[Show abstract][Hide abstract] ABSTRACT: Action observation is known to trigger predictions of the ongoing course of action and thus considered a hallmark example for predictive perception. A related task, which explicitly taps into the ability to predict actions based on their internal representations, is action segmentation; the task requires participants to demarcate where one action step is completed and another one begins. It thus benefits from a temporally precise prediction of the current action. Formation and exploitation of these temporal predictions of external events is now closely associated with a network including the basal ganglia and prefrontal cortex.
Because decline of dopaminergic innervation leads to impaired function of the basal ganglia and prefrontal cortex in Parkinson’s disease (PD), we hypothesised that PD patients would show increased temporal variability in the action segmentation task, especially under medication withdrawal (hypothesis 1).
Another crucial aspect of action segmentation is its reliance on a semantic representation of actions. There is no evidence to suggest that action representations are substantially altered, or cannot be accessed, in non-demented PD patients. We therefore expected action segmentation judgments to follow the same overall patterns in PD patients and healthy controls (hypothesis 2), resulting in comparable segmentation profiles. Both hypotheses were tested with a novel classification approach.
We present evidence for both hypotheses in the present study: classifier performance was slightly decreased when it was tested for its ability to predict the identity of movies segmented by PD patients, and a measure of normativity of response behaviour was decreased when patients segmented movies under medication-withdrawal without access to an episodic memory of the sequence. This pattern of results is consistent with hypothesis 1. However, the classifier analysis also revealed that responses given by patients and controls create very similar action-specific patterns, thus delivering evidence in favour hypothesis 2.
In terms of methodology, the use of classifiers in the present study allowed us to establish similarity of behaviour across groups (hypothesis 2). The approach opens up a new avenue that standard statistical methods often fail to provide and is discussed in terms of its merits to measure hypothesised similarities across study populations.
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairment in Parkinson's disease (PD) is often attributed to dopamine deficiency in the prefrontal-basal ganglia-thalamo-cortical loops. Although recent studies point to a close interplay between motor and cognitive abilities in PD, the so-called "motor loop" connecting supplementary motor area (SMA) and putamen has been considered solely with regard to the patients' motor impairment. Our study challenges this view by testing patients with the serial prediction task (SPT), a cognitive task that requires participants to predict stimulus sequences and particularly engages premotor sites of the motor loop. We hypothesized that affection of the motor loop causes impaired SPT performance, especially when the internal sequence representation is challenged by suspension of external stimuli. As shown for motor tasks, we further expected this impairment to be compensated by hyperactivity of the lateral premotor cortex (PM). We tested 16 male PD patients ON and OFF dopaminergic medication and 16 male age-matched healthy controls in an functional Magnetic Resonance Imaging study. All subjects performed two versions of the SPT: one with on-going sequences (SPT0), and one with sequences containing non-informative wildcards (SPT+) increasing the demands on mnemonic sequence representation. Patients ON (compared to controls) revealed an impaired performance coming along with hypoactivity of SMA and putamen. Patients OFF compared to ON medication, while showing poorer performance, exhibited a significantly increased PM activity for SPT+ vs. SPT0. Furthermore, patients' performance positively co-varied with PM activity, corroborating a compensatory account. Our data reveal a contribution of the motor loop to cognitive impairment in PD, and suggest a close interplay of SMA and PM beyond motor control.
[Show abstract][Hide abstract] ABSTRACT: Background
STN-DBS is well established to improve motor symptoms and quality of life in patients with PD. While non-motor symptoms are crucial for quality of life in these patients, only neuropsychiatric and neuropsychological symptoms have been systematically studied in a longitudinal design so far. However, these are only a part of the non-motor symptoms spectrum.
We hypothesized that STN-DBS is associated with a beneficial effect on a range of non-motor symptoms.
In this multicenter, open, prospective, international study (EuroInf-study, UKCRN10084/DRKS00006735) we investigated non-motor effects of STN-DBS in “real-life” use. We evaluated Non-motor Symptom Scale, and Questionnaire, PD Questionnaire-8, Scales for Outcomes of PD motor examination and complications, and activities of daily living preoperatively and at 6 months follow-up in 60 consecutive patients (35 male, mean age: 61.6 ± 7.8 years, mean disease duration: 10.4 ± 4.2 years).
All outcomes improved significantly at 6 months follow-up (PD Questionaire-8, p = 0.006; activities of daily living, p = 0.012; all others, p < 0.001; Wilcoxon signed-rank, respectively paired t-test; Bonferroni-correction). Post-hoc analyses of Non-motor Symptom Scale domains showed a significant reduction of sleep/fatigue and miscellaneous domains (p ≤ 0.001), perceptual problems/hallucinations (p = 0.036), and urinary (p = 0.018) scores. Effect sizes were “moderate” for Non-motor Symptom Scale, and motor complications, “large” for motor examination, and “small” for other outcomes.
This study provides evidence that bilateral STN-DBS improves non-motor burden in patients with PD and opens the door to a more balanced evaluation of DBS outcomes. Further randomized studies are needed to confirm these findings and compare DBS non-motor effects to other invasive therapies of advanced PD.
[Show abstract][Hide abstract] ABSTRACT: In patients with small-fiber neuropathy (SFN), noninvasive diagnostic tests that allow accurate monitoring of disease progression are urgently needed. The aim of this study was to assess corneal trigeminal small sensory nerves and immune cells by in vivo corneal confocal microscopy (CCM) in SFN.
In this prospective single-center study, 14 patients with histologically confirmed SFN were analyzed. CCM parameters [corneal nerve fiber density (NFD); the total number of nerves, main trunks, and branches; nerve tortuosity; and dendritic cell density] were compared with 14 age-matched healthy controls and correlated with clinical symptoms, disease course, and histopathological findings.
Corneal NFD (15,489.3 ± 5927.6 μm/mm vs. 22,687.1 ± 4328.7 μm/mm; P = 0.001) and the total number of nerves (10.4 ± 4.6/frame vs. 18.5 ± 4.8/frame; P < 0.0001) were significantly reduced in patients with SFN. In contrast, nerve tortuosity was significantly increased (2.2 ± 0.3 vs. 1.7 ± 0.5; P = 0.02). Corneal NFD did not correlate with intraepidermal NFD (ρ = -0.158; P = 0.5) or clinical symptoms (cold P = 0.1; prickling P = 0.2; burning P = 0.8; formication P = 0.7; stabbing P = 0.4; rubbing 0.1; pressure P = 0.1). The average dendritic cell density was increased in SFN (33.5 ± 57.5 cells/mm vs. 16.1 ± 13.7 cells/mm) but did not reach significance (P = 0.7).
CCM provides parameters that reliably indicate injury to sensory afferents of the trigeminal nerve in patients with SFN. Our data suggest that CCM may serve both as a noninvasive diagnostic test and as a surrogate marker in SFN.
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN) is a phosphoglycoprotein with important roles in tissue homeostasis, wound healing, immune regulation, and stress responses. It is expressed constitutively in the brain and upregulated during neuroinflammatory responses, e.g., after focal cerebral ischemia. To date, its effects on neural stem cells (NSC) remain to be elucidated and are, accordingly, subject of this study.
Primary fetal rat NSC were cultured as homogenous monolayers and treated with different concentrations of OPN. Fundamental properties of NSC were assessed following OPN exposure, including proliferative activity, survival under oxidative stress, migration, and differentiation potential. To elucidate a putative action of OPN via the CXC chemokine receptor type 4 (CXCR4), the latter was blocked with AMD3100. To investigate effects of OPN on endogenous NSC in vivo, recombinant OPN was injected into the brain of healthy adult rats as well as rats subjected to focal cerebral ischemia. Effects of OPN on NSC proliferation and neurogenesis in the subventricular zone (SVZ) were studied immunohistochemically.
OPN dose-dependently increased the number of NSC in vitro. As hypothesized, this effect was mediated through CXCR4. The increase in NSC number was due to both enhanced cell proliferation and increased survival, and was confirmed in vivo. Additionally, OPN dose-dependently stimulated the migration of NSC via CXCR4. Moreover, in the presence of OPN, differentiation of NSC led to a significant increase in neurogenesis both in vitro as well as in vivo after cerebral ischemia.
Data show positive effects of OPN on survival, proliferation, migration, and neuronal differentiation of NSC. At least in part these effects were mediated via CXCR4. Results suggest that OPN is a promising substance for the targeted activation of NSC in future experimental therapies for neurological disorders such as stroke.
[Show abstract][Hide abstract] ABSTRACT: The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight-adapted dietary tryptophan and phenylalanine-tyrosine depletion (PTD) techniques were used.
The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake.
Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group.
The present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations.
[Show abstract][Hide abstract] ABSTRACT: Cognitive training has been shown to be effective in improving cognitive functions in patients with Mild Cognitive Impairment (MCI). However, data on factors that may influence training gains including sociodemographic variables such as sex or age is rare. In this study, the impact of sex on cognitive training effects was examined in N = 32 age- and education-matched female (n = 16) and male (n = 16) amnestic MCI patients (total sample: age M = 74.97, SD = 5.21; education M = 13.50, SD = 3.11). Patients participated in a six-week multidomain cognitive training program including 12 sessions each 90 min twice weekly in mixed groups with both women and men. Various cognitive domains were assessed before and after the intervention. Despite comparable baseline performance in women and men, we found significant interaction effects Time × Sex in immediate (p = .04) and delayed verbal episodic memory (p= .045) as well as in working memory (p = .042) favoring the female MCI patients. In contrast, the overall analyses with the total sample did not reveal any significant within-subject effects Time. In conclusion, our results give preliminary evidence for stronger cognitive training improvements of female compared to male MCI patients. More generally, they emphasize the importance of sex-sensitive evaluations of cognitive training effects. Possible underlying mechanisms of the found sex differences are discussed and directions for future research are given.
[Show abstract][Hide abstract] ABSTRACT: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).
To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.
Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.
Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.
Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.
Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).
Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.
clinicaltrials.gov Identifier: NCT01829581.
JAMA The Journal of the American Medical Association 02/2015; 313(8):824-36. DOI:10.1001/jama.2015.0846 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Patients with Parkinson's disease (PD) can show impaired self-awareness of motor deficits (ISAm). We developed a new scale that measures ISAm severity of hyper- and hypokinetic movements in PD during medication on state and defined its psychometric criteria.
Included were 104 right-handed, non-depressed, non-demented patients. Concerning ISAm, 38 motor symptoms were assessed using seven tasks, which were performed and self-rated concerning presence of deficit (yes/no) by all patients. The whole procedure was videotaped. Motor symptoms were then evaluated by two independent experts, blinded for patient's ratings, concerning presence, awareness of deficit, and severity. Exploratory principal component analysis (promax rotation) was applied to reduce items. Principal axis factoring was conducted to extract factors. Reliability was examined regarding internal consistency, split-half reliability, and interrater reliability. Validity was verified by applying two additional measures of ISAm.
Of the initial 38 symptoms, 15 remained, assessed in five motor tasks and merged to a total severity score. Factor analysis resulted in a four factor solution (dyskinesia, resting tremor right hand, resting tremor left hand, bradykinesia). For all subscales and the total score, measures of reliability (values 0.64-0.89) and validity (effect sizes>0.3) were satisfactory. Descriptive results showed that 66% of patients had signs of ISAm (median 2, range 0-15), with ISAm being most distinct for dyskinesia.
We provide the first validation of a test for ISAm in PD. Using this instrument, future studies can further analyze the pathophysiology of ISAm, the psychosocial sequelae, therapeutic strategies and compliance with therapy.
Journal of the International Neuropsychological Society 02/2015; 21(03):1-10. DOI:10.1017/S1355617715000107 · 2.96 Impact Factor