The why behind the high: determinants of neurocognition during acute cannabis exposure.

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

Attenuated responses to attention-modulating drugs in the neuroligin-3R451C mouse model of autism.

Attention deficits are frequently reported within the clinical autism population. Despite not being a core diagnostic feature, some aetiological theories place atypical attention at the centre of autism development. Drugs used to treat attention dysfunction are therefore increasingly prescribed to autistic patients, though currently off-label with uncertain efficacy. We utilised a rodent-translated touchscreen test of sustained attention in mice carrying an autism-associated R451C mutation in the neuroligin-3 gene (Nlgn3R451C). In doing so, we replicated their cautious but accurate response profile and probed it using two widely prescribed attention-modulating drugs: methylphenidate (MPH) and atomoxetine (ATO). In wild-type mice, acute administration of MPH (3 mg/kg) promoted impulsive responding at the expense of accuracy, while ATO (3 mg/kg) broadly reduced impulsive responding. These drug effects were absent in Nlgn3R451C mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3R451C mice likely arises from their altered behavioural baseline and underlying neurobiology, highlighting caveats to the use of classic attention-modulating drugs across disorders and autism subsets. It further suggests that altered dopaminergic and/or norepinephrinergic systems may drive behavioural differences in the Nlgn3R451C mouse model of autism, supporting further targeted investigation.

Dopaminergic lesions of the anterior cingulate cortex of rats increase vulnerability to salient distractors.

The anterior cingulate cortex (ACC) has been shown to be critical to many aspects of executive function including filtering irrelevant information, updating response contingencies when reinforcement contingencies change and stabilizing task sets. Nonspecific lesions to this region in rats produce a vulnerability to distractors that have gained salience through prior associations with reinforcement. These lesions also exacerbate cognitive fatigue in tests of sustained attention but do not produce global attentional impairments nor do they produce distractibility to novel distractors that do not have a prior association with reinforcement. To determine the neurochemical basis of these cognitive impairments, dopaminergically selective lesions of the ACC were made in both male and female Long-Evans, hooded rats prior to assessment in two attentional tasks. Dopaminergic lesions of the ACC increase the vulnerability of subjects to previously reinforced distractors and impede formation of an attentional set. Lesioned rats were not more susceptible to the effects of novel, irrelevant stimuli in a test of sustained attention as has been previously shown. Additionally, the effects of dopaminergic lesions were found to differ based on sex. Lesioned female, but not male, rats were more vulnerable than sham-lesioned females to the effects of prolonged testing and the removal of reinforcement during a test of sustained attention. Together, these data support the hypothesis that dopamine in the ACC is critical to filtering distractors whose salience has been gained through reinforcement.

Cholinergic modulation of motor sequence learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal-occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Subanesthetic Ketamine Suppresses Locus Coeruleus-Mediated Alertness Effects: A 7T fMRI Study.

BACKGROUND: The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. METHODS: We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. RESULTS: We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. CONCLUSION: The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.

Naturalistic use of psychedelics does not modulate processing of self-related stimuli (but it might modulate attentional mechanisms): An event-related potentials study.

Classic psychedelics are able to profoundly alter the state of consciousness and lead to acute experiences of ego dissolution - the blurring of the distinction between representations of self and the external world. However, whether repeated use of psychedelics is associated with more prolonged and permanent modifications to the concept of self remains to be investigated. Therefore, we conducted a preregistered, cross-sectional study in which experienced psychedelics users (15 or more lifetime experiences with psychedelics; N = 56) were compared to nonusers (N = 57) in terms of neural reactivity to a Self-name (i.e., each participant's own name) stimulus, which is known to robustly activate a representation of self. Two control stimuli were additionally used: an Other-name stimulus, as a passive control condition in which no reaction was required, and a Target-name stimulus, to which participants provided a manual response and which thus constituted an active control condition. Analysis of the amplitude of the P300 ERP component evoked by the Self- or Target-names revealed no difference between the psychedelics users and nonusers. However, psychedelic users exhibited increased P300 amplitude during perception of Other-names. In addition, in comparison to nonusers, psychedelics users exhibited a smaller increase in P300 amplitude when processing the task-relevant Target-names (in relation to both Self- and Other-names). Therefore, our data suggests that regular naturalistic use of psychedelics may not be related to long-term changes in the representation of self, but it might potentially affect the allocation of attentional resources to task-relevant stimuli.

Over-the-counter analgesic usage: associations with attentional biases in young women.

The use of over-the-counter analgesics (OTCA) has been found to alter various aspects of emotional processing and has been linked to increased anxiety and depression symptoms. Attentional bias is an aspect of emotional processing that is closely related to anxiety and depression. Although OTCA and attentional bias have both been linked to anxiety and depression, the potential links between OTCA usage and attentional bias are not yet investigated. The present study aimed to determine whether the frequency of OTCA usage is associated with differences in attentional bias by comparing response-based measures of attentional bias in 62 women aged 19-30 years. The findings showed that the small group reporting high OTCA usage demonstrated more orientation avoidance to fearful stimuli than those reporting no or low usage. Based on these preliminary findings, further research on attentional bias and its relationship to high OTCA usage is recommended.

Attention and executive functioning in children and adolescents treated for high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group (COG).

OBJECTIVES: Survivors of childhood B-acute lymphoblastic leukemia (B-ALL) are at risk for difficulties with attention and executive functioning (EF) as a late effect of treatment. The present study aimed to identify treatment and demographic factors associated with risk for difficulties with EF in youth treated for high-risk B-ALL. METHOD: Children and adolescents with B-ALL treated on Children's Oncology Group (COG) protocol AALL0232 were randomized to high-dose or escalating-dose methotrexate (MTX), and either dexamethasone or prednisone during the induction phase. Neuropsychological functioning was evaluated via protocol AALL06N1, including performance-based and parent-report measures, for 177 participants (57% female, 81% white; mean age at diagnosis = 8.4 years; SD = 5.0) 8-24 months following treatment completion. RESULTS: Mean scores for all attention and EF measures were within the average range, with no significant differences as a function of MTX delivery or steroid treatment (all p > 0.05). In multivariable models, participants with US public insurance exhibited significantly greater parent-reported EF difficulties than those with US private or non-US insurance (p ≤ 0.05). Additionally, participants diagnosed under 10 years of age performed significantly more poorly on measures of attention (i.e., continuous performance task, p ≤ 0.05) and EF (i.e., verbal fluency and tower planning task, p ≤ 0.05). CONCLUSIONS: For survivors of pediatric B-ALL, treatment-related factors were not associated with attention or EF outcomes. In contrast, outcomes varied by demographic characteristics, including age and insurance type, an indicator of economic hardship. Future research is needed to more directly assess the contribution of socioeconomic status on cognitive outcomes in survivors.

Protective effect of melatonin against methamphetamine-induced attention deficits through miR-181/SIRT1 axis in the prefrontal cortex.

INTRODUCTION: Methamphetamine (METH) is an addictive psychostimulant with deleterious effects on the central nervous system. Chronic use of METH in high doses impairs cognition, attention and executive functions, but the underlying mechanisms are still unclear. Sirtuin 1 (SIRT1) is a post-translational regulator that is downregulated following METH neurotoxicity. Melatonin is a neuroprotective hormone that enhances mitochondrial metabolism. Here, we evaluated the effect of melatonin on METH-induced attention deficits disorder and the involvement of the miR-181/SIRT1 axis in melatonin neuroprotection. METHODS AND RESULTS: METH at a dose of 5 mg/kg was injected for 21 consecutive days. The animals were assigned to receive either melatonin or the vehicle after METH injections. Attention levels were evaluated with abject-based attention test. In the prefrontal cortex, the expression levels of miR-181a-5p, SIRT1, p53 and CCAR2, as well as the mtDNA copy numbers were evaluated using qRT-PCR and western blotting. The outcomes revealed that melatonin treatment following METH injections improved METH-induced attention deficits. METH toxicity can be associated with changes in the miR-181/SIRT1 axis, elevated levels of p53 and COXII, and decreased levels of mtDNA in the prefrontal cortex of adult rats. Interestingly, administration of melatonin can improve the expression of these molecules and reduces the toxic effects of METH. CONCLUSION: Melatonin ameliorated the neurotoxicity of METH in the prefrontal cortex and the miR-181/SIRT1 axis is involve in the protective effects of melatonin. However, melatonin can be potentially administrated to improve attention impairment in METH use disorders.

Effects of different doses of caffeine on cognitive performance in healthy physically active individuals.

PURPOSE: Caffeine is a potent central nervous system stimulant that increases the activity of the prefrontal cortex and can improve various cognitive skills. An improvement in these cognitive skills can lead to further benefits in athletic performance. Therefore, it is necessary to clarify the dose-response of caffeine on cognitive performance. This study aimed to determine the effects of different doses of caffeine on sport-related cognitive aspects. METHODS: Twenty-nine healthy physically active young adults were recruited. All participants completed three trials under the following conditions: (a) placebo, (b) 3 mg/kg, or (c) 6 mg/kg body mass of caffeine. In each trial, different cognitive abilities were evaluated with the following battery of tests: reaction time (Dynavision™ D2), anticipation (Bassin Anticipation Timer), sustained attention (Go/No-Go and Eriksen Flanker Test) and memory tests. Moreover, the side effects and the perceived sensation index were recorded 24 h after each test. RESULTS: Reaction time only improved following 6 mg/kg of caffeine intake (Physical reaction time: -0.04 s, 95% CI -0.08 to -0.01 s, P = 0.036, d = 0.5; Motor reaction time: -0.04 s, 95% CI -0.07 to -0.01 s, P = 0.008, d = 0.6) compared to the placebo condition. Anticipation, sustained attention, and memory were not affected after either caffeine dose intake (all P > 0.05). In addition, the 6 mg/kg dose of caffeine augmented the occurrence of the side effects of increased activeness (P = 0.046) and nervousness (P = 0.001). CONCLUSION: Acute intake of 6 mg/kg caffeine is effective in improving reaction time despite increasing the occurrence of side effects in healthy physically active young adults. STUDY REGISTRATION: This study has been registered in ClinicalTrials whose ID is: NCT05995314 (2023-08-08).

Effects of general anaesthesia in early childhood on local and global visual processing: a post hoc analysis of the APEX cohort study.

BACKGROUND: Preclinical studies suggest that early exposure to anaesthesia alters the visual system in mice and non-human primates. We investigated whether exposure to general anaesthesia leads to visual attention processing changes in children, which could potentially impact essential life skills, including learning. METHODS: This was a post hoc analysis of data from the APprentissages EXécutifs et cerveau chez les enfants d'âge scolaire (APEX) cohort study. A total of 24 healthy 9-10-yr-old children who were or were not exposed to general anaesthesia (for surgery) by a mean age of 3.8 (2.6) yr performed a visual attention task to evaluate ability to process either local details or general global visual information. Whether children were distracted by visual interference during global and local information processing was also assessed. RESULTS: Participants included in the analyses (n=12 participants exposed to general anaesthesia and n=12 controls) successfully completed (>90% of correct answers) the trial tasks. Children from both groups were equally distracted by visual interference. However, children who had been exposed to general anaesthesia were more attracted to global visual information than were control children (P=0.03). CONCLUSIONS: These findings suggest lasting effects of early-life exposure to general anaesthesia on visuospatial abilities. Further investigations of the mechanisms by which general anaesthesia could have delayed effects on how children perceive their visual environment are needed.

Examining the effects of caffeine during an auditory attention task.

Participants completed two sessions of an auditory attention task and intermittently responded to thought probes asking about their level of mind-wandering. After the first session one group received 200 mg of caffeinated chewing gum (n = 61) and another group received regular (placebo) chewing gum (n = 66). The gum was chewed for 20-minutes and then disposed of before beginning the second session. Participants who received caffeine showed a performance benefit as well as reported being more on task and fewer instances of spontaneous mind-wandering compared to those in the placebo group. Participants who received caffeine also reported greater positive affect and arousal, as well as less feelings of boredom, sleepiness, and mental effort required to stay on task compared to those who received placebo. These results suggest that caffeine may benefit attentional engagement as well as performance during a sustained attention task.

Effects of the active botanical blend "WKUP GT" on attention and cognitive functions after lunch in healthy volunteers.

OBJECTIVES: "WKUP GT", a low caffeine beverage consisting of carob, Guarana, Green Tea and Elderberry extracts was studied on attention and cognitive functions post-lunch in a pilot randomized double blind placebo controlled trial. METHODS: Thirty healthy volunteers were included in a crossover design trial, presenting five beverages randomly assigned to the following groups: placebo, "WKUP GT" (single, double or triple doses), or "caffeine" as an active control. Hemodynamic measurements were assessed as safety outcomes. The Cambridge Neuropsychological Test Automated Battery (CANTAB), was used to evaluate the patients when beverages were consumed 30 and 120 min after lunch (respectively Delta30 and Delta120 considering baseline). RESULTS: Drinking "caffeine" or "WKUP GT" after lunch, showed significant improvement (p < 0.05) in rapid visual information processing compared to placebo (Delta120 of "caffeine", "WKUP" single and double). In addition, improvement in Multitasking Test (Delta30 for "WKUP" double, and Delta120 for "caffeine" and "WKUP" triple compared to placebo) was observed. "WKUP" triple also showed significant improvement for "memory" when compared to placebo (Delta120). Compared to "caffeine", WKUP GT did not increase systolic blood pressure. CONCLUSION: "WKUP GT" showed improvements for attention, memory, psychomotor and executive function tasks after lunch without increase in pulse rate.

Neuroprotective effect of hormone replacement therapy: a review of the literature.

OBJECTIVE: Menopause is a physiological period characterized by the cessation of ovarian activity. Sequential changes during this transition affect multiple systems, including the brain. Sixty percent of women experience cognitive impairment. The objective of this review is to show the neuroprotective effect of hormone replacement therapy (HRT) through the different scales and whether there is a benefit of this in women. METHOD: A search was conducted in six databases. Eligibility criteria included women within 10 years of menopause, receiving HRT controlled with placebo, studies lasting more than 6 months and women without a history of chronic underlying pathology. RESULTS: A total of nine randomized controlled trials met the inclusion criteria. Regarding memory, two studies reported better performance of HRT with a significant odds ratio (OR) of 0.67; regarding attention, one study reported potential improvement in women receiving HRT with a significant OR of 0.87; and neuroimaging assessment found an increase in ventricular volume compared to placebo over a 3-year period. CONCLUSIONS: The early initiation of menopausal HRT in healthy women appears to yield a positive effect on certain cognitive aspects, such as attention and cortical volume in the central nervous system. These findings should be confirmed through future prospective studies.

GABAergic Involvement in Selective Attention.

Animals need to cope with abundant sensory information, and one strategy is to selectively direct attention to only the most relevant part of the environment. Although the cortical networks of selective attention have been studied extensively, its underlying neurotransmitter systems, especially the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), remain less well understood. Increased GABAA receptor activity because of administration of benzodiazepines such as lorazepam is known to slow reactions in cognitive tasks. However, there is limited knowledge about GABAergic involvement in selective attention. Particularly, it is unknown whether increased GABAA receptor activity slows the build-up of selectivity or generally widens attentional focus. To address this question, participants (n = 29) received 1 mg lorazepam and placebo (within-subjects, double-blind) and performed an extended version of the flanker task. The spatial distribution of selective attention was studied by systematically manipulating number and position of incongruent flankers; the temporal build-up was characterized using delta plots. An online task version was presented to an independent, unmedicated sample (n = 25) to verify task effects. Under placebo and in the unmedicated sample, only the number of incongruent flankers, but not their position, influenced RTs. Incongruent flankers impaired RTs more strongly under lorazepam than placebo, especially when adjacent to the target. Delta plot analyses of RT showed that this effect persisted even when participants reacted slowly, indicating that lorazepam-induced impairments in selective attention do not result from simply slowed down build-up of selectivity. Instead, our data indicate that increased GABAA receptor activity widens the attentional focus.

Prenatal choline supplementation improves child sustained attention: A 7-year follow-up of a randomized controlled feeding trial.

Numerous rodent studies demonstrate developmental programming of offspring cognition by maternal choline intake, with prenatal choline deprivation causing lasting adverse effects and supplemental choline producing lasting benefits. Few human studies have evaluated the effect of maternal choline supplementation on offspring cognition, with none following children to school age. Here, we report results from a controlled feeding study in which pregnant women were randomized to consume 480 mg choline/d (approximately the Adequate Intake [AI]) or 930 mg choline/d during the 3rd trimester. Sustained attention was assessed in the offspring at age 7 years (n = 20) using a signal detection task that showed benefits of maternal choline supplementation in a murine model. Children in the 930 mg/d group showed superior performance (vs. 480 mg/d group) on the primary endpoint (SAT score, p = .02) and a superior ability to maintain correct signal detections (hits) across the 12-min session (p = .02), indicative of improved sustained attention. This group difference in vigilance decrement varied by signal duration (p = .04). For the briefest (17 ms) signals, the 480 mg/d group showed a 22.9% decline in hits across the session compared to a 1.5% increase in hits for the 930 mg/d group (p = .04). The groups did not differ in vigilance decrement for 29 or 50 ms signals. This pattern suggests an enhanced ability to sustain perceptual amplification of a brief low-contrast visual signal by children in the 930 mg/d group. This inference of improved sustained attention by the 930 mg/d group is strengthened by the absence of group differences for false alarms, omissions, and off-task behaviors. This pattern of results indicates that maternal 3rd trimester consumption of the choline AI for pregnancy (vs. double the AI) produces offspring with a poorer ability to sustain attention-reinforcing concerns that, on average, choline consumption by pregnant women is approximately 70% of the AI.

Anterior Cingulate Cortex Ablation Disrupts Affective Vigor and Vigilance.

Despite many observations of anterior cingulate cortex (ACC) activity related to cognition and affect in humans and nonhuman animals, little is known about the causal role of the ACC in psychological processes. Here, we investigate the causal role of the ACC in affective responding to threat in rhesus monkeys (Macaca mulatta), a species with an ACC largely homologous to humans in structure and connectivity. Male adult monkeys received bilateral ibotenate axon-sparing lesions to the ACC (sulcus and gyrus of areas 24, 32, and 25) and were tested in two classic tasks of monkey threat processing: the human intruder and object responsiveness tasks. Monkeys with ACC lesions did not significantly differ from controls in their overall mean reactivity toward threatening or novel stimuli. However, while control monkeys maintained their reactivity across test days, monkeys with ACC lesions reduced their reactivity toward stimuli as days advanced. Critically, this attenuated reactivity was found even when the stimuli presented each day were novel, suggesting that ACC lesions did not simply cause accelerated adaptation to stimuli as they became less novel over repeated presentations. Rather, these results imply that the primate ACC is necessary for maintaining appropriate affective responses toward potentially harmful and/or novel stimuli. These findings therefore have implications for mood disorders in which responding to threat and novelty is disrupted.SIGNIFICANCE STATEMENT Decades of research in humans and nonhuman animals have investigated the role of the anterior cingulate cortex in a huge number and variety of psychological processes spanning cognition and affect, as well as in psychological and neurologic diseases. The structure is broadly implicated in psychological processes and mental and neurologic health, yet its causal role in these processes has largely gone untested, particularly in primates. Here we demonstrate that when anterior cingulate cortex is completely eliminated, rhesus monkeys are initially responsive to threats, but these responses attenuate rather than persist, resembling a pattern of behavior commonly seen in patients diagnosed with mood disorders.

Oxytocin Modulates the Intrinsic Dynamics Between Attention-Related Large-Scale Networks.

Attention and salience processing have been linked to the intrinsic between- and within-network dynamics of large-scale networks engaged in internal (default network [DN]) and external attention allocation (dorsal attention network [DAN] and salience network [SN]). The central oxytocin (OXT) system appears ideally organized to modulate widely distributed neural systems and to regulate the switch between internal attention and salient stimuli in the environment. The current randomized placebo (PLC)-controlled between-subject pharmacological resting-state fMRI study in N = 187 (OXT, n = 94; PLC, n = 93; single-dose intranasal administration) healthy male and female participants employed an independent component analysis approach to determine the modulatory effects of OXT on the within- and between-network dynamics of the DAN-SN-DN triple network system. OXT increased the functional integration between subsystems within SN and DN and increased functional segregation of the DN with both attentional control networks (SN and DAN). Whereas no sex differences were observed, OXT effects on the DN-SN interaction were modulated by autistic traits. Together, the findings suggest that OXT may facilitate efficient attention allocation by modulating the intrinsic functional dynamics between DN components and large-scale networks involved in external attentional demands (SN and DAN).

Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field.

Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.