Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals Modafinil Alters Intrinsic Functional Connectivity of the Right Posterior Insula: A Pharmacological Resting State fMRI Study Modafinil activates cortical and subcortical sites in the sleep-deprived state. Cerebral blood flow changes in man by wake-promoting drug, modafinil: a randomized double blind study. Modafinil modulates anterior cingulate function in chronic schizophrenia. The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition Modafinil affects mood, but not cognitive function, in healthy young volunteers. Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor Does Modafinil Enhance Cognitive Performance in Young Volunteers Who Are Not Sleep-Deprived? Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial Cognitive enhancing effects of modafinil in healthy volunteers A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study Influence of modafinil on somatosensory input processing in the human brain-stem Modafinil Improves Cognition and Attentional Set Shifting in Patients with Chronic Schizophrenia
Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function . Therefore , medications that improve cognition in these subjects may improve the success of therapy for their addiction , especially when cognitive behavioral therapies are used . Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers . We therefore conducted a r and omized , double-blind , placebo-controlled , cross-over study , using functional magnetic resonance imaging , to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent , MA-dependent , and healthy control participants .  Modafinil ( 200 mg ) and placebo were administered orally ( one single dose each ) , in counterbalanced fashion , 2 h before each of two testing sessions . Under placebo conditions , MA-dependent participants showed worse learning performance than control participants . Modafinil boosted learning in MA-dependent participants , bringing them to the same performance level as control subjects ; the control group did not show changes in performance with modafinil . After controlling for performance differences , MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants . The findings suggest that modafinil improves learning in MA-dependent participants , possibly by enhancing neural function in regions important for learning and cognitive control . These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence 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 Clinical Trials.gov UNLABELLED SUBJECT OBJECTIVES : To assess the effect of the wake-promoting drug modafinil on working memory and brain activation in the executive network , following a single night of sleep deprivation . DESIGN R and omized , placebo-controlled , 4-arm , double-blind evaluation of a single 200-mg dose of modafinil on working memory ( 1- , 2- , and 3-back)-related functional brain activation and performance following overnight sleep deprivation . SETTING General Clinical Research Center , Biomedical Imaging Center . SUBJECTS Eight medication-free men , aged 21 to 35 years . INTERVENTIONS Overnight sleep deprivation , single-dose 200-mg modafinil , functional magnetic resonance imaging MEASUREMENTS AND RESULTS Brain activation patterns and regional signal intensity based on the blood-oxygen level-dependent signal were assessed . The following reaction times were used as measures of performance : ( 1 ) attention in the scanner before functional scanning , ( 2 ) " back " responses during the active-task block , and ( 3 ) attention during the baseline task block . Contrast of activation maps among conditions revealed sleep-deprivation and drug effects , and their interactions . Performance in the deprived state was enhanced by modafinil only at an intermediate ( 2-back ) level of task difficulty and was associated with the recruitment of increased cortical activation volumes . Strong and consistent individual differences in performance were noted on the working memory tasks . CONCLUSIONS Modafinil effectively counters the adverse effects of overnight sleep deprivation on working memory but only when task difficulty is moderate , recruiting extensive areas in the executive network to do so . Interindividual differences in working-memory performance are stable trait characteristics To investigate the effects of a wake-promoting drug , modafinil on regional cerebral blood flow ( rCBF ) in healthy volunteers , we performed (99m)Tc-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 r and omized 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 st and ard 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 BACKGROUND Schizophrenia is associated with widespread cognitive deficits that have an impact on social function . Modafinil promotes wakefulness and is reported to enhance cognition . AIMS To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia . METHOD In a r and omised double-blind placebo-controlled crossover design , 19 patients received either modafinil ( 100 mg ) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging . RESULTS Seventeen patients completed the study and another underwent acute relapse 4 days post-drug . Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task . The anterior cingulate cortex signal correlated with cognitive performance , although only a subset of patients exhibited ' enhancement ' . CONCLUSIONS Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers . In a double-blind parallel group design study , 45 non-sleep-deprived middle-aged volunteers ( 20 men and 25 women , aged 50 - 67 years ) were r and omly allocated to receive two capsules containing placebo , 100 or 200 mg modafinil , and 3 h later they completed  100 mm visual analogue scales of mood and bodily symptoms  , before and after an extensive battery of cognitive tests [ pen and paper and the Cambridge Neuropsychological Test Automated Battery ( CANTAB ) ] . There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study . The group treated with modafinil ( 200 mg ) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability ( Clock Drawing Test ) compared with the placebo group . However , subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift ( ID/ED ) task than both the other groups . Thus , this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers Aims /hypothesisOur hypothesis is that reducing release of the inhibitory neurotransmitter gamma-aminobutyric acid ( GABA ) with modafinil will enhance symptomatic and hormonal responses to hypoglycaemia . Methods Nine healthy men received , in r and om order , two 100-mg doses of modafinil or placebo , followed by an insulin clamp in which plasma glucose was either reduced stepwise to 2.4 mmol/l or was sustained at euglycaemia ( four studies ) . Catecholamines , symptom scores and cognitive function were measured . Results Modafinil had no effect on the measured parameters during euglycaemia . During hypoglycaemia , autonomic symptom scores were significantly higher with modafinil ( increase at lowest plasma glucose concentration 271.3±118.9 vs 211.2±80.4/40 min , p=0.019 ) , and the heart rate response was increased ( 12,928±184 vs 6773±148 bpm/140 min , p=0.016 ) . Deterioration in performance of two cognitive tasks was reduced : Stroop colour – word test ( 613±204 vs 2375±161/65 min , p=0.009 ) and accuracy of a simple reaction task ( 11.3±1.8 vs 9.4±3.7 , p=0.039 ) . Conclusions /interpretationWe conclude that modafinil improves adrenergic sensitivity and some aspects of cognitive function at hypoglycaemia , possibly by reducing neuronal central GABA concentrations 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 ) question naire 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 Modafinil is a selective wakefulness-promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation . In a double-blind study we examined its effects in 30 healthy , non sleep-deprived students ( 19 men and 11 women , aged 19 - 23 years ) , who were r and omly allocated to placebo , 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms , before and after an extensive battery of cognitive tests ( pen and paper and CANTAB ) . There were no significant differences between the three treatment groups on any of the cognitive tests used in this study . There was a significant post-treatment change in the factor measuring ' somatic anxiety ' and in individual ratings of ' shaking ' , ' palpitations ' , ' dizziness ' , ' restlessness ' , ' muscular tension ' , ' physical tiredness ' and ' irritability ' , which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups . Further changes in mood were revealed after the stress of cognitive testing , with the 100 mg group showing greater increases in the ' psychological anxiety ' and the ' aggressive mood ' factors ( as measured from the Bond and Lader scales ) Patients with schizophrenia experience cognitive impairments associated with hypofunctioning of the frontal cortex . Modafinil , a novel wake-promoting agent , works through the sleep – wake centers of the brain to activate the cortex . This 4-week , open-label , pilot study evaluated adjunct modafinil in patients with schizophrenia or schizoaffective disorder . Eleven patients received once-daily oral doses of modafinil ( 100 mg/day , days 1–14 ; 100 or 200 mg/day , days 15–28 ) in addition to antipsychotic therapy . Modafinil significantly improved patients ' global functioning as assessed by a blinded clinician ( week 2 , P = 0.026 ; week 4 , P = 0.012 ) and the investigator ( week 3 , P = 0.035 ) . Modafinil significantly improved overall clinical condition , with 64 % and 82 % of patients rated as clinical ly improved at week 4 by a blinded clinician and the investigator respectively . Eighty-nine percent of patients considered themselves to be clinical ly improved . Modafinil significantly improved fatigue ( P = 0.025 , week 3 ) and tended to improve cognitive functioning scores . Control of positive symptoms was well maintained . Treatment-emergent adverse events included dry mouth ( n = 2 ) and hallucinations ( n = 2 ) . One patient discontinued the study because of hallucinations that were considered to be possibly related to inadequate antipsychotic therapy . Although preliminary , these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition , and reduces fatigue in patients with schizophrenia or schizoaffective disorder . Additional controlled studies are warranted Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients . An open-label , r and omized , pilot trial examined both the general and differential efficacy of 4 weeks of methylpheni date ( MPH ) and modafinil ( MOD ) in 24 brain tumor patients . Participants completed cognitive tests and self-report measures of fatigue , sleep disturbance , mood and quality of life at baseline and after 4 weeks . Following stimulant treatment , there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention . Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy . Inconsistent , differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD . There was also evidence of a general beneficial effect on patient-reported measures of fatigue , mood , and quality of life , with no statistically significant differences between treatment arms in these measures over time . The results from this small pilot study should be interpreted with caution , but appear to warrant additional research , in larger study sample s , targeting fatigue , processing speed and executive function , and exploring different doses of stimulants . Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment Abstract : In a double-blind , parallel groups study , 60 healthy student volunteers ( 29 men and 31 women , aged 19 - 22 years ) were r and omly allocated to receive placebo , 100 or 200 mg modafinil . Two hours later , in the early evening , they completed an extensive cognitive battery . The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session , and there were no treatment-associated changes in these or in mood ratings during the tests . Modafinil was without effect in several tests of reaction time and attention , but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention . Modafinil was without effect on spatial working memory , but the 100-mg group performed better in the backward part of the digit span test . Modafinil was without effect on verbal short-term memory ( story recall ) , but 100 mg improved digit span forward , and both doses improved pattern recognition , although this was accompanied by a slowing of response latency in the 200-mg group . There were no significant effects of modafinil compared with placebo in tests of long-term memory , executive function , visuospatial and constructional ability , or category fluency . These results suggest that the benefits of modafinil are not clearly dose-related , and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory , which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals Background Modafinil is a medication licensed for the treatment of narcolepsy . However , it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning . Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers , numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks . Interestingly , several clinical and pre clinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times . This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil . The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test ( HSCT ) . Methodology Sixty-four healthy volunteers received either a single dose ( 200 mg ) of modafinil ( n = 32 ) or placebo ( n = 32 ) in a r and omized , double-blind , placebo-controlled , parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT . Principal Findings Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo . However , participants in both groups made a similar number of errors on each of these measures , indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo . Conclusions This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT , a task that is highly sensitive to prefrontal executive function , without enhancing accuracy of performance . This finding may provide important clues to defining the limitations of modafinil as a putative cognitive enhancer . Trial Registration Clinical Trials.gov Abstract Rationale . Modafinil , a novel wake-promoting agent , has been shown to have a similar clinical profile to that of conventional stimulants such as methylpheni date . We were therefore interested in assessing whether modafinil , with its unique pharmacological mode of action , might offer similar potential as a cognitive enhancer , without the side effects commonly experienced with amphetamine-like drugs . Objectives . The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests . Methods . Sixty healthy young adult male volunteers received either a single oral dose of placebo , or 100 mg or 200 mg modafinil prior to performing a variety of tasks design ed to test memory and attention . A r and omised double-blind , between-subjects design was used . Results . Modafinil significantly enhanced performance on tests of digit span , visual pattern recognition memory , spatial planning and stop-signal reaction time . These performance improvements were complemented by a slowing in latency on three tests : delayed matching to sample , a decision-making task and the spatial planning task . Subjects reported feeling more alert , attentive and energetic on drug . The effects were not clearly dose dependent , except for those seen with the stop-signal paradigm . In contrast to previous findings with methylpheni date , there were no significant effects of drug on spatial memory span , spatial working memory , rapid visual information processing or attentional set-shifting . Additionally , no effects on paired associates learning were identified . Conclusions . These data indicate that modafinil selectively improves neuropsychological task performance . This improvement may be attributable to an enhanced ability to inhibit pre-potent responses . This effect appears to reduce impulsive responding , suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder Abstract . Rationale : In 1998 , the FDA approved modafinil for treating  excessive daytime sleepiness in narcoleptics , and this has raised questions about the appropriateness of this compound for enhancing alertness in sleep-deprived controls . This study explored the efficacy of modafinil for maintaining the performance of volunteers required to accomplish highly dem and ing tasks despite sleep loss . Objective : The principal objective was to determine whether prophylactic doses of modafinil would attenuate decrements in aviator performance and arousal throughout 2 days and 1 night without sleep . Methods : Six pilots were exposed to two 40-h periods of continuous wakefulness . In one , three 200-mg doses of modafinil were given and in the other , matching placebos were administered . Helicopter simulator flights , resting EEGs , and Profile of Mood States ( POMS ) question naires were evaluated . Results : Modafinil attenuated sleep deprivation effects on four of six flight maneuvers , reduced slow-wave EEG activity , and lessened self-reported problems with mood and alertness in comparison to placebo . The most noticeable benefits occurred between 0330 and 1130 hours , when the combined impact of sleep loss and the circadian trough was most severe . The most frequently observed drug side effects were vertigo , nausea , and dizziness . These could have been related to : 1 ) the motion-based testing , 2 ) the use of a simulator rather than an actual aircraft ( i.e. , " simulator sickness " ) , and /or 3 ) the administration of more than 400 mg modafinil . Conclusions : Modafinil is a promising countermeasure for  sleep loss in normals ; however , additional studies aim ed at reducing side effects are needed before it should be used in aviators OBJECTIVE Since high frequency oscillations ( HFOs ) evoked by upper limb stimulation are susceptible to arousal fluctuation , we verified whether administration of modafinil , a vigilance promoting drug , modifies such responses at different levels of the somatosensory system . METHODS HFOs were obtained in 6 healthy volunteers by 500 - 700 Hz filtering of right median nerve somatosensory evoked potentials , before and 2 hours after the administration of 100 mg modafinil . Raw data were further su bmi tted to brain electrical source analysis . RESULTS Modafinil significantly increased subcortical HFOs , as well as the strength of a dipolar source at the base of the skull . CONCLUSIONS Our data suggest that modafinil exerts its action also at the level of the brain-stem , where it interferes with the processing of somatosensory ascending inputs Modafinil , a novel cognitive enhancer , selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder ( ADHD ) . It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission . The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia . Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind , r and omized , placebo-controlled crossover study using a 200 mg dose of modafinil . Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD . Improvement was seen on short-term verbal memory span , with trends towards improved visual memory and spatial planning . This was accompanied by slowed response latency on the spatial planning task . No effect on stop-signal performance was seen . Importantly , significant improvement in attentional set shifting was seen , despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients . Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia , particularly because of its beneficial effects on attentional set shifting
We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function , only half show improvements in attention and learning and memory , and a few even report impairments in divergent creative thinking .
In contrast , when more complex assessment s are used , modafinil appears to consistently engender enhancement of attention , executive functions , and learning .
Importantly , we did not observe any preponderances for side effects or mood changes .
Modafinil is an FDA -approved eugeroic that directly increases cortical catecholamine levels , indirectly upregulates cerebral serotonin , glutamate , orexin , and histamine levels , and indirectly decreases cerebral gamma-amino-butrytic acid levels .
In addition to its approved use treating excessive somnolence , modafinil is thought to be used widely off-prescription for cognitive enhancement .
However , despite this popularity , there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy , non-sleep-deprived humans .