Modafinil alters intrinsic functional connectivity of the right posterior insula: a pharmacological resting state fMRI study

Nicoletta Cera, Armando Tartaro, Stefano L Sensi, Nicoletta Cera, Armando Tartaro, Stefano L Sensi

Abstract

Background: Modafinil is employed for the treatment of narcolepsy and has also been, off-label, used to treat cognitive dysfunction in neuropsychiatric disorders. In a previous study, we have reported that single dose administration of modafinil in healthy young subjects enhances fluid reasoning and affects resting state activity in the Fronto Parietal Control (FPC) and Dorsal Attention (DAN) networks. No changes were found in the Salience Network (SN), a surprising result as the network is involved in the modulation of emotional and fluid reasoning. The insula is crucial hub of the SN and functionally divided in anterior and posterior subregions.

Methodology: Using a seed-based approach, we have now analyzed effects of modafinil on the functional connectivity (FC) of insular subregions.

Principal findings: Analysis of FC with resting state fMRI (rs-FMRI) revealed increased FC between the right posterior insula and the putamen, the superior frontal gyrus and the anterior cingulate cortex in the modafinil-treated group.

Conclusions: Modafinil is considered a putative cognitive enhancer. The rs-fMRI modifications that we have found are consistent with the drug cognitive enhancing properties and indicate subregional targets of action.

Trial registration: ClinicalTrials.gov NCT01684306.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT Diagram.
Figure 1. CONSORT Diagram.
Flow diagram graphically describes the design of the study: enrollment, intervention, follow-up and data analysis.
Figure 2. Insula functional connectivity patterns before…
Figure 2. Insula functional connectivity patterns before drug/placebo treatment.
Image depicts functional connectivity patterns of the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention with a statistical significance set at p

Figure 3. Between-group comparison of the right…

Figure 3. Between-group comparison of the right posterior insula pattern before and after drug/placebo treatment.

Figure 3. Between-group comparison of the right posterior insula pattern before and after drug/placebo treatment.
Image depicts the map obtained after contrast T1 (drug>placebo) >T0 (drug>placebo) for the right posterior insula (PIrh). The map is overimposed on a Talairach atlas and in radiological convention (p

Figure 4. Between-group comparison of the four…

Figure 4. Between-group comparison of the four insula subregions before drug/placebo treatment.

Image depicts maps…

Figure 4. Between-group comparison of the four insula subregions before drug/placebo treatment.
Image depicts maps obtained after contrast T0 (Drug>Placebo) for the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention (pPlacebo). AIlh = anterior insula left hemisphere; AIrh = anterior insula right hemphere; Pilh = posterior insula left hemisphere; PIrh = posterior insula right hemisphere.

Figure 5. Insula functional connectivity patterns after…

Figure 5. Insula functional connectivity patterns after drug/placebo treatment.

Image depicts functional connectivity patterns of…

Figure 5. Insula functional connectivity patterns after drug/placebo treatment.
Image depicts functional connectivity patterns of the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention with a statistical significance of p
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References
    1. Kahbazi M, Ghoreishi A, Rahiminejad F, Mohammadi MR, Kamalipour A, et al. (2009) A randomized double-blind and placebo-controlled trial of modafinil in children and adolescents with attention deficit and hyperactivity disorder. Psychiatry research. 168(3): 234–237. - PubMed
    1. Dawson N, Thompson RJ, McVie A, Thomson DM, Morris BJ, et al. (2012) Modafinil reverses phencyclidine-induced deficits in cognitive flexibility cerebral metabolism and functional brain connectivity. Schizophrenia bulletin 38(3): 457–474. - PMC - PubMed
    1. Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS (2008a) Modafinil shifts human locus coeruleus to low-tonic high-phasic activity during functional MRI. Science 322(5908): 1700–1702. - PubMed
    1. Raggi A, Plazzi G, Pennisi G, Tasca D, Ferri R (2011) Cognitive evoked potentials in narcolepsy: a review of the literature. Neuroscience & Biobehavioral Reviews. 35(5): 1144–1153. - PubMed
    1. Nasr S, Wendt B, Steiner K (2006) Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice. J Affect Disord 95111–114. - PubMed
Show all 66 references
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SLS is supported by funds from the Italian Department of Education [Fondo per gli Investimenti della Ricerca di Base (FIRB) 2003; Programmi di Ricerca di Rilevante Interesse nazionale (PRIN) 2008]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure 3. Between-group comparison of the right…
Figure 3. Between-group comparison of the right posterior insula pattern before and after drug/placebo treatment.
Image depicts the map obtained after contrast T1 (drug>placebo) >T0 (drug>placebo) for the right posterior insula (PIrh). The map is overimposed on a Talairach atlas and in radiological convention (p

Figure 4. Between-group comparison of the four…

Figure 4. Between-group comparison of the four insula subregions before drug/placebo treatment.

Image depicts maps…

Figure 4. Between-group comparison of the four insula subregions before drug/placebo treatment.
Image depicts maps obtained after contrast T0 (Drug>Placebo) for the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention (pPlacebo). AIlh = anterior insula left hemisphere; AIrh = anterior insula right hemphere; Pilh = posterior insula left hemisphere; PIrh = posterior insula right hemisphere.

Figure 5. Insula functional connectivity patterns after…

Figure 5. Insula functional connectivity patterns after drug/placebo treatment.

Image depicts functional connectivity patterns of…

Figure 5. Insula functional connectivity patterns after drug/placebo treatment.
Image depicts functional connectivity patterns of the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention with a statistical significance of p
Similar articles
Cited by
References
    1. Kahbazi M, Ghoreishi A, Rahiminejad F, Mohammadi MR, Kamalipour A, et al. (2009) A randomized double-blind and placebo-controlled trial of modafinil in children and adolescents with attention deficit and hyperactivity disorder. Psychiatry research. 168(3): 234–237. - PubMed
    1. Dawson N, Thompson RJ, McVie A, Thomson DM, Morris BJ, et al. (2012) Modafinil reverses phencyclidine-induced deficits in cognitive flexibility cerebral metabolism and functional brain connectivity. Schizophrenia bulletin 38(3): 457–474. - PMC - PubMed
    1. Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS (2008a) Modafinil shifts human locus coeruleus to low-tonic high-phasic activity during functional MRI. Science 322(5908): 1700–1702. - PubMed
    1. Raggi A, Plazzi G, Pennisi G, Tasca D, Ferri R (2011) Cognitive evoked potentials in narcolepsy: a review of the literature. Neuroscience & Biobehavioral Reviews. 35(5): 1144–1153. - PubMed
    1. Nasr S, Wendt B, Steiner K (2006) Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice. J Affect Disord 95111–114. - PubMed
Show all 66 references
Publication types
MeSH terms
Associated data
Grant support
SLS is supported by funds from the Italian Department of Education [Fondo per gli Investimenti della Ricerca di Base (FIRB) 2003; Programmi di Ricerca di Rilevante Interesse nazionale (PRIN) 2008]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 4. Between-group comparison of the four…
Figure 4. Between-group comparison of the four insula subregions before drug/placebo treatment.
Image depicts maps obtained after contrast T0 (Drug>Placebo) for the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention (pPlacebo). AIlh = anterior insula left hemisphere; AIrh = anterior insula right hemphere; Pilh = posterior insula left hemisphere; PIrh = posterior insula right hemisphere.
Figure 5. Insula functional connectivity patterns after…
Figure 5. Insula functional connectivity patterns after drug/placebo treatment.
Image depicts functional connectivity patterns of the four subregions of bilateral insulae as assessed with rs-fMRI. Maps are overimposed on a Talairach atlas and in radiological convention with a statistical significance of p

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