Faculty Bibliography

Methylphenidate and the amphetamines are the most frequently used medications for treating attention-deficit/hyperactivity disorder (ADHD). These medications modulate both norepinephrine as well as dopamine. Methyl-phenidate is a pure blocker of the norepinephrine and dopamine transporters. The amphetamines also block reuptake of both catecholamines, but they also release all three monoamines, norepinephrine, dopamine, and serotonin, from presynaptic vesicles. Amphetamines are the most robust agents in increasing synaptic dopamine levels, since they do so regardless of the endogenous level of the relevant neurons. Stimulant-evoked synaptic increases of dopamine have been demonstrated in the striatum in humans, but pharmacologic effects are likely relevant to therapeutic action in other regions, particularly the prefrontal cortex. Blockade of noradrenergic reuptake in the prefrontal cortex may also indirectly increase prefrontal dopamine levels, but there is also evidence that noradrenergic effects are mediated by alpha-2a noradrenergic receptors. A recent study in non-human primates found that methylphenidate and atomoxetine both increased the efficiency of prefrontal pyramidal neurons, but via distinct mechanisms. Methylphenidate decreased non-specific signals, i.e., neuronal noise, via D1 receptors. By contrast, atomoxetine increased the strength of specific signals via activation of alpha-2 receptors. These findings, although in non-human primates, suggest that combinations of agents working on these complementary systems (D1 and alpha-2a) may be worth considering and evaluating rigorously in patients with ADHD with sub-optimal responses to monotherapy

Functional connectivity can be measured during task-based functional magnetic resonance imaging (fMRI), or in the absence of specific stimuli or tasks. In either case, the study of low frequency fluctuations in the BOLD signal reveals patterns of synchronization which delineate the intrinsic functional architecture of the brain. The scientific community now has available shared resources to accelerate the exploitation of resting state fMRI with the objectives of improving diagnostic methods and leading to better treatments grounded in neuroscience. Fomenting a collaborative scientific culture will accelerate our understanding of the underlying phenonmemna. Recently, the Spanish Resting State Network (SRSN) has joined this collaborative effort by creating a setting to facilitate collaboration among the various neuroscience research groups working in Spanish (http://www.nitrc.org/projects/srsn)

CONTEXT: Long-term 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 genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. DESIGN: Cross-sectional comparison. SETTING: Clinical Research Center at Brookhaven National Laboratory. PATIENTS: Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). MAIN OUTCOME MEASURES: The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis x MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. RESULTS: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. CONCLUSIONS: Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable developmental disorder characterized by a persistent impairing pattern of inattention and/or hyperactivity-impulsivity. Using families from a genetic isolate, the Paisa population from Colombia, and five independent datasets from four different populations (United States, Germany, Norway and Spain), a highly consistent association was recently reported between ADHD and the latrophilin 3 (LPHN3) gene, a brain-specific member of the LPHN subfamily of G-protein-coupled receptors that is expressed in ADHD-related regions, such as amygdala, caudate nucleus, cerebellum and cerebral cortex. To replicate the association between LPHN3 and ADHD in adults, we undertook a case-control association study in 334 adult patients with ADHD and 334 controls with 43 single nucleotide polymorphisms (SNPs) covering the LPNH3 gene. Single- and multiple-marker analyses showed additional evidence of association between LPHN3 and combined type ADHD in adulthood [P = 0.0019; df = 1; odds ratio (OR) = 1.82 (1.25-2.70) and P = 5.1e-05; df = 1; OR = 2.25 (1.52-3.34), respectively]. These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan

The polarized domains of myelinated axons are specifically organized to maximize the efficiency of saltatory conduction. The paranodal region is directly adjacent to the node of Ranvier and contains specialized septate-like junctions that provide adhesion between axons and glial cells and that constitute a lateral diffusion barrier for nodal components. To complement and extend earlier studies on the peripheral nervous system, electron tomography was used to image paranodal regions from the central nervous system (CNS). Our three-dimensional reconstructions revealed short filamentous linkers running directly from the septate-like junctions to neurofilaments, microfilaments, and organelles within the axon. The intercellular spacing between axons and glia was measured to be 7.4 +/- 0.6 nm, over twice the value previously reported in the literature (2.5-3.0 nm). Averaging of individual junctions revealed a bifurcated structure in the intercellular space that is consistent with a dimeric complex of cell adhesion molecules composing the septate-like junction. Taken together, these findings provide new insight into the structural organization of CNS paranodes and suggest that, in addition to providing axo-glial adhesion, cytoskeletal linkage to the septate-like junctions may be required to maintain axonal domains and to regulate organelle transport in myelinated axons. (c) 2010 Wiley-Liss, Inc