Diplopia in Parkinson's disease: Indication of a cortical phenotype with cognitive dysfunction?

Background: Visual disturbances are increasingly recognized as common non-motor symptoms in Parkinson's disease (PD). In PD patients, intermittent diplopia has been found to be associated with the presence of visual hallucinations and the Parkinson's psychosis spectrum. Here, we investigated whether diplopia in PD is associated with other non-motor traits and cognitive impairment. Methods: We investigated 50 non-demented PD patients with and without intermittent diplopia and 24 healthy controls for visual disturbances, as well as motor and non-motor symptoms. All participants underwent a neuropsychological test battery; visuospatial abilities were further evaluated with subtests of the Visual Object and Space Perception Battery (VOSP). The two PD patient groups did not differ significantly in age, symptom duration, motor symptom severity, frequency of visual hallucinations, or visual sensory efficiency. Results: PD patients with diplopia reported more frequent non-motor symptoms including more subjective cognitive problems and apathy without changes in global cognition measures compared to those without diplopia. PD patients with diplopia had greater impairment in several tests of visuospatial function (pentagon copying p = .002; number location p = .001; cube analysis p < .02) and object perception (p < .001) compared to PD patients without diplopia and healthy controls. By contrast, no consistent group differences were observed in executive function, memory, or language. Conclusions: PD patients with diplopia have a greater non-motor symptom burden and deficits in visuospatial function compared to PD patients without diplopia. PD patients with diplopia might be prone to a cortical phenotype with cognitive decline and apathy associated with worse prognosis

Modulation of Habit Formation by Levodopa in Parkinson's Disease

Dopamine promotes the execution of positively reinforced actions, but its role for the formation of behaviour when feedback is unavailable remains open. To study this issue, the performance of treated/untreated patients with Parkinson's disease and controls was analysed in an implicit learning task, hypothesising dopamine-dependent adherence to hidden task rules. Sixteen patients on/off levodopa and fourteen healthy subjects engaged in a Go/NoGo paradigm comprising four equiprobable stimuli. One of the stimuli was defined as target which was first consistently preceded by one of the three non-target stimuli (conditioning), whereas this coupling was dissolved thereafter (deconditioning). Two task versions were presented: in a ‘Go version’, only the target cue required the execution of a button press, whereas non-target stimuli were not instructive of a response; in a ‘NoGo version’, only the target cue demanded the inhibition of the button press which was demanded upon any non-target stimulus. Levodopa influenced in which task version errors grew from conditioning to deconditioning: in unmedicated patients just as controls errors only rose in the NoGo version with an increase of incorrect responses to target cues. Contrarily, in medicated patients errors went up only in the Go version with an increase of response omissions to target cues. The error increases during deconditioning can be understood as a perpetuation of reaction tendencies acquired during conditioning. The levodopa-mediated modulation of this carry-over effect suggests that dopamine supports habit conditioning under the task demand of response execution, but dampens it when inhibition is required. However, other than in reinforcement learning, supporting dopaminergic actions referred to the most frequent, i. e., non-target behaviour. Since this is passive whenever selective actions are executed against an inactive background, dopaminergic treatment could in according scenarios contribute to passive behaviour in patients with Parkinson's disease

Differential Influence of Levodopa on Reward-Based Learning in Parkinson's Disease

The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the “overdose hypothesis” which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients’ actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks

Abnormal Distracter Processing in Adults with Attention-Deficit-Hyperactivity Disorder

Background: Subjects with Attention-Deficit Hyperactivity Disorder (ADHD) are overdistractible by stimuli out of the intended focus of attention. This control deficit could be due to primarily reduced attentional capacities or, e. g., to overshooting orienting to unexpected events. Here, we aimed at identifying disease-related abnormalities of novelty processing and, therefore, studied event-related potentials (ERP) to respective stimuli in adult ADHD patients compared to healthy subjects. Methods: Fifteen unmedicated subjects with ADHD and fifteen matched controls engaged in a visual oddball task (OT) under simultaneous EEG recordings. A target stimulus, upon which a motor response was required, and non-target stimuli, which did not demand a specific reaction, were presented in random order. Target and most non-target stimuli were presented repeatedly, but some non-target stimuli occurred only once (‘novels’). These unique stimuli were either ‘relative novels ’ with which a meaning could be associated, or ‘complete novels’, if no association was available. Results: In frontal recordings, a positive component with a peak latency of some 400 ms became maximal after novels. In healthy subjects, this novelty-P3 (or ‘orienting response’) was of higher magnitude after complete than after relative novels, in contrast to the patients with an undifferentially high frontal responsivity. Instead, ADHD patients tended to smaller centro-parietal P3 responses after target signals and, on a behavioural level, responded slower than controls

Function of cortico-thalamo-basal ganglia network in cognitive processing

Inhalt der in dieser Arbeit dargestellten Studien ist es, spezifische Beiträge subkortikaler Strukturen zu höheren kognitiven Leistungen zu charakterisieren und innerhalb des Konzeptes ‚kortiko-basaler Kognition‘ zu konkretisieren. In einem neurophysiologischen Ansatz führten wir hierzu bei Tremorpatienten mit tiefer Hirnstimulation (THS) zeitgleich konventionelle Oberflächen-EEG- Untersuchungen und Ableitungen von den implantierten THS-Elektroden durch. Dadurch ließen sich Aufmerksamkeitsleistungen und antizipatorisches Verhalten sowohl mit kortikalen als auch thalamischen Aktivierungen assoziieren, wie auch deren chronometrische Beziehungen zueinander darstellen. In einem nächsten Schritt wurde auf einer rein behavioralen Ebene komplementär zum thalamischen der basalganglionäre Beitrag zu kortiko-basal prozessierten Aufmerksamkeitsleistungen untersucht. Um einen spezifischen Einfluss von basalganglionären Prozessen auf Leistungen der Exekutiven Kontrolle zu identifizieren, wurden modellhaft zwei Erkrankungen mit differentieller lokaler Neurodegeneration ausgewählt. Während die Parkinson’sche Erkrankung mit einer überwiegend subkortikalen Neurodegeneration einhergeht, betrifft bei der Alzheimer-Krankheit die zentralnervale Schädigung vornehmlich temporo- kortikale Hirnregionen. Schließlich erweiterten wir die Methodik um einen neuropharmakologischen Aspekt, indem kognitive Leistungen in Abhängigkeit dopaminerger Substitutionstherapie zum Ausgleich des nigrostriatalen Dopamindefizits bei Morbus Parkinson untersucht wurden. Unter der Annahme, dass bewusstes wie auch unbewusstes Verhalten kortiko-basal prozessiert wird, verknüpften wir die bereits untersuchte Aufmerksamkeitsleistung der bewussten Verhaltenskontrolle mit einer unbewussten, impliziten Lernanforderung. Zusammenfassend konnte in der Untersuchungsserie mit drei unterschiedlichen methodischen Ansätzen – neurophysiologisch, behavioral sowie neuropharmakologisch – gezeigt werden, dass subkortikale Strukturen wie der Thalamus und die Basalganglien als Teil des kortiko-basalen Netzwerkes einen spezifischen Beitrag zu kognitiven Prozessen wie selektive Aufmerksamkeit, Verhaltenskontrolle und implizites Lernen leisten. Klinisch relevant wird dies in der Einflussnahme dopaminerger Substitutionstherapie bei der Basalganglienerkrankung Morbus Parkinson. Der Ausgleich des basalganglionären Dopaminmangels beeinträchtigt das implizite, unbewusste Lernverhalten und sollte im Rahmen der medikamentösen Therapie Beachtung finden.The presented studies address the characterization of subcortical functions in cognitive processing and their role in the corticobasal network. Three studies used a neurophysiological method, simultaneous depth and scalp electroencephalograms (EEG), to record patients with essential tremor who were undergoing treatment by thalamic deep brain stimulation (DBS).The aim of these studies was to assess the timing and chronometric relation of thalamic versus cortical processes involved in selective attention, executive function, and anticipatory processes. Within a further study we evaluated the impact of the basal ganglia on executive function behaviorally, by examining patients with Parkinson’s disease (PD) and Alzheimer’s disease (AD) – diseases associated with different pathological correlates. PD is associated with a predominantly subcortical degeneration, whereas AD is associated with a cortical degeneration of the temporal lobe. In a final study, we utilized a neuropharmacological method in order to study the influence of dopamine intake on non-rewarded implicit learning in PD patients. The hypothesis was that implicit learning behavior depends on a functioning corticobasal ganglia, so an effect was expected via therapeutic compensation of the nigrostriatal dopamine deficit in PD. These studies utilize three different methods – neurophysiological, behavioral and neuropharmacological – to show that the thalamus and the basal ganglia are specifically involved in cognitive processes such as selective attention, executive function and implicit learning, as part of the corticobasal network. In respect to clinical aspects, therapeutic substitution of the subcortical dopamine deficit in PD patients can itself give rise to cognitive dysfunctions

Neuropathy in Parkinson's disease patients with intestinal levodopa infusion versus oral drugs.

BACKGROUND: Severe polyneuropathy has been observed in a number of patients treated for Parkinson's disease with Levodopa/Carbidopa intestinal gel infusion. This may reflect a rare individual complication or a systematic side effect. OBJECTIVE: To investigate whether peripheral nerve function differed between patients with oral treatment versus Levodopa/Carbidopa intestinal gel infusion. METHODS: In an observational design, data from median, tibial, and peroneal neurography were prospectively assessed and compared between patients with conventional drug treatment (n = 15) and with Levodopa/Carbidopa intestinal gel infusion (n = 15). The groups were matched for age and disease duration. In view of the medical risk profile for polyneuropathy, comorbidity and basic serological parameters were assessed. RESULTS: Axonal neuropathy was common in both patient groups. However, although group differences in risk factors for polyneuropathy were not evident, neurographic abnormalities were more severe in the patients treated with Levodopa/Carbidopa intestinal gel infusion than in the orally treated patients. In the group with Levodopa/Carbidopa intestinal gel infusion, the degree of neuropathic change correlated with weight lost since therapy initiation and with the drug dose. In contrast to the axonal abnormalities, conduction velocity was found normal in both groups. CONCLUSION: The results are compatible with the promotion of axonal neuropathy by Levodopa/Carbidopa intestinal gel infusion. This could be due to the intrinsically high levodopa doses associated with the therapy and/or malnutritional effects from intestinal drug application. The results should be corroborated by a larger longitudinal and controlled trial

ERP peak latencies.

<p>Mean peak-latencies in milliseconds (± SD) for the frontal novelty-P3 and the centro-parietal oddball-P3 for controls and patients.</p

Clinical data.

<p>Patients differed between on and off levodopa states and from controls with respect to the scores in the Unified Parkinson's Disease Rating Scale (UPDRS). Normal values without significant differences between groups were obtained in the Beck Depression Inventory (BDI), the Mini Mental State Examination (MMSE) and the Fatigue Severity Scale (FSS). All data are provided as mean values ± standard deviation.</p