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Studies have shown that x-rays delivered as arrays of parallel microplanar beams (microbeams), 25-to 90-m thick and spaced 100 -300 m on-center, respectively, spare normal tissues including the central nervous system (CNS) and preferentially damage tumors. However, such thin microbeams can only be produced by synchrotron sources and have other practical limitations to clinical implementation. To approach this problem, we first studied CNS tolerance to much thicker beams. Three of four rats whose spinal cords were exposed transaxially to four 400-Gy, 0.68-mm microbeams, spaced 4 mm, and all four rats irradiated to their brains with large, 170-Gy arrays of such beams spaced 1.36 mm, all observed for 7 months, showed no paralysis or behavioral changes. We then used an interlacing geometry in which two such arrays at a 90°angle produced the equivalent of a contiguous beam in the target volume only. By using this approach, we produced 90-, 120-, and 150-Gy 3.4 ؋ 3.4 ؋ 3.4 mm 3 exposures in the rat brain. MRIs performed 6 months later revealed focal damage within the target volume at the 120-and 150-Gy doses but no apparent damage elsewhere at 120 Gy. Monte Carlo calculations indicated a 30-m dose falloff (80 -20%) at the edge of the target, which is much less than the 2-to 5-mm value for conventional radiotherapy and radiosurgery. These findings strongly suggest potential application of interlaced microbeams to treat tumors or to ablate nontumorous abnormalities with minimal damage to surrounding normal tissue.

Anterior cingulate cortex (ACC) hypoactivations during cognitive processing characterize drug addicted individuals as compared with healthy controls. However, impaired behavioral performance or task disengagement may be crucial factors. We hypothesized that ACC hypoactivations would be documented in groups matched for performance on an emotionally salient task. Seventeen individuals with current cocaine use disorders (CUD) and 17 demographically matched healthy controls underwent functional magnetic resonance imaging during performance of a rewarded drug cue-reactivity task previously shown to engage the ACC. Despite lack of group differences in objective or subjective taskrelated performance, CUD showed more ACC hypoactivations throughout this emotionally salient task. Nevertheless, intensity of emotional salience contributed to results: (i) CUD with the largest rostroventral ACC [Brodmann Area (BA) 10, 11, implicated in default brain function] hypoactivations to the most salient task condition (drug words during the highest available monetary reward), had the least task-induced cocaine craving; (ii) CUD with the largest caudal-dorsal ACC (BA 32) hypoactivations especially to the least salient task condition (neutral words with no reward) had the most frequent current cocaine use; and (iii) responses to the most salient task condition in both these ACC major subdivisions were positively intercorrelated in the controls only. In conclusion, ACC hypoactivations in drug users cannot be attributed to task difficulty or disengagement. Nevertheless, emotional salience modulates ACC responses in proportion to drug use severity. Interventions to strengthen ACC reactivity or interconnectivity may be beneficial in enhancing top-down monitoring and emotion regulation as a strategy to reduce impulsive and compulsive behavior in addiction.blood-oxygen-level-dependent fMRI ͉ salience ͉ brain-behavior dissociation ͉ craving ͉ cocaine use I n the impaired response inhibition and salience attribution (I-RISA) model we have emphasized the role of the anterior cingulate (ACC) and orbitofrontal cortices (OFC) in core clinical symptoms of drug addiction that encompass attribution of enhanced salience to drug cues at the expense of the salience attributed to nondrug-related stimuli (1). Supporting this core I-RISA hypothesis, neuroimaging studies in drug addicted individuals demonstrate ACC and OFC hyperactivations during drug-related cue reactivity (2), including craving (3, 4) and hypoactivations during performance of neutrally valenced cognitive tasks (5-9). Because these hypoactivations in addicted individuals could reflect impaired performance (5-8) or decreased engagement (9), in the current study we set out to determine whether ACC hypoactivations in addiction can still be observed in groups matched for overt performance on an emotionally salient task. This is a crucial question because the clinical implications for such hypoactivations even in the absence of overt behavioral group differences may be pronounced. For example, t...

BackgroundDopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task.Methodology/Principal FindingsFor this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [11C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus.Conclusions/SignificanceThese findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.D rug addiction is a chronically relapsing disorder associated with dysregulated dopaminergic neurotransmission as well as functional impairments in the brain regions innervated by dopamine [e.g., the prefrontal cortex (PFC)] (1, 2). Psychostimulants such as cocaine have high abuse and dependence potential because of their ability to increase dopamine in limbic brain regions. Similarly to cocaine, methylphenidate (MPH; e.g., Ritalin) blocks the dopamine transporter increasing extracellular dopamine. However, although speed of uptake of both drugs is similar, rate of clearance of MPH from the brain is substantially slower than that for cocaine (90-vs. 20-min half-life), and these slower pharmacokinetic properties may contribute to the lower abuse potential for MPH (1). Both these neuropharmacological mechanisms, interference with the binding of the drug to its target and different (i.e., slower) pharmacokinetics, proved valuable in the management of heroin (e.g., with methadone and buprenorphine) and nicotine addiction (e.g., with nicotine patch and nicotine gum) (3). In contrast, adapting a similar pharmacological strategy (use of stimulant medications such as MPH) in individuals with cocaine-use disorders (CUD) did not decrease cocaine use or prevent relapse (1).Nevertheless, oral MPH decreases abnormal risk taking in patients with frontotemporal dementia (4) and children with attention deficit hyperactivity disorder (ADHD) (5). Furthermore, when on stimulant medication (including MPH), youth with ADHD showed a trend to improved inhibitor...

BackgroundChronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task.Methodology/Principal FindingsWe measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate.Conclusions/SignificanceThese findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

Context Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. Objective To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in men with cocaine use disorders (CUD) and healthy male controls. Design Cross-sectional comparison between 40 CUD and 42 controls scanned with magnetic resonance imaging (MRI) to assess GMV and genotyped for the MAOA polymorphism. The impact of cocaine addiction on GM was tested by 1) comparing CUD with controls, 2) testing diagnosis-by-MAOA interactions, and 3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GM beyond other factors. Outcome Measures GMV were derived from MRI with voxel-based-morphometry. Genotyping was performed for a functional polymorphism (a variable number tandem repeat or VNTR) in the promoter region of the MAOA gene with “high” and “low” alleles. Results 1) Individuals with CUD had reductions in GMV in the orbitofrontal (OFC), dorsolateral prefrontal (DLPFC) and temporal cortex, and hippocampus, compared to controls. 2) The OFC reductions were uniquely driven by CUD with low MAOA genotype and by lifetime cocaine use. 3) GMV in the DLPFC and hippocampus, was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Conclusions This study documents for the first time, the enhanced sensitivity of CUD low MAOA carriers to GM loss, specifically in the OFC, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, chronic alcohol use was a major contributor to GM loss in the DLPFC and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Methylphenidate (MPH) is a stimulant drug that amplifies dopamineric and noradrenergic signaling in the brain, which is believed to underlie its cognition enhancing effects. However, the neurobiological effects by which MPH improves cognition are still poorly understood. Here, functional magnetic resonance imaging (fMRI) was used together with working memory (WM) and visual attention (VA) tasks to test the hypothesis that 20 mg oral MPH would increase activation in the dorsal attention network (DAN) and deactivation in the default mode network (DMN) as well as improve performance during cognitive tasks in healthy men. The group of subjects that received MPH (MPH group; N = 16) had higher activation than the group of subjects who received no medication (control group: N = 16) in DAN regions (parietal and prefrontal cortex, regions increasingly activated with increased cognitive load) and had increased deactivation in the insula and posterior cingulate cortex (regions increasingly deactivated with increased cognitive load) and these effects did not differ for the VA and the WM tasks. These findings provide the first evidence that MPH enhances activation of the DAN whereas it alters DMN deactivation. This suggests that MPH (presumably by amplifying dopamine and noradrenergic signaling) modulates cognition in part through its effects on DAN and DMN.