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•N, N-dimethyltryptamine (DMT), a psychedelic tryptamine acting on 5-HT2A serotonin receptors induces perceptual distortions in visual space.•Inhaled DMT induces strong perceptual effects as shown by the Hallucinogen Rating Scale.•Inhaled DMT leads to increases in visual population receptive field sizes in V1. N, N-dimethyltryptamine (DMT) is a psychedelic tryptamine acting on 5-HT2A serotonin receptors, which is associated with intense visual hallucinatory phenomena and perceptual changes such as distortions in visual space. The neural underpinnings of these effects remain unknown. We hypothesised that changes in population receptive field (pRF) properties in the primary visual cortex (V1) might underlie visual perceptual experience. We tested this hypothesis using magnetic resonance imaging (MRI) in a within-subject design. We used a technique called pRF mapping, which measures neural population visual response properties and retinotopic maps in early visual areas. We show that in the presence of visual effects, as documented by the Hallucinogen Rating Scale (HRS), the mean pRF sizes in V1 significantly increase in the peripheral visual field for active condition (inhaled DMT) compared to the control. Eye and head movement differences were absent across conditions. This evidence for short-term effects of DMT in pRF may explain perceptual distortions induced by psychedelics such as field blurring, tunnel vision (peripheral vision becoming blurred while central vision remains sharp) and the enlargement of nearby visual space, particularly at the visual locations surrounding the fovea. Our findings are also consistent with a mechanistic framework whereby gain control of ongoing and evoked activity in the visual cortex is controlled by activation of 5-HT2A receptors.

•Cannabis is thought to modulate GABAergic interneuronal signaling in the cortex.•GABAergic networks support cortical gamma oscillations and functional connectivity.•MEG based visual entrainment tasks were used to probe gamma circuit integrity.•Gamma oscillations in early visual cortex remain intact with regular cannabis use.•Higher-order gamma functional connectivity was disrupted in those who use cannabis. Cannabis is a widely-used illicit substance in the United States, and heavy cannabis use has been linked to deficits across multiple cognitive domains. Mechanistically, cannabis affects endocannabinoid receptors densely distributed among GABAergic interneurons throughout the cortex and cerebellum. Such interneuronal networks are known to be crucial in the generation of fast neural gamma-band responses, which support perceptual and cognitive processing and have been frequently implicated in cannabis use. However, studies to date have tended to focus on higher-order processing supported by gamma oscillations, with limited work examining more fundamental aspects of gamma circuit integrity. Herein, 84 adults who regularly use cannabis and 90 demographically-matched nonusers underwent high-density magnetoencephalography during a visual entrainment task involving three gamma-band flicker frequencies (32, 40, and 48 Hz). The resulting data were imaged in the time-frequency domain and the dynamic neural time series were extracted and tested for effects of hemisphere, frequency, and group, and then used to compute whole-brain dynamic functional connectivity. Our results indicated strong gamma entrainment in the bilateral primary visual cortices (V1), with 32 Hz responses being the strongest across both groups (p < .001) and right V1 activity being stronger than left across groups and frequencies (p = .002). Additionally, there were group-by-condition interactions in connectivity maps (p < .005), with the cannabis group having elevated 32 Hz connectivity between V1 and higher-order visual regions relative to controls. These findings suggest that basic gamma circuitry remains intact despite heavy cannabis use, while gamma functional connectivity is preferentially affected and this may lead to the higher-order deficits.

Alcohol is a rich drug affecting both the γ-amino butyric acid (GABA) and glutamatergic neurotransmitter systems. Recent findings from both modeling and pharmacological manipulation have indicated a link between GABAergic activity and oscillations measured in the gamma frequency range (30-80 Hz), but there are no previous reports of alcohol's modulation of gamma-band activity measured by magnetoencephalography (MEG) or electroencephalography (EEG). In this single-blind, placebo-controlled crossover study, 16 participants completed two study days, on one day of which they consumed a dose of 0.8 g/kg alcohol, and on the other day a placebo. MEG recordings of brain activity were taken before and after beverage consumption, using visual grating and finger abduction paradigms known to induce gamma-band activity in the visual and motor cortices respectively. Time-frequency analyses of beamformer source reconstructions in the visual cortex showed that alcohol increased peak gamma amplitude and decreased peak frequency. For the motor task, alcohol increased gamma amplitude in the motor cortex. These data support the notion that gamma oscillations are dependent, in part, on the balance between excitation and inhibition. Disruption of this balance by alcohol, by increasing GABAergic inhibition at GABAA receptors and decreasing glutamatergic excitation at N-methyl-D-aspartic acid receptors, alters both the amplitude and frequency of gamma oscillations. The findings provide further insight into the neuropharmacological action of alcohol.

The effects of caffeine are mediated through its non-selective antagonistic effects on adenosine A1 and A2A adenosine receptors resulting in increased neuronal activity but also vasoconstriction in the brain. Caffeine, therefore, can modify BOLD FMRI signal responses through both its neural and its vascular effects depending on receptor distributions in different brain regions. In this study we aim to distinguish neural and vascular influences of a single dose of caffeine in measurements of task-related brain activity using simultaneous EEG–FMRI. We chose to compare low-level visual and motor (paced finger tapping) tasks with a cognitive (auditory oddball) task, with the expectation that caffeine would differentially affect brain responses in relation to these tasks. To avoid the influence of chronic caffeine intake, we examined the effect of 250mg of oral caffeine on 14 non and infrequent caffeine consumers in a double-blind placebo-controlled cross-over study. Our results show that the task-related BOLD signal change in visual and primary motor cortex was significantly reduced by caffeine, while the amplitude and latency of visual evoked potentials over occipital cortex remained unaltered. However, during the auditory oddball task (target versus non-target stimuli) caffeine significantly increased the BOLD signal in frontal cortex. Correspondingly, there was also a significant effect of caffeine in reducing the target evoked response potential (P300) latency in the oddball task and this was associated with a positive potential over frontal cortex. Behavioural data showed that caffeine also improved performance in the oddball task with a significantly reduced number of missed responses. Our results are consistent with earlier studies demonstrating altered flow-metabolism coupling after caffeine administration in the context of our observation of a generalised caffeine-induced reduction in cerebral blood flow demonstrated by arterial spin labelling (19% reduction over grey matter). We were able to identify vascular effects and hence altered neurovascular coupling through the alteration of low-level task FMRI responses in the face of a preserved visual evoked potential. However, our data also suggest a cognitive effect of caffeine through its positive effect on the frontal BOLD signal consistent with the shortening of oddball EEG response latency. The combined use of EEG–FMRI is a promising methodology for investigating alterations in brain function in drug and disease studies where neurovascular coupling may be altered on a regional basis. ► Caffeine reduced task related BOLD responses in visual and motor cortex. ► However, amplitude and latency of visual evoked potentials remained unaltered. ► Performance and frontal BOLD response in an auditory oddball task were enhanced. ► Correspondingly, caffeine reduced the latency of target-evoked potentials. ► EEG–FMRI can separate vascular and neural influences of caffeine in low consumers.

Using functional magnetic resonance imaging, we investigated the mechanism by which cholinergic enhancement improves working memory. We studied the effect of the cholinesterase inhibitor physostigmine on subcomponents of this complex function. Cholinergic enhancement increased the selectivity of neural responses in extrastriate cortices during visual working memory, particularly during encoding. It also increased the participation of ventral extrastriate cortex during memory maintenance and decreased the participation of anterior pre-frontal cortex. These results indicate that cholinergic enhancement improves memory performance by augmenting the selectivity of perceptual processing during encoding, thereby simplifying processing demands during memory maintenance and reducing the need for prefrontal participation.

Numerous studies demonstrate ketamine’s influence on resting-state functional connectivity (rsFC). Seed-based and static rsFC estimation methods may oversimplify FC. These limitations can be addressed with whole-brain, dynamic rsFC estimation methods. We assessed data from 27 healthy subjects who underwent two 3 T resting-state fMRI scans, once under subanesthetic, intravenous esketamine and once under placebo, in a randomized, cross-over manner. We aimed to isolate only highly robust effects of esketamine on dynamic rsFC by using eight complementary methodologies derived from two dynamic rsFC estimation methods, two functionally defined atlases and two statistical measures. All combinations revealed a negative influence of esketamine on dynamic rsFC within the left visual network and inter-hemispherically between visual networks (p < 0.05, corrected), hereby suggesting that esketamine’s influence on dynamic rsFC is highly stable in visual processing networks. Our findings may be reflective of ketamine’s role as a model for psychosis, a disorder associated with alterations to visual processing and impaired inter-hemispheric connectivity. Ketamine is a highly effective antidepressant and studies have shown changes to sensory processing in depression. Dynamic rsFC in sensory processing networks might be a promising target for future investigations of ketamine’s antidepressant properties. Mechanistically, sensitivity of visual networks for esketamine’s effects may result from their high expression of NMDA-receptors.

Among the serious consequences of alcohol abuse is the reduced ability to process visual information. Diminished vision from excessive consumption of alcohol has been implicated in industrial, home, and automobile accidents. Alcohol is also generally recognized as an inhibitor in the brain by potentiating GABA-ergic transmission. In this study, we focused on visual motion processing and explored whether moderate alcohol intoxication induced changes in inhibitory mediated motion repulsion in a center-surround configuration. We conducted a double-blind, placebo-controlled, within-subjects study on the effect of alcohol on visual motion repulsion. Each subject underwent three experimental conditions (no alcohol, placebo and moderate alcohol) on separate days. The order of the placebo and moderate alcohol conditions was counterbalanced. The results showed that the effects of the surround context on the perception of the center motion direction were similar in both the sober (no alcohol) and placebo conditions. However, contextual modulations were significantly stronger during intoxication compared to both the sober and placebo conditions. These results demonstrate that moderate alcohol consumption is associated with altered neural function in visual cortical areas and that motion repulsion deficits might reflect the inhibitory effects of alcohol on the central nervous system.

The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ∼80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations.

Neocortical cholinergic afferents are proposed to influence both selective attention and emotional processing. In a study of healthy adults we used event-related fMRI while orthogonally manipulating attention and emotionality to examine regions showing effects of cholinergic modulation by the anticholinesterase physostigmine. Either face or house pictures appeared at task-relevant locations, with the alternative picture type at irrelevant locations. Faces had either neutral or fearful expressions. Physostigmine increased relative activity within the anterior fusiform gyrus for faces at attended, versus unattended, locations, but decreased relative activity within the posterolateral occipital cortex for houses in attended, versus unattended, locations. A similar pattern of regional differences in the effect of physostigmine on cue-evoked responses was also present in the absence of stimuli. Cholinergic enhancement augmented the relative neuronal response within the middle fusiform gyrus to fearful faces, whether at attended or unattended locations. By contrast, physostigmine influenced responses in the orbitofrontal, intraparietal and cingulate cortices to fearful faces when faces occupied task-irrelevant locations. These findings suggest that acetylcholine may modulate both selective attention and emotional processes through independent, region-specific effects within the extrastriate cortex. Furthermore, cholinergic inputs to the frontoparietal cortex may influence the allocation of attention to emotional information.

The cholinergic neurotransmitter system has been proposed to be involved in the processing of probabilistic top-down information provided by endogenous cues in location-cueing paradigms. It has been shown that the behavioral and neural effects of a nicotinic cholinergic stimulation resemble the effects obtained by manipulating the validity of the spatial cues: enhancing cortical nicotine levels and decreasing cue validity both reduce the reaction time difference between invalidly and validly cued targets (ie, the ‘validity effect’) as well as neural activity related to attentional reorienting in parietal brain regions. In the present study, we investigated whether the behavioral and neural effects of nicotine in location-cueing paradigms are dependent upon different a priori cue validities. Twenty-four subjects were investigated in a double-blind placebo-controlled between-subject design with functional magnetic resonance imaging. Nicotine was administered to non-smoking volunteers via polacrilex gums (Nicorette ® , 2 mg) before performing a location-cueing paradigm with valid and invalid cues in the context of 90 and 60% cue validity in the MR scanner. Nicotine significantly reduced the validity effect in the 90% but not in the 60% cue validity condition. Fronto-parietal and cingulate regions showed stronger nicotinic reductions of reorienting-related neural activity in the high than in the low cue validity condition. Our data reveal an interaction effect between the pharmacological and cognitive modulation of attentional reorienting, which is evident at both a behavioral as well as the neuronal level.