Cognition-Related Functional Topographies in Parkinson's Disease: Localized Loss of the Ventral Default Mode Network.

Cognitive dysfunction in Parkinson's disease (PD) is associated with increased expression of the PD cognition-related pattern (PDCP), which overlaps with the normal default mode network (DMN). Here, we sought to determine the degree to which the former network represents loss of the latter as a manifestation of the disease process. To address this, we first analyzed metabolic images (fluorodeoxyglucose positron emission tomography [PET]) from a large PD sample with varying cognitive performance. Cognitive impairment in these patients correlated with increased PDCP expression as well as DMN loss. We next determined the spatial relationship of the 2 topographies at the subnetwork level. To this end, we analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from an independent population. This approach uncovered a significant PD cognition-related network that resembled previously identified PET- and rs-fMRI-based PDCP topographies. Further analysis revealed selective loss of the ventral DMN subnetwork (precuneus and posterior cingulate cortex) in PD, whereas the anterior and posterior components were not affected by the disease. Importantly, the PDCP also included a number of non-DMN regions such as the dorsolateral prefrontal and medial temporal cortex. The findings show that the PDCP is a reproducible cognition-related network that is topographically distinct from the normal DMN.

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.

Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: In patients with inflammatory bowel disease (IBD), restless legs syndrome (RLS) may occur as an extraintestinal disease manifestation. Iron deficiency (ID) or folate deficiency/vitamin B12 deficiency (FD/VB12D) has previously been described to cause RLS. Here, we determined the prevalence and severity of RLS in IBD patients and evaluated the effect of iron and/or folic acid/vitamin B12 supplementation. METHODS: Patients were screened for ID and RLS by a gastroenterologist. If RLS was suspected, a neurologist was consulted for definitive diagnosis and severity. Patients with RLS and ID, FD, or VB12D received supplementation and were followed-up at weeks 4 and 11 after starting supplementation. RESULTS: A total of 353 IBD patients were included. Prevalence for RLS was 9.4% in Crohn's disease (CD) and 8% in ulcerative colitis (UC). Prevalence for the subgroup of clinically relevant RLS (symptoms ≥ twice/week with at least moderate distress) was 7.1% (n = 16) for CD and 4.8% (n = 6) for UC. 38.7% of RLS patients presented with ID, FD, and/or VB12D. Most frequently ID was seen (25.8%; n = 8). Iron supplementation resulted in RLS improvement (p = 0.029) at week 4 in seven out of eight patients. CONCLUSION: Although the overall prevalence of RLS in IBD did not differ to the general population, clinically relevant RLS was more frequent in IBD patients and, therefore, it is important for clinicians to be aware of RLS symptoms. Though for definite diagnosis and proper treatment of RLS, a neurologist must be consulted. Additionally, iron supplementation of IBD patients with ID can improve RLS symptoms. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03457571.

Impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, and quality of life.

PURPOSE: Inflammatory bowel disease has been associated with neurological symptoms including restless legs syndrome. Here, we investigated the impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, mood, cognition, and quality of life. METHODS: Two groups of inflammatory bowel disease patients, with and without restless legs syndrome, were prospectively evaluated for sleep disorders, fatigue, daytime sleepiness, depression, anxiety, and health-related quality of life. Furthermore, global cognitive function, executive function, attention, and concentration were assessed in both groups. Disease activity and duration of inflammatory bowel disease as well as current medication were assessed by interview. Inflammatory bowel disease patients with and without restless legs syndrome were matched for age, education, severity, and duration of their inflammatory bowel disease. RESULTS: Patients with inflammatory bowel disease and clinically relevant restless leg syndrome suffered significantly more frequent from sleep disturbances including sleep latency and duration, more fatigue, and worse health-related quality of life as compared to inflammatory bowel disease patients without restless legs syndrome. Affect and cognitive function including cognitive flexibility, attention, and concentration showed no significant differences among groups, indicating to be not related to restless legs syndrome. CONCLUSIONS: Sleep disorders including longer sleep latency, shorter sleep duration, and fatigue are characteristic symptoms of restless legs syndrome in inflammatory bowel disease patients, resulting in worse health-related quality of life. Therefore, clinicians treating patients with inflammatory bowel disease should be alert for restless legs syndrome.

The single intake of levodopa modulates implicit learning in drug naïve, de novo patients with idiopathic Parkinson's disease.

Although dopamine is known to aggravate implicit learning, the exact impact on behaviour when feedback is unavailable remains unclear. Previous studies revealed that non-rewarded learning habits are affected in long-term dopaminergic treated patients with Parkinson's disease (PD). We studied the influence of a onetime levodopa intake on implicit learning in de novo, untreated PD patients. De novo PD patients (n = 22) before and after the single intake of levodopa and control subjects (n = 23) took part in a Go/NoGo paradigm. One stimulus was defined as target, which was first consistently preceded by one of three non-target stimuli (conditioning). This coupling was dissolved thereafter (deconditioning). In the 'Go version' subjects were asked to respond to the target by pressing a key, whereas in the 'NoGo version' response had to be inhibited. PD patients and controls (n = 14/n = 19) with an initial learning effect due to the target were included for further statistical analysis. Within the subgroup incorrect responses upon NoGo stimuli increased during the deconditioning phase. In contrast, the same patients failed to show any change after receiving 200 mg of levodopa. During the Go version, no change of the overall error rate between conditioning and deconditioning was detectable over all groups. Learning behaviour in untreated PD patients and healthy controls was indistinguishable. In contrast, the same patients varied in their implicit learning after one-time intake of levodopa, when actions had to be inhibited. Hence, the single intake of levodopa appears to modulate implicit learning behaviour in de novo PD patients.

Somatosensory symptoms in unmedicated de novo patients with idiopathic Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative condition presenting with motor and non-motor symptoms including somatosensory disturbances. As neuropathic syndromes in advanced PD patients are supposed to be due to antiparkinsonian medication, we studied the presence of somatosensory symptoms and peripheral nerve function in drug naïve patients with PD as well as age-matched healthy controls. Somatosensory symptoms and signs were investigated in 39 de novo PD patients and 32 age-matched healthy controls using the modified Toronto Clinical Neuropathy Scale. To elucidate potential underlying mechanisms, peripheral nerve function was analyzed with sensory and motor neurography. About two thirds of de novo diagnosed levodopa naïve PD patients (66.7 %) reported somatosensory symptoms in comparison to one third of the control group (31.2 %) (p = 0.003). The presence of PD (p = 0.017) was a predictive factor for the occurrence of somatosensory symptoms among all participants. In contrast to the significantly higher frequency of somatosensory symptoms in patients with PD compared to controls, neurographically based peripheral nerve function did not differ between the groups. Our results indicate that somatosensory symptoms are a PD feature, which can be found when diagnosed first and independently of dopaminergic treatment. As the electrophysiologically determined peripheral nerve function was not different from that obtained in the control group, somatosensory symptoms are inherent in early PD and may be, at least partially, of central origin.

Dysfunctional action control as a specific feature of Parkinson's disease.

Parkinson's disease (PD) is characterised by motor deficits as well as cognitive alterations, particularly concerning frontal lobe control. Here, we were interested in whether executive function is abnormal already early in PD, as well as whether this dysfunction worsens as a part of the dementia in PD. The following groups engaged in tasks addressing action control: PD patients with mild and advanced motor symptoms (aPD) without dementia, PD patients with dementia (PDD), patients with Alzheimer's disease (AD) and healthy subjects (CON). Subjects either had to perform or inhibit button presses upon go and no-go cues, respectively. These cues were preceded by pre-cues, either randomly instructive of right or left hand preparation (switch condition), or repetitively instructive for one side only (non-switch condition). PDD and aPD omitted more go responses than CON. Furthermore, PDD disproportionally committed failures upon no-go cues compared to CON. In the non-switch condition, PDD performed worse than AD, whose deficits increased to the level of PDD in the switch condition. Over all PD patients, task performance correlated with disease severity. Under the switch condition, task performance was low in both PDD and AD. In the non-switch condition, this also held true for advanced PD patients (with and without dementia), but not for AD. Thus, the deficits evident in PDD appear to develop from imbalanced inhibitory-to-excitatory action control generally inherent to PD. These results specify the concept of dysexecution in PD and differentiate the cognitive profile of PDD from that of AD patients.

Malnutritional neuropathy under intestinal levodopa infusion.

Levodopa/Carbidopa intestinal gel infusion (LCIG) for Parkinson's disease is under debate to provoke polyneuropathy (PNP). In our cohort of 20 thus treated patients, two developed debilitating axonal PNP with deficient pyridoxin and folate levels, and marginal cobalamin. Homocysteine was highly elevated. The neuropathies responded to vitamin replacement. We assume that LCIG can provoke PNP most likely of malnutritional origin. To avoid this side effect, the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary.

Speed effects of deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) accelerates reaction time (RT) in patients with Parkinson's disease (PD), particularly in tasks in which decisions on the response side have to be made. This might indicate that DBS speeds up both motor and nonmotor operations. Therefore, we studied the extent to which modifications of different processing streams could explain changes of RT under subthalamic DBS. Ten PD patients on-DBS and off-DBS and 10 healthy subjects performed a choice-response task (CRT), requiring either right or left finger button presses. At the same time, EEG recordings were performed, so that RTs could be assessed together with lateralized readiness potentials (LRP), indicative of movement preparation. Additionally, an oddball task (OT) was run, in which right finger responses to target stimuli were recorded along with cognitive P300 responses. Generally, PD patients off-DBS had longer RTs than controls. Subthalamic DBS accelerated RT only in CRT. This could largely be explained by analog shortenings of LRP. No DBS-dependent changes were identified in OT, neither on the level of RT nor on the level of P300 latencies. It follows that RT accelerations under DBS of the STN are predominantly due to effects on the timing of motor instead of nonmotor processes. This starting point explains why DBS gains of response speed are low in tasks in which reactions are initiated from an advanced level of movement preparation (as in OT), and high whenever motor responses have to be raised from scratch (as in CRT).

Thalamo-cortical processing of near-threshold somatosensory stimuli in humans.

Somatosensory stimuli elicit complex cortical responses that are discernible as somatosensory evoked potentials (SEPs) in scalp electroencephalographic recordings. Whereas earlier SEP components, occurring up to 100 ms after stimulus delivery, have been labeled 'preconscious', later responses have been associated with stimulus awareness. To date, how far these processes are primarily cortical or comprise additional subcortical operations remains open. Therefore, we recorded thalamic and scalp SEPs evoked by perceived as well as unperceived median nerve stimulation in neurosurgical patients with electrodes implanted into the ventral intermediate nucleus of the thalamus for deep brain stimulation. At stimulation intensities below perceptual threshold, only thalamic SEP components appeared consistently during the first 75 ms after stimulus delivery. Stimulation that was perceived by the patients elicited cortical as well as thalamic SEPs that lasted longer than 75 ms. These results indicate that the thalamus remains active after the primary propagation of a sensory signal to the cortex, and suggest that the transition from elementary to higher-order somatosensory processing is based on thalamo-cortical interactions.

Mental chronometry of target detection: human thalamus leads cortex.

Attentive monitoring of environmental stimuli is most fundamental for rapid target detection. The aim of this study was to assess the timing of thalamic versus cortical processes involved in this cognitive operation. To this end, simultaneous depth and scalp EEG was recorded in eight patients with essential tremor, undergoing thalamic deep brain stimulation (DBS), when the DBS electrodes could be accessed via their temporarily externalized leads. The patients performed an oddball task consisting of 300 presentations of one frequent and two rare visual cues, appearing in randomized order. One of the rare cues was defined as a target, the occurrences of which had to be indicated by a button press (motor condition) or silently counted (non-motor condition). At the scalp and the thalamus, event-related potentials (ERP) were largest upon target presentation, with peak latencies in the time domain of classical P300 responses. Remarkably, target-specific thalamic ERP emerged significantly prior to scalp P300. Furthermore, whereas scalp ERP had a higher amplitude upon rare than upon frequent non-target signals, thalamic ERP were independent of stimulus probability. This pattern was identified during motor and non-motor task execution. We conclude that the human thalamus specifically supports the early recognition of target events and can widely distribute this label through its divergent cortical projections.

Characterization of diplopia in non-demented patients with Parkinson's disease.

INTRODUCTION: Although diplopia is considered a frequent symptom of Parkinson's disease (PD), little is known about its clinical manifestation, associated mechanisms and treatment. Here we characterized binocular diplopia in non-demented PD patients in an interdisciplinary setting. METHODS: PD patients were prospectively screened for diplopia, visual hallucinations, problems with spatial perception, contrast sensitivity, presence of blurred vision, and history of ophthalmological comorbidities via interview. Two groups of PD patients, one with and one without diplopia, underwent clinical and ophthalmological assessment to characterize diplopia in these patients. Clinical features were investigated using the Unified Parkinson's Disease Rating Scale and the Non-Motor Symptoms Scale. RESULTS: The frequency of binocular diplopia was 29.6% (n = 37) in our cohort of 125 Parkinson's disease patients. Related mechanisms were heterogeneous including convergence insufficiency, strabismus, and motor fluctuations, as well as symptoms related to visual hallucinations. Diplopia was associated with other visual disturbances like visual hallucinations, blurred vision and problems with spatial perception. Beyond that, diplopia was found to be a predictive factor (3.2, odds ratio) for the occurrence of visual hallucinations in PD. CONCLUSION: Binocular diplopia represents a frequent and relevant symptom in PD patients. Different subtypes should be considered due to different associated mechanisms including ophthalmic pathology and motor fluctuation, as well as intermediate to higher level visual processes. Diplopia seems to be part of a continuous spectrum of positive visual symptoms in Parkinson's disease.

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.

Evaluation of a telemedical care programme for patients with Parkinson's disease.

We reviewed a telemedicine-based care model for drug optimization in Parkinson's disease. In this model patients send video recordings made in the home to the treating team via the Internet. These serve as the basis for making therapeutic decisions, in particular drug adjustments. Data from 78 patients were analysed with respect to outcome, method acceptance and management of the procedure. During the 30-day telemedicine programme, the patients recorded an average of 3.2 videos per day. The patients' motor score on the Unified Parkinson's Disease Rating Scale (UPDRS) was 31 points at enrolment and three months after ICP termination it was significantly lower at 24 points (P < 0.01), i.e. there was less impairment. The patients rated their condition better at the end than at the beginning of the programme: on a 6-point scale, the mean rating at the beginning was 3.2 and the mean rating at the end was 2.8 (P < 0.001). A blinded investigator rated the patients' videos on the same scale: at the beginning the mean score was 3.0 and at the end it was 2.8 (P < 0.05). The information from the questionnaire showed overall acceptance and practicability of the method. Both patients' and neurologists' use of the method was high. The method seems to be feasible for therapy optimization in Parkinson's disease, and of particular interest for patients with complex conditions who do not necessarily have to undergo hospital treatment.

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. CONCLUSION: The results demonstrate abnormal novelty processing in adult subjects with ADHD. In controls, the ERP pattern indicates that allocation of meaning modulates the processing of new stimuli. However, in ADHD such a modulation was not prevalent. Instead, also familiar, only context-wise new stimuli were treated as complete novels. We propose that disturbed semantic processing of new stimuli resembles a mechanism for excessive orienting to commonly negligible stimuli in ADHD.

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.