Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition

Clinical Brain Disorders Branch: Genes, Cognition, and Psychosis Program, NIMH, NIH, Bethesda, MD 20892, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 09/2010; 35(10):2101-9. DOI: 10.1038/npp.2010.83
Source: PubMed


Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.

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Available from: Fabio Sambataro, Jan 06, 2014
    • "Specifically, verbal memory impairment in MS tends to be primarily a function of poor acquisition of information, rather than retrieval failure (DeLuca et al., 1994; DeLuca, Gaudino, Diamond, be important to new learning and memory functioning (Packard & Goodman, 2012; Squire, 2004), specifically structures in subregions of the hippocampus (Engber et al., 1998). Other studies have shown increased activation in the prefrontal cortex after administration of modafinil in narcolepsy (Saletu et al., 2009), schizophrenia (Hunter, Ganesan, Wilkinson, & Spence, 2006), major depression (DeBattista, Doghramji, Menza, Rosenthal, & Fieve, 2003), attention deficit hyperactive disorder (ADHD; Taylor & Russo, 2000), detoxified alcohol-dependent patients (Saletu et al., 1993), and healthy volunteers (Minzenberg & Carter, 2008; Rasetti et al., 2010). It is thus possible that increased activity in the hippocampus , resulting from treatment with modafinil, will result in improved learning and memory. "
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    ABSTRACT: Purpose/objective: To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. Research Method/Design: Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. Results: No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. Conclusions/implications: Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions. (PsycINFO Database Record
    No preview · Article · Dec 2015 · Rehabilitation Psychology
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    • "Overall, what clearly emerged from these studies was that the more important brain regions (biomarkers) involved in anxiety-like behaviors are: the amygdala, hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) (Blackmon et al. 2011; Baur et al. 2012; Kuhn et al. 2011; Spampinato et al. 2009; Liao et al. 2010; Fuentes et al. 2012; Barros-Loscertales et al. 2006; Cherbuin et al. 2008). As concerns HARS measurements, although this is normally employed in a clinical context (Zhang et al. 2013), some neuroimaging studies employed this scale for assessing anxiety in healthy populations (Rasetti et al. 2010; Schunck et al. 2008), without providing a definite neural correlates of this scale. "
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    Full-text · Article · Jul 2014 · Brain and Behavior
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    • "During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. This study suggested that modafinil in low doses has a unique physiological profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety (Rasetti et al., 2010). The baseline performance sensitivity, and dopamine reuptake transporter affinity, indicates that modafinil could induce similar effects on the brain as psychostimulants like MPH. "
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    ABSTRACT: Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.
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