Publications by authors named "Antonella Peppe"

53 Publications

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

Sensors (Basel) 2021 Jan 29;21(3). Epub 2021 Jan 29.

IRCSS Fondazione Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy.

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 ( = 0.018), walking speed ( = 0.014), and toe clearance ( = 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.
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http://dx.doi.org/10.3390/s21030911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866385PMC
January 2021

Relationship between Muscular Activity and Postural Control Changes after Proprioceptive Focal Stimulation (Equistasi) in Middle-Moderate Parkinson's Disease Patients: An Explorative Study.

Sensors (Basel) 2021 Jan 14;21(2). Epub 2021 Jan 14.

Department of Information Engineering, University of Padova, 35131 Padova, Italy.

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.
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http://dx.doi.org/10.3390/s21020560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830724PMC
January 2021

Effects of COVID-19 Lockdown on Movement Disorders Patients With Deep Brain Stimulation: A Multicenter Survey.

Front Neurol 2020 16;11:616550. Epub 2020 Dec 16.

Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

The containment measures taken by Italian government authorities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the interruption of neurological activities of outpatient clinics. Vulnerable patients, as Parkinson's disease (PD) and dystonic patients with deep brain stimulation (DBS), may have an increased risk of chronic stress related to social restriction measures and may show a potential worsening of motor and psychiatric symptoms. This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was based on a structured survey administered during a telephone call. The questionnaire was designed to gather motor and/or psychiatric effects of the lockdown and coronavirus disease 2019 (COVID-19) epidemiologic information in PD and dystonic patients with a functioning DBS implant. One hundred four patients were included in the study, 90 affected by PD and 14 by dystonia. Forty-nine patients reported a subjective perception of worsening of global neurological symptoms (motor and/or psychiatric) related to the containment measures. In the multivariate analysis, having problems with the DBS device was the only independent predictor of motor worsening [odds ratio (OR) = 3.10 (1.22-7.91), = 0.018]. Independent predictors of psychiatric worsening were instrumental activities of daily living (IADL) score [OR = 0.78 (0.64-0.95), = 0.012] and problems with DBS [OR = 5.69 (1.95-16.62), = 0.001]. Only one patient underwent nasopharyngeal swabs, both negative, and no patient received a diagnosis of COVID-19. Lockdown restriction measures were associated with subjective worsening of motor and psychiatric symptoms in PD and dystonic patients treated with DBS, and they may have exacerbated the burden of neurological disease and increased the chronic stress related to the DBS management.
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http://dx.doi.org/10.3389/fneur.2020.616550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772207PMC
December 2020

Should We Consider Deep Brain Stimulation Discontinuation in Late-Stage Parkinson's Disease?

Mov Disord 2020 08 25;35(8):1379-1387. Epub 2020 May 25.

Department of Neuroscience "Rita Levi Montalcini,", University of Torino, Turin, Italy.

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.
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http://dx.doi.org/10.1002/mds.28091DOI Listing
August 2020

Proprioceptive Focal Stimulation (Equistasi®) May Improve the Quality of Gait in Middle-Moderate Parkinson's Disease Patients. Double-Blind, Double-Dummy, Randomized, Crossover, Italian Multicentric Study.

Front Neurol 2019 18;10:998. Epub 2019 Sep 18.

Parkinson Excellence Center of the Fresco Institute for Italy, Villa Margherita Clinic of Vicenza, Vicenza, Italy.

The object of the study was to evaluate the efficacy of Proprioceptive Focal Stimulation on Gait in middle-advanced Parkinson (PD) patients by a crossover, randomized, double Blind double dummy study using Equistasi®, a nano-technological device of the dimension of a plaster which generates High Frequency Vibration (FV). The efficacy of Gait Analysis (GA) on evaluating gait modification on Parkinson's disease (PD) Patients is already well-known. Therefore, GA was recorded in a group of PD patients using Equistasi® device and its placebo. Forty PD patients on optimal therapy were enrolled in the study. Patients were randomly assigned to receive active or sham stimulation for 8 weeks and, following a wash-out period, switched to an additional 8-week period with the reverse intervention. GA was performed at baseline and at the end of both 8-weeks treatment periods Clinical state was monitored by MDUPDRS part III. Active stimulation induced a significant improvement in Mean Velocity (Velocity), Stride Length (SL), Stance (STA), and Double Support (DST) percentage, both in left and right stride. The ANOVA analysis using H&Y stage as a factor, showed that DST and MDUPDRS III scores improved significantly more in the more severely affected subjects. The findings obtained in this randomized controlled study show the efficacy of mechanical focal vibration, as stimulation of the proprioceptive system, in PD and encourage further investigation. The effect of the device on more severe patients may open a new possibility to identify the most appropriate candidate for the management of gait disturbances and postural instability with FV delivered with Equistasi®.
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http://dx.doi.org/10.3389/fneur.2019.00998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760030PMC
September 2019

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

Sensors (Basel) 2019 May 7;19(9). Epub 2019 May 7.

Fondation S. Lucia IRCSS, 00142 Rome, Italy.

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.
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http://dx.doi.org/10.3390/s19092101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539920PMC
May 2019

Apathy in individuals with Parkinson's disease associated with mild cognitive impairment. A neuropsychological investigation.

Neuropsychologia 2018 09 19;118(Pt B):4-11. Epub 2018 May 19.

IRCCS Fondazione Santa Lucia, Rome, Italy; Tor Vergata University, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.neuropsychologia.2018.05.016DOI Listing
September 2018

Neurophysiological and clinical effects of blindfolded balance training (BBT) in Parkinson's disease patients: a preliminary study.

Eur J Phys Rehabil Med 2019 Apr 9;55(2):176-182. Epub 2018 May 9.

Santa Lucia Foundation, Scientific Institute for Research and Care, Rome, Italy.

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.
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http://dx.doi.org/10.23736/S1973-9087.18.05126-2DOI Listing
April 2019

Targeting gait and life quality in persons with Parkinson's disease: Potential benefits of Equine-Assisted Interventions.

Parkinsonism Relat Disord 2018 02 11;47:94-95. Epub 2017 Dec 11.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1016/j.parkreldis.2017.12.003DOI Listing
February 2018

Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients.

Parkinsonism Relat Disord 2017 01 17;34:31-37. Epub 2016 Oct 17.

Non-Invasive Brain Stimulation Unit, Neurologia Clinica e Comportamentale, Fondazione Santa Lucia IRCCS, Rome, Italy; Department of System Medicine, Policlinico di Tor Vergata, Rome, Italy; Stroke Unit, Policlinico Tor Vergata, Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.parkreldis.2016.10.009DOI Listing
January 2017

The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson's disease subjects.

Can J Physiol Pharmacol 2016 Apr 10;94(4):455-61. Epub 2016 Feb 10.

a Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Via Ardeatina 354, 00142 Rome, Italy.

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.
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http://dx.doi.org/10.1139/cjpp-2015-0322DOI Listing
April 2016

Loss of fractal gait harmony in Parkinson's Disease.

Clin Neurophysiol 2016 Feb 2;127(2):1540-1546. Epub 2015 Dec 2.

Santa Lucia Foundation, I.R.C.C.S., via Ardeatina 306, 00179 Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.clinph.2015.11.016DOI Listing
February 2016

Brain-derived neurotrophic factor serum levels correlate with cognitive performance in Parkinson's disease patients with mild cognitive impairment.

Front Behav Neurosci 2015 15;9:253. Epub 2015 Sep 15.

IRCCS, Fondazione Santa Lucia Rome, Italy.

Brain-derived neurotrophic factor (BDNF) is a trophic factor regulating cell survival and synaptic plasticity. Recent findings indicate that BDNF could be a potential regulatory factor for cognitive functioning in normal and/or neuropathological conditions. With regard to neurological disorders, recent data suggest that individuals with Parkinson's disease (PD) may be affected by cognitive deficits and that they have altered BDNF production. Therefore, the hypothesis can be advanced that BDNF levels are associated with the cognitive state of these patients. With this in mind, the present study was aimed at exploring the relationship between BDNF serum levels and cognitive functioning in PD patients with mild cognitive impairment (MCI). Thirteen PD patients with MCI were included in the study. They were administered an extensive neuropsychological test battery that investigated executive, episodic memory, attention, visual-spatial and language domains. A single score was obtained for each cognitive domain by averaging z-scores on tests belonging to that specific domain. BDNF serum levels were measured by enzyme-linked immunoassay (ELISA). Pearson's correlation analyses were performed between BDNF serum levels and cognitive performance. Results showed a significant positive correlation between BDNF serum levels and both attention (p < 0.05) and executive (p < 0.05) domains. Moreover, in the executive domain we found a significant correlation between BDNF levels and scores on tests assessing working memory and self-monitoring/inhibition. These preliminary data suggest that BDNF serum levels are associated with cognitive state in PD patients with MCI. Given the role of BDNF in regulating synaptic plasticity, the present findings give further support to the hypothesis that this trophic factor may be a potential biomarker for evaluating cognitive changes in PD and other neurological syndromes associated with cognitive decline.
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http://dx.doi.org/10.3389/fnbeh.2015.00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569860PMC
October 2015

Time-based prospective memory functioning in mild cognitive impairment associated with Parkinson's disease: relationship with autonomous management of daily living commitments.

Front Hum Neurosci 2015 10;9:333. Epub 2015 Jun 10.

Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation Rome, Italy ; Medicina dei Sistemi, Università Tor Vergata Rome, Italy.

Objective: Prospective memory (PM), that is, the ability to keep in memory and carry out intentions in the future, is reported to be impaired in individuals with Parkinson's disease (PD). PM failure may be also associated with reduced daily living functioning in these patients. Little is known, however, about the relationship between mild cognitive impairment (MCI) and time-based PM functioning in PD patients and the possible impact of PM deficits on patients' autonomy in daily living. Here we aimed to investigate whether MCI associated with PD affects time-based PM. We also wished to determine whether PM impairment accounts for reduced autonomous management of medication in these patients.

Method: The study included 48 PD patients with MCI, 33 PD patients without cognitive disorders (PDN) and 20 healthy controls. The time-based PM procedure required that subjects perform an action after a fixed time. The PM procedure was incorporated in the standard neuropsychological assessment. One score was computed for the ability to retrieve the intention (prospective component) and one for remembering the action to be executed (retrospective component). The Pill Questionnaire was administered to assess the ability to manage medication.

Results: PD patients with MCI performed less accurately in the PM procedure than HC and tended to perform poorer than PDN. Moreover, in PD patients with MCI, accuracy on the prospective component of the PM task and performance on the Modified Card Sorting Test significantly predicted the ability to manage medication.

Conclusions: RESULTS document that reduced efficiency of time-based PM processes in PD is specifically related to the presence of MCI. The same data indicate that PM weakness may be associated with impaired daily living functioning and decreased autonomy.
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http://dx.doi.org/10.3389/fnhum.2015.00333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458690PMC
June 2015

A pilot study on the effect of cognitive training on BDNF serum levels in individuals with Parkinson's disease.

Front Hum Neurosci 2015 16;9:130. Epub 2015 Mar 16.

Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation Rome, Italy.

Parkinson's disease (PD) patients, besides motor dysfunctions, may also display mild cognitive deficits (MCI) which increase with disease progression. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a role in the survival of dopaminergic neurons and in the regulation of synaptic connectivity. Moreover, the brain and peripheral level of this protein may be significantly reduced in PD patients. These data suggest that a cognitive rehabilitation protocol aimed at restoring cognitive deficits in PD patients may also involve changes in this neurotrophin. Thus, in this pilot study we evaluated the effect of a cognitive rehabilitation protocol focused on the training of executive functioning and measured BDNF serum levels in a group of PD patients with mild cognitive impairment, as compared to the effect of a placebo treatment (n = 7/8 group). The results showed that PD patients undergoing the cognitive rehabilitation, besides improving their cognitive performance as measured with the Zoo Map Test, also displayed increased serum BDNF levels as compared to the placebo group. These findings suggest that BDNF serum levels may represent a biomarker of the effects of cognitive rehabilitation in PD patients affected by MCI. However, the functional significance of this increase in PD as well as other neuropathological conditions remains to be determined.
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http://dx.doi.org/10.3389/fnhum.2015.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360779PMC
April 2015

Prospective memory performance in individuals with Parkinson's disease who have mild cognitive impairment.

Neuropsychology 2015 Sep 2;29(5):782-91. Epub 2015 Feb 2.

Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation.

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.
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http://dx.doi.org/10.1037/neu0000184DOI Listing
September 2015

Prospective memory performance of patients with Parkinson's disease depends on shifting aptitude: evidence from cognitive rehabilitation.

J Int Neuropsychol Soc 2014 Aug 26;20(7):717-26. Epub 2014 Jun 26.

1Department of Clinical and Behavioral Neurology,IRCCS Santa Lucia Foundation,Rome,Italy.

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.
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http://dx.doi.org/10.1017/S1355617714000563DOI Listing
August 2014

Dopamine treatment and cognitive functioning in individuals with Parkinson's disease: the "cognitive flexibility" hypothesis seems to work.

Behav Neurol 2014 30;2014:260896. Epub 2014 Jan 30.

I.R.C.C.S. Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy ; Clinical Neurology, University of Rome, "Tor Vergata", Via Orazio Raimondo 18, 00173 Rome, Italy.

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.
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http://dx.doi.org/10.1155/2014/260896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006594PMC
December 2014

Free and cued recall memory in Parkinson's disease associated with amnestic mild cognitive impairment.

PLoS One 2014 23;9(1):e86233. Epub 2014 Jan 23.

Behavioural and Clinical Neurology Laboratory, I.R.C.C.S. Fondazione S. Lucia, Rome, Italy ; Dipartimento di Medicina dei Sistemi, Rome University "Tor Vergata", Rome, Italy.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086233PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900509PMC
November 2014

The golden ratio of gait harmony: repetitive proportions of repetitive gait phases.

Biomed Res Int 2013 4;2013:918642. Epub 2013 Jun 4.

Santa Lucia Foundation, IRCCS, Rome, Italy.

In nature, many physical and biological systems have structures showing harmonic properties. Some of them were found related to the irrational number φ 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 φ, 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 φ (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.
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http://dx.doi.org/10.1155/2013/918642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687768PMC
February 2014

Decreased event-based prospective memory functioning in individuals with Parkinson's disease.

J Neuropsychol 2013 Sep 1;7(2):153-63. Epub 2013 Jul 1.

I.R.C.C.S. Fondazione Santa Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.1111/jnp.12024DOI Listing
September 2013

The serendipity case of the pedunculopontine nucleus low-frequency brain stimulation: chasing a gait response, finding sleep, and cognition improvement.

Front Neurol 2013 5;4:68. Epub 2013 Jun 5.

Department of Neuroscience, "Tor Vergata" University , Rome , Italy ; IRCCS, Fondazione Santa Lucia , Rome , Italy.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapy for Parkinson's disease (PD) but its effects on non-motor facets may be detrimental. The low-frequency stimulation (LFS) of the pedunculopontine nucleus (PPN or the nucleus tegmenti pedunculopontini - PPTg-) opened new perspectives. In our hands, PPTg-LFS revealed a modest influence on gait but increased sleep quality and degree of attentiveness. At odds with potential adverse events following STN-DBS, executive functions, under PPTg-ON, ameliorated. A recent study comparing both targets found that only PPTg-LFS improved night-time sleep and daytime sleepiness. Chances are that different neurosurgical groups influence either the PPN sub-portion identified as pars dissipata (more interconnected with GPi/STN) or the caudal PPN region known as pars compacta, preferentially targeting intralaminar and associative nucleus of the thalamus. Yet, the wide electrical field delivered affects a plethora of en passant circuits, and a fine distinction on the specific pathways involved is elusive. This review explores our angle of vision, by which PPTg-LFS activates cholinergic and glutamatergic ascending fibers, influencing non-motor behaviors.
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http://dx.doi.org/10.3389/fneur.2013.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672779PMC
June 2013

Parkinsonian patients with deficits in the dysexecutive spectrum are impaired on theory of mind tasks.

Behav Neurol 2013 Jan;27(4):523-33

IRCCS Fondazione Santa Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.3233/BEN-129018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214465PMC
January 2013

Deep brain stimulation of pedunculopontine tegmental nucleus: role in sleep modulation in advanced Parkinson disease patients: one-year follow-up.

Sleep 2012 Dec 1;35(12):1637-42. Epub 2012 Dec 1.

I.R.C.C.S. Fondazione Santa Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.5665/sleep.2234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490356PMC
December 2012

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

Front Syst Neurosci 2011 5;5:17. Epub 2011 Apr 5.

Istituto di Ricovero e Cura a Carattere Scientifico Fondazione S. Lucia, Roma, Italy.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (-30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy.
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http://dx.doi.org/10.3389/fnsys.2011.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078559PMC
July 2011

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature.

Brain 2010 Nov 23;133(11):3423-33. Epub 2010 Aug 23.

Department of Radiology, I.R.C.C.S. Foundation Santa Lucia, Via Ardeatina 306, 00179 Rome.

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.
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http://dx.doi.org/10.1093/brain/awq212DOI Listing
November 2010

Intensity-dependent facial emotion recognition and cognitive functions in Parkinson's disease.

J Int Neuropsychol Soc 2010 Sep 27;16(5):867-76. Epub 2010 Jul 27.

I.R.C.C.S. Santa Lucia Foundation, Rome, Italy.

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.
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http://dx.doi.org/10.1017/S1355617710000755DOI Listing
September 2010

Prevalence and characteristics of alexithymia in Parkinson's disease.

Psychosomatics 2010 Jan-Feb;51(1):22-8

I.R.C.C.S. Fondazione Santa Lucia, Roma, Italy.

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.
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http://dx.doi.org/10.1176/appi.psy.51.1.22DOI Listing
April 2010

Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: focus on sleep and cognitive domains.

J Neurol Sci 2010 Feb 17;289(1-2):44-8. Epub 2009 Sep 17.

IRCCS Fondazione S. Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.jns.2009.08.017DOI Listing
February 2010