Spontaneous and deliberate creative cognition during and after psilocybin exposure.

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin.

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one's self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

High reward expectancy during methylphenidate depresses the dopaminergic response to gain and loss.

Dopamine plays an important role in goal-directed behavior, through its modulatory influence on striatal neurons. It is unclear whether tonic dopamine levels, which regulate the vigor of acting, interact with the phasic dopamine response to reward that drives instrumental behavior. In a randomized placebo-controlled study in healthy volunteers, we show that methylphenidate, a drug that increases tonic dopamine levels, systematically reduced striatal phasic BOLD responses to gain and loss in a gambling task as measured with fMRI. It also increased response vigor and reward expectancy-related BOLD signals in the ventral striatum. These findings suggest that striatal tonic dopamine levels constitute an average reward expectation signal that modulates the phasic dopaminergic response to reward. This offers opportunities for treatment of behavioral disorders associated with abnormal reward sensitivity.

Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes.

The dopamine ß-hydroxylase (DßH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic 'reward' circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 µg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.

Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit.

Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.

The BOLD correlates of the visual P1 and N1 in single-trial analysis of simultaneous EEG-fMRI recordings during a spatial detection task.

Simultaneous EEG-fMRI measurements can combine the high spatial resolution of fMRI with the high temporal resolution of EEG. Therefore, we applied this approach to the study of peripheral vision. More specifically, we presented visual field quadrant fragments of checkerboards and a full central checkerboard in a simple detection task. A technique called "integration-by-prediction" was used to integrate EEG and fMRI data. In particular, we used vectors of single-trial ERP amplitude differences between left and right occipital electrodes as regressors in an ERP-informed fMRI analysis. The amplitude differences for the regressors were measured at the latencies of the visual P1 and N1 components. Our results indicated that the traditional event-related fMRI analysis revealed mostly activations in the vicinity of the primary visual cortex and in the ventral visual stream, while both P1 and N1 regressors revealed activation of areas in the temporo-parietal junction. We conclude that simultaneous EEG-fMRI in a spatial detection task can separate visual processing at 100-200 ms from stimulus onset from the rest of the information processing in the brain.

Effect of the static magnetic field of the MR-scanner on ERPs: evaluation of visual, cognitive and motor potentials.

OBJECTIVE: This work investigates the influence of the static magnetic field of the MR-scanner on ERPs extracted from simultaneous EEG-fMRI recordings. The quality of the ERPs after BallistoCardioGraphic (BCG) artifact removal, as well as the reproducibility of the waveforms in different environments is investigated. METHODS: We consider a Detection, a Go-Nogo and a Motor task, eliciting peaks that differ in amplitude, latency and scalp topography, repeated in two situations: outside the scanner room (0T) and inside the MR-scanner but without gradients (3T). The BCG artifact is removed by means of three techniques: the Average Artifact Subtraction (AAS) method, the Optimal Basis Set (OBS) method and the Canonical Correlation Analysis (CCA) approach. RESULTS: The performance of the three methods depends on the amount of averaged trials. Moreover, differences are found on both amplitude and latency of ERP components recorded in two environments (0T vs 3T). CONCLUSIONS: We showed that, while ERPs can be extracted from simultaneous EEG-fMRI data at 3T, the static magnetic field might affect the physiological processes under investigation. SIGNIFICANCE: The reproducibility of the ERPs in different recording environments (0T vs 3T) is a relevant issue that deserves further investigation to clarify the equivalence of cognitive processes in both behavioral and imaging studies.

Assessment of cerebral visual impairment with the L94 visual perceptual battery: clinical value and correlation with MRI findings.

In this article we describe visual perceptual abilities of a clinical population, referred for visual problems to our multidisciplinary team and assessed with the five computer tasks from the L94 visual perceptual battery. Clinical and neuroimaging findings were correlated with the findings on this task battery. Seventy children (35 males, 35 females) constituted our cohort. Age ranged from 4 to 20 years (mean 7y [SD 3y]). Forty children were born before 37 weeks gestational age. Thirty-six children had cerebral palsy (CP), of whom 24 had spastic diplegia, five had spastic hemiplegia, and four had spastic quadriplegia. Three children had ataxic CP. Perceptual visual impairment (PVI) was established in comparison to the performance age obtained on non-verbal intelligence subtests, instead of chronological age. Our results suggest that children with a history of preterm birth and a clinical CP picture are most at risk for a specific PVI. Correlations among other clinical variables did not define a clinical subgroup more at risk. Children with periventricular leucomalacia were almost equally represented in both PVI and non-PVI groups. Normal magnetic resonance imaging did not exclude the presence of PVI. In these children, however, we found another impairment profile, more in favour of dorsal stream impairment.

The variety of visual perceptual impairments in pre-school children with perinatal brain damage.

To study the selectivity of visual perceptual impairment in children with early brain injury, eight visual perceptual tasks (L94), were administered to congenitally disabled children both with and without risk for cerebral visual impairment (CVI). The battery comprised six object-recognition and two visuoconstructive tasks. Seven tasks were newly designed. For these normative data are presented (age 2.75-6.50 years). Because the recognition tasks required object naming, each item included a canonical control drawing and visual perceptual ability was evaluated relative to the non-verbal intelligence level, instead of chronological age. In 22 multiple disabled children with no indications of CVI, the frequency of impairment did not exceed that in the reference sample for any L94 task. In contrast, in 57 5-year-old children who were at risk for CVI due to pre-maturity or birth asphyxia, a significant increase in the frequency of impairment was seen on six L94 tasks (range 12-38%). However, only five children had more than two impairments, indicating that the deficits were selective, not pervasive. We conclude that early brain lesions interfere with the functioning of particular visual subsystems, yet leave other subsystems intact and functioning within the normal range.

Relation between visual perceptual impairment and neonatal ultrasound diagnosis of haemorrhagic-ischaemic brain lesions in 5-year-old children.

Visual-perceptual abilities were assessed in 5-year-old children with the following neonatal neurological conditions: born preterm with normal ultrasound scan (NL, n=17); born preterm with ultrasound diagnosis of intraventricular haemorrhage (IVH, n=17); born preterm with ultrasound diagnosis of periventricular leukomalacia (PVL, n=12); born term with hypoxic-ischaemic encephalopathy (HIE, n=11). Visual-perceptual ability was evaluated with the L94: eight visual-perceptual tasks designed to evaluate different aspects of visual perception at the preschool level in children with multiple disabilities. Impairment was established in comparison to the performance age obtained on non-verbal intelligence subtests, instead of chronological age. Frequency of L94 impairment was highest in children with PVL, while children with IVH did not differ from the NL control group. Impairment rates were increased also in children with transient periventricular echodensities, and in children with HIE. Impairments were only moderately related to the delay of visual acuity maturation in infancy.

Separating visual perception and non-verbal intelligence in children with early brain injury.

The relationship between impairments of visual perception and of non-verbal intelligence was studied in 28 children who, due to the nature of their neurological pathology, were at risk for visual perceptual impairments (high-risk), and 18 mentally disabled children without such risk (low-risk). Their age range was 3-14 years. A child was considered specifically visual-perceptually impaired (VPI) if performance on the De Vos task, a visual object recognition task, was weaker than expected from the baseline performance level obtained on non-verbal intelligence subtests. Accordingly, 22 high-risk children (79%) were classified VPI, against only four low-risk children (22%). Comparing intelligence data of children with and without VPI revealed a WPPSI non-verbal to verbal intelligence impairment in the former. At the subtest level, comparing five verbal and five non-verbal WPPSI subtests, and five subtests from the Snijders-Oomen non-verbal intelligence scale, revealed a difference only on Animal House. The absence of any systematic effects of specific visual perceptual impairment on intelligence subtest performance leads us to conclude that in these children VPI and selective non-verbal intelligence impairment coexist as two separate and irreducible deficits.

Impaired visual perceptual performance on an object recognition task in children with cerebral visual impairment.

Visual perceptual ability and grating acuity were studied in 22 children with cerebral visual impairment (CVI). In most studies indicating visual perceptual impairments in CVI children, the evidence is weakened by the co-presence of reduced nonverbal, relative to verbal, intelligence, which in itself might account for the impaired performance on visual perceptual tasks. Our aim was to show that CVI children's performance on a visual perceptual task is weaker than can be expected from their nonverbal intelligence scores, thus demonstrating an impairment that is specific to visual perception. To this end, we used an object recognition task consisting of 60 line drawings depicting common objects in various aberrant ways. For each drawing, the age was established at which 9 out of 10 normal children could recognise the object depicted. This information was used to select the subset of drawings appropriate for each of the CVI subjects' nonverbal intelligence level, expressed as an age equivalent. Recognition performance on this subset of drawings was impaired in 16 children (72.7%), but was unrelated to visual acuity. We conclude that these children have a specific visual perceptual impairment, which is not reducible to any nonverbal intelligence impairments they might suffer.