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Keywords:

  • modafinil;
  • rCBF;
  • SPECT;
  • statistical parametric mapping;
  • wakefulness

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

To investigate the effects of a wake-promoting drug, modafinil on regional cerebral blood flow (rCBF) in healthy volunteers, we performed 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo administration. Twenty-one healthy subjects received single doses of 400 mg modafinil or placebo in a double blind randomized crossover study design. Administrations of modafinil or placebo in a subject were separated by a 2-week washout. Brain SPECT was performed twice before and 3 h after modafinil or placebo administration. For statistical parametric mapping analysis, all SPECT images were spatially normalized to the standard SPECT template and then smoothed using a 12-mm full width at half-maximum Gaussian kernel. The paired t-test was used to compare pre- versus post-modafinil and pre- versus post-placebo SPECT images. Differences in rCBF between post-modafinil and post-placebo conditions were also tested. Modafinil decreased Epworth and Stanford sleepiness scales whereas placebo did not. The post-modafinil condition was associated with increased rCBF in bilateral thalami and dorsal pons, whereas the post-placebo condition showed increased rCBF in a smaller area of the dorsal pons when compared with the drug naïve baseline condition. Compared with the post-placebo condition, the post-modafinil condition showed higher rCBF in bilateral frontopolar, orbitofrontal, superior frontal, middle frontal gyri, short insular gyri, left cingulate gyrus, left middle/inferior temporal gyri, left parahippocampal gyrus, and left pons. In healthy volunteers, modafinil increased wakefulness and rCBF in the arousal-related systems and in brain areas related to emotion and executive function.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

Modafinil, 2-[(diphenylmethyl)-sulfinyl acetamide], is a novel wake-promoting agent that is used to treat excessive daytime sleepiness associated with sleep disorders. Previous placebo-controlled trials have concluded that modafinil reduces objective excessive daytime sleepiness in narcoleptic patients (US Modafinil in Narcolepsy Multicenter Study Group., 1998, 2000), and in sleep-deprived normal subjects (Lagarde et al., 1995). Moreover, modafinil is becoming increasingly popular because of its safety profile, and studies in healthy volunteers (Wong et al., 1999) and narcoleptics (US Modafinil in Narcolepsy Multicenter Study Group., 1998, 2000) have demonstrated only low levels of adverse effects for modafinil. The side effect most often encountered appears to be headache, which occurs when modafinil doses are high or are increased too rapidly, the other reported side effects are insomnia or nervousness, which are usually transient and dose-dependent (Boivin et al., 1993). The mechanism underlying the effect of modafinil is the subject of much debate. Not only is its molecular target uncertain, but there is also much debate regarding its neuroanatomic site of action. Low to moderate doses of modafinil increase c-Fos activation in specific brain areas, e.g. histaminergic cells in the tuberomammillary nucleus (TMN), hypocretin-containing cells in the perifornical area of the posterior lateral hypothalamus (Lin et al., 1996), and in a portion of the central nucleus of the amygdale (Scammell et al., 2000). Modafinil treatment attenuated activity in the sleep-promoting ventrolateral preoptic area, most likely secondary to increased inhibitory input from TMN cells (Chemelli et al., 1999; Scammell et al., 2000), and at higher doses, the striatum and cingulate cortex were also activated (Scammell et al., 2000). Hypocretin cell activation may play an important role in wake state control, but modafinil-induced wakefulness in narcoleptic humans and animals deficient in hypocretin suggests that hypocretin cell activation is not essential for the wake-promoting effects of modafinil. Activation of cell groups such as histaminergic cells in the TMN, hypocretin-containing cells in hypothalamus, and certain cells in the amygdala, occurs secondary to the expression of increased wakefulness, because c-Fos expression in these cell groups increases in naturally occurring wakefulness.

Recent functional MRI study revealed that modafinil resulted in extensive recruitment of subcortical-thalamic and cortical (executive network) areas during working memory task after a single night of sleep deprivation and that single 200-mg dose of modafinil reversed subjective estimates of sleepiness and objective performance measures only at intermediate levels of task difficulty (Thomas and Kwong, 2006).

The aim of the present study was to investigate regional cerebral blood flow (rCBF) changes by modafinil administration in the normal human brain. To achieve this, we performed 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo administration in young, healthy non-sleep deprived subjects.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

Subjects

Twenty-one right-handed healthy volunteers (mean age: 20.3 years old, range 20–26) who have normal sleep–wake rhythm with a nocturnal sleep time of >7 h a day participated in the study. All participants underwent history–taking, which including details of night sleep and daytime sleepiness, by sleep specialists (Hong SB, Joo EY) using a detailed sleep questionnaire. Subjects who reported moderate to heavy snoring, sleep apnea, daytime sleepiness, and insomnia or other sleep disorders were excluded. In addition, we excluded the following; those on CNS stimulants, smokers, those with a focal neurological deficit, those with a neurological or psychiatric disease, those with a medical history of antidepressant use, drug or alcohol abuse, or of drug-addiction or hypertension, and those with cardiac dysrhythmia or who were pregnant.

Study design

In the present randomized, double blind, crossover study, each subject was asked to visit five times during the 19-day-study period (Fig. 1). The crossover design was chosen to minimize the data variability that would have been introduced if two different groups of subjects had been enrolled. On the day prior to modafinil or placebo ingestion, all subjects underwent a brain SPECT baseline study (first SPECT). Subsequently, Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), and reaction time tasks were administered to evaluate vigilance and motor dexterity. On the following day subjects took either modafinil 400 mg or placebo, and 3 h later a radiotracer was administered intravenously (i.v.) for a second SPECT scanning. ESS, SSS, and reaction time tasks were performed within 30 min after SPECT study. After a 14-day washout period, subjects reperformed baseline vigilance and motor dexterity. On the following day the subjects were again administered placebo or modafinil and 3 h later were administered radiotracer i.v. for third SPECT scanning and vigilance and motor dexterity tests. The order of drug intake (modafinil versus placebo) was randomized and subjects and investigators were unaware of the identities of the drugs administered. The modafinil and placebo tablets were indistinguishable and were prepared independently by a hospital pharmacist. Thus, neither the patients nor the investigators were aware of the identities of the treatments administered. The investigation time-point of 3 h after drug ingestion was chosen after considering peak published modafinil plasma levels (Moachon et al., 1996).

image

Figure 1.  Study protocol. Each subject was scheduled to visit five times during the study period (19 days). During first visit, all participants performed a prestudy assessment, which included a sleep questionnaire to exclude subjects with sleep disorders. During second visit, prior to modafinil or placebo administration, all subjects underwent 99mTc-ethylcysteinate dimer brain SPECT scanning baseline study, and performed Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), and reaction time tasks. During third visit, subjects were administered either modafinil (400 mg) or placebo and 3 h later were administered a radiotracer i.v. for second SPECT scanning. They also underwent ESS, SSS, and reaction time tasks within 30 min of each other. After a 14-day washout period, during fourth visit subjects underwent ESS, SSS and reaction time tasks. During fifth visit, subjects were administered either placebo or modafinil depending on which had been administered during third visits, and 3 h later were administered radiotracer for a third SPECT scanning, and subsequent ESS, SSS and reaction time tasks. Orders modafinil and placebo administration were randomized and subjects and investigators were unaware of the identities of drugs administered.

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Reaction time tasks

Subjects were seated individually in a dimly lit, sound attenuated, electrically shielded room. Tasks were performed 3 h after drug ingestion (between 11:00 and 12:00 hours) using auditory and visual paradigms. For the auditory task, we presented a dichotic sequence of low (1000 Hz) and high tones (2000 Hz). 80% of the 200 stimuli administered during a task were of low tone (non-target) and the remainders were of high tone (target). Stimulus duration was 50 ms, interstimulus interval was 2 s, and the tone intensity was 80 dB SPL. Subjects were asked to distinguish high and low tones by button pressing with an index finger. For the visual task, stimuli were presented on a computer monitor, placed 1 m in front of a subject. A random series of stimuli were presented every 2 s of 200 ms duration. During this task, 200 stimuli were presented, which consisted of target and non-target images with probabilities of 20% and 80%, respectively. The target stimulus was a large circle (diameter 12 cm) and the non-target stimulus was a small circle (diameter 4 cm).

Subjects were instructed to respond to target stimuli by pushing a button with the right index finger as quickly as possible. Constant EEG and visual monitoring was performed to ensure that subjects did not falling asleep momentarily during tasks.

99mTc-ethylcysteinate dimer (99mTc-ECD) brain SPECT

99mTc-ECD was injected i.v. for SPECT studies. Brain SPECT scans were performed within 30–60 min of radiotracer injection (25 mCi) using a three-headed Triad XLT system equipped with low-energy and high-resolution collimators (Trionix Research Laboratory, Twinsburg, OH, USA). The transaxial system resolution of the camera used was 6.9 mm full width at half maximum. Images were reconstructed using filtered back-projection and a Butterworth filter. Attenuation correction was performed using Chang’s method (attenuation coefficient = 0.12 cm−1; Chang, 1978). The SPECT voxel dimension was 3.56 × 3.56 × 3.56 mm (x, y, z). SPECT studies were performed before modafinil/placebo administration. All participants were asked to refrain from caffeinated beverages but were allowed to drink water from 7:00 hours until the end of the SPECT study. Subjects were instructed not to fall asleep after the ECD injection. Wakefulness after ECD injection was monitored using four EEG channels, two EOG channels, and using single channel EMG.

Informed consent was obtained from all patients after the study protocol, SPECT study procedure, and potential hazards associated with radioisotope injection had been explained. The Institutional Review Board of Samsung Medical Center authorized the informed consent form used and the study protocol, which included the administration of a radioactive substance and SPECT scanning.

Statistical parametric mapping (SPM) analyses of brain SPECT images obtained before versus after modafinil or placebo administration, and on-modafinil versus on-placebo conditions

Pre and post-modafinil/placebo SPECT images were manipulated using MATLAB 6.3 (The Mathworks, Inc., Natick, MA, USA) incorporated into SPM 2 software (Wellcome Department of Cognitive Neurology, Institute of Neurology, University of London, UK). Raw SPECT images (interfile 3.0 format) were converted to Analyze format. Before the spatial normalization of pre- and post-modafinil/placebo SPECT images using a standard SPECT template, post-modafinil/placebo SPECT images were realigned to pre-modafinil/placebo SPECT images for each subject, and realigned matrixes and subject mean images were saved. Using these realignment processes, all post-modafinil/placebo SPECT images were correctly registered to pre-modafinil/placebo SPECT images. Mean images were spatially normalized into a standard SPECT template using a 12-parameter affine transformation and a nonlinear transformation, and the normalization parameters of each subject mean image were then adjusted to realigned pre/post-modafinil/placebo SPECT images of same subjects. The accuracy of the spatial normalization was checked using a cross-registration function. Spatially normalized images were then smoothed by convolution using an isotopic Gaussian kernel with a 14-mm full width at half maximum to increase the signal to noise ratio (Joo et al., 2004, 2005).

Scaling of counts was based on normalization of white matter counts across the study conditions. Normalization that includes white and gray matter voxels would be problematic. Because white matter is known to be less affected by the experimental effect or disease condition (Spence et al., 2006), the level of rCBF in whole brain was normalized with the mean count of white matters. Moreover, no experimental data were demonstrated that white matter is mainly affected by modafinil.

After normalization, one-way repeated measures anova (within subjects) was applied to compare three conditions of the same subjects (condition-1: pretreatment baseline group; condition-2: after modafinil administration; condition-3: after placebo administration). Then post hoc paired comparisons were performed between pre- and post-placebo administration, pre- and post-modafinil administration, or post-placebo and post-modafinil administrations. The height threshold was set at an uncorrected < 0.001 and the extended threshold to kE > 50 (Friston et al., 1996). Results were displayed on the 2D planes of a single subject SPM2 T1 template.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

Modafinil or placebo effects on vigilance (Epworth Sleepiness Scale and the Stanford Sleepiness Scale) in healthy volunteers

Modafinil (400 mg) administration significantly decreased ESS from 4.3 ± 2.8 to 3.8 ± 2.7 (= 0.036, paired t-test) and SSS from 2.6 ± 1.1 to 1.9 ± 1.0 (= 0.001). However, placebo administration did not change ESS (3.7 ± 2.0–4.2 ± 2.6, = 0.116) or SSS (2.2 ± 0.5–2.0 ± 0.6, = 0.379).

Effects of modafinil or placebo on auditory and visual reaction time tasks in healthy volunteers

Subjects accurately reported 97.7% of target stimuli under both auditory and visual test conditions (range: 93–100%) before and after modafinil and placebo administration. Mean reaction times were not changed after modafinil administration for the auditory (1.728 ± 0.080–1.726 ± 0.073 s, = 0.756, paired t-test) or the visual task (1.717 ± 0.065–1.724 ± 0.092 s, = 0.676). Placebo administration also did not change mean reaction times to auditory (1.699 ± 0.037–1.727 ± 0.071 s, = 0.099) or visual tasks (1.697 ± 0.031–1.725 ± 0.074 s, = 0.066).

SPM analyses of brain SPECT images obtained before versus after modafinil or placebo administration, and on-modafinil versus on-placebo conditions

SPM analysis showed that the ‘on-modafinil’ condition was associated with increased rCBF in bilateral thalami (intralaminar, ventrolateral, and dorsolateral nuclei) and in brainstem (mid- and dorsal pons) at the uncorrected < 0.001, whereas the ‘on-placebo’ condition was associated with increased rCBF in smaller areas of the mid- to dorsal pons than the ‘off-placebo’ condition at the uncorrected < 0.001. Significant rCBF increase was observed in bilateral frontopolar, orbitofrontal, superior frontal, middle frontal gyri, short insular gyri, left cingulate gyrus, left middle and inferior temporal gyri, left parahippocampal gyrus, and left mid to dorsal pons of brainstem in the ‘on-modafinil’ condition as compared with the ‘on-placebo’ condition at the uncorrected < 0.001, and rCBF increase of these areas was also significant at false discovery rate (FDR) corrected < 0.05 (Fig. 2, Table 1) (Genovese et al., 2002). No brain area showed rCBF decrease after modafinil or placebo administration.

image

Figure 2.  Brain regions showing significant rCBF changes after modafinil or placebo administration in healthy volunteers. (a) On-modafinil versus Off-modafinil: Modafinil increased rCBF in bilateral thalami and in mid- and dorsal pons of the brainstem on T1 template overlaid MR coronal and sagittal images. (b) On-placebo versus Off-placebo: Placebo increased rCBF in smaller regions in the mid- and dorsal pons of the brainstem on axial, coronal and sagittal images. (c) On-modafinil versus On-placebo: Modafinil increased rCBF in bilateral orbitofrontal cortices, left dorsolateral prefrontal cortex (first imaging session from left side), left superior/middle frontal gyri, bilateral anterior insular gyri (second imaging session), left lateral and basal temporal areas (third imaging session), and in left anterior cingulate cortex, left mid- and dorsal pons of the brainstem (fourth and fifth imaging sessions in right side). Left to right panel order represents coronal images of the brain taken in the anterior to posterior direction. Left sides of images represent brain left sides. (a), (b), (c) were all significant at the uncorrected P < 0.001. (c) was also significant at FDR corrected < 0.05.

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Table 1.   SPM results showing MNI coordinates and significance levels of brain regions with increased rCBF after modafinil or placebo administration in healthy volunteers
LocationSideMNI coordinates (mm)TPeak ZUncorrected P-value
xyz
  1. MNI, Montreal Neurologic Institute; B, bilateral; L, left; R, right.

  2. *False discovery rate corrected < 0.05, extent threshold kE > 50.

Increased rCBF of on-modafinil condition compared with off-modafinil condition
 ThalamusR16−14104.343.910.00005
L−16−1663.523.270.001
 PonsB−2−30−305.784.900.0000005
Increased rCBF of on-placebo condition compared with off-placebo condition
 PonsB2−28−224.554.060.00002
Increased rCBF of on-modafinil condition compared with on-placebo condition*
 Frontopolar gyrusL−186664.013.650.00013
R156623.653.480.0003
 Orbitofrontal gyrusL−2648−166.405.280.00000007
R3454−44.403.950.00004
 Superior frontal gyrusL−1028404.814.240.000011
R818564.363.920.00004
 Middle frontal gyrusL−4018504.964.350.000007
R3420−143.833.520.00022
 Short insular gyrusL−3818−64.544.050.00003
 Cingulate gyrusL−840224.053.680.00012
 Middle temporal gyrusL−64−20−145.854.950.0000004
 Inferior temporal gyrusL−42−2−365.014.390.000006
 Parahippocampal gyrusL−18−20−244.984.370.0000063
 PonsL−6−32−345.194.510.000003

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

In the present study, we examined the effects of modafinil on regional rCBF in healthy volunteers without sleep deprivation compared with those of placebo.

Increased rCBF in thalamus, pons, and anterior cingulate cortex after modafinil administration

After modafinil administration, rCBF increased in bilateral thalami (ventrolateral, dorsolateral, and intralaminar nuclei) in healthy volunteers. Previous animal studies showed that modafinil dose-dependently increased glutamate release of ventrolateral and ventromedial thalamic nuclei in microdialysis (Ferraro et al., 1997) and increased 2-deoxyglucose uptake in the centrolateral nucleus, one of the intralaminar thalamic nuclei in autoradiography (Engber et al., 1998). Intralaminar thalamic nuclei are present in the non-specific ascending reticular activating system and are functionally associated with attention, arousal, and consciousness (Percheron et al., 1993).

Modafinil is also known to activate α1- and β-adrenergic receptors (Duteil et al., 1990) in the locus coeruleus of brainstem, which project diffusely to the forebrain and cerebral cortices, play an integral role in cortical activation (Jones and Yang, 1985). Moreover, an in vivo microdialysis study showed that modafinil potently increased dialysate serotonin levels in the dorsal raphe nucleus (Ferraro et al., 2002). The rCBF increase in mid- and dorsal brainstem in our study overlapped the loci of the locus coeruleus and dorsal raphe nuclei.

A previous H215O PET study in healthy volunteers showed that rCBF was most rapidly re-established in centrencephalic regions (e.g. brainstem and thalamus) upon awakening from stage 2 sleep, suggesting that the reactivation of these regions underlies the reestablishment of conscious awareness. Across the ensuing 15 min of wakefulness, further increases in rCBF were evident primarily in anterior cingulate cortex, suggesting that the dissipation of sleep inertia effects (postawakening performance and alertness deficits) is effected by reactivation of these regions (Balkin et al., 2002).

In the present study, modafinil significantly reduced ESS and SSS, but placebo did not, which suggests that modafinil increases the alertness of normal subjects. Moreover, our findings of increased rCBF in intralaminar thalamic nuclei, brainstem, and anterior cingulate cortex support the previous findings of animal studies that the vigilance-promoting action of modafinil is related to the activation of the arousal-related systems in man.

Increased rCBF in the limbic system (orbitofrontal cortex, insular gyrus, and parahippocampal gyrus)

The limbic system primarily controls emotion, motivation, and emotional association with memory. The ventromedial prefrontal cortex such as subcallosal gyrus is known to participate in awareness and emotional processing (Adolphs et al., 2002).

Normal subjects reported increases in ratings of psychological anxiety and aggressive mood after ingesting 100 mg of modafinil (Randall et al., 2003). A functional MRI study showed that modafinil modifies activity in the hippocampus and frontal cortex, which play important roles in anxiety, cognition and alertness (Ellis et al., 1999). Variations of baseline CBF in the orbitofrontal cortex were found to correlate with changes in salivary-cortisol level and heart rate caused by stress tasks (Wang et al., 2005).

Mesial temporal lobe epilepsy patients with emotional disturbances showed glucose hypometabolism in the anterior insula (Bouilleret et al., 2002) and animal studies have shown that the anterior insula connects mainly to the entorhinal and periamygdaloid cortices (Insausti et al., 1987). These observations suggest that emotional changes induced by modafinil administration may be related to the increased rCBF in the limbic system.

Increased rCBF in dorsolateral prefrontal and anterior cingulate cortices

Working memory is often viewed as an executive function, and the anterior cingulate cortex is primarily involved in attention and working memory in combination with the dorsolateral prefrontal cortex (Posner et al., 1988).

The influence that modafinil has on executive functions is controversial. Single doses of 100 or 200 mg of modafinil were not found to improve cognitive task performance in sleep-deprived healthy subjects (Randall et al., 2003, 2005). However, other studies have concluded that identical doses of modafinil-enhanced performance as assessed using digital span, visual pattern recognition memory, spatial planning, and stop-signal reaction time tests (Turner et al., 2003).

Several functional MRI studies have investigated the effects of modafinil on executive function. In schizophenia patients, a single dose of 100 mg increased dorsolateral prefrontal cortex activation during the purposeful modulation of motor activity (Hunter et al., 2006) and increased anterior cingulate activation during performing a working memory protocol (Spence et al., 2005). In eight healthy volunteers, a single 200-mg dose of modafinil enhanced the performance at an intermediate level of task difficulty during working memory after overnight sleep deprivation, which was associated with the recruitment of increased cortical activation volumes (Thomas and Kwong, 2006). These functional MRI findings are consistent with our rCBF results.

In the present study, no significant differences in visual or auditory reaction time tasks were observed between those on- and off-modafinil or between those on- and off-placebo. But the subjects in our study are healthy volunteers, do not have excessive daytime sleepiness and were not sleep deprived during the study period. Furthermore, the baseline attention and motor dexterity levels of our subjects were very high (mean accuracy rate of tasks, 97.7%). Thus our findings suggest that it is very difficult to detect a drug effect on the reaction time in normal subjects without sleep deprivation although our participants’ subjective sleepiness estimated by the ESS was significantly decreased.

Modafinil effect on rCBF in healthy volunteers versus narcolepsy patients

There are quite a few conflicting reports concerning the locus of modafinil effect. We performed the SPECT studies to investigate the effects of modafinil on rCBF in narcolepsy patients (unpublished data). Chronic modafinil treatment 4 weeks increased rCBF in right dorsolateral and anterior cingulate cortices. The on-modafinil condition was also associated with decreased rCBF in bilateral fronto-temporal cortices and cerebellum compared with the off-modafinil condition although the reason why modafinil reduces rCBF in several regions of narcoleptic brains remains unclear. However, long-term placebo administration did not show significant rCBF changes in those patients. On the contrary, the present study showed that a single dose of modafinil increased rCBF mainly in thalamus and pons as well as prefrontal and cingulate cortices in healthy volunteers. There were no brain areas showing reduced rCBF by modafinil administration. To our knowledge, there have been no SPECT studies comparing rCBF changes between single dose and long-term administrations of modafinil in either narcolepsy patients or healthy volunteers. The applicability of the short-term effects to chronic drug therapy is very limited because there are known changes in the rate of metabolism, drug-induced changes in receptor density or efficiency of receptor coupling, and sensitization in chronic drug therapy. Thus short-term effect of modafinil administration may be different from the effect of a long-term administration. Furthermore, it may be possible that modafinil has different effects on rCBF depending upon whether subjects are healthy volunteers or narcolepsy patients.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

The present study demonstrates that a single dose of modafinil increased rCBF in the thalamus, brainstem, insular cortex, and parts of the limbic system, which are related to arousal, attention, executive function, and emotion in healthy volunteers without sleep deprivation. This study is the first to investigate the effects of modafinil on rCBF in healthy volunteers.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References

This study was supported by the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of the Republic of Korea (no. M103KV010017-07K2201-01710), by the Samsung Biomedical Research Institute (no. SBRI C-A7-426-1), and by the Good Health R&D Project, Ministry of Health & Welfare, Republic of Korea (no. A050462). We thank Kyung-Han Lee, MD and Soh-Hee Chung, RN for their help during the acquisition of brain SPECT images.

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  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. References
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