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Introduction: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study., Methods: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year., Results: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms., Discussion: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Studies indicate that the dopaminergic system (DAS) supports individual flexible behaviour. While flexibility is quintessential to effective dyadic motor interactions, whether DAS mediates adaptations of one's own motor behaviour to that of a partner is not known. Here, we asked patients with Parkinson's Disease (PD) to synchronize their grasping movements with those of a virtual partner in conditions that did (Interactive) or did not (Cued) require to predict and adapt to its actions. PD performed the task during daily antiparkinsonian treatment ('On' condition) or after drug-withdrawal ('Off' condition). A group of healthy individuals also served as control group. In the Interactive condition, PDs performed better and found the interaction more enjoyable when in 'On' than in 'Off' condition. Crucially, PD performance in the 'On' condition did not differ from that of healthy controls. This pattern of results hints at the key role of the DAS in supporting the flexible adaptation of one's own actions to the partner's during motor interactions., (© The Author(s) 2023. Published by Oxford University Press.)

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., (© 2021 British Psychological Society.)

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. Research question, tailored design of the study, experimental acquisition overview, main findings, and conclusions., (© 2021. International Federation for Medical and Biological Engineering.)

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.

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.

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., (© 2020 International Parkinson and Movement Disorder Society.)

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.

Background: Recent evidence supports the hypothesis that rehabilitative strategies based on sensorimotor stimulation in the neurorehabilitation of Parkinson's disease (PD) may be useful to improve gait in PD patients., Aim: We supposed that sensorimotor stimulation produces modulation of anticipatory postural adjustments (APAs) arising from the supplementary motor area (SMA). We aimed to investigate the clinical and neurophysiological effects of a blindfolded balance training (BBT)., Design: Randomized controlled trial., Setting: Italian hospital., Population: Sixteen PD patients., Methods: The patients were randomized in two groups, one group treated with two-weeks BBT and one group treated with two-weeks of physical therapy (PT). We assessed gait parameters (swing, stance, double stance phase of cycle gait) and neurophysiological measurement (functional connectivity between SMA and motor area M1) before and after treatments., Results: We found a decrease of stance and double stance phase and increase of swing phase respect to gait cycle, in BBT group compared to PT group, paralleled by a selective modulation in functional connectivity between M1 and SMA for BBT group., Conclusions: Our findings support that BBT represents a complementary rehabilitative strategy, based on visual deprivation and proprioceptive perturbation in recovery of gait in PD patients, in short time window, likely involving vestibular system and its connections with motor areas., Clinical Rehabilitation Impact: The use of vestibular system stimulation, involving SMA-M1 circuits, may be useful to improve gait control in PD patients.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Prospective memory (PM) is the ability to keep in memory and realize future intentions. We aimed at investigating whether in Parkinson's disease (PD) PM deficits are related to mild cognitive impairment (MCI). Other aims were to investigate the cognitive abilities underlying PM performance, and the association between PM performance and measures of daily living functioning., Method: The study included 15 PD patients with single domain MCI, 15 with multiple domain MCI, 17 PD patients without cognitive disorders (PDNC) and 25 healthy controls (HCs). All subjects were administered a PM procedure that included focal (PM cue is processed in the ongoing task) and nonfocal (PM cue is not processed in the ongoing task) conditions. PD patients were administered an extensive neuropsychological battery and scales to assess daily living abilities., Results: PD patients with MCI (both single and multiple domains) showed lower accuracy on all PM conditions than both HC and PDNC patients. This was predicted by their scores on shifting indices. Conversely, PM accuracy of PDNC patients was comparable to HCs. Regression analyses revealed that PD patients' PM performance significantly predicted scores on daily living scales Conclusions: Results suggest that PM efficiency is not tout-court reduced in PD patients, but it specifically depends on the presence of MCI. Moreover, decreased executive functioning, but not episodic memory failure, accounts for a significant proportion of variance in PM performance. Finally, PM accuracy indices were found to be associated with measures of global daily living functioning and management of medication., ((c) 2015 APA, all rights reserved).)

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.

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.

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.

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., (© 2013 The British Psychological Society.)

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.

Study Objective: Sleep disorders are frequent non-motor symptoms in Parkinson disease (PD), probably due to multifactorial pathogeneses including disease progression, dopaminergic drugs, or concomitant illness. In recent years, the pedunculopontine tegmental (PPTg) nucleus has been considered a surgical target for deep brain stimulation (DBS) in advanced PD patients. As it is involved in controlling the sleep-wake cycle, we investigated the long-lasting effects of PPTg-DBS on the sleep of five PD patients implanted in both the PPTg and the subthalamic nucleus (STN) by rating two subjective clinical scales for sleep: the Parkinson's Disease Sleep Scale (PDSS), and the Epworth Sleepiness Scale (ESS)., Study Design: Sleep scales were administered a week before surgery (T0), three months after DBS (T1), and one year later (T2). In this study, STN-DBS was kept constantly in ON, and three different patterns of PPTg-DBS were investigated: STN-ON (PPTg switched off); PPTg-ON (PPTg stimulated 24 h/day); PPTg-cycle (PPTg stimulated only at night)., Results: In post-surgery follow-up, PD patients reported a marked improvement of sleep quality in all DBS conditions. In particular, stimulation of the PPTg nucleus produced not only a remarkable long-term improvement of nighttime sleep, but unlike STN-DBS, also produced significant amelioration of daytime sleepiness., Conclusion: Our study suggests that PPTg-DBS plays an important role in reorganizing regular sleep in PD patients.

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.

Patients with Parkinson's disease (PD) frequently display non-motor symptoms. In this study, we investigated intensity-dependent facial emotion recognition in patients with PD and healthy controls (HC), matched for age, gender, and education, and its relationship to individual cognitive domains. Seventy patients with PD and 70 HC were submitted to a clinical, neuropsychological, and psychopathological evaluation. Facial emotion recognition performance was assessed using the Penn Emotion Recognition Test (PERT). The patients with PD recognized fewer low- and high-intensity facial expressions of disgust than HC. This effect was selective, because their global ability to recognize emotions was intact. Both patients with PD and HC recognized high-intensity better than low-intensity emotions, except for disgust, which was recognized better at low intensity. In the patients with PD, overall facial emotion recognition and selective disgust recognition performances were related to deficits in many neuropsychological domains (verbal and visuo-spatial memory, attention, praxis, and verbal fluency). The ability to recognize emotions is a complex cognitive process requiring the integrity of several functions. Therefore, it is likely that structural or functional derangement of the discrete neural pathways involved in these cognitive functions in patients with PD makes it difficult for them to recognize emotions expressed by others.

Background: Alexithymia, a reduction in the tendency to think about emotions, together with a difficulty in identifying and describing feelings, has been characterized as a personality trait, but may be secondary to other pathological conditions., Objective: The authors aimed at investigating alexithymia in Parkinson's disease (PD)., Method: Seventy PD patients and 70 control subjects were administered the 20-item Toronto Alexithymia Scale., Results: The authors found that 21.4% of PD patients and 10.0% of controls could be classified as alexithymic. PD patients and controls significantly differed on global levels of alexithymia. However, univariate analyses showed that PD patients differed significantly only on the subscale investigating difficulty describing and communicating feelings., Conclusion: These results indicate that some facets of alexithymia are a relevant feature of PD, possibly in relation to the neuropathological changes that characterize the disease.

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.

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.

Introduction: Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have particular difficulty in producing verbs in a word generation situation. Two alternative explanations for this deficit have been proposed: the "motor" theory (verbs as action representawcttions) and the "grammatical" theory (verbs as lexical category). The aim of this study was to investigate the "motor" theory by exploring the neuronal substrates of action-related word production., Methods: Event-related functional magnetic resonance with a 3T magnetic resonance imaging (MRI) was used to explore brain activity during two overt oral language tasks, i.e., object naming (ON) and generation of action-verbs (GenA), in 14 non-demented PD patients using a common set of object drawings. The objects used were either man-made objects (MMO) or manipulable biological objects (MBO). Stimuli and tasks were randomized across subjects. Neuroimaging data were analyzed using SPM2., Results: Reaction times in GenA(MBO) were significantly longer than in the other three conditions (ON(MBO), ON(MMO), GenA(MMO)). The distribution of brain activities associated with each condition resembled that reported in previous studies on healthy subjects using similar tasks; a comparison between GenA and ON revealed slight differences located above all in the premotor and prefrontal cortices, particularly as regards GeneA(MBO)>ON(MMO). Furthermore, we found positive correlations between the severity of the motor deficit (as assessed by the Unified Parkinson's Disease Rating Scale - UPDRS score) and brain activity, particularly during GenA(MBO), in the pre- and post-central gyri bilaterally, left frontal operculum, left supplementary motor area (SMA) and right superior temporal cortex., Conclusions: The direct comparison in our study of brain activity during the production of action-words and of object names did not reveal any major differences. However, our results point to a relationship between motor system dysfunction in PD and the extent of activation in verb generation, a task which implies in-depth processing of semantic representation of actions.

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 18-24 h 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.

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.

The present study was aimed at investigating the effect of acute levodopa administration on the performance of a group of individuals with Parkinson's disease (PD) on a time-based prospective memory task. Twenty PD patients and 15 healthy controls were administered a task that required executing three actions after 10 min had elapsed in three consecutive trials. Scores were computed for correct recall of the intention to perform the actions and for correct execution of the actions. PD participants were evaluated after a 12-hr drug wash-out in two conditions: (1) after levodopa administration ("on"); (2) without drug administration ("off"). In the "on" condition, PD patients were significantly more accurate in retrieving the intention to perform the actions than in the "off" condition and their performance was actually comparable to that of healthy controls. The increased accuracy in complying with the prospective memory task following levodopa medication supports the idea that dopamine depletion plays a role in the prospective memory deficits observed in PD patients.

This study investigated prospective memory and its relationship to executive and memory functions in persons with Parkinson's disease (PD). Twenty-three individuals with PD and 25 healthy comparison participants participated in the study. In the prospective memory tasks, participants were asked to execute 3 actions after 20 min (time-based condition) or after a timer ring (event-based condition). A score was computed for the correct recall of the intention to perform the actions (prospective component) and for the correct execution of the actions (retrospective component). Participants with PD also received an extensive neuropsychological test battery. PD participants were less accurate than comparison participants in the prospective component of the time-based but not the event-based task. Individuals with PD were also impaired on the retrospective component of both tasks. In the PD group, a general trend toward significant correlations was found between performance level on the prospective memory component of the time-based task and scores on executive and working memory measures. These results document that prospective memory is impaired in PD possibly in relation to a dysregulation of cognitive functions associated with frontal systems.

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.

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.

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.

There are recent reports that alexithymia may be associated with brain dysfunction involving frontal lobes or right hemisphere regions. However, little is known about the relationship between alexithymia and cognitive deficits in Parkinson's disease (PD). The authors investigated the neuropsychological correlates of alexithymia in a population of 70 nondemented PD patients and 70 controls. Alexithymia was screened using the 20-item version of the Toronto Alexithymia Scale (TAS-20). Standardized scales that measure verbal episodic memory, executive functions, abstract reasoning, and visual-spatial and language abilities were adopted. PD patients with alexithymia performed worse than both PD patients without alexithymia and controls with or without alexithymia on tasks requiring visual-spatial processing. Moreover, regression analyses showed that, in PD patients, but not in controls, poor performance on a constructional praxis task predicted high scores on the TAS-20 subscale, which assesses difficulty in identifying emotions. These data evidence an association between alexithymia and visual-spatial processing alterations in PD patients, supporting the view that the right hemisphere could be specifically involved in the modulation of some facets of alexithymia.

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.

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.

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.

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.

The peduncolopontine nucleus modulates locomotor activity and dysfunction in this nucleus may be responsible for the gait and postural impairments seen in Parkinson's disease and other movement disorders. We report the first surgical exploration and implantation of deep brain stimulating electrodes of the peduncolopontine nucleus area in two Parkinson's disease patients to examine the safety and the potential benefit of chronic electrical stimulation at this site. Under local anesthesia, the peduncolopontine nucleus was approached from a coronal burr hole using a trajectory that was 78-80 degrees and 62-64 degrees on the coronal and sagittal planes. Microrecordings helped to identify neurons in peduncolopontine nucleus and the adjacent substantia nigra pars reticulata. Chronic deep brain stimulating electrodes were implanted within the peduncolopontine nucleus in a manner similar to that practiced with deep brain stimulating surgery at other targets. Peduncolopontine nucleus neurons were characterized by small and broad multiunits (230 muV, 2.5 ms, 14.6 Hz). Caudal to this area, neurons firing at higher frequency, approximately 70 Hz, characteristic of nigral neuronal discharges, were encountered, followed by 2 mm of cells similar to those recorded in the dorsal peduncolopontine nucleus area. After deep brain stimulating electrodes implantation, acute intraoperative stimulation (up to 3 V) was performed with two stimulation frequencies in each session. Stimulation at 80 Hz has little discernable effect. On the other hand, stimulation at 10 Hz fostered a subjective feeling of 'well-being' and a time-locked amelioration of the clinical scores. These findings demonstrate that the stereotactic approach of peduncolopontine nucleus is safe. The target may reliably be identified by microrecordings. Low-frequency stimulation may produce acute improvements in motor function.

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.

Object: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets., Methods: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects., Conclusions: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.

Alterations in temporal estimation have been observed in Parkinson's disease (PD) and have been associated with dopaminergic dysfunction. To investigate whether deep brain stimulation might reverse these abnormalities in PD, patients treated with electrode implantation for subthalamic deep brain stimulation were required to reproduce time intervals in different experimental conditions (off deep brain stimulation/off therapy, on deep brain stimulation/off therapy, on therapy/off deep brain stimulation). Patients treated with deep brain stimulation in off deep brain stimulation/off therapy displayed the anomalous pattern of responses typically observed in PD. When subthalamic deep brain stimulation was turned on these abnormalities were significantly attenuated. Our findings reveal that subthalamic deep brain stimulation improves time perception in PD patients, supporting the critical role of basal ganglia in this cognitive function, probably mediated by facilitated thalamo-cortical projections to the prefrontal cortex.

Purpose: Although the effects of subthalamic nucleus stimulation on the control of motor symptoms in patients with Parkinson's disease have been demonstrated, to our knowledge there are no data on effects of this treatment on voiding. We evaluated differences in urodynamic findings in patients with Parkinson's disease during on and off subthalamic nucleus stimulation status., Materials and Methods: We evaluated 3 males and 2 females with Parkinson's disease. All patients had undergone surgical bilateral implantation of subthalamic nucleus electrodes 4 to 9 months before our observation. Urodynamic evaluation was performed during chronic subthalamic nucleus stimulation and 30 minutes after turning off the stimulators. Certain parameters were evaluated, including bladder compliance and capacity, first desire to void volume, bladder volume of appearance (reflex volume) and amplitude of detrusor hyperreflexic contractions, maximum flow, detrusor pressure at maximum flow and detrusor-sphincter coordination. Results were compared statistically., Results: Statistically significant differences in urodynamic data obtained during on and off subthalamic nucleus stimulation status were noted. In particular bladder capacity and reflex volume were increased for on status (median 320 versus 130 ml., p = 0.043 and 250 versus 110, p = 0.043, respectively). The amplitude of detrusor hyperreflexic contractions was decreased for on status but the difference was not significant (median 23 versus 37 cm. H2O, p = 0.223). No differences were noted in the other urodynamic parameters considered during the filling and voiding phases., Conclusions: Our experience shows that subthalamic nucleus stimulation seems to be effective for decreasing detrusor hyperreflexia in Parkinson's disease cases. This finding confirms a role for basal ganglia in voiding control.

Visual-spatial working memory (WM) impairment is frequently associated with the early stage of Parkinson's disease (PD). The aim of this study was to evaluate the performance of a group of PD patients in visual-spatial and visual-object WM tasks and to investigate the effect of administering the dopaminergic agonist apomorphine (experiment 1) or the dopamine precursor L-dopa (experiment 2) on the performance of tests assessing these functions. To study WM processes, the PD patients and age-matched normal controls were given an n-back task paradigm. In both experiments, the PD patients were submitted to two evaluations: one after a 12-hour therapy washout and the other 15 min after a subcutaneous infusion of apomorphine (average 0.04 mg/kg) or 20/30 min after L-dopa intake (200 mg p.o.). The apomorphine infusion had a worsening effect on reaction times in both visual-spatial and visual-object WM tasks, but it did not influence performance accuracy. Instead, L-dopa administration had a ameliorative effect on accuracy and reaction times in both visual-spatial and visual-object tasks. These results highlight the role of dopamine in the modulation of the WM function in PD patients., (Copyright 2003 S. Karger AG, Basel)