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To date, clinical expert opinion is the gold standard diagnostic technique for Parkinson's disease (PD), and continuous monitoring is a promising candidate marker. This study assesses the feasibility and performance of a new wearable tool for supporting the diagnosis of Parkinsonian motor syndromes. The proposed method is based on the use of a wrist-worn measuring system, the execution of a passive, continuous recording session, and a computation of two digital biomarkers (i.e., motor activity and rest tremor index). Based on the execution of some motor tests, a second step is provided for the confirmation of the results of passive recording. In this study, fifty-nine early PD patients and forty-one healthy controls were recruited. The results of this study show that: (a) motor activity was higher in controls than in PD with slight tremors at rest and did not significantly differ between controls and PD with mild-to-moderate tremor rest; (b) the tremor index was smaller in controls than in PD with mild-to-moderate tremor rest and did not significantly differ between controls and PD patients with slight tremor rest; (c) the combination of the said two motor parameters improved the performances in differentiating controls from PD. These preliminary findings demonstrate that the combination of said two digital biomarkers allowed us to differentiate controls from early PD.

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BACKGROUND: The current gold standard for evaluating normal and impaired motor performances includes the use of the information provided by the patient and the Unified Parkinson's Disease Rating Scale (UPDRS). However, clinical rating scales are typically subjective and their time-limited duration may fail to capture daily fluctuations in motor symptoms resulting from Parkinson's disease. Recently, a new tool has been proposed for objective and continuous assessment of movement disorders based on the evaluation of frequential data content from multi-axial sensors and the identification of specific movement patterns typically associated with disorders. This reduces the probability of confusing physiological or pathological movements occurring at the same frequency with a different movement pattern. However, the data provided by the tool have not yet been compared with the information provided by the typically used clinical rating scales. OBJECTIVES: The aim of this work is to investigate the possible relationship between UPRDS scores and the information provided by the tool for continuous and long-term monitoring. MATERIALS AND METHODS: In this study, 20 patients with hand tremor were recruited. The UPDRS scoring was performed by a neurologist. Then, continuous monitoring was performed; data were acquired by means of the proposed wrist-worn-device "PD-Watch" for 24 h and then processed in order to get information and indexes on motor symptoms. Finally, these indexes were correlated to the UPDRS scores. RESULTS: Results show that the concise indexes provided by the tool correlate well with some items in UPDRS Part III, and this correlation has allowed to provide a more direct and immediate meaning to the values of the concise indexes detected by the tool. CONCLUSIONS: While results need to be extended with further studies, this can be considered useful information in the context of clinical trials and routine clinical practice for assessing motor symptoms and movement disorders.

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The clinical assessment of Parkinson's disease (PD) symptoms is typically performed with neurological examinations and simple motor tests. However, this only takes into account the severity of motor symptoms during the length of the recording and fails to capture variations in a patient's motor state, which change continuously during the day. Most of the current methods for long-term monitoring of extrapyramidal symptoms are based on the use of a wearable magneto-inertial device that evaluates the frequential content of signals in the range of movement disorders. However, the typical daily motor activities performed by patients may have a power spectrum into the same range of motor symptoms, and habitual activity may be indistinguishable from that due to movement disorders. In this work, we report a new device and method for the continuous and long-term monitoring of tremor due to PD and other movement disorders to reduce the probability of mistaking the discrimination between extrapyramidal symptoms and normal daily activity. The method is based on the evaluation of frequential data content from multi-axial sensors and on the identification of specific movement patterns that Parkinsonian and extrapyramidal symptoms are typically associated with. In this study, 16 patients with movement disorders were recruited. While results need to be extended with further studies and clinical trials, the proposed device appears promising and suitable for the use as part of clinical trials and routine clinical practice for supporting the evaluation of motor symptoms, disease progression, and the quantification of therapeutic effects.

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The flexion or flexor reflex (FR) recorded in the lower limbs in humans (LLFR) is a widely investigated neurophysiological tool. It is a polysynaptic and multisegmental spinal response that produces a withdrawal of the stimulated limb and resembles (having several features in common) the hind-paw FR in animals. The FR, in both animals and humans, is mediated by a complex circuitry modulated at spinal and supraspinal level. At rest, the LLFR (usually obtained by stimulating the sural/tibial nerve and by recording from the biceps femoris/tibial anterior muscle) appears as a double burst composed of an early, inconstantly present component, called the RII reflex, and a late, larger and stable component, called the RIII reflex. Numerous studies have shown that the afferents mediating the RII reflex are conveyed by large-diameter, low-threshold, non-nociceptive A-beta fibers, and those mediating the RIII reflex by small-diameter, high-threshold nociceptive A-delta fibers. However, several afferents, including nociceptive and non-nociceptive fibers from skin and muscles, have been found to contribute to LLFR activation. Since the threshold of the RIII reflex has been shown to correspond to the pain threshold and the size of the reflex to be related to the level of pain perception, it has been suggested that the RIII reflex might constitute a useful tool to investigate pain processing at spinal and supraspinal level, pharmacological modulation and pathological pain conditions. As stated in EFNS guidelines, the RIII reflex is the most widely used of all the nociceptive reflexes, and appears to be the most reliable in the assessment of treatment efficacy. However, the RIII reflex use in the clinical evaluation of neuropathic pain is still limited. In addition to its nocifensive function, the LLFR seems to be linked to posture and locomotion. This may be explained by the fact that its neuronal circuitry, made up of a complex pool of interneurons, is interposed in motor control and, during movements, receives both peripheral afferents (flexion reflex afferents, FRAs) and descending commands, forming a multisensorial feedback mechanism and projecting the output to motoneurons. LLFR excitability, mediated by this complex circuitry, is finely modulated in a state- and phase-dependent manner, rather as we observe in the FR in animal models. Several studies have demonstrated that LLFR excitability may be influenced by numerous physiological conditions (menstrual cycle, stress, attention, sleep and so on) and pathological states (spinal lesions, spasticity, Wallenberg's syndrome, fibromyalgia, headaches and so on). Finally, the LLFR is modulated by several drugs and neurotransmitters. In summary, study of the LLFR in humans has proved to be an interesting functional window onto the spinal and supraspinal mechanisms of pain processing and onto the spinal neural control mechanisms operating during posture and locomotion.

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Transcranial magnetic stimulation (TMS) has been used to assess characteristics of the corticomotor control of the jaw muscles, but less is known about the cortical control of the human tongue and its modification by training. The aim of the present study was to determine the effect of training humans in a novel tongue-protrusion task for 1 week on corticomotor excitability as assessed by changes in electromyographic activity elicited in the tongue musculature by TMS, and in the tongue cortical motor map revealed by TMS. Eleven healthy subjects participated. Stimulus-response curves were generated from the motor evoked potentials (MEPs) recorded in the tongue musculature and, from the first dorsal interosseos (FDI) muscle as a control, at three time periods: at baseline, immediately after the 1-week training period, and at 2-weeks follow-up. In addition, the corticomotor representations of the tongue and FDI muscles were mapped on a 1 x 1 cm scalp grid. The tongue-training task required each subject to protrude the tongue onto a force transducer placed in front of the subject, and consisted of a relax-protrude-hold-relax cycle lasting 12.5 s with 1 N as the target at the hold phase. The subjects repeated this task for 60 min every day for 1 week. All subjects reported moderate levels of fatigue in the tongue during the first training day; however, these subjective reports decreased during the week (ANOVA P<0.001), and the subjects showed a progressive increase in their ability to perform the task successfully ( P<0.001). The threshold for evoking MEPs by TMS in the tongue musculature was significantly decreased after the last training day compared with baseline and the 2-weeks follow-up ( P<0.001). The amplitude of the MEPs in the tongue musculature was significantly increased at higher intensities of TMS after the last training day but returned to baseline values at the 2-weeks follow-up (P = 0.005). No significant effect of the training on MEPs in the FDI was observed (P = 0.493). Analysis of the corticomotor topographic maps revealed a significant ( P<0.05) increase in excitability and, hence, the cortical area from which TMS could evoke MEPs in the tongue, although the center of gravity representation for the tongue or FDI muscles remained stable. The present findings suggest that a specific and reversible plasticity of the corticomotor excitability related to tongue muscle control can be induced when humans learn to perform successfully a novel tongue task.

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Cutaneous laser stimulation activates predominantly the A-delta and C mechano-heat nociceptors. Applied to the perioral region, low intensity CO(2)-laser pulses evoke reproducible trigeminal cortical evoked potentials (LEPs). High intensity CO(2)-laser stimuli induce a reflex response in the contracted jaw-closing muscle, the so-called laser silent period (LSP). Both LEPs and LSP provide a useful tool to study the physiology of the trigeminal nociceptive system. In ten healthy subjects we recorded the subjective ratings of the perioral laser stimulation and the trigeminal LEPs and LSP before, during and after homotopic experimental tonic muscle (infusion of hypertonic saline into the masseter muscle) and tonic skin pain (topical application of capsaicin to the cheek). LEPs were recorded from the vertex at two stimulus intensities: low (1.1 x pain threshold, PTh) and high (1.5 x PTh). LSP from masseter and temporalis muscles were recorded bilaterally through surface electromyographic (EMG) electrodes. CO(2)-laser pulses were applied to the perioral region (V2/V3) on the painful and non-painful side. The amplitude of LEPs increased with higher stimulus intensities (P<0.0001), but were suppressed by 42.3+/-5.3% during experimental muscle pain (P<0.0001) and by 41.6+/-3.2% during skin pain (P<0.0001). No pain-related effects were observed for the N and P latency of the LEPs (P> 0.20). The LSP in the masseter and temporalis muscles had similar onset-latency (80+/-5 ms), offset-latency (111+/-5 ms) and duration (31+/-4 ms). Experimental pain had no effect on the onset- and offset-latency (P>0.05). Experimental pain, whether from muscle or from skin, reduced the degree of suppression (P<0.01) and the area under the EMG curve (P< 0.005) of the LSP. The LSP was still suppressed during the post-pain recordings when the skin pain had disappeared (P<0.05). In all experiments experimental tonic pain decreased the subjective ratings of the perioral laser stimulation (P< 0.001). Experimental tonic pain, either from muscle or from skin, induced bilateral inhibitory effects on the trigeminal laser evoked potentials and brainstem reflex responses and on the subjective ratings of the laser pulses. These effects could be mediated through the activation of segmental and suprasegmental inhibitory systems that may function interdependently.

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