Piero Ruggeri

Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor

The cerebellum is involved in the generation of essential tremor (ET) and cerebellar timing function is altered in patients with ET showing an increased variability of rhythmic hand movements. Using a sensor‐engineered glove, we evaluated motor behaviour during repetitive finger tapping movements in 15 patients with ET and in 11 age‐ and gender‐matched normal subjects. In addition, we investigated whether, in patients with ET, an inhibitory repetitive transcranial magnetic stimulation (1 Hz‐rTMS) over lateral cerebellum was able to change timing properties and motor behaviour. Patients with ET showed a longer touch duration (TD) and a lower inter tapping interval (ITI) than normal subjects. The temporal variability of the movement (coefficient of variation of ITI) was increased in patients with ET. Neither clinical rating scale or tremor measurements correlated with any parameter of motor performance in the ET group. 1 Hz‐rTMS over ipsilateral lateral cerebellum transiently affected the performance of patients with ET, by reducing TD values and normalizing ITI values. After 1 Hz‐rTMS, the coefficient of variation of ITI was restored to values similar to those of normal subjects. We postulate that the strategy to increase TD, probably adopted to allow a better perception of movement, can affect ITI and its variability. The results support the idea that the cerebellum plays a central role in the selection of motor strategy of rhythmic finger movements, particularly in terms of temporal organization of movement.

Reduction of Bradykinesia of Finger Movements by a Single Session of Action Observation in Parkinson Disease

Background. Action observation influences motor performance in healthy subjects and persons with motor impairments. Objective. To understand the effects of action observation on the spontaneous rate of finger movements in patients with Parkinson disease (PD). Methods. Participants, 20 with PD and 14 healthy controls, were randomly divided into 2 groups. Those in the VIDEO group watched video clips showing repetitive finger movements paced at 3 Hz, whereas those in the ACOUSTIC group listened to an acoustic cue paced at 3 Hz. All participants performed a finger sequence at their spontaneous pace at different intervals (before, at the end of, 45 minutes after, and 2 days after training); 8 participants with PD were recruited for a sham intervention, watching a 6-minute video representing a static hand. Finally, 10 patients participated in the same protocol used for the VIDEO group but were tested in the on and off medication states. Results. Both VIDEO and ACOUSTIC training increased the spontaneous rate in all participants. VIDEO intervention showed a greater effect over time, improving the spontaneous rate and reducing the intertapping interval to a larger extent than ACOUSTIC 45 minutes and 2 days after training. Action observation significantly influenced movement rate in on and off conditions, but 45 minutes after training, the effect was still present only in the on condition. No effect was observed after sham intervention. Conclusions. These findings suggest that the dopaminergic state contributes to the effects of action observation, and this training may be a promising approach in the rehabilitation of bradykinesia in PD.

Postural control after a strenuous treadmill exercise

The effect of a strenuous treadmill exercise on body stability and the mechanisms associated with it have been studied with two different experimental protocols. The former investigation was based on stabilometric and metabolic measurements performed in basal condition and after a strenuous treadmill exercise whilst the latter dealt with the study of the early postural response to a 3s-bilateral soleus muscle vibration after the strenuous exercise. Our exercise protocol was able to induce an important generalized metabolic fatigue, as assessed by the obtained peak values in the measured metabolic parameters, and resulting in a short-lasting body destabilization. A linear relationship between sway path and oxygen uptake was found. Thus, the short duration of body instability could be likely due to the quite rapid recovery of oxygen uptake. Further, the fatigue-induced body instability did not associate with changes in the early postural response to soleus muscle vibration. The present study cannot rule out the possibility that further central and/or peripheral mechanisms, influencing the postural control, may play a role in the fatigue-induced changes in body sway.

Effect of microelectrophoretically applied corticosterone on raphe neurones in the rat.

The effect of microelectrophoretic application of corticosterone (CS) on single neurones of raphe nuclei (RN) were investigated in rats under urethane anaesthesia. Ejecting currents generally ranged from 5 to 40 nA. CS produced an excitatory effect in 61% and no effect in 39% of the neurones. None of the 54 neurones studied was inhibited by CS. These quite homogeneous data support the hypothesis that RN are involved in the regulation of most of the nervous functions in which glucocorticoid hormones have been implicated.

Motor cortical plasticity induced by motor learning through mental practice.

Several investigations suggest that actual and mental actions trigger similar neural substrates. Motor learning via physical practice results in long-term potentiation (LTP)-like plasticity processes, namely potentiation of M1 and a temporary occlusion of additional LTP-like plasticity. However, whether this neuroplasticity process contributes to improve motor performance through mental practice remains to be determined. Here, we tested skill learning-dependent changes in primary motor cortex (M1) excitability and plasticity by means of transcranial magnetic stimulation (TMS) in subjects trained to physically execute or mentally perform a sequence of finger opposition movements. Before and after physical practice and motor-imagery practice, M1 excitability was evaluated by measuring the input-output (IO) curve of motor evoked potentials. M1 LTP and long-term depression (LTD)-like plasticity was assessed with paired-associative stimulation (PAS) of the median nerve and motor cortex using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), respectively. We found that even if after both practice sessions subjects significantly improved their movement speed, M1 excitability and plasticity were differentially influenced by the two practice sessions. First, we observed an increase in the slope of IO curve after physical but not after MI practice. Second, there was a reversal of the PAS25 effect from LTP-like plasticity to LTD-like plasticity following physical and MI practice. Third, LTD-like plasticity (PAS10 protocol) increased after physical practice, whilst it was occluded after MI practice. In conclusion, we demonstrated that MI practice lead to the development of neuroplasticity, as it affected the PAS25- and PAS10- induced plasticity in M1. These results, expanding the current knowledge on how MI training shapes M1 plasticity, might have a potential impact in rehabilitation.

Therapeutic Use of Creatine in Brain or Heart Ischemia: Available Data and Future Perspectives

Creatine (Cr) is essential in safeguarding ATP levels and in moving ATP from its production site (mitochondria) to the cytoplasmic regions where it is used. Moreover, it has effects unrelated to energy metabolism, such as free radical scavenging, antiapoptotic action, and protection against excitotoxicity. Recent research has studied Cr‐derived compounds (Cr benzyl ester and phos‐pho–Cr–magnesium complex) that reproduce the neuroprotective effects of Cr while better crossing the neuronal plasma membrane and, hopefully, the blood–brain barrier (BBB). Intracellular levels of Cr can be increased by incubation with Cr or some of its derivatives, and this increase is protective against anoxic or ischemic damage. A large amount of experimental evidence shows that pretreatment with Cr is capable of reducing the damage induced by ischemia or anoxia in both heart and brain, and that such treatment may also be useful even after stroke or myocardial infarction (MI) has already occurred. Cr has been safely administered to patients affected by several neurological diseases, yet it has never been tested in human brain ischemia, the condition where its rationale is strongest. Phosphocreatine (PCr) has been administered after human MI, where it proved to be safe and probably helpful. Cr should be tested in the prophylactic protection against human brain ischemia and either Cr or PCr should be further tested in MI. Moreover, Cr‐ or PCr‐derived drugs should be developed in order to overcome these molecules’ limitations in crossing the BBB and the cell plasma membrane.

Insulin Sensitivity and Glucose Effectiveness Estimated by the Minimal Model Technique in Spontaneously Hypertensive and Normal Rats

This study was performed to compare glucose metabolism in anaesthetised spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) in an attempt to clarify whether this animal model of hypertension approximates the insulin‐resistant state seen in human hypertension. With this aim the minimal model of glucose kinetics was applied to glucose and insulin data derived from a 12‐sample, 120 min intravenous glucose tolerance test (IVGTT) performed in ten SHR and nine WKY rats under pentobarbital anaesthesia. This method provided two metabolic indices: the glucose effectiveness, SG, which quantifies the ability of glucose per se to enhance its rate of disappearance and to inhibit hepatic glucose production, and the insulin sensitivity, SI, which measures the ability of insulin to enhance plasma glucose disappearance and to inhibit hepatic glucose production. Systolic and diastolic arterial pressures in the SHR group were significantly higher (P < 0.0005) than in the WKY group. Mean SG and SI estimates from the SHR group (SG = 16.2 (± 2.0) × 10‐2 dl min‐1 kg‐1 and SI = 12.5 (± 1.9) × 10‐4 dl min‐1 kg‐1 (μU ml‐1)‐1) were not significantly different (P > 0.05) from mean estimates that characterised the WKY group (SG = 13.1 (± 1.5) × 10‐2 dl min‐1 kg‐1 and SI = 15.8 (± 4.3) × 10‐4 dl min‐1 kg‐1 (μU ml‐1)‐1). This result is in contrast with reported findings from humans in which insulin sensitivity is significantly reduced in the presence of hypertension.

Age‐related analysis of insulin resistance, body weight and arterial pressure in the Zucker fatty rat

The evolution with ageing of insulin resistance, body weight (BW) and mean arterial pressure (MAP) was studied in a group of Zucker fatty rats (ZFRs, n= 22), between 7 and 16 weeks of age, compared with an age‐matched control group of Zucker lean rats (ZLRs, n= 22). The minimal model of glucose kinetics was applied to estimate glucose effectiveness, SG, and insulin sensitivity, SI, from insulinaemia and glycaemia measured during a 70 min intravenous glucose tolerance test. No correlation was found between SG and age in both ZFR and ZLR groups. No significant changes in mean SG between the two groups indicated no alteration of glucose‐mediated glucose disposal. Estimates of SI from individual ZFRs were independent of age and, on average, showed 83% reduction (P < 0.001) compared with the ZLR group. Despite the lack of alteration of SI with age, the ZFR group showed an age‐related increase of MAP, which correlated with increasing BW (r = 0.71 and P < 0.001). These results support the hypothesis that in our ZFRs, as a suitable genetic model of obesity and hypertension, insulin resistance is fully established at the age of 7 weeks and remains practically unaltered until at least the sixteenth week. An age‐related increase in arterial pressure, observed in this strain, relates more properly to increasing BW, rather than insulin resistance. Development of hypertension with increasing age and BW may result from an enhanced insulin‐mediated activity of the sympathetic nervous system, as observed in our previously reported study.

Training based on mirror visual feedback influences transcallosal communication

Mirror visual feedback (MVF) therapy has been demonstrated to be successful in neurorehabilitation, probably inducing neuroplasticity changes in the primary motor cortex (M1). However, it is not known whether MVF training influences the hemispheric balance between the M1s. This topic is of extreme relevance when MVF training is applied to stroke rehabilitation, as the competitive interaction between the two hemispheres induces abnormal interhemispheric inhibition (IHI) that weakens motor function in stroke patients. In the present study, we evaluated, in a group of healthy subjects, the effect of motor training and MVF training on the excitability of the two M1s and the IHI between M1s. The IHI from the ‘active’ M1 to the opposite M1 (where ‘active’ means the M1 contralateral to the moving hand in the motor training and the M1 of the seen hand in the MVF training) increased, after training, in both the experimental conditions. Only after motor training did we observe an increase in the excitability of the active M1. Our findings show that training based on MVF may influence the excitability of the transcallosal pathway and support its use in disorders where abnormal IHI is a potential target, such as stroke, where an imbalance between the affected and unaffected M1s has been documented.

Role of nitric oxide in the control of the heart rate within the nucleus ambiguus of rats.

The aim of this study was to determine whether NO plays a role in the control of heart rate (HR) within the nucleus ambiguus (NA). Experiments were performed in 29 male Wistar rats anaesthetized with urethane. Microinjections of the NO-donor sodium nitroprusside (SNP; 5 mmol) as well as of L-arginine (L-arg; 50 mmol) into functionally identified cardioinhibitory sites within the NA significantly decreased HR (−57.7 ± 8.4 and −53.8 ± 3.2 bpm, respectively), whereas the NO-synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) significantly increased HR (+40 ± 2.7 bpm). Bilateral vagotomy and i.v. injection of atropine (0.5 mg/kg) always abolished the HR decrease induced by SNP and L-arg, whereas propranolol did not affect the HR responses. These results demonstrated that NO mechanisms within the NA play a role in the parasympathetic control of the HR.