Modafinil modulation of the default mode network

RationaleThe default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.ObjectivesIn the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.MethodsEighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.ResultsThere was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.ConclusionsModafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil

Towards responsible use of cognitive-enhancing drugs by the healthy

In this article, we propose actions that will help society accept the benefits of enhancement, given appropriate research and evolved regulation. Prescription drugs are regulated as such not for their enhancing properties but primarily for considerations of safety and potential abuse. Still, cognitive enhancement has much to offer individuals and society, and a proper societal response will involve making enhancements available while managing their risks

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism

A Retrospective Review of Supratherapeutic Modafinil Exposures

Modafinil is a non-amphetamine wakefulness-promoting agent used for the treatment of various sleep disorders characterized by excessive daytime sleepiness. There is little information in the medical literature with respect to supratherapeutic doses of this medication. We performed a retrospective review of the California Poison Control System database for all cases of single-substance ingestion of modafinil with follow-up to a known outcome for the time period 1998–2008. Data collected included age, gender, dose ingested, clinical effects, and medical outcome. There were a total of 87 patients, 53 (61%) of which were female. Patient ages ranged from 1.25 to 72 years with a mean of 30 years; 17 (20%) patients were aged 6 years or less. Thirty-three (38%) were intentional overdoses. Most commonly reported effects were tachycardia (n = 23), agitation (n = 14), anxiety (n = 11), headache (n = 8), hypertension (n = 6), dystonia/tremor (n = 6), and dizziness (n = 5). Forty-nine patients (56%) were managed at home, and 38 (44%) were managed in a healthcare setting. Therapies administered included activated charcoal (n = 8), benzodiazepines (n = 7), antihistamines (n = 2), intravenous fluids (n = 2), haloperidol (n = 2), and beta-blockers (n = 1). Effects were classified as none (n = 22), minor (n = 54), and moderate (n = 11). No major effects and no deaths occurred. Effects of modafinil overdose appear to be mild in most cases, with tachycardia and CNS symptoms predominating. Clinically significant effects requiring treatment occurred in a small number of patients

Oral dosing of rodents using a palatable tablet

Rationale: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents. Objectives: To demonstrate a novel administrative technique – palatable gelatine tablets – as a stress-free route of oral delivery. Methods: 24 male Lister hooded rats were sacrificed for brain tissue analysis at varying time-points after jelly administration of 30 mg/kg of the wake-promoting drug modafinil. A second group of 22 female rats were tested on locomotor activity after 30 mg/kg modafinil, or after vehicle jellies, with the locomotor data compared to the brain tissue concentrations at the corresponding times. Results: Modafinil was present in the brain tissue at all time-points, reducing in concentration over time. The pattern of brain tissue modafinil concentration is comparable to previously reported results following oral gavage. Modafinil-treated rats were more active than control rats, with greater activity during the later time-periods – similar to that previously reported following intraperitoneal injection of 40 mg/kg modafinil. Conclusions: Palatable jelly tablets are an effective route of administration of thermally-stable orally-bioavailable compounds, eliminating the stress/discomfort and health risk of oral gavage and presenting as an alternative to previously reported palatable routes of administration where high protein and fat levels may adversely affect appetite for food reward, and uptake rate in the gastrointestinal tract.Publisher PDFPeer reviewe

Brain Imaging Studies in Pathological Gambling

This article reviews the neuroimaging research on pathological gambling (PG). Because of the similarities between substance dependence and PG, PG research has used paradigms similar to those used in substance use disorder research, focusing on reward and punishment sensitivity, cue reactivity, impulsivity, and decision making. This review shows that PG is consistently associated with blunted mesolimbic-prefrontal cortex activation to nonspecific rewards, whereas these areas show increased activation when exposed to gambling-related stimuli in cue exposure paradigms. Very little is known, and hence more research is needed regarding the neural underpinnings of impulsivity and decision making in PG. This review concludes with a discussion regarding the challenges and new developments in the field of neurobiological gambling research and comments on their implications for the treatment of PG

A systematic review of physiological methods in rodent pharmacological MRI studies

Rationale: Pharmacological magnetic resonance imaging (phMRI) provides an approach to study effects of drug challenges on brain processes. Elucidating mechanisms of drug action helps us to better understand the workings of neurotransmitter systems, map brain function or facilitate drug development. phMRI is increasingly used in preclinical research employing rodent models; however, data interpretation and integration are complicated by the use of different experimental approaches between laboratories. In particular, the effects of different anaesthetic regimes upon neuronal and haemodynamic processes and baseline physiology could be problematic. Objectives: This paper investigates how differences in phMRI research methodologies are manifested and considers associated implications, placing particular emphasis on choice of anaesthetic regimes. Methods: A systematic review of rodent phMRI studies was conducted. Factors such as those describing anaesthetic regimes (e.g. agent, dosage) and parameters relating to physiological maintenance (e.g. ventilatory gases) and MRI method were recorded. Results: We identified 126 eligible studies and found that the volatile agents isoflurane (43.7 %) and halothane (33.3 %) were most commonly used for anaesthesia, but dosage and mixture of ventilatory gases varied substantially between laboratories. Relevant physiological parameters were usually recorded, although 32 % of studies did not provide cardiovascular measures. Conclusions: Anaesthesia and animal preparation can influence phMRI data profoundly. The variation of anaesthetic type, dosage regime and ventilatory gases makes consolidation of research findings (e.g. within a specific neurotransmitter system) difficult. Standardisation of a small(er) number of preclinical phMRI research methodologies and/or increased consideration of approaches that do not require anaesthesia is necessary to address these challenges