Serotonergic mechanisms in Parkinson's Disease: Opposing results from preclinical and clinical data.

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

Verbal fluency in Parkinson's disease: results of a two minute fluency test

Background: Patients suffering from Parkinson's disease (PD) are often reported to have an impaired performance on tests measuring executive functioning, such as fluency tasks. Aim: To investigate whether verbal fluency is impaired in PD patients (n = 25) compared with healthy controls (n = 15) using a 2-min semantic and phonemic verbal fluency test. A 2-min version of the fluency task was used to allow for more switches between clusters to study retrieval strategies more adequately. Results: No differences in performance on both semantic and phonemic fluency tasks between the PD patients and the control persons were found. Moreover, both groups appeared to use the same retrieval strategies. Conclusion: Patients suffering from PD appear to use the same strategies for producing words as healthy controls do. Different pathways may be involved in switching clusters during the fluency task than in other types of switching that may be impaired in PD, such as motor switching and concept-shifting

Effects of acute tryptophan depletion on cognition, memory and motor performance in Parkinson's disease

Background: Parkinson's disease (PD) is a neuropsychiatric disease, which is not only characterized by motor symptoms, but also by cognitive and psychiatric symptoms. It is hypothesized that some of the non-motor symptoms are related to the serotonergic deficiency that is present in PD. Aim: To study the influence of serotonin on cognition, memory and motor performance in PD. Methods: In a double blind, randomized, placebo-controlled, cross-over design, the effect of acute tryptophan depletion (ATD) on the Visual Verbal Learning Task (VVLT), the Concept Shifting Task (CST), Simple Reaction Time Task (SRT), Finger Precuing Task (FPT) and the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS, Section 3) was investigated in 15 PD patients in early stages of their disease and 15 healthy volunteers, matched for age, sex and educational status. Results: With the exception of the absence of a differential effect for PD patients with the long interval of the SRT, ATD produced similar effects in PD patients and control subjects on all tasks. These included impairment of delayed recall and delayed recognition on the VVLT, and improved SRT and FPT for 'short intervals'. The UPDRS in patients remained unaffected after ATD. Conclusion: Serotonin does not appear to play a disease-specific role in cognition and reaction time in early stage PD patients, nor does acute reduction of cerebral serotonin levels affect motor symptoms in a clinically relevant way

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 Parkinson's 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 gyms (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 Alzheimer's 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 mu s (pulse width), and varying amplitudes of 1, 3, 30, and 150 mu A 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 mu A normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 mu A 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

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