Short-term plasticity of the motor cortex compensates for bradykinesia in Parkinson's disease.

Patients with Parkinson's disease (PD) show impaired short-term potentiation (STP) mechanisms in the primary motor cortex (M1). However, the role played by this neurophysiological abnormality in bradykinesia pathophysiology is unknown. In this study, we used a multimodal neuromodulation approach to test whether defective STP contributes to bradykinesia. We evaluated STP by measuring motor-evoked potential facilitation during 5 Hz-repetitive transcranial magnetic stimulation (rTMS) and assessed repetitive finger tapping movements through kinematic techniques. Also, we used transcranial alternating current stimulation (tACS) to drive M1 oscillations and experimentally modulate bradykinesia. STP was assessed during tACS delivered at beta (ß) and gamma (γ) frequency, and during sham-tACS. Data were compared to those recorded in a group of healthy subjects. In PD, we found that STP was impaired during sham- and γ-tACS, while it was restored during ß-tACS. Importantly, the degree of STP impairment was associated with the severity of movement slowness and amplitude reduction. Moreover, ß-tACS-related improvements in STP were linked to changes in movement slowness and intracortical GABA-A-ergic inhibition during stimulation, as assessed by short-interval intracortical inhibition (SICI). Patients with prominent STP amelioration had greater SICI reduction (cortical disinhibition) and less slowness worsening during ß-tACS. Dopaminergic medications did not modify ß-tACS effects. These data demonstrate that abnormal STP processes are involved in bradykinesia pathophysiology and return to normal levels when ß oscillations increase. STP changes are likely mediated by modifications in GABA-A-ergic intracortical circuits and may represent a compensatory mechanism against ß-induced bradykinesia in PD.

Assessing the interaction between L-dopa and γ-transcranial alternating current stimulation effects on primary motor cortex plasticity in Parkinson's disease.

L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (γ) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-γ-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-γ-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during γ-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-γ-tACS. The amount of change produced by iTBS-γ-tACS was similar in patients OFF and ON therapy. Finally, γ-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical γ oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state. These results suggest a lack of interaction between L-dopa and γ-tACS effects at the M1 level. The possible neural substrate underlying iTBS-γ tACS effects, that is, γ-resonant GABA-A-ergic interneurons activity, may explain our findings.

Dystonia, chorea, hemiballismus and other dyskinesias.

Hyperkinesias are heterogeneous involuntary movements that significantly differ in terms of clinical and semeiological manifestations, including rhythm, regularity, speed, duration, and other factors that determine their appearance or suppression. Hyperkinesias are due to complex, variable, and largely undefined pathophysiological mechanisms that may involve different brain areas. In this chapter, we specifically focus on dystonia, chorea and hemiballismus, and other dyskinesias, specifically, levodopa-induced, tardive, and cranial dyskinesia. We address the role of neurophysiological studies aimed at explaining the pathophysiology of these conditions. We mainly refer to human studies using surface and invasive in-depth recordings, as well as spinal, brainstem, and transcortical reflexology and non-invasive brain stimulation techniques. We discuss the extent to which the neurophysiological abnormalities observed in hyperkinesias may be explained by pathophysiological models. We highlight the most relevant issues that deserve future research efforts. The potential role of neurophysiological assessment in the clinical context of hyperkinesia is also discussed.

Relationship between risk and protective factors and clinical features of Parkinson's disease.

BACKGROUND: Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. OBJECTIVE: The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample of PD patients. METHODS: Six hundred ninety-four patients with PD participated. Patients underwent a clinical evaluation assessing motor symptoms and motor complications as well as non-motor symptoms severity. Information regarding pharmacological treatment was also collected. Risk and protective factors were previously identified in the present population and included coffee consumption, cigarette smoking, and physical activity as protective factors and a family history of PD, dyspepsia, exposure to toxic agents and general anesthesia as risk factors. Multiple regression models were used to investigate the relationship between risk factors and clinical variables. RESULTS: Coffee consumption predicted older age at onset (B: 0.527; CI: 0.195; 0.858) and milder motor symptom severity (B: 1.383; CI: 2.646; -0.121). Non-motor symptom severity was more severe in patients with dyspepsia before PD (B: 13.601; CI 5.019; 22.182) and milder in patients who performed physical activity before PD (B: 11.355; CI: 16.443; -6.266). We found no relationship between risk factors and motor complications, motor subtype and pharmacological treatment. CONCLUSIONS: Risk and protective factors of PD development may influence PD clinical features. This finding may represent the first step in the development of new preventive approaches able to delay disease onset and mitigate the extent of clinical manifestations.

Functional disconnection of the dentate nucleus in essential tremor.

Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of disconnection of the dentate nucleus (DN), the main output cerebellar pathway, still needs clarification. In this study, we evaluated DN functional connectivity (FC) changes and their relationship with motor and non-motor symptoms in ET. We studied 25 ET patients and 26 healthy controls. Tremor severity was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and tremor amplitude and frequency were evaluated using kinematic techniques. Cognitive profile was assessed by montreal cognitive assessment (MoCA) and frontal assessment battery (FAB). All participants underwent a 3 T MRI protocol including resting-state blood oxygenation level dependent and diffusion tensor sequences. We used a seed-based approach to investigate DN FC and to explore the diffusion properties of cerebellar peduncles. There was significantly decreased DN FC with cortical, subcortical, and cerebellar areas in ET patients compared with healthy controls. Correlation analysis showed that: (1) the DN FC with the supplementary motor area, pre and postcentral gyri, and prefrontal cortex negatively correlated with FTM-TRS score and disease duration; (2) DN FC changes in the thalamus and caudate negatively correlated with peak tremor frequency, changes in the cerebellum positively correlated with tremor amplitude, and changes in the bilateral thalamus negatively correlated with tremor amplitude, and (3) DN FC with the associative prefrontal and parietal cortices, basal ganglia, and thalamus positively correlated with the MoCA score. Diffusion abnormalities were found in the three cerebellar peduncles, which did not correlate with clinical scores.

Neurophysiological studies on atypical parkinsonian syndromes.

There have been a relatively large number of experimental investigations using neurophysiological techniques in patients with atypical parkinsonian syndromes (APs), including progressive supranuclear palsy, cortico-basal syndrome and multiple system atrophy. Earlier studies focused on the startle, blink and trigemino-cervical reflexes and showed several brainstem abnormalities. Studies using transcranial magnetic stimulation have revealed a number of abnormalities in primary motor cortex and inter-hemispheric connectivity. More recent studies have highlighted the role of cerebellar dysfunction and have reported altered movement kinematics. Neurophysiological abnormalities in APs reflect degeneration or functional changes at multiple brain levels. In the majority of cases, APs share common abnormalities even though some neurophysiological changes differ among the various APs. Evidence of a correlation between neurophysiological abnormalities and clinical signs and symptoms in APs is limited. This paper provides an update on the results of experimental investigations using neurophysiological techniques in APs and also reviews similarities and differences between APs and Parkinson's disease. The potential role of neurophysiological abnormalities in the clinical context of APs is also discussed.

Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome.

AIM: To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). METHODS: We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software. RESULTS: Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS. CONCLUSIONS: Evaluating the dentate nucleus size and its functional connectivity may help to differentiate patients with PSP from those with CBS.

Reduced facial expressiveness in Parkinson's disease: A pure motor disorder?

BACKGROUND AND AIMS: Impaired emotional facial expressiveness is an important feature in Parkinson's disease (PD). Although there is evidence of a possible relationship between reduced facial expressiveness and altered emotion recognition or imagery in PD, it is unknown whether other aspects of the emotional processing, such as subjective emotional experience (alexithymia), might influence hypomimia in this condition. In this study wee aimed to investigate possible relationship between reduced facial expressiveness and altered emotion processing (including facial recognition and alexithymia) in patients with PD. METHODS: Forty PD patients and seventeen healthy controls were evaluated. Facial expressiveness was rated on video recordings, according to the UPDRS-III item 19 and using an ad hoc scale assessing static and dynamic facial expression and posed emotions. Six blind raters evaluated the patients' videos. Emotion facial recognition was tested using the Ekman Test; alexithymia was assessed using Toronto Alexithymia Scale (TAS-20). RESULTS: PD patients had a significantly reduced static and dynamic facial expressiveness and a deficit in posing happiness and surprise. They performed significantly worse than healthy controls in recognizing surprise (p=0.03). The Ekman total score positively correlated with the global expressiveness (R^2=0.39, p=0.01) and with the expressiveness of disgust (R^2=0.32, p=0.01). The occurrence of alexithymia was not different between PD patients and HC; however, a significant negative correlation between the expressiveness of disgust was found for a subscore of TAS (R^2=-.447, p=0.007). CONCLUSIONS: Reduced facial expressiveness in PD may be in part related to difficulties with emotional recognition in a context of an unimpaired subjective emotional experience.

Cerebellar continuous theta burst stimulation in essential tremor.

The pathophysiological mechanisms of essential tremor (ET) are still not entirely clear. In the present study, we aimed to investigate the cerebello-thalamo-cortical connectivity in ET using the cerebellar continuous theta burst stimulation (cTBS) and possible effects on tremor and reaching movements. Sixteen patients with ET and 11 healthy subjects underwent two experimental sessions: (i) cTBS over the right cerebellar hemisphere (real cerebellar cTBS) and (ii) cTBS over the neck muscles (sham cerebellar cTBS). The two sessions were performed at least 1 week apart. The effects of real and sham cerebellar cTBS were quantified as excitability changes on contralateral primary motor cortex, as well as possible changes of postural tremor and reaching movements on the ipsilateral arm. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials from the right first dorsal interosseous muscle. Tremor was rated clinically. Objective assessment of tremor and reaching movements was performed using kinematic techniques. Real cerebellar cTBS reduced the excitability in the contralateral primary motor cortex in healthy subjects though not in patients with ET. There was no significant change in tremor severity and reaching movements, as assessed by clinical examination or kinematic techniques, after real or sham cerebellar cTBS in patients with ET. Finally, there was no correlation between individual changes of M1 excitability and kinematic measures of tremor and reaching movement abnormalities in patients with ET. The results suggest that functional cerebello-thalamo-cortical connectivity tested by cTBS is abnormal in ET and that cerebellar cTBS does not ameliorate tremor in this condition.

The brighter side of music in dystonia.

OBJECTIVE: To report a patient with genetically proven DYT1 dystonia who shows dramatic improvement in symptoms while playing the piano. DESIGN: Case study. SETTING: Sobell Department for Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, England. PATIENT: A 49-year-old right-handed male civil servant. MAIN OUTCOME MEASURES: The patient was videotaped, and electromyographic activity was recorded from the splenius capitis, sternocleidomastoid, and orbicularis oculi muscles, while he was (1) at rest, (2) playing an electric piano with auditory feedback, and (3) playing an electric piano without auditory feedback (ie, when the sound of the piano is turned off). RESULTS: At baseline, the patient had generalized dystonia with prominent upper limb, neck, and facial involvement. While he was playing the piano, there was an instant and almost complete improvement in dystonia symptoms. The improvement was also noticeable when he played the piano without auditory feedback. There was a significant reduction in electromyographic activity for all recorded muscles when he played the piano, compared with his baseline electromyographic activity. CONCLUSION: This is a unique case of "paradoxical" improvement in dystonia symptoms with activity (ie, playing a piano), in contrast to the typical worsening of dystonia symptoms with activity. We discuss the possible mechanisms underlying this phenomenon. One of the most intriguing features of primary dystonia is the variability of abnormal muscle activity relative to the context in which movement is attempted (eg, the exquisite task specificity of focal hand dystonia or the phenomenon of the geste antagoniste). We present a unique case of an amateur pianist with genetically proven DYT1 dystonia who shows dramatic improvement in generalized dystonia symptoms while playing piano.