Neocortical Activity Is Boosted by Modafinil During Cognitive Tasks

The neocortex contains brain areas specialized for higher perceptual and cognitive processing, including associative learning. The ACC and the dopamine-rich striatal region to which it projects are major neural circuitry involved in these abilities.

In a randomized, double-blind, placebo-controlled, within-subjects crossover study, modafinil improved behavioral and neural performance on an associative learning task in MA-dependent participants. This effect was accompanied by increased activation in the bilateral insula/ventrolateral prefrontal cortex.

Anterior Cingulate Cortex

The anterior cingulate cortex (ACC) is a part of the forebrain that forms a collar around the corpus callosum and relays neural signals between the right and left hemispheres. It is divided into two distinct subregions, the dorsal and ventral anterior cingulate cortex, that play essential roles in numerous activities including cognitive control functions such as attention allocation, error and novelty detection, working memory modulation, and response conflict resolution; emotion regulation involving anxiety, fear, aggression, anger, empathy, and sadness; perceiving physical pain, and regulating autonomic functions like heart rate and blood pressure.

Neuroimaging studies indicate that the dorsal ACC subregion is primarily associated with rational cognition, while the ventral ACC subregion is related to emotional information processing and cognition. During a task requiring the comparison of an unfamiliar to familiar stimulus, the dorsal ACC showed stronger activation for the familiar stimulus and weaker activity for the unfamiliar. This is consistent with the idea that the dorsal ACC is responsible for bottom-up information processing and interpreting stimuli.

However, when researchers compared the accuracy and reaction time (RT) of participants during placebo and modafinil sessions, they found no significant difference in performance between the two conditions. This indicates that the underlying mechanism of Modafinil Malaysia improvement in cognitive function is not related to changes in the dorsal ACC.

Instead, the fMRI results indicated that modafinil increases activity in the right superior frontal gyrus (IFG), which is connected to both the dorsolateral prefrontal cortex (dmPFC) and the dorsal anterior cingulate cortex (ACC). It is also linked to the amygdala, which is involved in emotional reactivity.

When the amygdala is triggered by a particular stimulus, it receives a signal from the ACC that helps control the emotional response, allowing the brain to respond in an appropriate way. The modafinil-induced decrease in amygdala reactivity may be due to the drug’s influence on the ACC to suppress negative feedback from the amygdala and reduce its reactivity. This is in line with other neuroimaging studies showing that the dopamine-releasing drugs amphetamine and cocaine decrease activity in the ACC. The ACC is also linked to the hypothalamus, which governs the body’s reward and punishment systems.

Locus Coeruleus

The locus coeruleus-norepinephrine (LC-NE) system is a brainstem neuromodulatory system that regulates arousal, vigilance, mood, and cognitive states. It projects extensively throughout the central nervous system, including ascending visceral pathways to the spinal cord, basal forebrain, and prefrontal cortex (FPC), as well as descending pathways to the amygdala, hypothalamus, cerebellum, and sensory cortices.

The LC-NE system is activated by salient, unexpected stimuli and may also be stimulated by conditioned responses to awaited behaviorally significant events. These stimuli can be either spontaneous, as in the case of orienting responses, or elicited via the conditioned reflex as in the case of cortical threat-conditioned response (CCR). In the latter instance, LC phasic activity enables adaptive adjustments to forebrain networks that mediate cognition on a trial-by-trial basis.

In humans, fMRI has shown that LC-NE activity is related to performance on tasks that require cognitive control. Specifically, a higher LC-NE volume is associated with better attentional performance and a biological index of brain maintenance known as “BrainPAD.” The pharmacological modulator modafinil increases low-tonic and high-phasic LC-NE activity, thereby increasing LC-neocortex functional connectivity.

While it has been hypothesized that the LC-NE system facilitates the prefrontal cortex during cognitive processes such as attention, there is no direct evidence of this to date. However, it is conceivable that protracted activation of this system during normal aging would promote cognitive stimulation and contribute to the development of Cognitive Reserve.

To test this hypothesis, a large sample of healthy adults were administered modafinil during a task-based fMRI study and LC-neocortex fMRI measurements were recorded. Bayesian modeling revealed that LC-neocortex volume was positively associated with attentional performance and with BrainPAD, suggesting that the Noradrenergic Theory of Cognitive Reserve is valid.

As a control, analyses were also performed on other core neuromodulators, such as the serotoninergic dorsal raphe nucleus and midbrain dopaminergic nuclei (ventral tegmental area, VTA, and substantia nigra pars compacta, SNc). However, these analyses did not reveal a relationship between LC-neocortex connectivity and task performance or BrainPAD, and are therefore unlikely to influence the Noradrenergic Theory of Cognitive reserve. Moreover, because serotonin is synthesised in the pons very closely to NE but modulates markedly different processes, it can be used as a control region.

Anterior Insular Cortex

In addition to its role in enhancing cognition, Modaheal 200 can also boost neural activity in the anterior insular cortex (AIC). This region is thought to represent interoceptive sensory information. Specifically, AIC is believed to process ascending visceromotor and somatosensory inputs with attention systems to identify salient stimuli.

This activity is thought to facilitate adaptive behavior by allowing individuals to perceive the effects of their actions on their own body. AIC has also been linked to arousal and emotion processing, as well as arousal-dependent learning. For example, AIC activity is increased during emotional facial expressions, and patients with insular lesions display a deficit in processing these stimuli.

The AIC is involved in both conscious and unconscious emotion processing. This is a consequence of the fact that it receives cholinergic input from the locus coeruleus and sends projections to both the periaqueductal gray and the precentral gyrus. In chronic pain, alterations of this cholinergic input might dysregulate the interaction between these two brain regions and contribute to aversive learning in neuropathic pain conditions [108].

A recent study found that modafinil boosts AIC activity during fearful face processing. This is likely due to the effect of modafinil on the neurotransmitter system that regulates serotonin, gamma aminobutyric acid, and hypocretin/orexin. It is also mediated by dopamine. Modafinil enhances dopamine release through the inhibition of the dopamine transporter, which increases extracellular levels of this neurotransmitter in the AIC and in the LC (Volkow et al., 2009).

In the current study, participants underwent a series of behavioral experiments that required them to spit out an oral stimulus. fMRI data showed that modafinil boosted activity in both IPS and VS during the experiment, with stronger connectivity between these regions under expected than unexpected trials. This pattern of connectivity is consistent with the notion that the AIC represents interoceptive sensory information and plays a crucial role in adaptive responses to unpredictable environmental stimuli.

However, AIC activity was also boosted under placebo trials, suggesting that the AIC responds to other factors, such as expectation or mood states, in addition to modulating IPS and VS activation. Future research will be necessary to identify additional mechanisms underlying AIC function and its contribution to cognitive processes.

Ventrolateral Prefrontal Cortex

The lateral prefrontal cortex (VLPFC) is involved in many cognitive processes, including decision making, planning, and monitoring. It is also involved in the encoding of mappings between knowledge stored in posterior brain areas and decisions made in frontal areas. Neurons in VLPFC respond to visual stimuli that are related to the task at hand, such as faces. These face-responsive neurons are clustered in three distinct regions: the lateral arcuate sulcus in area 45; close to this is the inferior prefrontal dimple in area 12/47; and finally the lateral orbital prefrontal cortex in area 12.

VLPFC is implicated in emotional processing as well, including the ability to discriminate between a happy or sad expression, and it is one of several brain regions that appear to be involved in emotion regulation. A series of studies examining the role of the ventromedial prefrontal cortex in emotion regulation have shown that it may regulate emotions in part by influencing (controlling) activity patterns in other brain regions.

Modafinil increases VLPFC activity during a variety of cognitive tasks. For example, in a study of medication-free narcolepsy patients, modafinil administration was associated with improved performance on the Pauli test for simple arithmetic and increased VLPFC activity by EEG (Blanquie et al, 2010). In addition, a double-blind placebo-controlled trial of healthy participants undergoing simulated night shift work found that a four-day course of modafinil significantly reduced errors on WCST and Hayling sentence completion tasks, a measure of cognitive control that is associated with activation in dorsolateral PFC and anterior cingulate cortex (Nathaniel-James and Frith, 2004).

Modafinil also increases electrically evoked (5HT) but not spontaneous (5HT) efflux from cortical synaptosomes in a concentration-dependent manner (Ferraro et al, 2000). This demonstrates that the vigilance-enhancing properties of modafinil are related to an increase in cellular GABA release. The NE antagonist DSP-4 and the DA autoreceptor agonist quinpirole block the effects of modafinil in lateral PFC, suggesting that this effect is mediated by ascending DA systems. This enhanced lateral PFC-neocortex connectivity, or resonance, may help explain how the procognitive effects of modafinil are mediated.