Alterations in the default mode network (DMN) are associated with aging. We assessed age-dependent changes of DMN interactions and correlations with a battery of neuropsychological tests, to understand the differences of DMN directed connectivity between young and older subjects. Using a novel multivariate analysis method on resting-state functional MRI data from fifty young and thirty-one healthy older subjects, we calculated intra- and inter-DMN 4-nodes directed pathways. For the old subject group, we calculated the partial correlations of inter-DMN pathways with: psychomotor speed and working memory, executive function, language, long-term memory and visuospatial function. Pathways connecting the DMN with visual and limbic regions in older subjects engaged at BOLD low frequency and involved the dorsal posterior cingulate cortex (PCC), whereas in young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) cortex and the DMN, were SM efferent in the young subjects and SM afferent in the older subjects. Most DMN efferent pathways correlated with reduced speed and working memory. We suggest that the reduced sensorimotor efferent and the increased need to control such activities, cause a higher dependency on external versus internal cues thus suggesting how physical activity might slow aging.

• MeSH
• Memory, Short-Term MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Brain Mapping * methods   MeSH
• Brain * diagnostic imaging   MeSH
• Neural Pathways MeSH
• Aged MeSH
• Aging MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

What is the neural substrate of our capability to properly react to changes in the environment? It can be hypothesized that the anterior cingulate cortex (ACC) manages repetitive stimuli in routine conditions and alerts the dorsolateral prefrontal cortex (PFC) when stimulation unexpectedly changes. To provide evidence in favor of this hypothesis, intracerebral stereoelectroencephalographic (SEEG) data were recorded from the anterior cingulate and dorsolateral PFC of eight epileptic patients in a standard visual oddball task during presurgical monitoring. Two types of stimuli (200 ms duration) such as the letters O (frequent stimuli; 80% of probability) and X (rare stimuli) were presented in random order, with an interstimulus interval between 2 and 5 s. Subjects had to mentally count the rare (target) stimuli and to press a button with their dominant hand as quickly and accurately as possible. EEG frequency bands of interest were theta (4-8 Hz), alpha (8-12 Hz), beta (14-30 Hz), and gamma (30-45 Hz). The directionality of the information flux within the EEG rhythms was indexed by a directed transfer function (DTF). The results showed that compared with the frequent stimuli, the target stimuli induced a statistically significant increase of DTF values from the anterior cingulate to the dorsolateral PFC at the theta rhythms (P < 0.01). These results provide support to the hypothesis that ACC directly or indirectly affects the oscillatory activity of dorsolateral PFC by a selective frequency code under typical oddball conditions. (c) 2007 Wiley-Liss, Inc.

• MeSH
• Action Potentials physiology   MeSH
• Biological Clocks physiology   MeSH
• Gyrus Cinguli anatomy & histology   physiology   MeSH
• Adult MeSH
• Mental Processes physiology   MeSH
• Electroencephalography methods   MeSH
• Evoked Potentials physiology   MeSH
• Financing, Organized MeSH
• Data Interpretation, Statistical MeSH
• Cognition physiology   MeSH
• Humans MeSH
• Brain Mapping MeSH
• Young Adult MeSH
• Neural Pathways anatomy & histology   physiology   MeSH
• Neurons physiology   MeSH
• Neuropsychological Tests MeSH
• Signal Processing, Computer-Assisted MeSH
• Prefrontal Cortex anatomy & histology   physiology   MeSH
• Photic Stimulation MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH

INTRODUCTION: Studies in the sensorimotor system of older versus young individuals have shown alterations in functional connectivity and organization. Our objective was to explore the implications of these differences in terms of local organizations, and to identify processes that correlate with neuropsychological parameters. METHODS: Using a novel multivariate analysis method on resting-state functional MRI data obtained from 50 young and 31 older healthy individuals, we identified directed 4-node functional pathways within the sensorimotor system and examined their correlations with neuropsychological assessments. RESULTS: In young individuals, the functional pathways were unidirectional, flowing from the primary motor and sensory cortices to higher motor and visual regions. In older individuals, the functional pathways were more complex. They originated either from the calcarine sulcus or the insula and passed through mutually coupled high-order motor areas before reaching the primary sensory and motor cortices. Additionally, the pathways in older individuals that resembled those found in young individuals exhibited a positive correlation with years of education. DISCUSSION: The flow pattern of young individuals suggests efficient and fast information transfer. In contrast, the mutual coupling of high-order motor regions in older individuals suggests an inefficient and slow transfer, a less segregated and a more integrated organization. The differences in the number of sensorimotor pathways and of their directionality suggests reduced efferent degenerated pathways and increased afferent compensated pathways. Furthermore, the positive effect of years of education may be associated with the Cognitive Reserve Hypothesis, implying that cognitive reserve could be maintained through specific information transfer pathways.

• Publication type
• Journal Article MeSH

Dopamine depletion in the axons of Parkinson's disease (PD) patients precedes depletion in cell bodies thus proposing that macroscopic connectivity can be used to understand disease mechanism. A novel multivariate functional connectivity analysis, based on high order coherence among four fMRI BOLD signals was applied on resting-state fMRI data of controls and PD patients (OFF and ON medication states) and unidirectional multiple-region pathways in the sensorimotor system were identified. Pathways were classified as "preserved" (unaffected by the disease), "damaged" (not observed in patients) and "corrected" (observed in controls and in PD-ON state). The majority of all pathways were feedforward, most of them with the pattern "S1→M1→SMA." Of these pathways, 67% were "damaged," 28% "preserved," and 5% "corrected." Prefrontal cortex (PFC) afferent and efferent pathways that corresponded to goal directed and habitual activities corresponded to recurrent circuits. Eighty-one percent of habitual afferent had internal cue (i.e., M1→S1→), of them 79% were "damaged" and the rest "preserved." All goal-directed afferent had external cue (i.e., S1→M1→) with third "damaged," third "preserved," and third "corrected." Corrected pathways were initiated in the dorsolateral PFC. Reduced connectivity of the SMA and PFC resulted from reduced sensorimotor afferent to these regions. Reduced sensorimotor internal cues to the PFC resulted with reduced habitual processes. Levodopa effects were for pathways that started in region reach with dopamine receptors. This methodology can enrich understudying of PD mechanisms in other (e.g., the default mode network) systems.

• MeSH
• Levodopa MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain Mapping MeSH
• Neural Pathways MeSH
• Rest MeSH
• Parkinson Disease * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The level of spinal cord injury (SCI) affects baroreflex regulation of blood pressure. While a parasympathetic cardiac chronotropic effect is preserved, baroreflex response could be impaired by sympathetic dysfunction under the SCI level. This study was aimed to evaluate the baroreflex function in SCI patients by the analysis of causal interaction between systolic blood pressure (SBP) and inter-beat intervals (IBI). Blood pressure was continuously recorded in 13 cervical SCI patients (CSCI), nine thoracic SCI (ThSCI) and 13 able-bodied controls (Con) during two phases: sitting (PS) and orthostatic challenge (PO). Beat-to-beat SBP and IBI sequences were obtained from continuous blood pressure recording. Closed loop of SBP-IBI interaction was mathematically opened by bivariate autoregressive model; causal coherence and baroreflex sensitivity (BRS) were calculated in baroreflex direction. Coherence quantifies causal synchronicity between SBP and IBI. The gain of transfer function from SBP to IBI represents BRS. PS (medians of CSCI/ThSCI/Con) coherence was 0.28/0.33/0.25 (no significant difference) and PS BRS was 6.98/7.54/6.66 (no difference). PO coherence was 0.18/0.58/0.45 (CSCI < ThCSI and Con; p < 0.01) and PO BRS was 2.38/5.87/6.22 (CSCI < ThCSI and Con; p < 0.01). For position change effect, there was no change in CSCI coherence; for ThSCI and Con, PS < PO (p < 0.05). For BRS in the CSCI group, PS < PO (p < 0.01); for ThSCI and Con, there was no change. BRS and coherence correlated negatively with SCI level (p < 0.01). In conclusion, baroreflex dysfunction in SCI patients was detected using causal analysis methods during orthostatic challenge only. Baroreflex dysfunction is probably an important mechanism of the more expressed blood pressure decrease associated with CSCI. The severity of autonomic dysfunction was related to SCI level.

• MeSH
• Baroreflex physiology   MeSH
• Adult MeSH
• Blood Pressure physiology   MeSH
• Humans MeSH
• Spinal Cord Injuries physiopathology   MeSH
• Posture physiology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

In our previous studies we described functional expression of organic cation transporter 3 (OCT3) and multidrug and toxin extrusion 1 (MATE1) protein in the rat placenta. Since metformin is a substrate of both OCT3 and MATE1, in this study we used the model of dually perfused rat placenta to investigate the role of these transporters in metformin passage across the placenta. We observed concentration-dependent transplacental clearance of metformin in both maternal-to-fetal and fetal-to-maternal directions; in addition metformin crossed the placenta from the fetal to maternal compartment even against its concentration gradient. This transport was completely inhibited by MPP(+), a common OCT3 and MATE1 inhibitor. Furthermore, we observed that the oppositely directed H(+)-gradient can drive the secretion of metformin from placenta to maternal circulation, confirming apical efflux of metformin from trophoblast by MATE1. In conclusion, we suggest an important role of OCT3 and MATE1 in the transplacental transfer of metformin.

• MeSH
• Antiporters metabolism   MeSH
• Hypoglycemic Agents metabolism   MeSH
• Rats MeSH
• Maternal-Fetal Exchange MeSH
• Metformin metabolism   MeSH
• Placenta metabolism   MeSH
• Rats, Wistar MeSH
• Organic Anion Transporters, Sodium-Independent metabolism   MeSH
• Organic Cation Transport Proteins metabolism   MeSH
• In Vitro Techniques MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The past years have seen an incredible increase in the quality and success rates of treatments in pediatric medicine. One of the resulting major challenges refers to the management of primary or secondary residual executive function deficits in affected children. These deficits lead to problems in the ability to acquire, understand, and apply abstract and complex knowledge and to plan, direct, and control actions. Executive functions deficits are important to consider because they are highly predictive of functioning in social and academic aspects of daily life. We argue that current clinical practice does not sufficiently account for the complex cognitive processes in this population. This is because widely applied pharmacological interventions only rarely account for the complexity of the underlying neuronal mechanisms and do not fit well into possibly powerful "individualized medicine" approaches. Novel treatment approaches targeting deficits in executive functions in seriously ill children could focus on neuronal oscillations, as these have some specific relations to different aspects of executive function. Importantly, such treatment approaches can be individually tailored to the individuals' deficits and can be transferred into home-treatment or e-health solutions. These approaches are easy-to-use, can be easily integrated into daily life, and are becoming increasingly cost-effective.

• Publication type
• Journal Article MeSH

• MeSH
• Cell Membrane enzymology   MeSH
• Yeasts MeSH
• Aspartic Acid MeSH
• Glutamic Acid MeSH
• Mutagenesis, Site-Directed MeSH
• Energy Transfer MeSH

OBJECT: The authors present the long-term results of nerve grafting and neurotization procedures in their group of patients with brachial plexus injuries and compare the results of "classic" methods of nerve repair with those of end-to-side neurorrhaphy. METHODS: Between 1994 and 2006, direct repair (nerve grafting), neurotization, and end-to-side neurorrhaphy were performed in 168 patients, 95 of whom were followed up for at least 2 years after surgery. Successful results were achieved in 79% of cases after direct repair and in 56% of cases after end-to-end neurotization. The results of neurotization depended on the type of the donor nerve used. In patients who underwent neurotization of the axillary and the musculocutaneous nerves, the use of intraplexal nerves (motor branches of the brachial plexus) as donors of motor fibers was associated with a significantly higher success rate than the use of extraplexal nerves (81% compared with 49%, respectively, p = 0.003). Because of poor functional results of axillary nerve neurotization using extraplexal nerves (success rate 47.4%), the authors used end-to-side neurorrhaphy in 14 cases of incomplete avulsion. The success rate for end-to-side neurorrhaphy using the axillary nerve as a recipient was 64.3%, similar to that for neurotization using intraplexal nerves (68.4%) and better than that achieved using extraplexal nerves (47.4%, p = 0.19). CONCLUSIONS: End-to-side neurorrhaphy offers an advantage over classic neurotization in not requiring sacrifice of any of the surrounding nerves or the fascicles of the ulnar nerve. Typical synkinesis of muscle contraction innervated by the recipient nerve with contraction of muscles innervated by the donor was observed in patients after end-to-side neurorrhaphy.

• MeSH
• Anastomosis, Surgical methods   MeSH
• Adult MeSH
• Financing, Organized MeSH
• Middle Aged MeSH
• Humans MeSH
• Spinal Nerves transplantation   MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Nerve Transfer MeSH
• Recovery of Function MeSH
• Brachial Plexus surgery   injuries   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Comparative Study MeSH

The wide variety of protein structures and functions results from the diverse properties of the 20 canonical amino acids. The generally accepted hypothesis is that early protein evolution was associated with enrichment of a primordial alphabet, thereby enabling increased protein catalytic efficiencies and functional diversification. Aromatic amino acids were likely among the last additions to genetic code. The main objective of this study was to test whether enzyme catalysis can occur without the aromatic residues (aromatics) by studying the structure and function of dephospho-CoA kinase (DPCK) following aromatic residue depletion. We designed two variants of a putative DPCK from Aquifex aeolicus by substituting (a) Tyr, Phe and Trp or (b) all aromatics (including His). Their structural characterization indicates that substituting the aromatics does not markedly alter their secondary structures but does significantly loosen their side chain packing and increase their sizes. Both variants still possess ATPase activity, although with 150-300 times lower efficiency in comparison with the wild-type phosphotransferase activity. The transfer of the phosphate group to the dephospho-CoA substrate becomes heavily uncoupled and only the His-containing variant is still able to perform the phosphotransferase reaction. These data support the hypothesis that proteins in the early stages of life could support catalytic activities, albeit with low efficiencies. An observed significant contraction upon ligand binding is likely important for appropriate organization of the active site. Formation of firm hydrophobic cores, which enable the assembly of stably structured active sites, is suggested to provide a selective advantage for adding the aromatic residues.

• MeSH
• Aquifex enzymology   genetics   MeSH
• Bacterial Proteins chemistry   genetics   MeSH
• Phosphotransferases (Alcohol Group Acceptor) chemistry   genetics   MeSH
• Catalytic Domain MeSH
• Catalysis MeSH
• Mutagenesis, Site-Directed MeSH
• Protein Structure, Secondary MeSH
• Amino Acid Substitution MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH