Marleen Wingen

Sustained attention and serotonin: a pharmaco-fMRI study

Evidence suggests that stimulation of serotonergic function in healthy humans causes an impairment of sustained attention. The present study assessed the influence of increased serotonin levels on brain areas involved in sustained attention.

Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI

Serotonergic neurotransmission has been implicated in memory impairment. It is uncLear however if memory performance is mediated through general 5-HT availability, through specific 5-HT receptors or both. The aim of the present study was to assess the contribution of 5-HT reuptake inhibition and specific blockade of 5-HT1A and 5-HT2A receptors to memory impairment. The study was conducted according to a randomized, double-blind, placebo-controlled, four-way cross-over design including 16 healthy volunteers. The treatment consisted of oral administration of escitalopram 20 mg + placebo, escitalopram 20 mg + ketanserin 50 mg, escitalopram 20 mg + pindolol 10 mg and placebo on 4 separate days with a washout period of minimum 7 days. Different memory tasks were performed including verbal memory, spatial working memory and reversal learning. Escitalopram showed an impairing effect on immediate verbal recall which nearly reached statistical significance. No effects of escitalopram were found on other types of memory. In combination with pindolol, immediate verbal recall was significantly impaired. Escitalopram in combination with ketanserin impaired spatial working memory significantly. No effects were found on reversal learning. Selective impairment of immediate verbal recall after a 5-HT1A partial agonist and selective impairment of spatial working memory performance after 5-HT2A receptor antagonist, both in combination with a selective serotonergic reuptake inhibitor (escitalopram), suggests that 5-HT1A and 5-HT2A receptors are distinctly involved in verbal and spatial memory.

Escitalopram Decreases Cross-Regional Functional Connectivity within the Default-Mode Network

The default-mode network (DMN), which comprises medial frontal, temporal and parietal regions, is part of the brain’s intrinsic organization. The serotonergic (5-HT) neurotransmitter system projects to DMN regions from midbrain efferents, and manipulation of this system could thus reveal insights into the neurobiological mechanisms of DMN functioning. Here, we investigate intrinsic functional connectivity of the DMN as a function of activity of the serotonergic system, through the administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram. We quantified DMN functional connectivity using an approach based on dual-regression. Specifically, we decomposed group data of a subset of the functional time series using spatial independent component analysis, and projected the group spatial modes to the same and an independent resting state time series of individual participants. We found no effects of escitalopram on global functional connectivity of the DMN at the map-level; that is, escitalopram did not alter the global functional architecture of the DMN. However, we found that escitalopram decreased DMN regional pairwise connectivity, which included anterior and posterior cingulate cortex, hippocampal complex and lateral parietal regions. Further, regional DMN connectivity covaried with alertness ratings across participants. Our findings show that escitalopram altered intrinsic regional DMN connectivity, which suggests that the serotonergic system plays an important role in DMN connectivity and its contribution to cognition. Pharmacological challenge designs may be a useful addition to resting-state functional MRI to investigate intrinsic brain functional organization.

Involvement of Inferior Parietal Lobules in Prospective Memory Impairment During Acute MDMA (Ecstasy) Intoxication: An Event-Related fMRI Study

Prospective memory refers to the realization of delayed intentions. Several studies have shown that 3,4-methylenedioxy-methamphetamine (MDMA) users perform worse on measures of prospective memory as compared to nondrug users. Interpretation of these data may be limited because of polydrug use, psychosocial stressors, and increased psychopathology that have been reported in MDMA users. This study was designed to directly assess the pharmacological effect of MDMA on prospective memory and brain activity in a double-blind, placebo-controlled, cross-over study. Twelve recreational MDMA users received MDMA 75 mg and placebo and performed an objective prospective memory task during functional imaging. During prospective memory task performance subjects were engaged in a foreground task that consisted of a simple reaction time to visual stimuli (Go trials) and a prospective task of withholding a response during trials that were part of a dynamic memory set (No go trials). Behavioral data showed that a single dose of MDMA increased prospective memory failures in the No go trials, and that number of prospective memory failures was positively correlated to MDMA concentration in plasma. Functional imaging showed that MDMA decreased BOLD activation during Go trials in the thalamus (left), putamen (left), precuneus (left), and the inferior parietal lobules (bilateral), as compared to placebo. During No go trials, MDMA reduced BOLD deactivation in the inferior parietal lobules (bilateral), as compared to placebo. It is concluded that the loss of deactivation in inferior parietal lobules may account for increments in memory failures observed during MDMA intoxication.

Memory and mood during the night and in the morning after repeated evening doses of MDMA

Previously it has been shown that MDMA causes memory impairment during daytime testing. However, MDMA is usually taken in the evening or during the night. In addition, it is known that sleep deprivation also causes memory impairment. The present study aimed to assess whether evening doses of MDMA added to, or interacted with the memory impairment due to sleep deprivation. Fourteen healthy subjects participated in a double-blind, placebo-controlled, two-way cross-over study. Treatments consisted of MDMA 75 and 50 mg divided over the evening or double placebo. Memory tests and subjective measures of mood were conducted at baseline and three times post dosing that is at 6.30 pm, 9.30 pm, 1.30 am and 7 am, respectively —1.5, 1.5, 5.5 and 11 h relative to drug intake (first dose). Memory performance detoriated progessively over time as a function of sleep loss, independent of treatment. MDMA added to this impairment as indicated by a significant main effect of MDMA on verbal and spatial memory performance. Mood ratings and response speed revealed an MDMA by Time interaction. After administration of MDMA response speed improved and feelings of vigor, friendliness, elation, anxiety, confusion, arousal and positive mood increased in magnitude during the night, while all these parameters returned to placebo-like levels on the final morning session. It is concluded that evening doses of MDMA selectively impair memory performance, and that this impairment is additional to the effect of sleep deprivation on memory performance.

MDMA intoxication and verbal memory performance: a placebo-controlled pharmaco-MRI study

The aim of the present study was to identify the neural substrate underlying memory impairment due to a single dose of MDMA (3,4-methylenedioxymethamphetamine) by means of pharmaco-MRI. Based on previous behavioral results it was hypothesized that this deficit could be attributed to a specific influence of MDMA on encoding. Fourteen Ecstasy users participated in this double-blind, placebo-controlled, within-subject study with two treatment conditions: MDMA (75 mg) and placebo. Memory performance was tested by means of a word learning task including two words lists, one addressing reading processes (control task, CWL) and a second (experimental task, EWL) addressing encoding and reading processes. Behavioral data showed that under the influence of MDMA, EWL performance was worse than placebo. Imaging data showed that Encoding was situated mainly in (pre)frontal, temporal and parietal areas. MDMA by Encoding interaction was situated in three areas: the left middle frontal gyrus (BA10), the right fusiform gyrus (BA19), and the left cuneus (BA18). Behavioral and functional data only correlated in BA10. It appeared that EWL performance caused BOLD signal change in BA10 during placebo treatment but not during MDMA intoxication. It is concluded that MDMA influences middle frontal gyrus processes resulting in impoverished memory encoding.

Driving Performance of Depressed Patients who are Untreated or Receive Long-Term Antidepressant (SSRI/SNRI) Treatment

Introduction Depression is a mental disorder likely to affect everyday functions. The present study aimed to assess actual driving performance of depressed patients who were without specific antidepressant treatment or received long-term antidepressant treatment. Methods A standardized on-the-road driving test was used to assess standard deviation of lateral position (SDLP) in 3 patient groups receiving either no antidepressant treatment (with or without benzodiazepine medication) or treatment with selective serotonin/noradrenalin reuptake inhibitors for a period of 6-52 weeks. Severity of depression was assessed using Becks Depression Inventory and the Hamilton Depression Rating Scale. The performance of patient groups was compared to healthy controls. Results The mean SDLP of untreated and treated patients was significantly higher than that of healthy controls. Driving impairment in the long-term treated group was significantly less than in the untreated groups. SDLP was positively correlated to severity of depression across all groups. Discussion It is concluded that symptoms of depression are a major cause of driving impairment. Reductions in severity of depression through antidepressant treatment reduce severity of driving impairment.

Depressief en onder behandeling van antidepressiva: wat betekent dit voor de rijvaardigheid?

Depressie en antidepressiva kunnen het cognitief functioneren verstoren en daarmee ook de rijvaardigheid. Weinig onderzoek is gedaan naar rijvaardigheid bij depressieve patiënten. In een recent onderzoek werd nagegaan wat het effect is van langdurig antidepressivagebruik op rijvaardigheid en cognitie bij depressieve patiënten behandeld voor 6-52 weken met ssris (Selective Serotonin Reuptake Inhibitors) of snris (Serotonin and Noradrenalin Reuptake Inhibitors). De resultaten lieten zien dat depressieve patiënten onder behandeling van antidepressiva een verslechterde rijvaardigheid hadden, zoals bleek uit een verhoogde standaarddeviatie van de laterale positie (een maat voor slingeren) en een vertraagde aanpassing van het reactievermogen op snelheidsveranderingen. Geconcludeerd kan worden dat depressieve patiënten onder langdurige behandeling van antidepressiva slechter rijden dan gezonde vrijwilligers. Resterende depressieve klachten zijn hier waarschijnlijk de oorzaak van.