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Abstract Apathy is frequently reported in individuals with Parkinson's disease (PD) and is hypothesized to be associated with frontal-striatal related cognitive functions. Available data, however, do not provide univocal results. Moreover, this relationship has been poorly investigated in PD patients with mild cognitive impairment (MCI). This study was aimed at investigating the association between severity of apathy of PD patients and their performance on neuropsychological tests investigating executive abilities. Individuals with PD (i.e., with and without MCI) and healthy controls (HCs) were administered a neuropsychological test battery that investigated episodic memory, language, short-term memory and attention, visual-spatial abilities and executive functions. Subjects were also administered additional neuropsychological tests to evaluate the different executive subcomponents (i.e., planning/abstract reasoning, self-monitoring/response inhibition, working memory, shifting and fluency). The Apathy Evaluation Scale (AES) was administered to assess apathy severity. Linear regression analyses were applied to the data; results showed that in the PD group with MCI, the best cognitive factor associated to the AES score was patients' scores on the executive tests and, in particular, their scores on tests examining planning/abstract reasoning. By contrast, in the PD group without MCI, the cognitive performance was not significantly associated to apathy severity. Findings of the study document a specific association between reduced efficiency of the executive system and apathy severity in individuals with PD and MCI. This association indirectly supports the hypothesis of a relationship between motivational disorders and dysregulation of the activity of the frontal-striatal networks in PD patients. Highlights • The association between cognitive disorders and apathy is proposed. • Executive functioning predicts apathy severity in Parkinson's disease. • The involvement of frontal-striatal dysregulation in apathy is suggested. [ABSTRACT FROM AUTHOR]

This study investigated the effect of cognitive training aimed at improving shifting ability on Parkinson’s disease (PD) patients’ performance of prospective memory (PM) tasks. Using a double-blind protocol, 17 PD patients were randomly assigned to two experimental arms. In the first arm (n=9) shifting training was administered, and in the second (placebo) arm (n=8), language and respiratory exercises. Both treatments consisted of 12 sessions executed over 4 weeks. PM and shifting measures (i.e., Trail Making Test and Alternate Fluency Test) were administered at T0 (before treatment) and T1 (immediately after treatment). A mixed analysis of variance was applied to the data. To evaluate the effects of treatment, the key effect was the interaction between Group (experimental vs. placebo) and Time of Assessment (T0 vs. T1). This interaction was significant for the accuracy indices of the PM procedure (p<.05) and for the performance parameters of the shifting tasks (p≤.05). Tukey’s HSD tests showed that in all cases passing from T0 to T1 performance significantly improved in the experimental group (in all cases p≤.02) but remained unchanged in the placebo group (all p consistently>.10). The performance change passing from T0 to T1 on the Alternate Fluency test and the PM procedure was significantly correlated (p<.05). Results show that the cognitive training significantly improved PD patients’ event-based PM performance and suggest that their poor PM functioning might be related to reduced shifting abilities. (JINS, 2014, 20, 1–10) [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Understanding the mental states of others entails a number of cognitive processes known as Theory of Mind (ToM). A relationship between ToM deficits and executive disorders has been hypothesized in individuals with Parkinson's disease (PD). The present study was aimed at investigating the effect of dysexecutive deficits on ToM abilities in PD patients without dementia. Participants included 30 PD patients and 30 healthy subjects (HC). PD patients were divided into two groups according to their executive test performance: patients with poor (dysexecutive group; n=15) and normal (executively unimpaired group; n=15) performance. All participants were administered faux pas recognition written stories. The dysexecutive PD patients performed less accurately than both HC and executively unimpaired PD individuals on all faux pas story questions (p< 0.05); the executively unimpaired PD group performed as accurately as the HC group on the ToM tasks. Results of the study clearly demonstrate that PD is not tout court associated with ToM impairments and that these may occur in PD patients as a function of the degree of their executive impairment. Our findings also indirectly confirm previous data on the role of the prefrontal regions in mediating ToM capacities. [ABSTRACT FROM AUTHOR]

The study was aimed at investigating the contribution of retrospective memory to prospective memory ( PM) functioning in people with Parkinson's disease ( PD). Twenty patients with PD without dementia and 20 normal controls were recruited. In the PM procedure, sequences of words were presented; in the inter-sequence delay, participants had to repeat sequence in the same or reverse order (ongoing task). At the occurrence of a target word, participants had to press a button on the keyboard ( PM response). To evaluate the contribution of retrospective memory to PM performance, we manipulated the retrospective memory load of the target words (i.e., one vs. four words). The results show that patients with PD were poorer than controls in all PM conditions ( p < .01). The memory load did not modulate differentially the PM performance of individuals in the two groups. Moreover, in PD patients, the ability to retrieve the target words in the episodic memory task was associated, at a lesser extent than in healthy controls, with the ability to activate the prospective intention at the occurrence of a target word. Our findings confirm PM decline in patients with PD without dementia. This flaw cannot be entirely explained by decreased retrospective memory. Altered self-retrieval processes might explain reduced PM performance of these individuals. This is a very relevant finding in the perspective of cognitive therapeutic intervention on PM that, in patients with PD, could be focused on mechanisms other than retrospective memory ones. [ABSTRACT FROM AUTHOR]

Abstract: Very few studies have investigated the relationship between dopaminergic therapy and working memory (WM) functioning in Parkinson''s disease (PD) patients. The aim of the present study was to explore the effects of pharmacological treatment with pergolide (a D1 +D2 receptor agonist) and pramipexole (a D2 +D3 receptor agonist) on performance in visual–spatial, visual-object, and verbal WM tasks in PD patients. Participants included 19 “de novo” PD patients and 13 healthy controls (HC). The experimental task consisted of an n-back paradigm with verbal, visual-object, or visual–spatial stimuli. PD patients performed the task twice: after 18–24h of therapy wash-out and after administration of pergolide (nine patients) or pramipexole (ten patients). HCs performed the task only once, without drug administration. Depending on how they performed in the “Off” and “On” therapy conditions, the nine PD patients each were classified into groups of low performers (i.e., performance on the n-back paradigm was below the median value of the experimental sample) and high performers (i.e., performance was above the median value). One PD patient was excluded from the analysis because his performance pattern clearly revealed that he was an outlier. In the low performer PD patients, administration of both pergolide and pramipexole improved accuracy on all WM tasks. No effect of the drugs was found in the high performer patients. The results of the present study show that stimulation of dopaminergic receptors improves high-level WM processes in PD patients, possibly by modulating activity in frontal–striatal circuits. [Copyright &y& Elsevier]

Abstract: The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus—STN or the internal pallidus—GPi) plus an innovative one (CM/Pf) in well-identified Parkinson’s disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation—DBS – in STN – , n =2) and disabling involuntary movements, partially responsive to GPi–DBS (n =6). When considering global UPDRS scores, CM/Pf–DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Word clustering (i.e., the ability to reproduce the same word pairs in consecutive recall trials of an unrelated word list) has been extensively investigated as a proxy of subjective organization (SO) of memorandum. In healthy subjects and in groups of brain‐damaged patients, the rate of SO generally predicts accuracy of word list recall. This study aimed at evaluating SO in the performance of patients with Parkinson's disease (PD) on a word list recall task in order to investigate the basic mechanisms of episodic memory impairment that are frequently observed in these patients. For this purpose, 56 PD patients, who were stratified according to the presence and quality of mild cognitive impairment (MCI), and a group of healthy controls (HCs) were administered a word list task and an extensive battery of neuropsychological tests. Results showed that recall accuracy on the word list task progressively decreased passing from HC to PD patients without cognitive impairment, to patients with single‐domain dysexecutive MCI and to patients with multiple‐domain dysexecutive and amnesic MCI. Conversely, only the latter PD group showed a lower SO score than that achieved by the other groups. In the overall PD group, correlational and regression analyses demonstrated that SO scores and a composite score of executive functions were not reciprocally related, but both provided an independent and significant contribution to the prediction of word list recall accuracy. These data are discussed in terms of the contribution of executive functions and hippocampal storage processes to the onset of memory impairment in PD. [ABSTRACT FROM AUTHOR]

Abstract: We used fMRI to investigate the neurofunctional basis of externally and internally timed movements in Parkinson''s disease (PD) patients. Ten PD patients whose medication had been withheld for at least 18h and 11 age- and sex-matched healthy controls were scanned while performing continuation paradigm with a visual metronome. Compared with the controls, PD patients displayed an intact capability to store and reproduce movement frequencies but with a significantly increased movement latencies. No differences in BOLD response were found in both groups when comparing the continuation with the preceding synchronization phase and viceversa, except for activity in visually related regions. Relative to healthy controls during the synchronization phase, PD patients exhibited an overall signal increase in the cerebellum and frontostriatal circuit (putamen, SMA and thalamus) activity together with specific brain areas (right inferior frontal gyrus and insula cortex) that are also implicated in primary timekeeper processes. By contrast, in the continuation phase the only neural network involved to a greater extent by the PD group was the cerebello-thalamic pathway. The lack of neurofunctional differences between the two timing phases suggests that rhythmic externally and internally guided movements engage similar neural networks in PD and matched healthy controls. Moreover, between-group comparison indicates that PD patients OFF medication may compensate for their basal ganglia–cortical loop''s dysfunction using different motor pathways involving cerebellum and basal ganglia relays during the two phases of rhythmic movement. [Copyright &y& Elsevier]

In Parkinson’s disease, the subthalamic nucleus (STN) is a common target for functional neurosurgery. Recent investigations have suggested that physiological non-motor stimuli may dramatically alter STN firing properties. By maintaining long-lasting micro-recordings of STN single units in Parkinson’s disease (PD) patients, here we show that the neurons that are responsive to passive movements are also strongly modulated by altered vigilance state (awake vs. sleep). In addition, sleep was characterized by a distinctive irregular train-like firing pattern. These findings suggest that the reduction of the somato-sensory input modifies rigidity and, hence, STN discharge mode. Further, it is suggested that specific STN electrophysiological features are potential targets for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Axial disorders, including postural deformities, postural instability, and gait disturbances, are among the most disabling symptoms of Parkinson's disease (PD). Equistasi®, a wearable proprioceptive stabilizer device, has been proposed as neurological rehabilitative device for this set of symptoms. To investigate the effects of the device on gait and balance, 24 participants affected by PD were enrolled in this crossover double-dummy, randomized, controlled study. Subjects were assessed four times before and after 8 weeks treatment with either active or placebo device; one-month wash-out was taken between treatments, in a 20-week timeframe. Gait analysis and instrumented Romberg test were performed with the aid of a sterofotogrammetric system and two force plates. Joint kinematics, spatiotemporal parameters of gait and center of pressure parameters were extracted. Paired T-test (p < 0.05) was adopted after evidence of normality to compare the variables across different acquisition sessions; Wilcoxon was adopted for non-normal distributions. Before and after the treatment with the active device, statistically significant improvements were observed in trunk flexion extension and in the ankle dorsi-plantarflexion. Regarding balance assessment, significant improvements were reported at the frequencies corresponding to vestibular system. These findings may open new possibilities on PD's rehabilitative interventions. [ABSTRACT FROM AUTHOR]

The aim of the present work was to evaluate verbal working memory in patients affected by Parkinson’s disease (PD). In particular, tests that explore the functionality of the Articulatory Loop and of the Central Executive during verbal tasks were given. PD patients displayed normal phonological similarity, word length and word frequency effects in a Word span task, thus demonstrating adequate retention capacity of the phonological store, normal functioning of the articulatory rehearsal mechanism and a normal contribution of lexical-semantic knowledge to verbal immediate recall. In the Brown-Peterson task, PD patients showed abnormal performance decay on the letter recall task when articulatory rehearsal was inhibited by a serial subtraction concurrent task. These data provide evidence for normal functioning of the Articulatory Loop in PD patients. However, when the verbal recall task is more attention demanding, PD patients show deficient performance levels, presumably due to depleted processing resources by the Central Executive. [ABSTRACT FROM AUTHOR]

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered.Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment.Results: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred.Conclusions: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood.Objectives: By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients.Methods: PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group.Results: STN-DBS enhanced early global TMS-evoked activity (∼45-80ms) and high-alpha TMS-evoked oscillations (11-13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80-130ms) and beta TMS-evoked oscillations (13-30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values.Conclusions: Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30-T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III - Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action. [ABSTRACT FROM AUTHOR]

Objective Recently, an intrinsic fractal harmonic structure was found underlying the rhythm of physiological walking, but it has not yet been investigated in subjects with a neurological disease. The aim of this study was to determine if and how this harmonic structure is altered in patients with Parkinson’s Disease. Methods Gait analysis of 70 patients with Parkinson’s Disease in pharmacological phase on was performed, the findings of which we compared with reference data of age-matched healthy subjects. Fifteen patients were retested after a washout period of 12 h. Results Alterations in all spatio-temporal gait parameters and gait indices with regard to symmetry, coordination, and harmony were noted, but after correction for multicollinearity bias, only the latter correlated significantly with Unified Parkinson’s Disease Rating Scale motor score ( p = 0.001). The fractal gait structure underwent even more extensive alterations in pharmacological off phase ( p < 0.05). Conclusions The intrinsic gait harmony was altered in patients with Parkinson’s Disease and significantly correlated to motor severity. It could be partially recovered by assumption of L-dopa. Significance Loss of harmony is a quantitatively assessable gait benchmark in Parkinson’s Disease. It seems to be dependent on dopaminergic but also on non-dopaminergic networks. [ABSTRACT FROM AUTHOR]

The hypothesis has been advanced that memory disorders in individuals with Parkinson’s disease (PD) are related to either retrieval or consolidation failure. However, the characteristics of the memory impairments of PD patients with amnestic mild cognitive impairment have not been clarified. This study was aimed at investigating whether memory deficits in PD patients with amnestic mild cognitive impairment (PDaMCI) are due to failure of retrieval or consolidation processes. Sixteen individuals with PDaMCI, 20 with amnestic mild cognitive impairment without PD (aMCINPD), and 20 healthy controls were recruited. Participants were administered the Free and Cued Selective Reminding Test. An index of cueing was computed for each subject to capture the advantage in retrieval of cued compared to free recall. Individuals with PDaMCI performed worse than healthy controls on the free recall (p<0.01) but not the cued recall (p>0.10) task, and they performed better than aMCINPD subjects on both recall measures (p<0.01). The index of cueing of subjects with PD was comparable to that of healthy controls (p>0.10) but it was significantly higher than that of the aMCINPD sample (p<0.01). Moreover, PD patients’ performance on free recall trials was significantly predicted by scores on a test investigating executive functions (i.e., the Modified Card Sorting Test; p = 0.042). Findings of the study document that, in subjects with amnestic mild cognitive impairment associated to PD, episodic memory impairment is related to retrieval rather than to consolidation failure. The same data suggest that, in these individuals, memory deficits might be due to altered frontal-related executive functioning. [ABSTRACT FROM AUTHOR]

In nature, many physical and biological systems have structures showing harmonic properties. Some of them were found related to the irrational number ɸ known as the golden ratio that has important symmetric and harmonic properties. In this study, the spatiotemporal gait parameters of 25 healthy subjects were analyzed using a stereophotogrammetric system with 25 retroreflective markers located on their skin. The proportions of gait phases were compared with ɸ, the value of which is about 1.6180. The ratio between the entire gait cycle and stance phase resulted in 1.620 ± 0.058, that between stance and the swing phase was 1.629 ± 0.173, and that between swing and the double support phase was 1.684 ± 0.357. All these ratios did not differ significantly from each other (F = 0.870, P = 0.422, repeated measure analysis of variance) or from ɸ (P = 0.670,0.820,0.422, resp., t-tests). The repetitive gait phases of physiological walking were found in turn in repetitive proportions with each other, revealing an intrinsic harmonic structure. Harmony could be the key for facilitating the control of repetitive walking. Harmony is a powerful unifying factor between seemingly disparate fields of nature, including human gait. [ABSTRACT FROM AUTHOR]

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinson’s disease and 22 control subjects underwent 3-T magnetic resonance imaging with T2*-weighted, whole-brain T1-weighted and diffusion tensor imaging scans. The mean R2* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinson’s disease and control subjects. Comparisons were also performed using voxel-based analysis of R2*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinson’s disease displayed significantly higher R2* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinson’s disease from controls. The markers comprising discriminating combinations were R2* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinson’s physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R2*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinson’s disease and, possibly, of other subcortical pathologies. [ABSTRACT FROM PUBLISHER]

Abstract: Between 2005 and 2007, six patients affected by idiopathic Parkinson''s disease (IPD) were submitted to the bilateral implantation (and subsequent deep brain stimulation — DBS) of the pedunculopontine nucleus (PPN) plus the subthalamic nucleus (STN). This review synthesizes the effects of PPN low-frequency stimulation on non-motor functions, focusing on patient sleep quality and cognitive performance. If not associated to STN-DBS, PPN-DBS promoted a modest amelioration of patient motor performance. However, during PPN-DBS, they experienced on the one hand a significant improvement in executive functions and working memory, on the other hand a beneficial change in sleep architecture. Overall, the limited sample hampers definite conclusions. Yet, although the PPN-DBS induced motor effects are quite disappointing (discouraging extended trials based upon the sole PPN implantation), the neuropsychological profile supports the contention by which in selected PD patients, with subtle cognitive deficits or vanished efficacy of previous implanted STN, PPN-DBS might still represent a reliable and compassionate option. [Copyright &y& Elsevier]

Abstract: The present paper was aimed at investigating the effect of low-frequency electrical stimulation (25 Hz) of the peduncolopontine (PPN) area on working memory (WM) functioning in patients with Parkinson''s disease (PD). Five PD patients who underwent simultaneous PPN area- and subthalamic nucleus-deep brain stimulation (DBS) implantation participated in the study. PD patients were evaluated in the morning at least 12 h after antiparkinsonian therapy withdrawal in two conditions: i) after continuous PPN area stimulation (Off Therapy/On PPN: “On” condition); ii) at least 120 min after PPN area had been switched “Off” (Off Ther/Off PPN: “Off” condition). The experimental WM task consisted of an n-back paradigm with verbal and visual-object stimuli. PD patients showed a consistent response time decrease on both the verbal and the visual-object tasks passing from the “Off” to the “On” condition (p < 0.05). However, the accuracy score did not significantly differ between the two experimental conditions. The present findings, although preliminary, suggest that PPN area stimulation facilitates the speed processing of information in the content of WM, possibly through the modulation of the attentional resources. [Copyright &y& Elsevier]

Abstract: Combined deep brain stimulation of the subthalamic (STN) and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced Parkinson''s disease. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. We studied five advanced Parkinson''s disease patients who underwent combined deep brain stimulation (STN + PPN). Overall cognitive profile did not change. On the contrary, an interesting trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) was found when stimulating the STN, and also the PPN, when the STN was switched off. These findings replicate previous observations on the STN, and provide the rationale for further investigation of the role of the PPN in processing linguistic grammar. [Copyright &y& Elsevier]

Bilateral peduncolopontine nucleus (PPN) and subthalamic nucleus (STN) deep brain stimulation (DBS) was performed in six-advanced Parkinson’s disease (PD) patients. We report the effect of both PPN-DBS (25 Hz) and STN-DBS (185 Hz) on patient spinal reflex excitability by utilizing the soleus-Hoffman reflex (HR) threshold. Compared to controls ( n = 9), patients showed an increase of HR-threshold, which was scarcely affected by levodopa, but significantly reduced by DBS. In particular, we found that PPN-DBS alone, or plus STN-DBS induced a complete recovery of HR-threshold up to control values. The HR-threshold changes, although do not allow to investigate the contribution of specific intraspinal pathways, suggest that PPN may play a key-role in modulating spinal excitability in PD possibly by improving the basal ganglia-brainstem descending system activity. [ABSTRACT FROM AUTHOR]

Abstract: The basal ganglia have been associated with temporal processing in ranges of milliseconds and seconds. However, results from PD patient studies are elusive. Time perception in these patients has been tested with different approaches including repetitive movement tasks (i.e. finger tapping) and cognitive tasks (i.e. time reproduction), and both abnormal and normal performances have been reported for different time intervals. Furthermore, when PD patients were required to learn two target durations in the same session when they were off medication, they overestimated the short duration and underestimated the long duration in the seconds range. This pattern of temporal accuracy was described as a “migration effect” and was interpreted as a dysfunctional representation of memory for time (Malapani, C., Rakitin, B. C., Levy, R., Meck, W. H., Deweer, B., Dubois, B., et al. (1998). Coupled temporal memories in Parkinson''s disease: A dopamine-related dysfunction. Journal of Cognitive Neuroscience, 10, 316–331). Here, we controlled the emergence of similar behaviour also during millisecond time processing in PD patients. A time reproduction task was employed in which subjects were required to estimate intervals in millisecond (500ms) and few second (2000ms) ranges. In the first experiment, these intervals were tested in the same session to verify whether the migration effect was present also between time intervals in different millisecond and few second ranges. In a second experiment, they were not intermingled but were tested in two separate sessions to verify whether abnormalities depended on a selective perceptual deficit of the time intervals tested (i.e. millisecond or second ranges). All experiments were performed in both off and on therapy conditions. Our results demonstrated that PD patients showed no deficits in time estimation for time intervals in either the millisecond or few second range when the different time intervals were tested in separate sessions. This negative finding was obtained in both on and off conditions. However, when the different ranges were tested in the same session, we found that PD patients were impaired selectively for time intervals in the seconds range. Our data seem to indicate that time processing in PD patients for time intervals spanning up to 2s is unimpaired and that abnormalities in such temporal scale may emerge only when patients have to deal with different durations, when timing involves further cognitive processes such as memory and attention. [Copyright &y& Elsevier]

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive. [ABSTRACT FROM AUTHOR]

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92–3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of Equistasi®, a wearable device, on the relationship between muscular activity and postural control changes in a sample of 25 Parkinson's disease (PD) subjects. Gait analysis was carried out through a six-cameras stereophotogrammetric system synchronized with two force plates, an eight-channel surface electromyographic system, recording the activity of four muscles bilaterally: Rectus femoris, tibialis anterior (TA), biceps femoris, and gastrocnemius lateralis (GL). The peak of the envelope (PoE) and its occurrence within the gait cycle (position of the peak of the envelope, PPoE) were calculated. Frequency-domain posturographic parameters were extracted while standing still on a force plate in eyes open and closed conditions for 60 s. After the treatment with Equistasi®, the mid-low (0.5–0.75) Hz and mid-high (0.75–1 Hz) components associated with the vestibular and somatosensory systems, PoE and PPoE, displayed a shift toward the values registered on the controls. Furthermore, a correlation was found between changes in proprioception (power spectrum frequencies during the Romberg Test) and the activity of GL, BF (PoE), and TA (PPoE). Results of this study could provide a quantitative estimation of the effects of a neurorehabilitation device on the peripheral and central nervous system in PD. [ABSTRACT FROM AUTHOR]

Background: For people with Parkinson'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'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. [ABSTRACT FROM AUTHOR]

In nature, many physical and biological systems have structures showing harmonic properties. Some of them were found related to the irrational number ɸ known as the golden ratio that has important symmetric and harmonic properties. In this study, the spatiotemporal gait parameters of 25 healthy subjects were analyzed using a stereophotogrammetric system with 25 retroreflective markers located on their skin. The proportions of gait phases were compared with ɸ, the value of which is about 1.6180. The ratio between the entire gait cycle and stance phase resulted in 1.620 ± 0.058, that between stance and the swing phase was 1.629 ± 0.173, and that between swing and the double support phase was 1.684 ± 0.357. All these ratios did not differ significantly from each other (F = 0.870, P = 0.422, repeated measure analysis of variance) or from ɸ (P = 0.670,0.820,0.422, resp., t-tests). The repetitive gait phases of physiological walking were found in turn in repetitive proportions with each other, revealing an intrinsic harmonic structure. Harmony could be the key for facilitating the control of repetitive walking. Harmony is a powerful unifying factor between seemingly disparate fields of nature, including human gait. [ABSTRACT FROM AUTHOR]