Combined EEG and immersive virtual reality unveil dopaminergic modulation of error monitoring in Parkinson's Disease.

Detecting errors in your own and others' actions is associated with discrepancies between intended and expected outcomes. The processing of salient events is associated with dopamine release, the balance of which is altered in Parkinson's disease (PD). Errors in observed actions trigger various electrocortical indices (e.g. mid-frontal theta, error-related delta, and error positivity [oPe]). However, the impact of dopamine depletion to observed errors in the same individual remains unclear. Healthy controls (HCs) and PD patients observed ecological reach-to-grasp-a-glass actions performed by a virtual arm from a first-person perspective. PD patients were tested under their dopaminergic medication (on-condition) and after dopaminergic withdrawal (off-condition). Analyses of oPe, delta, and theta-power increases indicate that while the formers were elicited after incorrect vs. correct actions in all groups, the latter were observed in on-condition but altered in off-condition PD. Therefore, different EEG error signatures may index the activity of distinct mechanisms, and error-related theta power is selectively modulated by dopamine depletion. Our findings may facilitate discovering dopamine-related biomarkers for error-monitoring dysfunctions that may have crucial theoretical and clinical implications.

Impacto de la Terapia de Alto Flujo de Oxigeno (TAFO) en un Hospital Pediátrico de la Provincia de Buenos Aires / Impact of High Flow Oxygen Therapy (TAFO) in a Pediatric Hospital of the Province of Buenos Aires

Introducción: Las infecciones respiratorias agudas bajas (IRAB), representan la causa más frecuente de consulta e internación en los meses de invierno. La insuficiencia respiratoria aguda es la complicación que motiva la internación de los pacientes y la necesidad de Unidad Terapia Intensiva (UTI).El objetivo del trabajo fue describir los resultados de la implementación de la Terapia de Alto Flujo (TAFO) en pacientes con IRAB grave internados en Terapia Intermedia Métodos: Estudio prospectivo y descriptivo que incluyó pacientes de 1 a 36 meses internados en Terapia Intermedia en el Hospital Sor María Ludovica de la ciudad de La Plata, desde junio de 2018 a septiembre de 2019. Se ingresaron a TAFO pacientes sin respuesta al tratamiento con oxígeno a bajo flujo. El ingreso a UTI se consideró fracaso de la TAFO Resultados: De 760 pacientes internados con IRAB, 91(11,9%) ingresaron a TAFO de los cuales 59 (64,8 %) tuvieron respuesta favorable con disminución de la frecuencia respiratoria (FR), frecuencia cardiaca (FC) y mejoría de la mecánica respiratoria; el resto (35,2%) pasó a UTI por fracaso terapéutico. Presentaron complicaciones a la TAFO el 5,5% de los pacientes Conclusión: La TAFO fue una terapéutica segura, de fácil utilización que, a través de un aporte de oxígeno conocido, permitió la corrección de la hipoxemia, logrando la disminución de la FR, FC y mejoría de la mecánica respiratoria, dándole mayor comodidad al paciente durante su enfermedad

Introduction: Respiratory infections remain the major cause of outpatient consultation and hospital admissions during the winter season. Lower respiratory illness may cause severe acute respiratory insufficiency and hypoxemic respiratory failure, thus determining the need for hospitalization and eventual intensive care (ICU). The purpose of this paper is to describe the results of High Flow Oxygen Therapy (HFOT) implementation for patients with acute lower respiratory infections (ALRI) admitted to intermediate therapy unit. Methods: Prospective and descriptive study which included patients from age 1 to 36 months, hospitalized at intermediate therapy care unit at "Sor María Ludovica", Hospital, in La Plata, from June, 2018 to September, 2019. Patients who did not show any improvement to low flow oxygen therapy were the subjects of this study. Further submission to ICU was considered as HFOT failure Results: From 760 patients hospitalized with ALRI, 91 (11.9%) were admitted to TAFO. Fifty nine, (64.8%) had a favorable response with decreased respiratory and heart frequency rate, and an improvement of the work of breathing. The rest (35.1%) went to ICU due to therapeutic failure. Five point five percent of patients presented complications to TAFO. Conclusion: HFOT was a safe, easy to implement therapy treatment which improved the hypoxemic respiratory failure. This therapy reduced the respiratory and heart rate, and yielded a better and lower respiratory work, making patients more comfortable during illness

Does Dopamine Depletion Trigger a Spreader Lexical-Semantic Activation in Parkinson's Disease? Evidence from a Study Based on Word Fluency Tasks.

It has been hypothesised that, in Parkinson's disease (PD), dopamine might modulate spreading activation of lexical-semantic representations. We aimed to investigate this hypothesis in individuals with PD without dementia by assessing word frequency and typicality in verbal fluency tasks. We predicted that the average values of both of these parameters would be lower in PD patients with respect to healthy controls (HC). We administered letter-cued and category-cued fluency tasks to early PD patients in two experimental conditions: the tasks were administered both after 12-18 hours of dopaminergic stimulation withdrawal ("OFF" condition) and after the first daily dose of dopaminergic therapy ("ON" condition). HC were also given the two tasks in two conditions with the same intersession delay as PD patients but without taking drugs. Results showed that in both OFF and ON treatment conditions PD patients did not differ from HC in word frequency or typicality. Moreover, in the PD group, no significant difference was found between the experimental conditions. Our results show that semantic spreading was not altered in the PD sample examined; this suggests that in early PD the functioning of the semantic system is relatively independent from the activity of dopamine brain networks.

Blindfolded Balance Training in Patients with Parkinson's Disease: A Sensory-Motor Strategy to Improve the Gait.

Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson's Disease (PD) compared to patients treated with standard physical therapy (PT). Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage. Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups. Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient's rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications.

Wearing-off detection in clinical practice: the wearing off real practice key (WORK-PD) study in Parkinson's disease.

OBJECTIVE: Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. METHODS: 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. RESULTS: Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. CONCLUSIONS: The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support.

Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: a fMRI study.

Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato-frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in "ON" dopaminergic treatment state (DTS) and in "OFF" DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the "motor" theory of verb processing.

The clinical efficacy of L-DOPA and STN-DBS share a common marker: reduced GABA content in the motor thalamus.

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (-30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

BACKGROUND AND PURPOSE: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. METHODS: Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS)--Section III] and a battery of cognitive testing. RESULTS: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P < 0.05) and executive functions whilst the UPDRS revealed a modest (-21%) and variable treatment effect. CONCLUSIONS: Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD.

Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: effects on gait in Parkinson's disease.

OBJECTIVE: This study examines the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) and pedunculopontine tegmentum (PPTg) DBS in advanced Parkinson's disease using gait analysis. METHODS: Five people underwent bilateral DBS in both the STN and PPTg. Gait analysis was performed one year after neurosurgery using an optoelectronic system. The effects of DBS (STN, PPTg and STN+PPTg) were studied in two clinical conditions: without (Off) and during (On) antiparkinsonian therapy. RESULTS: PPTg and STN DBS were associated with changes in spatio-temporal and kinematics variables. CONCLUSIONS: Although experimental data cannot be generalized widely due to the small sample, PPTg DBS appears to affect the neuronal circuits subserving gait.

Pathological gambling from dopamine agonist and deep brain stimulation of the nucleus tegmenti pedunculopontine.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

Deep brain stimulation of CM/PF of thalamus could be the new elective target for tremor in advanced Parkinson's Disease?

Aim of this study was to investigate whether Deep Brain Stimulation (DBS) of the Centre Median Nucleus/Parafascicular (CM/PF) Complex is useful in reducing extrapyramidal symptoms in advanced Parkinson's Disease (PD) patients. In particular, we compared the action of CM/PF and subthalamic nucleus (STN) DBS on resting hand tremor using EMG surface of ulnar and radial right-hand muscles. Our results show that C/M DBS is very effective in reducing tremor, indicating this complex as a new target in advanced PD patients.

Global Mobility Task: index for evaluating motor impairment and motor rehabilitation programs in Parkinson's disease patients.

OBJECTIVE: In this study, the validity of a motor task, i.e., the Global Mobility Task (GMT), was assessed in a group of Parkinson's disease (PD) patients. PATIENTS AND METHODS: Fifty-eight PD patients (mean age: 68.7 years) and 18 healthy subjects (mean age: 65.8 years) were enrolled in the study. The GMT measures the ability of an adult to roll over on the floor and stand up in five steps using two parameters: 'Time' and 'Score', i.e., the time needed and the ability to perform each step of the task. As the GMT has never been evaluated before, internal consistency and concurrent and discriminative validity were considered in assessing its characteristics in a group of PD patients at the beginning and at the end of a motor rehabilitation program. To determine whether the GMT could also quantify the extrapyramidal impairment, we compared data collected using this task with data obtained using clinical scales such as the Unified Parkinson's Disease Rating Scale III (UPDRS part III) and Hoehn & Yahr's score. RESULTS: Results showed that the GMT had good consistency and inter-rater reproducibility, was closely related to clinical scales and was able to detect the amelioration of extrapyramidal symptoms at the end of the motor rehabilitation program. CONCLUSION: we propose the GMT as a tool for measuring impaired mobility in PD patients and for evaluating the objective effects of motor rehabilitation programs.

Does gait analysis quantify motor rehabilitation efficacy in Parkinson's disease patients?

SUBJECTS: Sixteen rigid-akinetic idiopathic Parkinson's disease patients (PD) and 13 healthy control subjects (controls) were included in this study. METHODS: Gait analysis was performed using an optoelectronic system. The experimental design involved double evaluation of PD patients (before and after motor rehabilitation program) and a single evaluation of controls. ANOVA was performed in both groups for each gait variable (kinetic and kinematic) and for clinical conditions. RESULTS: Analysis of kinetic data highlighted a statistically significant difference for all gait variables studied between controls and PD patients either before, or in the same PD patients before and after the motor rehabilitation program. After the rehabilitation program, natural walking speed increased (p<.000). The stance percentage was significantly decreased in the single support (p<.000). After the rehabilitation program, the double support limb phase did not show a reduction in statistical significance. Kinematic data showed statistical differences between controls and PD patients in hip, knee and ankle joint angles, both before and after the motor rehabilitation program. CONCLUSION: Our results confirm that gait analysis is a valid tool for evaluating changes in PD patients' ability to walk and for quantifying the improvements gained through a motor rehabilitation program.

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Alexithymia in Parkinson's disease is related to severity of depressive symptoms.

The authors investigated the possible relationship between depression and alexithymia in a population of hospitalized patients suffering from Parkinson's disease (PD). Fifty-eight PD patients without dementia participated in the study. Alexithymia was screened using the 20 item version of the Toronto Alexithymia Scale (TAS 20). Depression was diagnosed using a Structured Clinical Interview (SCID I) for DSM-IV. Severity of depression was evaluated with the Beck Depression Inventory (BDI). The prevalence of Alexithymia was about 21%. PD patients with major depression were significantly more alexithymic (TAS 20 average score = 61.4) than PD patients without depression (TAS 20 average score = 47.4) and, also, tended to be more alexithymic than PD patients with minor depression (MiD; TAS 20 average score =50.6), whereas no difference was found between PD patients with MiD and PD patients without depression. Moreover, high scores obtained on the BDI were found to strongly predict high level of alexithymia in these patients. These results extend to a cohort of PD patients previous data from the literature evidencing a strong association between alexithymia and severity of depressive symptoms.

Major and minor depression in Parkinson's disease: a neuropsychological investigation.

Previous studies have failed to distinguish the differential contribution of major and minor depression to cognitive impairment in patients with idiopathic Parkinson's disease (PD). This study was aimed at investigating the relationships among major depression (MD), minor depression (MiD) and neuropsychological deficits in PD. Eighty-three patients suffering from PD participated in the study. MD and MiD were diagnosed by means of a structured interview (SCID-I) based on the DSM-IV criteria, and severity of depression was evaluated by the Beck Depression Inventory. For the neuropsychological assessment, we used standardized scales that measure verbal and visual episodic memory, working memory, executive functions, abstract reasoning and visual-spatial and language abilities. MD patients performed worse than PD patients without depression on two long-term verbal episodic memory tasks, on an abstract reasoning task and on three measures of executive functioning. The MiD patients' performances on the same tests fell between those of the other two groups of PD patients but did not show significant differences. Our results indicate that MD in PD is associated with a qualitatively specific neuropsychological profile that may be related to an alteration of prefrontal and limbic cortical areas. Moreover, the same data suggest that in these patients MiD and MD may represent a gradual continuum associated with increasing cognitive deficits.

rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease.

The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.

Pergolide effect on cognitive functions in early-mild Parkinson's disease.

In the present study, we evaluated the effect of pergolide, a mixed D1/D2 agonist, on cognitive function in mild Parkinson's disease (PD). After a two-week wash-out phase, twenty patients with a Hoehn and Yahr score

Delayed administration may improve entacapone effects in parkinsonian patients non-responding to the drug.

BACKGROUND: Entacapone is a COMT inhibitor used in Parkinson's disease (PD) patients, as an adjunctive therapy to L-dopa in order to prolong its bioavailability and thus its clinical effect. However, previous studies reported entacapone-induced L-dopa to have lower C(max) and delayed t(max) values, coupled with a delayed onset of the clinical effect, possibly suggesting an interference between the two drugs. The aim of our study was to evaluate whether a delayed entacapone administration in association with standard L-dopa/carbidopa, may in some subjects improve the entacapone effects on L-dopa AUC and thus on the clinical 'on time' duration. METHODS: Twenty-eight idiopathic advanced PD patients were blindly evaluated in three different test days, following administration of carbidopa/L-dopa or carbidopa/L-dopa plus co-administered entacapone or plus entacapone administered with 30 min of delay. RESULTS: The AUC, the 'on time' and UPDRS score of the whole group were improved by both modalities of entacapone administration. An ex post analysis showed that the delayed entacapone administration produced a significant improvement in a subgroup of 10 non-responding patients to the co-administration. CONCLUSION: We suggest that the delayed administration should be attempted in the subjects not improved by entacapone co-administration.