A mindful approach to controlling intrusive thoughts.

Intrusive thoughts of negative experiences can pose a threat to our well-being. To some extent, unwanted memories can be intentionally controlled via an executive control mechanism that downregulates the occurrence of intrusions. Mindfulness training can improve executive control. It is not known whether mindfulness training can be used as an intervention to improve intentional memory control and reduce intrusions. To this end, 148 healthy participants completed a 10-day app-based mindfulness training or an active control task. At baseline, inhibitory control and working memory were assessed as measures of executive functioning. Post-mindfulness training, intrusions were assessed via the Think/No-Think task. It was expected that mindfulness training would reduce intrusions. Furthermore, we hypothesised that this would be moderated by baseline executive functioning. Results revealed that, contrary to our hypothesis, both groups increased equally in dispositional mindfulness between baseline and post-test. As such, our exploratory analysis revealed that higher dispositional mindfulness across both groups resulted in fewer intrusions and enhanced the ability to downregulate intrusions over time. Furthermore, this effect was moderated by inhibitory control at baseline. These results provide insight into factors that can improve the ability to control unwanted memories, which could have considerable implications for treatments in psychopathologies characterized by the frequent occurrence of intrusive thoughts. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 11th March, 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.17605/OSF.IO/U8SJN .

No interaction between rivastigmine and citalopram on memory and novelty processing in healthy human volunteers.

BACKGROUND: Animal literature suggests an interaction between acetylcholine and serotonin on cognitive functions. AIMS: The aim of the current study was to assess whether both neurotransmitters interact during memory and novelty processing in humans. METHODS: We tested the interaction between acetylcholine and serotonin on cognitive functions in healthy volunteers by means of treatment with rivastigmine and citalopram, respectively. RESULTS: The main result of the study showed that during the verbal learning task participants significantly recalled fewer words after citalopram treatment than after rivastigmine or placebo during both the immediate and delayed recall tasks. Rivastigmine was not able to reverse the impairing effect of citalopram. CONCLUSIONS: This finding is in line with previous studies in which we manipulated acetylcholine and serotonin in different manners. Taken together, these studies in humans do not support the notion from animal studies that these two neurotransmitters interact on cognitive functions.

Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults.

The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 µg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 µg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

Role of acetylcholine and serotonin in novelty processing using an oddball paradigm.

The processing of novel stimuli is known to take place in the hippocampus and frontal cortex, and is influenced by the cholinergic system. This ability is crucial to help detect changes in the environment and adapt behaviour accordingly. Previous research has shown that acetylcholine (ACh) can interact with serotonin (5-HT) at the hippocampal level, which may have consequences for cognitive functioning. However, little is known about the exact nature of this ACh and 5-HT interaction as well their possible interactive effects on novelty processing. We investigated the interactive role of ACh and 5-HT in novelty processing in healthy young participants. Levels of these neurotransmitters were manipulated with the muscarinic M1 antagonist biperiden, and with acute tryptophan depletion (ATD). Participants received either placebo, biperiden, ATD, or a combination of both in a double-blind cross-over design. Auditory event-related potentials (ERPs) were recorded while a novelty oddball task was presented. Our results showed that biperiden affected ERP components considered to reflect attentional mechanisms; it increased the P50 amplitude and decreased that of the P200. Furthermore, a decrease of N100 amplitude by ATD was reversed by biperiden. The treatments did not affect the mismatch negativity (MMN) component, which is elicited when a deviant stimulus is presented in a sequence of repetitive stimuli. Importantly, biperiden decreased the amplitude of the ERP component related to novelty processing (P3a). The current study's results did not reveal an interactive effect of ACh and 5-HT on novelty processing. However, the data do suggest that ACh is involved in novelty processing and that it influences basic stimulus processing, without affecting sound-discrimination accuracy.

Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans.

RATIONALE: One of the most often reported cognitive deficits of acute cannabis administration is an impaired recall of previously learned information. OBJECTIVE: The aim of the present study was to determine whether cannabis-induced memory impairment in humans is mediated via glutamatergic or cholinergic pathways. METHODS: Fifteen occasional cannabis users participated in a double-blind, placebo-controlled, six-way cross-over study. On separate test days, subjects received combinations of pretreatment (placebo, vardenafil 20 mg or rivastigmine 3 mg) and treatment (placebo or 1,376 mg cannabis/kg body weight). Cognitive tests were administered immediately after inhalation of treatment was finished and included measures of memory (visual verbal learning task, prospective memory test, Sternberg memory test), perceptual-motor control (critical tracking task), attention (divided attention task) and motor impulsivity (stop signal task). RESULTS: The results of this study demonstrate that subjects under the influence of cannabis were impaired in all memory tasks, in critical tracking, divided attention and the stop signal task. Pretreatment with rivastigmine attenuated the effect of cannabis on delayed recall and showed a trend towards significance on immediate recall. When cannabis was given in combination with vardenafil, there were no significant interaction effects in any of the tasks. CONCLUSIONS: The present data therefore suggest that acetylcholine plays an important role in cannabis-induced memory impairment, whereas similar results for glutamate have not been demonstrated in this study.

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Cognitive effects of methylphenidate and levodopa in healthy volunteers.

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory.

PDE2 and PDE10, but not PDE5, inhibition affect basic auditory information processing in rats.

Phosphodiesterase type 2 (PDE2), type 10 (PDE10), and type 5 (PDE5) have been considered as relevant targets for cognition enhancement. Although it is well established that PDE inhibitors (PDE-Is) improve memory functions in animals, the effects on auditory information processing are less clear. The aim of this study was to test the effects of PDE2 (BAY 60-7550), PDE5 (vardenafil) and PDE10 (PQ-10) inhibition on sensory gating in rats. Vehicle or 1mg/kg of a specific PDE-I was given orally 30min before testing. EEG was recorded from the hippocampus, striatum and vertex. Sensory gating was found for the N1 in the vertex and hippocampus, as revealed by diminished amplitudes to S2 compared to S1. Administration of PDE-Is did not affect sensory gating. However, PDE2 inhibition increased the P1 peak after presentation of S1 at the vertex and PQ-10 increased the N1 peak in general compared to vehicle treatment at the hippocampus. PDE2 and PDE10 inhibition affect auditory information processing in general, whereas PDE5 inhibition has no effect. These findings suggest that the positive effects of PDE5 inhibition on cognition previously found in animals are possibly the results of an effect on higher cognitive functioning specifically, whereas the cognition enhancing effects of PDE2 and PDE10 inhibition might also be influenced by effects on earlier stages of information processing.

The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study.

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil. During encoding of words, the P300 was generally smaller after vardenafil treatment. Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after vardenafil treatment. Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals.

Higher, faster, stronger: the effect of dynamic stimuli on response preparation and CNV amplitude.

The contingent negative variation (CNV) is a slow negative shift in the electroencephalogram (EEG), observed during response preparation. To optimalize the CNV paradigm, this study developed a task using dynamic stimuli and next combined this task with a Go/No-go test. In the first experiment, 19 healthy volunteers were subjected to the classic Traffic light (TL) task and the new dynamic Lines task. In the Lines task, response time was faster and CNV amplitude was larger compared to the TL task. In the second experiment, 20 healthy participants were tested on a Go/No-go version of the Lines task. Response times increased as the probability of response requirement decreased. CNV amplitude was larger when probability of response requirement was higher. In conclusion, the dynamic task promotes response preparation. The new tasks may be especially valuable in groups with attention difficulties (i.e. elderly or ADHD patients).

The PDE5 inhibitor vardenafil does not affect auditory sensory gating in rats and humans.

RATIONALE: Sensory gating is an adaptive mechanism of the brain to prevent overstimulation. Patients suffering from clinical disorders such as Alzheimer's disease or schizophrenia exhibit a deficit in gating, which indicates not only an impairment in basic information processing that might contribute to the cognitive problems seen in these patients. Phosphodiesterase type 5 inhibitors (PDE5-Is) have been shown to improve cognition in rodents in various behavioural tasks and might consequently be an interesting target for cognition enhancement. However, the effects of PDE5-Is on sensory gating are not known yet. OBJECTIVES: This work aims to study the effects of PDE5 inhibition on auditory sensory gating in rats and humans. METHODS: In the rat study, vehicle or 0.3-3 mg/kg of the PDE5-I vardenafil was given orally 30 min before testing and electrode locations were the vertex, hippocampus and the striatum. The human subjects received placebo, 10-20 mg vardenafil 85 min before testing and sensory gating was measured at the cortex (Fz, Fcz and Cz) electrodes. RESULTS: Significant gating was only found for the N1 component in rats while all three peaks P1, N1 and P2 showed gating in humans, i.e. the response to the second sound click was decreased as compared with the first for these deflections. Administration of vardenafil did neither have an effect on sensory gating in rats nor in humans. CONCLUSIONS: These findings imply that positive effects of PDE5 inhibition on cognition are not mediated by more early phases of information processing.

Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers.

RATIONALE: Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate. OBJECTIVE: In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers. METHODS: In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test. RESULTS: Declarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning. CONCLUSIONS: To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.

The effects of acute tryptophan depletion on brain activation during cognition and emotional processing in healthy volunteers.

Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.

Effects of L-histidine depletion and L-tyrosine/L-phenylalanine depletion on sensory and motor processes in healthy volunteers.

BACKGROUND AND PURPOSE: Animal studies show that histamine plays a role in cognitive functioning and that histamine H3-receptor antagonists, which increase histaminergic function through presynaptic receptors, improve cognitive performance in models of clinical cognitive deficits. In order to test such new drugs in humans, a model for cognitive impairments induced by low histaminergic functions would be useful. Studies with histamine H1-receptor antagonists have shown limitations as a model. Here we evaluated whether depletion of L-histidine, the precursor of histamine, was effective in altering measures associated with histamine in humans and the behavioural and electrophysiological (event-related-potentials) effects. EXPERIMENTAL APPROACH: Seventeen healthy volunteers completed a three-way, double-blind, crossover study with L-histidine depletion, L-tyrosine/L-phenylalanine depletion (active control) and placebo as treatments. Interactions with task manipulations in a choice reaction time task were studied. Task demands were increased using visual stimulus degradation and increased response complexity. In addition, subjective and objective measures of sedation and critical tracking task performance were assessed. KEY RESULTS: Measures of sedation and critical tracking task performance were not affected by treatment. L-histidine depletion was effective and enlarged the effect of response complexity as measured with the response-locked lateralized readiness potential onset latency. CONCLUSIONS AND IMPLICATIONS: L-histidine depletion affected response- but not stimulus-related processes, in contrast to the effects of H1-receptor antagonists which were previously found to affect primarily stimulus-related processes. L-histidine depletion is promising as a model for histamine-based cognitive impairment. However, these effects need to be confirmed by further studies.

Histamine H1 receptor blockade predominantly impairs sensory processes in human sensorimotor performance.

BACKGROUND AND PURPOSE: Centrally active antihistamines impair cognitive performance, particularly sensorimotor performance. The aim of the present study was to further elucidate the scarcely studied subprocesses involved in sensorimotor performance, which may be affected by H1 receptor blockade. Better knowledge about the cognitive deficits associated with histamine dysfunction can contribute to better treatment of clinical disorders in which histamine hypofunction may be a contributing factor, such as in schizophrenia. EXPERIMENTAL APPROACH: Interactions of dexchlorpheniramine with specific task manipulations in a choice reaction time task were studied. Task demands were increased at the level of sensory subprocesses by decreasing stimulus quality, and at the level of motor subprocesses by increasing response complexity. A total of 18 healthy volunteers (9 female) aged between 18 and 45 years participated in a three-way, double-blind, crossover design. Treatments were single oral doses of 4 mg dexchlorpheniramine, 1 mg lorazepam and placebo. Behavioural effects were assessed by measuring reaction times and effects on brain activity by event-related potentials. KEY RESULTS: Dexchlorpheniramine significantly slowed reaction times, but did not significantly interact with task manipulations. However, it did significantly interact with stimulus quality, as measured by event-related potentials. Lorazepam slowed reaction times and interacted with perceptual manipulations, as shown by effects on reaction times. CONCLUSIONS AND IMPLICATIONS: The results confirm that the histamine system is involved in sensory information processing and show that H1 blockade does not affect motoric information processing. Histamine hypofunction in clinical disorders may cause impaired sensory processing, which may be a drug target.

Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink.

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.

With long intervals, inter-stimulus interval is the critical determinant of the human P300 amplitude.

Previous research, using short inter-stimulus intervals (1-4 s), suggests that the P300 of the human event-related potential during oddball and single-stimulus tasks is mainly affected by target-to-target interval (TTI). The present study tested the validity of this claim at longer intervals in a learning task. Participants were assigned to either an oddball task with an inter-stimulus interval (ISI) of 9-20 s or a single-stimulus task with an ISI of 9-20 or 40-90 s and had to learn when to respond to the stimuli. In the oddball task, the target elicited larger amplitudes than did the standard. When comparing the stimuli from the short- and long-ISI conditions with the target from the oddball condition, it was found that the P300 was more positive at long-ISI stimuli than at short-ISI stimuli or oddball targets, and short-ISI stimuli and oddball targets elicited equally large P300 amplitudes. These results suggest that, in oddball tasks with long intervals, besides cognitive factors, ISI rather than TTI affects the P300 amplitude.

Enhanced re-habituation of the orienting response of the human event-related potential.

Previous studies found the amplitude of the orienting response (OR) of the human event-related potential to decrease with repeated stimulus presentations. This decrease has been suggested to reflect short-term habituation and/or long-term habituation, both of which are learning processes. However, this earlier research failed to provide direct evidence supporting this claim. The present study attempted to show that the OR pattern shares one important feature of habituation: an enhanced response decrement across stimulus-presentation blocks (enhanced re-habituation). Participants received four blocks of 25 auditory stimulus presentations and showed an OR decrement both within (short-term habituation) and across (long-term habituation) blocks. Importantly, the OR decreased more rapidly during later than initial trial blocks, suggesting enhanced re-habituation. The latter result supports the notion that the amplitude decrement reflects an elementary learning process.

Auditory evoked magnetic fields to speech stimuli in newborns--effect of sleep stages.

The aim of the study was to examine whether a newborn can detect changes in a speech stimulus consisting of a fricative followed by a vowel /su/. In addition, we studied possible effect of the two sleep stages (active and quiet sleep) on the evoked magnetic responses. In young children (6 years), the same stimulus evokes a prominent deflection, consisting of two peaks. The first one (P1m) is evoked by the beginning of the fricative consonant and has a latency of about 145 ms. The second peak (P2m) with a latency of 340 ms, is evoked by the switch to the vowel. In newborns (n = 10), the waveform resembled that of the older children but latencies of the corresponding peaks were longer, 190 and 435 ms, correspondingly. The results suggest that already the newborn brain detects the change inside the auditory speech stimulus, namely the fricative sound changing into a vowel. However, the immaturity of the brain is reflected in the prolonged latencies. In addition, the responses were higher in amplitude in quiet sleep than in active sleep (F (1.9) = 36.5; p < 0.0002). This is in line with the enhanced somatosensory magnetic fields to tactile stimulation in quiet compared to active sleep in newborns.