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Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement-based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward associations, such that, at the instant a specific stimulus is presented, it activates a specific action, based on the expectation that that particular action will likely incur reward (or avoid punishment); and (2) the comparison of predicted and actual outcomes to determine whether the specific stimulus-action association yielded the intended outcome or needs revision. Animal electrophysiology and human fMRI studies converge on the notion that dissociable neural circuitries centered on the striatum are differentially involved in different components of this learning process. The modulatory role of dopamine (DA) in these respective circuits and component processes is of particular relevance to the study of reward-based learning in patients diagnosed with Parkinson's disease (PD). Here we show that the first component process, learning to predict which actions yield reward (supported by the anterior putamen and associated motor circuitry) is impaired when PD patients are taken off their DA medication, whereas DA medication has no systematic effects on the second processes, outcome evaluation (supported by caudate and ventral striatum and associated frontal circuitries). However, the effects of DA medication on these processes depend on dosage, with larger daily doses leading to a decrease in predictability of stimulus-action-reward relations and increase in reward-prediction errors. (Contains 5 figures and 2 tables.)

The current study investigated the effects of Parkinson's disease (PD) on the ability to resolve conflicts when performance emphasized speed vs. response accuracy. PD patients and healthy controls (HC) completed a Simon task, and a subset of participants provided movement-related potential (MRP) data to investigate motor cortex activation and inhibition associated with conflict resolution. Both groups adjusted performance strategically with speed or accuracy instructions. The groups experienced similar susceptibility to making fast errors in conflict trials, but PD patients were less proficient compared to HC at suppressing incorrect responses, especially under speed pressure. Analysis of MRPs showed attenuated inhibition of the motor cortex controlling the conflicting response in PD patients compared to HC. These results confirm the detrimental effects of PD on inhibitory control mechanisms with speed pressure and also suggest that a downstream effect of inhibitory dysfunction in PD might be due to diminished inhibition of the motor cortex. [ABSTRACT FROM AUTHOR]

Introduction: Freezing of gait (FOG) is a clinical phenomenon with major life impairments and significant reduction in quality of life for affected patients. FOG is a feature of Parkinson's disease and a hallmark of primary progressive FOG, currently reclassified as Progressive Supranuclear Palsy-progressive gait freezing (PSP-PGF). The pathophysiology of FOG and particularly PGF, which is a rare degenerative disorder with a progressive natural history of gait decline, is poorly understood. Mechanistically, changes in oscillatory activity and synchronization in frontal cortical regions, the basal ganglia, and the midbrain locomotor region have been reported, indicating that dysrhythmic oscillations and coherence could play a causal role in the pathophysiology of FOG. Deep brain stimulation and spinal cord stimulation (SCS) have been tested as therapeutic neuromodulation avenues for FOG with mixed outcomes., Methods: We analyzed gait and balance in 3 patients with PSP-PGF who received percutaneous thoracic SCS and utilized magnetoencephalography (MEG), electroencephalography, and electromyography to evaluate functional connectivity between the brain and spine., Results: Gait and balance did not worsen over a 13-month period. This observation was accompanied by decreased beta-band spectral power in the whole brain and particularly in the basal ganglia. This was accompanied by increased functional connectivity in and between the sensorimotor cortices, basal ganglia, temporal cortex, and cerebellum, and a surge in corticomuscular coherence when SCS was paired with visual cues., Conclusion: Our results suggest synergistic activity between brain and spinal circuits upon SCS for FOG in PGF, which may have implications for future brain-spine interfaces and closed-loop neuromodulation for patients with FOG., (© 2024 S. Karger AG, Basel.)

Parkinson's disease (PD) is a neurological disorder associated primarily with overt motor symptoms. Several studies show that PD is additionally accompanied by impairments in covert cognitive processes underlying goal-directed motor functioning (e.g., action planning, conflict adaptation, inhibition), and that dopaminergic medication may modulate these action control components. In this review we aim to leverage findings from studies in this domain to elucidate the role of dopamine (DA) in action control. A qualitative review of studies that investigated the effects of medication status (on vs. off) on action control in PD suggests a component-specific role for DA in action control, although the expression of medication effects depends on characteristics of both the patients and experimental tasks used to measure action control. We discuss these results in the light of findings from other research lines examining the role of DA in action control (e.g., animal research, pharmacology), and recommend that future studies use multi-method, within-subject approaches to model DA effects on action control across different components as well as underlying striatal pathways (ventral vs. dorsal)., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Basal ganglia dysfunction in Parkinson's disease (PD) is thought to generate deficits in action control, but the characterization of these deficits have been qualitative rather than quantitative. Patients with PD typically show prolonged response times on tasks that instantiate a conflict between goal-directed processing and automatic response tendencies. In the Simon task, for example, the irrelevant location of the stimulus automatically activates a corresponding lateralized response, generating a potential conflict with goal-directed choices. We applied a new computational model of conflict processing to two sets of behavioral data from the Simon task to quantify the effects of PD and dopaminergic (DA) medication on action control mechanisms. Compared to healthy controls (HC) matched in age gender and education, patients with PD showed a deficit in goal-directed processing, and the magnitude of this deficit positively correlated with cognitive symptoms. Analyses of the time-course of the location-based automatic activation yielded mixed findings. In both datasets, we found that the peak amplitude of the automatic activation was similar between PD and HC, demonstrating a similar degree of response capture. However, PD patients showed a prolonged automatic activation in only one dataset. This discrepancy was resolved by theoretical analyses of conflict resolution in the Simon task. The reduction of interference generated by the automatic activation appears to be driven by a mixture of passive decay and top-down inhibitory control, the contribution of each component being modulated by task demands. Our results suggest that PD selectively impairs the inhibitory control component, a deficit likely remediated by DA medication. This work advances our understanding of action control deficits in PD, and illustrates the benefit of using computational models to quantitatively measure cognitive processes in clinical populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n = 19) or without (n = 18) ICB. An incentive-based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Objectives: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson's disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action., Methods: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time)., Results: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs., Conclusions: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665-674).

Frontal-basal ganglia circuitry dysfunction caused by Parkinson's disease impairs important executive cognitive processes, such as the ability to inhibit impulsive action tendencies. Subthalamic Nucleus Deep Brain Stimulation in Parkinson's disease improves the reactive inhibition of impulsive actions that interfere with goal-directed behavior. An unresolved question is whether this effect depends on stimulation of a particular Subthalamic Nucleus subregion. The current study aimed to 1) replicate previous findings and additionally investigate the effect of chronic versus acute Subthalamic Nucleus stimulation on inhibitory control in Parkinson's disease patients off dopaminergic medication 2) test whether stimulating Subthalamic Nucleus subregions differentially modulate proactive response control and the proficiency of reactive inhibitory control. In the first experiment, twelve Parkinson's disease patients completed three sessions of the Simon task, Off Deep brain stimulation and medication, on acute Deep Brain Stimulation and on chronic Deep Brain Stimulation. Experiment 2 consisted of 11 Parkinson's disease patients with Subthalamic Nucleus Deep Brain Stimulation (off medication) who completed two testing sessions involving of a Simon task either with stimulation of the dorsal or the ventral contact in the Subthalamic Nucleus. Our findings show that Deep Brain Stimulation improves reactive inhibitory control, regardless of medication and regardless of whether it concerns chronic or acute Subthalamic Nucleus stimulation. More importantly, selective stimulation of dorsal and ventral subregions of the Subthalamic Nucleus indicates that especially the dorsal Subthalamic Nucleus circuitries are crucial for modulating the reactive inhibitory control of motor actions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Parkinson's Disease patients with predominant gait dysfunction appear to have reduced cortical thickness compared to other motor phenotypes. The extent to which advancing age or disease duration impact the pattern of these distinctions is unclear., Objective: We examine if PD patients with predominant signs of postural instability and gait dysfunction are distinguished by distinct patterns of cerebral atrophy, and how these differences are influenced by age and disease duration., Methods: The Unified Parkinson's Disease Rating Score (UPDRS) was administered to 196 PD patients (age = 61.4±8.9yrs) in the Off and On dopamine state. All completed a structural T1-weighted brain MRI. We defined 3 motor phenotypes: tremor dominant, akinetic-rigid, and postural instability with gait disorder. General linear modeling quantified cortical thickness in relation to disease duration, and motor improvement after dopaminergic therapy. Cortical thickness and subcortical volumes were compared between the three motor subtypes, after controlling for disease duration and age., Results: We identified 177/196 patients who met criteria for a motor subtype. When corrected for disease duration, postural-instability patients had marked cortical thinning of the bilateral frontal-temporal and posterior cortical regions (cuneus/precuneus). After regressing for age, reduced frontal thickness was evident in patients with gait dysfunction. Widespread cortical thinning was associated with increasing disease duration and reduced motor improvement to dopaminergic therapy., Conclusions: Results emphasize that the profile of motor signs, especially prominent gait manifestations, relate to cortical thinning in distinct regions. Unique patterns of atrophy appear to be driven by advancing pathology related to age and disease duration.

Recent research showed a correlation between cognitive decline and a decrease of EEG gamma activity. In the present double-blind randomized control study, we investigated whether gamma and beta neurofeedback protocols, that have been shown to modulate performance on cognitive control and memory in young adults, also leads to increased brain activity and cognitive performance in elderly. Twenty older adults either performed eight 30-min gamma neurofeedback session or beta neurofeedback session within a period of 21 days. Cognitive performance was determined before and after the training through an IQ and memory task and we added a subjective well-being questionnaire. Both neurofeedback training protocols resulted in a significant increase of the brain activity within each training session, suggesting that the aging brain is still trainable. However, we found no effects on cognitive performance or transfer of the feedback beyond the trainings. We discuss several possible reasons for the lack of training on rest measurements and cognition and ways to improve the feedback protocols for future studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Most studies on physiological effects of emotion-inducing images and sounds examine stimulus locked variables reflecting a state of at most a few seconds. We here aimed to induce longer lasting emotional states using blocks of repetitive visual, auditory, and bimodal stimuli corresponding to specific valence and arousal levels. The duration of these blocks enabled us to reliably measure heart rate variability as a possible indicator of arousal. In addition, heart rate and skin conductance were determined without taking stimulus timing into account. Heart rate was higher for pleasant and low arousal stimuli compared to unpleasant and high arousal stimuli. Heart rate variability and skin conductance increased with arousal. Effects of valence and arousal on cardiovascular measures habituated or remained the same over 2-min intervals whereas the arousal effect on skin conductance increased. We did not find any effect of stimulus modality. Our results indicate that blocks of images and sounds of specific valence and arousal levels consistently influence different physiological parameters. These parameters need not be stimulus locked. We found no evidence for differences in emotion induction between visual and auditory stimuli, nor did we find bimodal stimuli to be more potent than unimodal stimuli. The latter could be (partly) due to the fact that our bimodal stimuli were not optimally congruent.

We evaluated the impact of the 1999 Belgian dioxin incident on the blood plasma polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels among 232 Belgian blood donors (74% men, mean age 47 years). The Red Cross made plasma samples from before the incident of these donors available. A second plasma sample was collected during the second half of 2000. The sum of the 17 PCDD/F congeners was significantly lower in 2000 compared to 1998 (417 pg/g fat versus 445 pg/g fat, respectively). This could be completely attributed to the significant decrease of OctaCDD (301 pg/g fat in 2000 versus 277 pg/g fat in 1998). Moreover a slight but significant decrease was observed for 2,3,7,8-TetraCDF and for 1,2,3,4,6,7,8-HeptaCDF. 1,2,3,7,8-PentaCDF and 2,3,4,7,8-PentaCDF however showed a slight but significant increase (respective levels in 1998 were 0.004 and 14.5 pg/g fat compared to 0.006 and 17.9 pg/g fat in 2000). Given their significantly higher presence in incident related food samples this increase can be attributed to the food contamination episode. However, the total toxicity remained unchanged (22.9 in 1998 versus 23.1 pg WHO-TEQ/g fat, p>0.05). Moreover the observed congener profiles and the total PCDD/F levels were similar to those of other European non-occupationally exposed populations. In conclusion, the 1999 PCB/dioxin incident was traceable in the plasma profiles (rise of the two specific PCDF congeners), but comparison of the results for both years indicates that the changes were too small to cause an adverse public health effect.

The chemically activated luciferase gene expression (CALUX) in vitro cell bioassay is a bioanalytical tool that is increasingly being used by research and commercial laboratories for the screening and relative quantification of dioxins and dioxin-like compounds in sample extracts. Since CALUX analyses provide a biological response to all aryl hydrocarbon receptor active compounds present in a given sample extract containing a complex mixture of chemicals, interpretation of results is significantly more complexthan of chemical analyses. Operators in the laboratory can adjust many parameters when performing CALUX analyses, and the applied procedure strongly affects the result and, hence, the interpretation of the results. This paper examines critical methodological parameters and aspects of the CALUX bioassay that can affect the quality and accuracy of the analyses. Moreover, the study aims to identify the ways that alteration of these parameters influences CALUX measurements. A greater understanding of these characteristics will lead to increased accuracy, precision, and reproducibility of the widely used CALUX bioassay within and between research laboratories.

Among the different analytical tools proposed as an alternative to the very expensive gas chromatography high-resolution mass spectrometry (GC-HRMS) analyses of polychlorodibenzo-p-dioxin and polychlorodibenzofurans, Chemically Activated LUciferase gene eXpression (CALUX) in vitro cell bioassay is very promising. It allows the analyses of a high number of samples since it is relatively fast, inexpensive, and sensitive. However, this technique is not yet widely applied for screening or environmental monitoring. The main reasons are probably the lack of validation and the difficulty in interpreting the global biological response of the bioassay. In this paper, the strict quality control criteria set up for the validation of CALUX are described. The validation has shown good repeatability (relative standard deviation (RSD) = 9%) and good within-lab reproducibility (RSD = 15%) of the results. The quantification limit, in the conditions applied in this paper, is 1.25 pg CALUX-TEQ/g fat. Comparison of CALUX and GC-HRMS analysis was made forvarious marine matrixes (fishes, mussels, starfishes, sea birds, and marine mammals). Good correlations are usually observed, but there are systematic differences between the results. Attempts are made to identify the origin of the discrepancy between the two methods.

Perfluorooctanesulfonyl fluoride based compounds have been used in a wide variety of consumer products, such as carpets, upholstery, and textiles. These compounds degrade to perfluorooctanesulfonate (PFOS), a persistent metabolite that accumulates in tissues of humans and wildlife. Previous studies have reported the occurrence of PFOS, perfluorohexanesulfonate (PFHxS), perfluorooctanoate (PFOA), and perfluorooctanesulfonamide (PFOSA) in human sera collected from the United States. In this study, concentrations of PFOS, PFHxS, PFOA, and PFOSA were measured in 473 human blood/serum/plasma samples collected from the United States, Colombia, Brazil, Belgium, Italy, Poland, India, Malaysia, and Korea. Among the four perfluorochemicals measured, PFOS was the predominant compound found in blood. Concentrations of PFOS were the highest in the samples collected from the United States and Poland (>30 ng/mL); moderate in Korea, Belgium, Malaysia, Brazil, Italy, and Colombia (3 to 29 ng/mL); and lowest in India (<3 ng/mL). PFOA was the next most abundant perfluorochemical in blood samples, although the frequency of occurrence of this compound was relatively low. No age- or gender-related differences in the concentrations of PFOS and PFOA were found in serum samples. The degree of association between the concentrations of four perfluorochemicals varied, depending on the origin of the samples. These results suggested the existence of sources with varying levels and compositions of perfluorochemicals, and differences in exposure patterns to these chemicals, in various countries. In addition to the four target fluorochemicals measured, qualitative analysis of selected blood samples showed the presence of other perfluorochemicals such as perfluorodecanesulfonate (PFDS), perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorododecanoic acid (PFDoA), and perfluoroundecanoic acid (PFUnDA) in serum samples, at concentrations approximately 5- to 10-fold lower than the concentration of PFOS. Further studies should focus on identifying sources and pathways of human exposure to perfluorochemicals.