Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy

Dopaminergic Modulation of Prospective Memory in Parkinson’s Disease

Growing interest is present in literature on the study of prospective memory functioning in Parkinson's disease (PD). Current data indicate that prospective memory may be impaired in PD and a relationship with general executive dysfunctioning has been suggested. However, although the dopamine dependency of cognitive dysfunction in PD has been widely investigated, poor is known on the dopaminergic modulation of PM. In the present study we explored the effect of acute administration of levodopa on the performance of a PD sample (n=20) in a time-based prospective memory task. PD patients were evaluated in the morning after a 12-hour therapy wash-out in two experimental conditions: i) after levodopa assumption ("on"); ii) without drug administration ("off"). The experimental task required to execute three uncorrelated actions after 10' for three consecutive trials. Distinct scores for the spontaneous recall of the intention to perform the actions (prospective component) and for the correct execution of the actions (retrospective component) have been computed. Results showed that in the "off" condition PD patients were selectively impaired on the prospective component of the task. However, L-dopa administration significantly improved PD patients' performance actually restoring the prospective memory deficit. These results support a critical role of dopaminergic modulation in prospective memory processes in PD patients, possibly through the replacement of dopamine levels in fronto-striatal pathways

Auditory Cue Based on the Golden Ratio Can Improve Gait Patterns in People with Parkinson’s Disease

The harmonic structure of walking relies on an irrational number called the golden ratio (ϕ): in healthy subjects, it coincides with the stride-to-stance ratio, and it is associated with a smooth gait modality. This smoothness is lost in people with Parkinson’s disease (PD), due to deficiencies in the execution of movements. However, external auditory cues seem to facilitate movement, by enabling the timing of muscle activation, and helping in initiating and modulating motor output. Based on a harmonic fractal structure of gait, can the administration of an auditory cue based on individual’s ϕ-rhythm improve, in acute, gait patterns in people with PD? A total of 20 participants (16 males, age 70.9 ± 8.4 years, Hoehn and Yahr stage-II) were assessed through stereophotogrammetry: gait spatio-temporal parameters, and stride-to-stance ratio were computed before, during, and after the ϕ-rhythm administration. Results show improvements in terms of stride length (p = 0.018), walking speed (p = 0.014), and toe clearance (p = 0.013) when comparing gait patterns before and after the stimulus. Furthermore, the stride-to-stance ratio seems to correlate with almost all spatio-temporal parameters, but it shows the main changes in the before–during rhythm comparison. In conclusion, ϕ-rhythm seems an effective cue able to compensate for defective internal rhythm of the basal ganglia in PD

Dopamine Treatment and Cognitive Functioning in Individuals with Parkinson’s Disease: The “Cognitive Flexibility” Hypothesis Seems to Work

Background. Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). Objective. To investigate above hypotheses in individuals with Parkinson's disease (PD). Methods. Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) “off” condition, about 18 hours after dopamine dose and (ii) “on” condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. Results. Passing from the “off” to the “on” state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P<0.05); no significant effect was found on low-flexibility tasks. Conclusions. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals

Dopamine Treatment and Cognitive Functioning in Individuals with Parkinson’s Disease: The “Cognitive Flexibility” Hypothesis Seems to Work

Background. Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). Objective. To investigate above hypotheses in individuals with Parkinson's disease (PD). Methods. Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) “off” condition, about 18 hours after dopamine dose and (ii) “on” condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. Results. Passing from the “off” to the “on” state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P<0.05); no significant effect was found on low-flexibility tasks. Conclusions. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals

Focal Vibration Training (Equistasi^®) to Improve Posture Stability. A Retrospective Study in Parkinson’s Disease

Background: For people with Parkinson&#8217;s disease (PD), falls are a critical point. Focal vibration training (FVT) may represent a valid tool to improve postural performances and reduce the risk of falls. The aim of this study was to evaluate the efficacy of FVT to improve the postural stability in PD patients. Methods: Since October 2015, 55 consecutive PD patients have been selected (T0) for an approach including FVT associated with a rehabilitative protocol (RP); after eight weeks (T1), those patients showing a relevant improvement in the clinical rating scales ((Timed Up and Go (TUG), Tinetti, Unified Parkinson&#8217;s disease rating scale (UPDRS) Part III, Berg Balance scale (BBS) and falls rate scale), continued with the FVT protocol (FVTRP group). The remaining patients continued with only the RP (RP group). In July 2018, we have extrapolated the data of the last clinical visit (T2) to observe any differences in the rate of falls. Results: The FVTRP group shows a decrement in the rate of falls from 2.1 to 1.25 (p 0.036) and a stability of the levodopa equivalent daily dosage (LEDD). The RP group shows an increment of LEDD and stability in falls. Conclusions: FVT has been confirmed as a valid tool to enhance the effect of the rehabilitation protocol aimed at postural training