STUDIES ON THE EFFECTS OF MODAFINIL ON BRAIN DOPAMINE SIGNALING Modafinil, a wake-promoting drug used in the treatment of sleep disorders, may enhance cognition and is used off-label for the treatment of cognitive dysfunction in some psychiatric disorders (i.e., schizophrenia, ADHD). The mechanisms of action of modafinil are not well understood but are believed to differ from those of stimulant medications (such as methylphenidate and amphetamine), which increase dopamine (a neurotransmitter in the brain essential for movement, cognition, motivation, reward and learning/conditioning) in the brain by targeting the dopamine transporters, a mechanism that underlies the abuse potential of these drugs. However, there is growing evidence that dopamine may also play a role in the mode of action of modafinil. The purpose of this study was to assess the effects of modafinil on dopamine brain signaling. The study used PET imaging to assess if therapeutic doses of modafinil would elevate extracellular dopamine in the brain by blocking the dopamine transporter. The study was done in 10 healthy men who were tested twice with placebo and with modafinil (half were given 200 mg, which is the dose recommended for narcolepsy and the other half 400 mg, which is a dose shown to be beneficial for the treatment of ADHD). The study showed that modafinil acutely increased dopamine levels and blocked dopamine transporters in the striatum including the nucleus accumbens, which is a brain region critical for the rewarding effects of drugs of abuse. Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for therapeutics as well as its use as a cognitive enhancer by healthy individuals, these results suggest that risk for addiction in vulnerable persons merits heightened awareness. STUDIES ON THE INVOLVEMENT OF STRIATAL AND PREFRONTAL REGIONS IN INHIBITORY CONTROL IN ADDICTION Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects, when instructed to purposefully control their craving responses to drug-conditioned stimuli, can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-218Ffluoro-D-glucose to measure brain glucose metabolism (a marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to purposefully inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 33 post 63;p<0.001) but not when subjects were instructed to inhibit craving (pre 32 post 33). Comparisons with baseline showed visual activation for both cocaine-cue conditions and limbic inhibition (accumbens, orbitofrontal, insula, cingulate) when subjects purposefully inhibited craving (p<0.001). Comparison between cocaine-cue conditions showed lower metabolism with purposeful inhibition in right orbitofrontal cortex and right accumbens (p<0.005), which was associated with right inferior frontal activation (r = -0.62, P <0.005). Decreases in metabolism in brain regions that process the predictive (nucleus accumbens) and motivational value (orbitofrontal cortex) of drug-conditioned stimuli was elicited by instruction to inhibit cue-induced craving. This suggests that cocaine abusers may retain some ability to inhibit craving and that strengthening fronto-accumbal regulation may be therapeutically beneficial in addiction. STUDIES ON THE EFFECTS OF LOW-FIELD MAGNETIC STIMULATION ON BRAIN FUNCTION Echo Planar Imaging (EPI), the gold standard technique for functional MRI (fMRI), is based on fast magnetic field gradient switching that induces electric (E) fields in the brain and could influence neuronal activity. However, the direct effect of EPI fields on brain function has not been investigated. Here we assess the effects of EPI on brain glucose metabolism with positron emission tomography (PET) and 2-fluoro-2-deoxy-D-glucose (18F-FDG), which we used as a marker of brain function. Fifteen healthy male subjects were in a 4 T magnet during the 18FDG uptake period (25 minutes after injection) twice: with (ON) and without (OFF) EPI readout gradients pulses along the z-axis (Gz: 25 mT/m;250 microsecond rise-time;920 Hz frequency). The E-field induced by these EPI gradient pulses is non homogeneous and increases linearly from the gradients isocenter (radial and z directions), which allowed us to assess the relationship between the strength of the local E and regional changes in metabolism. The metabolic images were normalized to the average metabolic activity in the plane that was positioned at the gradients isocenter (plane parallel to corpus callosum) that had equivalent E = 0 for ON and OFF conditions. Statistical parametric analyses used to identify regions that differed between ON versus OFF (p <0.05, corrected for multiple comparisons) showed that metabolism was significantly lower in areas at the poles of the brain (inferior occipital and orbitofrontal and superior parietal and frontal cortices). Moreover the magnitude of the metabolic decrements was significantly correlated with the estimated strength of E (r = 0.71, p <0.0001);the stronger the induced E-field the larger the decreases. These data provide evidence that EPI sequences affect neuronal activity, which may influence the activation/deactivation patterns detected by fMRI studies. STUDIES ON THE INVOLVEMENT OF THE BRAIN DA REWARD PATHWAY IN ADHD ADHD is characterized by deficits in attention and hyperactivity/impulsivity and there is increasing evidence that reward processing is disrupted. The purpose of this study was to determine if the dopamine reward pathway (meso-accumbens) is disrupted in ADHD. We used PET and 11Ccocaine to measure dopamine transporters (presynaptic DA marker) and 11Craclopride to measure dopamine D2/D3 receptors (postsynaptic DA marker) in 53 non-medicated adults with ADHD and 44 healthy controls. Statistical parametric mapping (SPM) was used to compare 11Ccocaines and 11Cracloprides specific binding in brain between controls and ADHD subjects, which were used as measures of dopamine transporter and dopamine d2 receptor availability respectively. We showed that for both 11Ccocaine and 11Craclopride, specific binding was significantly lower in ADHD than in controls (SPM p<0.005) in an area that included the left nucleus accumbens, ventral caudate, midbrain and hypothalamus. These findings were corroborated by independently drawn regions of interest. The D2/D3 receptors measures in accumbens correlated negatively with ratings of inattention (r=>0.31, p<0.004). The disruption of the dopamine reward pathway (midbrain and nucleus accumbens) could explain the impaired responses to reinforcement in ADHD and higher risk for drug abuse. These findings support therapeutic strategies to enhance motivation and reinforcement in ADHD and identify the nucleus accumbens, which is a region implicated in substance abuse risk, as a legitimate target for ADHD medications.
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