Bart Scholtissen

Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel-based morphometry.

Apathy is generally defined as a disorder of motivation and is considered one of the most common neuropsychiatric disturbances in Parkinsons disease (PD). Only few studies addressed the neuroanatomical correlates of apathy in PD. The aim of this article was to determine the structural correlates of apathy in PD patients. Fifty‐five PD patients underwent a neuropsychiatric and neuropsychological examination, and a 3 T magnetic resonance imaging scan was acquired. A voxel‐based multiple regression analysis was used to calculate correlation between gray matter density and severity measures of apathy. Apathy correlates with decreased cognitive functioning and more depressive symptoms but not with more severe motor symptoms. High apathy scores were correlated with low gray matter density values in a number of cortical brain areas: the bilateral precentral gyrus (BA 4, 6), the bilateral inferior parietal gyrus (BA 40), the bilateral inferior frontal gyrus (BA 44, 47), the bilateral insula (BA 13), the right (posterior) cingulate gyrus (BA 24, 30, 31), and the right precuneus (BA 31). Apathy in PD correlates with reduced gray matter density in a number of brain regions. The involvement of the cingulate gyrus and inferior frontal gyrus is in line with the results of earlier studies addressing apathy in patients with Alzheimers disease or depressive disorder. Further studies addressing the pathogenesis of apathy are needed.

Acute and separate modulation of motor and cognitive performance in parkinsonian rats by bilateral stimulation of the subthalamic nucleus.

The subthalamic nucleus (STN) is involved in motor and cognitive performance through its key role in the basal ganglia-thalamocortical circuits, but how these different modalities (motor and cognition) are controlled (similar vs. dissimilar) has not yet been elucidated. In the present study, the effects of bilateral STN deep brain stimulation (DBS) on motor and cognitive performance were investigated in a rat model of Parkinson disease (PD). After being trained in a choice reaction time (CRT) task, rats received bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width), and varying amplitudes of 1, 3, 30, and 150 microA during the CRT task. Finally, rats were sacrificed and the brains processed for staining to determine the dopaminergic lesion (TH immunohistochemistry) and localization of the electrode tip (HE histochemistry). Bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc) and increased motor time (MT), proportion of premature responding (PR), and reaction time (RT). Bilateral STN stimulation with an amplitude of 3 microA normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 microA reversed the lesion-induced deficits in MT and RT. Our data show for the first time that bilateral STN stimulation differentially affected the 6-OHDA-induced motor and cognitive deficits. This means that basal ganglia-thalamocortical motor and associative circuits responsible for specific motor and cognitive performance, which are processed through the STN, have unique physiological properties that can acutely and separately be modulated by specific electrical stimuli.

Serotonergic mechanisms in Parkinson’s disease: opposing results from preclinical and clinical data

Summary.Parkinson’s disease (PD) is a neuropsychiatric disease affecting approximately 1–2% of the general population. The classical triad of symptoms, tremor, rigidity, and bradykinesia is mainly caused by degeneration of dopaminergic neurons from the substantia nigra. However, other neurotransmitter systems also show signs of degeneration, among which the serotonergic system. The exact role of serotonin in PD remains unclear. We present here a review about functional serotonergic interventions and serotonergic imaging studies in PD, and will go into the importance of combining preclinical and clinical research data in order to gain more insight into the role of serotonin in PD. More specifically, the present review is aimed at bridging the gap between data from animal models of PD and data from human research.

Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: A pooled analysis of nine studies

Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory.

The Serotonergic Hypothesis for Depression in Parkinson's Disease: an Experimental Approach.

The serotonergic hypothesis for depression in Parkinsons disease (PD) states that the reduced cerebral serotonergic activity that occurs in PD constitutes a biological risk factor for depression. The aim of our study was to assess the serotonergic hypothesis of depression in PD patients using an experimental approach. In a double-blind, randomized order, placebo-controlled crossover design, the response on the Profile of Mood States (POMS) questionnaire to acute tryptophan depletion (ATD) was studied in 15 PD nondepressed patients and 15 control subjects, without a prior personal or family history of depression. PD patients had lower (worse) baseline scores on the sadness, fatigue and vigor subscales of the POMS, in both ATD and the placebo condition, but not on the tension and anger subscales. There was however neither a significe between group effect, nor significe within-group effect due to ATD. We could find no evidence of a specific serotonergic vulnerability of PD patients for depression. Therefore, our results do not support the serotonergic hypothesis for depression in PD.

Challenging the serotonergic system in Parkinson disease patients: effects on cognition, mood, and motor performance.

Background: Parkinson disease (PD) is a neuropsychiatric disease that is characterized by motor and neuropsychiatric symptoms. Multiple neurotransmitter systems, including the serotonergic system, are involved in the pathophysiology of this disease. The exact role of the serotonergic system in PD is still unclear. Objective: To investigate the role of serotonin on specific aspects of cognition, mood, and motor performance in PD. Methods: In a double-blind, randomized, placebo-controlled, crossover design, the effects of a nonspecific serotonergic challenge with citalopram, a selective serotonin reuptake inhibitor, and a 5-HT1a receptor-specific challenge with buspirone on the Visual Verbal Learning Task, Concept Shifting Task, Profile of Mood State Questionnaire, motor section of the Unified Parkinson Disease Rating Scale (section 3), Simple Reaction Time Task, and Finger Precuing Task were studied in 21 PD patients in early stages of their disease and 21 age-, sex-, and education-matched healthy volunteers. Results: The serotonergic challenges resulted in similar effects for both groups. No changes of scores on the cognitive tasks (Visual Verbal Learning Task and Concept Shifting Task) were observed. Results of the Profile of Moods State Questionnaire indicated that, at baseline, PD patients scored less than controls on all 5 subscales. Motor performance (measured by reaction time) was negatively affected by the interventions. Conclusions: The effects of nonspecific and 5-HT1a receptor-specific challenging of the serotonergic neurotransmitter system had similar effects in both PD patients and healthy control subjects. These findings indicate that serotonergic function is not impaired in early PD and that serotonin, although involved in the pathophysiology of PD, does not seem to play a direct role in cognition, mood, and motor performance in PD patients, but may be involved in hypokinesia.

Functional investigations into the role of dopamine and serotonin in partial bilateral striatal 6-hydroxydopamine lesioned rats

In Parkinsons disease (PD), several neurotransmitter systems, such as the dopaminergic and serotonergic system, show signs of degeneration. This led to the suggestion that alterations in the serotonergic system play a role in the pathophysiology of PD. Partial bilateral dopaminergic lesions of the caudate putamen complex (CPu) of rats induced by 6-hydroxydopamine (6-OHDA) produce behavioral symptoms mimicking PD. In the present study, the role of serotonin and dopamine was investigated both behaviorally and neuroanatomically. In a reaction time task, motor initiation and motor performance were impaired in the lesioned animals compared to controls. The performance of rats treated with d-amphetamine or serotonergic ligands (DOI and ketanserin) in the reaction time task indicated that 5-HT and DA appear to be agonistically related in the CPu. The relation was the same in both control and 6-OHDA lesioned rats. 12 weeks after lesioning, motor initiation recovered, whereas motor performance did not. Parallel to the behavioral study, a second group of animals was lesioned and, at 3 days, 6 weeks and 12 weeks after lesioning, a subgroup was killed to obtain a qualitative indication of the degree of 6-OHDA lesion. Over the three time points, a substantial recovery of tyrosine hydroxylase staining in the CPu was visible. Taken together, since serotonergic ligands have the same effect as dopaminergic ligands on reaction time responding indicated that 5-HT and DA release are agonistically linked in control and 6-OHDA lesioned rats.

Dissociable effects of histamine H1 antagonists on reaction-time performance in rats

The most pronounced side effect of antiallergic histaminergic drugs (H1 antagonists) is sedation. These effects have been linked with the effects of histaminergic drugs on central H1 receptors. In the present study, we investigated the dose-response relationship of different antihistamines on the performance in a reaction-time task that has been developed for rats. The dose-response relationship of diphenhydramine, cetirizine and terfenadine were examined for the various behavioural measures in this task (i.e., reaction time, motor time, premature responses and number of trials completed). In addition, the effects of scopolamine were assessed to evaluate the cholinergic profile in this task. Diphenhydramine did not reliably affect the reaction time, but increased the motor time and the proportion of premature responses, and decreased the number of trials completed in a session. A low dose of cetirizine decreased the reaction time, whereas an increase in reaction time was found for the high dose. The motor time was increased after both doses of cetirizine. Terfenadine did not affect the responding of rats in the reaction-time task at the doses tested. The effects of scopolamine were very similar to those of diphenhydramine. The reaction-time task used in this study was able to dissociate different types of antihistamines on aspects of psychomotor function, which were likely to be related to central muscarinic or H1 antagonism. These findings suggest that the reaction-time task may be a sensitive tool for assessing effects of drugs on psychomotor function.

Executive control in Parkinson's disease: Effects of dopaminergic medication and deep brain stimulation on anti-cue keypress performance

Using an anti-cue keypress task, we examined executive control in Parkinsons disease (PD) patients treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN) and dopaminergic medication. Across sessions, we varied stimulation (on, off) and dopaminergic medication (on, off). Reaction time (RT) results of the PD patients and their age-matched controls showed a consistent pattern of RT costs and benefits generated by anti-cues with short and long preparation intervals, respectively. This pattern was evident in all sessions, except when DBS stimulation and medication were off. In this condition PD patients showed no RT benefits. These findings are discussed in terms of an executive control process that suppresses the automatic but inappropriate response activation generated by anti-cues. In PD this mechanism is severely compromised but it can be remediated by dopaminergic medication and DBS, suggesting an essential role of the basal ganglia in the selection and suppression of competing responses.

Response preparation in Parkinson's disease: Automatic vs. controlled processing

Using a finger cuing paradigm, we investigated response preparation in Parkinsons disease (PD). The central question was whether PD individuals are differentially affected by preparatory cues that specify a more automatic response set configuration (that induces within-hand preparation) as opposed to a more controlled one (that induces between-hands preparation). Reaction times (RTs) and error rates were measured in 20 non-demented individuals with PD and 20 healthy control participants with a long and short preparation interval (500 ms and 2000 ms). RT benefits and/or costs were measured for cues indicating a within- and between-hands motor preparatory set. Overall, RTs were significantly longer, and errors more frequent, for PD participants than for control participants. More importantly, in comparison with control subjects, PD individuals showed a significant deficit in between-hands preparation but not in within-hand preparation. Furthermore, longer preparation intervals slowed down cued RTs of the control participants, but not those of the PD individuals. Together, these findings suggest that whereas automatic response preparation processes are spared in PD, controlled response preparation processes operate at a slower rate and/or are delayed in time.