Central involvement in peripheral disease: melanopsin pathway impairment in chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) compromises functions of the peripheral nervous system (PNS). Recently, however, symptoms such as cognitive deficits, visual dysfunction and circadian disorders were reported, compatible with additional involvement of the central nervous system (CNS) in CIDP. Against this background, we were interested in the functional state of melanopsin-expressing retinal ganglion cells (mRGCs) as a potential biomarker for sleep-wake abnormalities and CNS involvement in CIDP. Based on a chromatic pupillometry protocol, we examined the integrity of the melanopsin system in a prospective case-control study in 20 persons with CIDP compared to 20 controls without CIDP. The results were referred to clinical measures of disease severity and sleep behaviour. Patients with CIDP had a significantly reduced melanopsin-mediated post-illumination pupil response (PIPR) compared to healthy controls (25% versus 36%; P < 0.01). This reduction correlated with disease severity (r = 0.478, P < 0.05). Further, patients with CIDP reported diminished sleep quality (P < 0.05); however, there was no significant correlation with the melanopsin-mediated PIPR. The results demonstrate an impairment of mRGC function related to CIDP. Since the PIPR reduction correlated with disease severity, it could be an easily available biomarker for CNS affection in CIDP, a condition defined as PNS disorder.

Theory of mind and executive dysfunction in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Although chronic inflammatory demyelinating polyneuropathy (CIDP) is understood as a disease affecting the peripheral nervous system, mild cognitive dysfunction, particularly in the executive domain, has been described to form part of the condition. Here our interest lay in CIDP-related theory of mind (ToM) capacities as an aspect of social cognition relevant for many aspects of everyday life. METHODS: Twenty-nine patients with CIDP and 23 healthy controls participated in this study. They were subjected to overview cognitive testing, different executive function (EF) tasks, as well as to the Faux Pas Recognition Task (FPRT) for assessing cognitive ToM and the Reading the Mind in the Eyes Test (RMET) with respect to affective ToM. RESULTS: Persons with CIDP and controls did not differ with respect to their overall cognitive state. However, in the German verbal fluency standard, the digit span forward and the digit span backward tests used as EF tasks patients performed significantly worse than controls. Further, performance was abnormally low in the FPRT, whilst the groups did not differ with respect to RMET results. The FPRT and digit span backward results correlated with each other. CONCLUSIONS: Patients with CIDP showed deficits in cognitive ToM performance together with EF dysfunction, whilst affective ToM was preserved. Altogether, the results suggest that low cognitive ToM capacities in patients with CIDP arise as a particular aspect of disease-related executive dysfunction.

Theory of mind deficits in Parkinson's disease are not modulated by dopaminergic medication.

Introduction: Patients with Parkinson's disease (PD) exhibit deficits in social cognition, particularly with respect to Theory of Mind (ToM) capacities. It is unclear whether they are associated with PD-related dopamine deficiency and modulated by levodopa replacement therapy. Methods: A total of 15 persons with PD and 13 healthy controls (HC) participated in the study. They performed different neuropsychological tasks, including the Faux Pas Recognition Test (FPRT), assessing different dimensions of cognitive ToM (e.g., detection, inappropriateness, intentions), and the Reading the Mind in the Eyes Test (RMET) as an index of affective ToM. Persons with PD were tested twice, once under their regular treatment and another time after at least 18 h of levodopa withdrawal (MED-ON and MED-OFF, respectively). On either occasion, serum drug levels and motor symptom severity [Unified Parkinson's Disease Rating Scale (UPDRS)] were measured. Results: MED-ON and MED-OFF conditions in patients with PD were confirmed by higher serum drug levels in the former than in the latter state and a corresponding amelioration of the motor deficit. In so doing, no performance difference in any ToM-related task was identified as a function of the levodopa therapy. Generally, patients performed worse than controls in both affective and cognitive ToM tests. Conclusion: Patients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions.

Aberrant neural processing of event boundaries in persons with Parkinson's disease.

The perception of everyday events implies the segmentation into discrete sub-events (i.e. event segmentation). This process is relevant for the prediction of upcoming events and for the recall of recent activities. It is thought to involve dopaminergic networks which are strongly compromised in Parkinson's disease (PD). Indeed, deficits of event segmentation have been previously shown in PD, but underlying neuronal mechanisms remain unknown. We therefore investigated 22 persons with PD and 22 age-matched healthy controls, who performed an event segmentation task with simultaneous electroencephalography (EEG). Both groups had to indicate by button press the beginning of sub-events within three movies showing persons performing everyday activities. The segmentation performance of persons with PD deviated significantly from that of controls. Neurophysiologically, persons with PD expressed reduced theta (4-7 Hz) activity around identified event boundaries compared to healthy controls. Together, these results point to disturbed event processing in PD. According to functions attributed to EEG activities in particular frequency ranges, the PD-related theta reduction could reflect impaired matching of perceptual input with stored event representations and decreased updating processes of event information in working memory and, thus, event boundary identification.

Tracing embodied word production in persons with Parkinson's disease in distinct motor conditions.

Embodied cognition theories posit direct interactions between sensorimotor and mental processing. Various clinical observations have been interpreted in this controversial framework, amongst others, low verb generation in word production tasks performed by persons with Parkinson's disease (PD). If this were the consequence of reduced motor simulation of prevalent action semantics in this word class, reduced PD pathophysiology should result in increased verb production and a general shift of lexical contents towards particular movement-related meanings. 17 persons with PD and bilateral deep brain stimulation (DBS) of the subhtalamic nucleus (STN) and 17 healthy control persons engaged in a semantically unconstrained, phonemic verbal fluency task, the former in both DBS-off and DBS-on states. The analysis referred to the number of words produced, verb use, and the occurrence of different dimensions of movement-related semantics in the lexical output. Persons with PD produced fewer words than controls. In the DBS-off, but not in the DBS-on condition, the proportion of verbs within this reduced output was lower than in controls. Lowered verb production went in parallel with a semantic shift: in persons with PD in the DBS-off, but not the DBS-on condition, the relatedness of produced words to own body-movement was lower than in controls. In persons with PD, DBS induced-changes of the motor condition appear to go along with formal and semantic shifts in word production. The results are compatible with the idea of some impact of motor system states on lexical processing.

Relation between event segmentation and memory dysfunction in Parkinson's disease.

The perception of everyday events is thought to imply the segmentation into discrete sub-events. Involvement of dopaminergic networks in this process could relate to particular problems of persons with Parkinson's disease (PD) to recall recent activities. In an event segmentation task, persons with PD and healthy controls had to indicate the beginning of sub-events within three movies showing persons performing everyday activities. In a subsequent recognition task, they should judge whether presented pictures of sub-events were part of the watched movies. In a final order memory task, they had to arrange pictures in the sequence in which they had occurred. With respect to the overall segmentation behavior, persons with PD diverged from healthy controls only in the most familiar of the three demonstrated everyday activities. Moreover, persons with PD compared to healthy controls showed generally worse event recognition and committed more errors in the order memory task. These memory deficits were the higher, the more the segmentation moved away from the 'normative' segmentation pattern identified in healthy controls. The findings suggest that dysfunctional structuring of sensory event information contributes to deficient event representations of ongoing everyday activities and recall problems of these recently perceived events in persons with PD.

Metabolomic profiles predict individual multidisease outcomes.

Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.

Dopamine-Related Reduction of Semantic Spreading Activation in Patients With Parkinson's Disease.

Impaired performance in verbal fluency (VF) tasks is a frequent observation in Parkinson's disease (PD). As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication (ON) as well as after drug withdrawal (i.e., OFF), and in a sample of age-matched healthy volunteers (both groups n = 26). Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates.

Altered event processing in persons with Parkinson's disease.

Persons with Parkinson's disease (PD) often show particular problems in seemingly simple routines despite relatively preserved cognitive function. We therefore investigated the processing of everyday events on behavioral and neurophysiological levels in a PD and control group. The participants had to indicate via button press whether three sequentially presented sub-events described a previously defined event (e.g., going grocery shopping). Sub-event sequences were either correct or included an event that did not belong to the event (content violation), or events were chronologically wrong (temporal violation). During task execution event-related potentials (ERPs) were recorded. Generally, the PD group showed less accurate performance independently from task conditions, and reaction times to temporal violations were particularly slow compared to the control group. Regarding ERP results, the control group showed a right lateralized N400 effect in response to content violations, which was absent in the PD group indicating altered content event processing. Concerning the reanalysis of content event violations, the expression of late positive components (LPCs) was similar between both groups. Upon temporal violations, both groups also showed a LPC with a tendentially earlier onset in the PD group, resembling positive components indicative of novelty processing. Together, these findings suggest poor event prediction in PD, which may originate from weak event representation or retrieval and possibly relate to prevalent behavioral dysfunctions in everyday life in PD.

Effects of thalamic and basal ganglia deep brain stimulation on language-related functions - Conceptual and clinical considerations.

Deep Brain Stimulation (DBS) is a therapy for various neurological movement disorders. It acts predominantly on motor symptoms, but may unfold a number of mostly subtle cognitive effects. In this regard, reports on particular language-related DBS sequels are comparably frequent, but difficult to overlook, given the heterogeneity of targeted structures in the brain, treated diseases, assessment methods and results reported. Accordingly, available knowledge was organized with respect to important aspects, such as the main DBS loci and surgical versus neuromodulatory therapy actions. Current views of biolinguistic underpinnings of the reviewed data, their clinical relevance and potential implications are discussed.

[Hallucinations in Patients with Idiopathic Parkinson's Disease]. / Halluzinationen bei Patienten mit idiopathischem Parkinson-Syndrom.

Patients with idiopathic Parkinson's disease develop symptoms of the hallucination-psychosis spectrum in more than 20%. Most common are visual hallucinations. The pathogenesis of hallucinations mainly depends on disease duration, the distribution and extent of alpha-synuclein pathology, and modulating effects of the dopaminergic therapy. When managing PD hallucinations both anti-delirogenic actions and medication management are important. However, decrease in dopaminergic medication may lead to critical worsening of akinesia. If appropriate neuroleptic medication - essentially quetiapin or clozapin - can be considered. Instead, anti-dopaminergic neuroleptics should not be used owing to their pro-akinetic side-effects. Here, we provide therapy recommendations to manage PD hallucinations based on an up-to-date targeted review of the literature and expert-based empirical evidence.

THN 102 for Excessive Daytime Sleepiness Associated with Parkinson's Disease: A Phase 2a Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

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.

Thalamic but Not Subthalamic Neuromodulation Simplifies Word Use in Spontaneous Language.

Several investigations have shown language impairments following electrode implantation surgery for Deep Brain Stimulation (DBS) in movement disorders. The impact of the actual stimulation, however, differs between DBS targets with further deterioration in formal language tests induced by thalamic DBS in contrast to subtle improvement observed in subthalamic DBS. Here, we studied speech samples from interviews with participants treated with DBS of the thalamic ventral intermediate nucleus (VIM) for essential tremor (ET), or the subthalamic nucleus (STN) for Parkinson's disease (PD), and healthy volunteers (each n = 13). We analyzed word frequency and the use of open and closed class words. Active DBS increased word frequency in case of VIM, but not STN stimulation. Further, relative to controls, both DBS groups produced fewer open class words. Whereas VIM DBS further decreased the proportion of open class words, it was increased by STN DBS. Thus, VIM DBS favors the use of relatively common words in spontaneous language, compatible with the idea of lexical simplification under thalamic stimulation. The absence or even partial reversal of these effects in patients receiving STN DBS is of interest with respect to biolinguistic concepts suggesting dichotomous thalamic vs. basal ganglia roles in language processing.

Impact of deep brain stimulation of the subthalamic nucleus on natural language in patients with Parkinson's disease.

BACKGROUND: In addition to the typical motor symptoms, a majority of patients suffering from Parkinson's disease experience language impairments. Deep Brain Stimulation of the subthalamic nucleus robustly reduces motor dysfunction, but its impact on language skills remains ambiguous. METHOD: To elucidate the impact of subthalamic deep brain stimulation on natural language production, we systematically analyzed language samples from fourteen individuals (three female / eleven male, average age 66.43 ± 7.53 years) with Parkinson's disease in the active (ON) versus inactive (OFF) stimulation condition. Significant ON-OFF differences were considered as stimulation effects. To localize their neuroanatomical origin within the subthalamic nucleus, they were correlated with the volume of tissue activated by therapeutic stimulation. RESULTS: Word and clause production speed increased significantly under active stimulation. These enhancements correlated with the volume of tissue activated within the associative part of the subthalamic nucleus, but not with that within the dorsolateral motor part, which again correlated with motor improvement. Language error rates were lower in the ON vs. OFF condition, but did not correlate with electrode localization. No significant changes in further semantic or syntactic language features were detected in the current study. CONCLUSION: The findings point towards a facilitation of executive language functions occurring rather independently from motor improvement. Given the presumed origin of this stimulation effect within the associative part of the subthalamic nucleus, this could be due to co-stimulation of the prefrontal-subthalamic circuit.

Age-related dissociation of N400 effect and lexical priming.

The use of contextual information is an important capability to facilitate language comprehension. This can be shown by studying behavioral and neurophysiological measures of accelerated word recognition when semantically or phonemically related information is provided in advance, resulting in accompanying attenuation of the respective event-related potential, i.e. the N400 effect. Against the background of age-dependent changes in a broad variety of lexical capacities, we aimed to study whether word priming is accomplished differently in elderly compared to young persons. 19 young (29.9 ± 5.6 years) and 15 older (69.0 ± 7.2 years) healthy adults participated in a primed lexical decision task that required the classification of target stimuli (words or pseudo-words) following related or unrelated prime words. We assessed reaction time, task accuracy and N400 responses. Acceleration of word recognition by semantic and phonemic priming was significant in both groups, but resulted in overall larger priming effects in the older participants. Compared with young adults, the older participants were slower and less accurate in responding to unrelated word-pairs. The expected N400 effect was smaller in older than young adults, particularly during phonemic word and pseudo-word priming, with a rather similar N400 amplitude reduction by semantic relatedness. The observed pattern of results is consistent with preserved or even enhanced lexical context sensitivity in older compared to young adults. This, however, appears to involve compensatory cognitive strategies with higher lexical processing costs during phonological processing in particular, suggested by a reduced N400 effect in the elderly.

A Vector Space Model for Neural Network Functions: Inspirations From Similarities Between the Theory of Connectivity and the Logarithmic Time Course of Word Production.

The present report examines the coinciding results of two study groups each presenting a power-of-two function to describe network structures underlying perceptual processes in one case and word production during verbal fluency tasks in the other. The former is theorized as neural cliques organized according to the function N = 2 i - 1, whereas the latter assumes word conglomerations thinkable as tuples following the function N = 2 i . Both theories assume the innate optimization of energy efficiency to cause the specific connectivity structure. The vast resemblance between both formulae motivated the development of a common formulation. This was obtained by using a vector space model, in which the configuration of neural cliques or connected words is represented by a N-dimensional state vector. A further analysis of the model showed that the entire time course of word production could be derived using basically one single minimal transformation-matrix. This again seems in line with the principle of maximum energy efficiency.

Instrumental Assessment of Stepping in Place Captures Clinically Relevant Motor Symptoms of Parkinson's Disease.

Fluctuations of motor symptoms make clinical assessment in Parkinson's disease a complex task. New technologies aim to quantify motor symptoms, and their remote application holds potential for a closer monitoring of treatment effects. The focus of this study was to explore the potential of a stepping in place task using RGB-Depth (RGBD) camera technology to assess motor symptoms of people with Parkinson's disease. In total, 25 persons performed a 40 s stepping in place task in front of a single RGBD camera (Kinect for Xbox One) in up to two different therapeutic states. Eight kinematic parameters were derived from knee movements to describe features of hypokinesia, asymmetry, and arrhythmicity of stepping. To explore their potential clinical utility, these parameters were analyzed for their Spearman's Rho rank correlation to clinical ratings, and for intraindividual changes between treatment conditions using standard response mean and paired t-test. Test performance not only differed between ON and OFF treatment conditions, but showed moderate correlations to clinical ratings, specifically ratings of postural instability (pull test). Furthermore, the test elicited freezing in some subjects. Results suggest that this single standardized motor task is a promising candidate to assess an array of relevant motor symptoms of Parkinson's disease. The simple technical test setup would allow future use by patients themselves.

Increased conceptual switching by dopaminergic treatment in patients with Parkinson's disease.

Cognitive changes including reduced word production in verbal fluency (VF) tasks are frequently observed in Parkinson's disease (PD) with ambiguous effects of dopaminergic medication on these symptoms. Here, we studied the impact of dopaminergic medication on specific cognitive components underlying VF task performance in 21 participants with PD on their regular medication and following dopamine withdrawal compared with healthy controls. We used temporal cluster analysis (TCA) to differentiate phases of VF output relating to fast automatic lexical activation ('clusters') and slower attention-demanding shifts ('switches'). Dopaminergic medication led to increased switching and, in non-alternating VF tasks, to the formation of smaller and shorter word clusters. The number of switches was correlated with higher cognitive scores and showed an inverse relationship with VF error rates. Increased switching operations during VF task performance can be interpreted in view of nigrostriatal dopaminergic roles for balancing system state versus change propensities. The additional effect on word clustering suggests a modulation of semantic spreading activation mechanisms underlying lexical search, presumably involving non-nigrostriatal, e.g., mesocortical dopaminergic networks.

Small Semantic Networks in Individuals with Autism Spectrum Disorder Without Intellectual Impairment: A Verbal Fluency Approach.

Individuals with Autism Spectrum Disorder (ASD) experience a variety of symptoms sometimes including atypicalities in language use. The study explored differences in semantic network organisation of adults with ASD without intellectual impairment. We assessed clusters and switches in verbal fluency tasks ('animals', 'human feature', 'verbs', 'r-words') via curve fitting in combination with corpus-driven analysis of semantic relatedness and evaluated socio-emotional and motor action related content. Compared to participants without ASD (n = 39), participants with ASD (n = 32) tended to produce smaller clusters, longer switches, and fewer words in semantic conditions (no p values survived Bonferroni-correction), whereas relatedness and content were similar. In ASD, semantic networks underlying cluster formation appeared comparably small without affecting strength of associations or content.