Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder.

Endophentoypes, quantifiable traits lying on the causal chain between a clinical phenotype and etiology, can be used to accelerate genomic discovery in obsessive-compulsive disorder (OCD). Here we identify the neuroanatomic changes that are shared by 22 OCD adult and adolescent patients and 25 of their unaffected siblings who are at genetic risk for the disorder. Comparisons were made against 47 age and sex matched healthy controls. We defined the surface morphology of the striatum, globus pallidus and thalamus, and thickness of the cerebral cortex. Patients with OCD show significant surface expansion compared with healthy controls, following adjustment for multiple comparisons, in interconnected regions of the caudate, thalamus and right orbitofrontal cortex. Their unaffected siblings show similar, significant expansion, most marked in the ventromedial caudate bilaterally, the right pulvinar thalamic nucleus and the right orbitofrontal cortex. These regions define a network that has been consistently implicated in OCD. In addition, both patients with OCD and unaffected siblings showed similar increased thickness of the right precuneus, which receives rich input from the thalamic pulvinar nuclei and the left medial temporal cortex. Anatomic change within the orbitofrontostriatal and posterior brain circuitry thus emerges as a promising endophenotype for OCD.

Self-crosslinked fibrous collagen/chitosan blends: Processing, properties evaluation and monitoring of degradation by bi-fluorescence imaging.

Porous collagen/chitosan scaffolds with different Collagen:Chitosan (Coll:Ch) ratios were prepared by freeze-drying followed by self-crosslinking via dehydrothermal treatment (DHT) and characterized as biomaterials for tissue engineering. Cy7 and Cy5.5 fluorochromes were covalently grafted to collagen and chitosan, respectively. Thus, it was possible, using optical fluorescence imaging of the two fluorochromes, to simultaneously track their in vivo biodegradation, in a blend scaffold form. The fluorescence signal evolution, due to the bioresorption, corroborated with histological analysis. In vitro cytocompatibility of Coll:Ch blend scaffolds were evaluated with standardized tests. In addition, the scaffolds showed a highly interconnected porous structure. Extent of crosslinking was analyzed by convergent analysis using thermogravimetry, Fourier Transform Infrared Spectroscopy and PBS uptake. The variations observed with these techniques indicate strong interactions between collagen and chitosan (covalent and hydrogen bonds) promoted by the DHT. The mechanical properties were characterized to elucidate the impact of the different processing steps in the sample preparation (DHT, neutralization and sterilization by ß-irradiation) and showed a robust processing scheme with low impact of Coll:Ch composition ratio.

Polyelectrolyte complexes via desalting mixtures of hyaluronic acid and chitosan-Physicochemical study and structural analysis.

Polyelectrolyte complexes (PECs) were prepared from Chitosan (CS) and Hyaluronic Acid (HYA) homogeneous mixtures of aqueous solutions. The method consisted of preparing a homogeneous mixture of the two polysaccharides via charge screening at high salt concentrations. Then, the mixture was dialyzed, leading to the controlled self-assembly of the two polyelectrolytes. Critical parameters like the chitosan degree of acetylation (DA) and molar mass (Mw), the residual salt concentration and the molar charge ratio r=nNH3(+) (CS)/nCOO(-) (HYA) accounted for the transition from homogeneous aqueous solutions to colloidal suspensions (r=0.1) or gel coacervates (r=0.5). The influence of the DA and Mw of CS was evaluated by visual observations, light scattering and rheological measurements. For low values of r, Small Angle X-ray Scattering (SAXS) experiments revealed that the HYA nanostructure was weakly affected by the presence of PECs. On the contrary, the structure was impacted when increasing r, revealing a heterogeneous aggregate morphology with ladder-like chain interactions.

Thresholds of electrically induced defence reaction of the rat: short- and long-term adaptation mechanisms.

The thresholds of electrically induced defence reaction of the rat were studied through the logistic fitting of the response output. When stepwise increasing stimuli were applied at the dorsal midbrain, hierarchically organized mean thresholds, spaced 10 microA apart, were observed for immobility, running and jumping defensive behaviours. The parallel threshold functions of these responses, ranked in the above order, denote that they have distinct output probabilities when induced with sequential stepwise increasing stimuli. In contrast, when single daily stimuli were given in a random order, virtually superimposed threshold functions were obtained for these defensive behaviours. In this case, since the same output probabilities would be expected for immobility, running and jumping behaviours, the defence system seems to operate in a state of maximum entropy. The above data suggest that the dorsal midbrain, including the deep collicular layers and the periaqueductal gray, may encode hierarchical or non-hierarchical defensive patterns which, respectively, mimic either the attentive behaviour of the prey watching the approaching predator or its chaotic behaviour when cornered by a sudden attack. On the other hand, whereas quite stable thresholds were observed for the somatic defensive responses when 5 stimulation sessions were repeated over 15 days, the defecation and micturition output underwent a marked and progressive lessening. Since these autonomic responses have long been considered as reliable indexes of fear, their attenuation throughout the repeated sessions could express the rat adaptation to fear by the recurrence of the aversive experience. Taken together, these data suggest that while short-term neuronal adaptation could be responsible for the hierarchical threshold structure of the short interval stepwise stimulation, long-term neuronal adaptation could underlie the selective decrease of defecation and micturition responses over repeated sessions of intracranial stimulation.

A fuzzy logic model for hand posture control using human cortical activity recorded by micro-ECog electrodes.

This paper presents a fuzzy logic model to decode the hand posture from electro-cortico graphic (ECoG) activity of the motor cortical areas. One subject was implanted with a micro-ECoG electrode array on the surface of the motor cortex. Neural signals were recorded from 14 electrodes on this array while Subject participated in three reach and grasp sessions. In each session, Subject reached and grasped a wooden toy hammer for five times. Optimal channels/electrodes which were active during the task were selected. Power spectral densities of optimal channels averaged over a time period of 1/2 second before the onset of the movement and 1 second after the onset of the movement were fed into a fuzzy logic model. This model decoded whether the posture of the hand is open or closed with 80% accuracy. Hand postures along the task time were decoded by using the output from the fuzzy logic model by two methods (i) velocity based decoding (ii) acceleration based decoding. The latter performed better when hand postures predicted by the model were compared to postures recorded by a data glove during the experiment. This fuzzy logic model was imported to MATLABSIMULINK to control a virtual hand.

Human motor cortical activity recorded with Micro-ECoG electrodes, during individual finger movements.

In this study human motor cortical activity was recorded with a customized micro-ECoG grid during individual finger movements. The quality of the recorded neural signals was characterized in the frequency domain from three different perspectives: (1) coherence between neural signals recorded from different electrodes, (2) modulation of neural signals by finger movement, and (3) accuracy of finger movement decoding. It was found that, for the high frequency band (60-120 Hz), coherence between neighboring micro-ECoG electrodes was 0.3. In addition, the high frequency band showed significant modulation by finger movement both temporally and spatially, and a classification accuracy of 73% (chance level: 20%) was achieved for individual finger movement using neural signals recorded from the micro-ECoG grid. These results suggest that the micro-ECoG grid presented here offers sufficient spatial and temporal resolution for the development of minimally-invasive brain-computer interface applications.

Wetting transition on hydrophobic surfaces covered by polyelectrolyte brushes.

We study the wetting by water of complex "hydrophobic-hydrophilic" surfaces made of a hydrophobic substrate covered by a hydrophilic polymer brush. Polystyrene (PS) substrates covered with polystyrene- block-poly(acrylic acid) PS- b-PAA diblock copolymer layers were fabricated by Langmuir-Schaefer depositions and analyzed by atomic force microscopy (AFM) and ellipsometry. On bare PS substrate, we measured advancing angles theta A = 93 +/- 1 degrees and receding angles theta R = 81 +/- 1 degrees . On PS covered with poorly anchored PS- b-PAA layers, we observed large contact angle hysteresis, theta A approximately 90 degrees and theta R approximately 0 degrees , that we attributed to nanometric scale dewetting of the PS- b-PAA layers. On well-anchored PS- b-PAA layers that form homogeneous PAA brushes, a wetting transition from partial to total wetting occurs versus the amount deposited: both theta A and theta R decrease close to zero. A model is proposed, based on the Young-Dupre equation, that takes into account the interfacial pressure of the brush Pi, which was determined experimentally, and the free energy of hydration of the polyelectrolyte monomers Delta G PAA (hyd), which is the only fitting parameter. With Delta G PAA (hyd) approximately -1300 J/mol, the model renders the wetting transition for all samples and explains why the wetting transition depends mainly on the average thickness of the brush and weakly on the length of PAA chains.