People sometimes solve problems with a unique process called insight, accompanied by an “Aha!” experience. It has long been unclear whether different cognitive and neural processes lead to insight versus noninsight solutions, or if solutions differ only in subsequent subjective feeling. Recent behavioral studies indicate distinct patterns of performance and suggest differential hemispheric involvement for insight and noninsight solutions. Subjects solved verbal problems, and after each correct solution indicated whether they solved with or without insight. We observed two objective neural correlates of insight. Functional magnetic resonance imaging (Experiment 1) revealed increased activity in the right hemisphere anterior superior temporal gyrus for insight relative to noninsight solutions. The same region was active during initial solving efforts. Scalp electroencephalogram recordings (Experiment 2) revealed a sudden burst of high-frequency (gamma-band) neural activity in the same area beginning 0.3 s prior to insight solutions. This right anterior temporal area is associated with making connections across distantly related information during comprehension. Although all problem solving relies on a largely shared cortical network, the sudden flash of insight occurs when solvers engage distinct neural and cognitive processes that allow them to see connections that previously eluded them.

Objectives-Functional MRI (fMRI) holds the promise of non-invasive mapping of human brain function in both health and disease. Yet its sensitivity and reliability for mapping higher cognitive function are still being determined. Using verbal fluency as a task, the objective was to ascertain the consistency of fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes. Comparison was made with previous PET studies. Methods-Using a 1.5 Tesla magnet and an echoplanar pulse sequence, whole brain fMRI was obtained from 12 normal right handed subjects (6 males and 6 females) as they performed a verbal fluency task. However, decremental responses were seen over a much larger area of the posterior cortex than had been anticipated by prior studies. The ability to see a response in each subject individually suggests that fMRI may be useful in the preinterventional mapping of pathological states, and oVers a non-invasive alternative to the Wada test for assessment of hemispheric dominance. There were no gross diVerences in the pattern of activation between male and female subjects. (J Neurol Neurosurg Psychiatry 1998;64:492-498)

Neurofeedback (NF) is an electroencephalographic (EEG) biofeedback technique for training individuals to alter their brain activity via operant conditioning. Research has shown that NF helps reduce symptoms of several neurological and psychiatric disorders, with ongoing research currently investigating applications to other disorders and to the enhancement of non-disordered cognition. The present article briefly reviews the fundamentals and current status of NF therapy and research and illustrates the basic approach with an interim report on a pilot study aimed at developing a new NF protocol for improving cognitive function in the elderly. EEG peak alpha frequency (PAF) has been shown to correlate positively with cognitive performance and to correlate negatively with age after childhood. The present pilot study used a double-blind controlled design to investigate whether training older individuals to increase PAF would result in improved cognitive performance. The results suggested that PAF NF improved cognitive processing speed and executive function, but that it had no clear effect on memory. In sum, the results suggest that the PAF NF protocol is a promising technique for improving selected cognitive functions.

Purpose: Unfractionated heparin reduces metastasis in many murine models. Multiple mechanisms are proposed, particularly anticoagulation and/or inhibition of P-selectin and L-selectin. However, the doses used are not clinically tolerable and other heparins are now commonly used. We studied metastasis inhibition by clinically relevant levels of various heparins and investigated the structural basis for selectin inhibition differences. Experimental Design: Five clinically approved heparins were evaluated for inhibition of P-selectin and L-selectin binding to carcinoma cells. Pharmacokinetic studies determined optimal dosing for clinically relevant anticoagulant levels in mice. Experimental metastasis assays using carcinoma and melanoma cells investigated effects of a single injection of various heparins. Heparins were compared for structural relationships to selectin inhibition. Results: One (Tinzaparin) of three low molecular weight heparins showed increased selectin inhibitory activity, and the synthetic pentasaccharide, Fondaparinux, showed none when normalized to anticoagulant activity. Experimental metastasis models showed attenuation with unfractionated heparin and Tinzaparin, but not Fondaparinux, at clinically relevant anticoagulation levels. Tinzaparin has a small population of high molecular weight fragments not present in other low molecular weight heparins, enriched for selectin inhibitory activity. Conclusions: Heparin can attenuate metastasis at clinically relevant doses, likely by inhibiting selectins. Equivalent anticoagulation alone with Fondaparinux is ineffective. Clinically approved heparins have differing abilities to inhibit selectins, likely explained by size distribution. It should be possible to size fractionate heparins and inhibit selectins at concentrations that do not have a large effect on coagulation. Caution is also raised about the current preference for smaller heparins. Despite equivalent anticoagulation, hitherto unsuspected benefits of selectin inhibition in various clinical circumstances may be unwittingly discarded.P-selectin and L-selectin are C-type lectins that recognize sialylated, fucosylated, sulfated ligands. P-selectin is stored within resting platelets and endothelial cells and translocates to the cell surface upon activation. L-selectin is constitutively expressed on most leukocyte types and mediates their interactions with endothelial ligands. Both selectins promote the initial tethering of leukocytes during extravasation at sites of inflammation. P-selectin also plays a role in hemostasis. Endogenous ligands for P-selectin and L-selectin (such as PSGL-1) are expressed on leukocytes and endothelial cells (for general reviews on selectins and their ligands, see refs. 1 -6).P-selectin and L-selectin also have pathologic roles in many diseases involving inflammation and reperfusion (7 -9), as well as in carcinoma metastasis. Many tumor cells express selectin ligands and an inverse relationship between tumor selectin ligand expression and survival has been rep...

People can solve problems in more than one way. Two general strategies involve (A) methodical, conscious, search of problem-state transformations, and (B) sudden insight, with abrupt emergence of the solution into consciousness. This study elucidated the influence of initial resting brain-state on subjects' subsequent strategy choices. High-density electroencephalograms (EEGs) were recorded from subjects at rest who were subsequently directed to solve a series of anagrams. Subjects were divided into two groups based on the proportion of anagram solutions derived with self-reported insight versus search. Reaction-time and accuracy results were consistent with different cognitive problem-solving strategies used for solving anagrams with versus without insight. Spectral analyses yielded group differences in resting-state EEG supporting hypotheses concerning insight-related attentional diffusion and right-lateralized hemispheric asymmetry. These results reveal a relationship between resting-state brain activity and problem-solving strategy, and, more generally, a dependence of event-related neural computations on the preceding resting-state. KeywordsAttention; Creativity; Hemispheric Asymmetry; Insight; Problem Solving; Resting State Systematic, relatively stable, patterns of resting-state brain activity are associated with aspects of personality, intelligence, psychopathology, and neurological disorder (Davidson, 2003;John et al., 1988;Kumari et al., 2004;Thatcher et al., 2005), perhaps reflecting subtle differences in neuroanatomy or neurotransmitter levels (John et al., 1988). The existence of such associations suggests the possibility that resting-state neural activity may also be correlated with individual differences in the event-related, goal-oriented, cognitive processes that people use to negotiate the world around them, such as those used in problem solving.The present study examined the hypothesis that resting-state neural activity influences the cognitive strategies people use to solve problems, in particular, the general strategies which result in problem solutions derived either by methodical search or by sudden insight. Determining whether the tendency to solve problems by search versus insight is influenced by Send editorial correspondence to John Kounios,

Hematogenous carcinoma metastasis is supported by aggregated platelets and leukocytes, forming tumor cell emboli. Early tumor cell-platelet interactions can be mediated by P-selectin binding to tumor cell surface ligands and this process is blocked by heparin. We previously showed that L-selectin deficiency also attenuates experimental metastasis. However, the mechanisms and timing of L-selectin action remained unknown. Here, we study how L-selectin facilitates establishment of pulmonary metastatic foci in syngeneic mice by using experimental metastasis to time events following entry of tumor cells into the bloodstream. Although L-selectin deficiency did not affect platelet aggregation or initial tumor cell embolization, the association of leukocytes with tumor cells was reduced and tumor cell survival was diminished 24 hours later. Temporal inhibition of L-selectin by a function-blocking antibody reduced metastasis. Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals. Thus, heparin apparently works at these time points primarily by blocking L-selectin. Endogenous L-selectin ligands were concomitantly induced adjacent to established intravascular tumor cell emboli in a similar time window when leukocytes were also present. Metastasis was attenuated in mice missing these induced endogenous L-selectin ligands due to fucosyltransferase-7 deficiency. Thus, L-selectin facilitation of metastasis progression involves leukocyte-endothelial interactions at sites of intravascular arrest supported by local induction of L-selectin ligands via fucosyltransferase-7. These data provide the first explanation for how leukocyte L-selectin facilitates tumor metastasis. (Cancer Res 2006; 66(3): 1536-42)

Twenty-four congenitally blind children between 3 and 9 years of age were studied for the prevalence of "autistic-like" features, as assessed by teacher reports and by systematic observations of the children's behaviour. A comparison between the 15 blind children who had IQs over 70 and 10 sighted children group-matched for age and verbal ability revealed that a number of autistic-like features were more common in the blind. When the nine blind children who had IQs less than 70 were compared with nine group-matched autistic children, the picture that emerged was of substantial overlap in clinical presentation, despite subtle differences on clinical impression. Similar results were obtained when blind subgroups were reconstituted according to the children's nonautistic or autistic-like clinical presentation, rather than IQ. These findings are discussed in relation to competing theories concerning the development of autism and "theory of mind".

Therapeutic proteins are exposed to various wetted surfaces that could shed sub-visible particles. In this work we measured the adsorption of a monoclonal antibody (mAb) to various microparticles, characterized the adsorbed mAb secondary structure, and determined the reversibility of adsorption. We also developed and used a front-face fluorescence quenching method to determine that the mAb tertiary structure was near-native when adsorbed to glass, cellulose and silica. Initial adsorption to each of the materials tested was rapid. During incubation studies, exposure to the air-water interface was a significant cause of aggregation but acted independently of the effects of microparticles. Incubations with glass, cellulose, stainless steel or Fe 2 O 3 microparticles gave very different results. Cellulose preferentially adsorbed aggregates from solution. Glass and Fe 2 O 3 adsorbed the mAb but did not cause aggregation. Adsorption to stainless steel microparticles was irreversible, and caused appearance of soluble aggregates upon incubation. The secondary structure of mAb adsorbed to glass and cellulose was near-native. We suggest that the protocol described in this work could be a useful preformulation stress screening tool to determine the sensitivity of a therapeutic protein to exposure to common surfaces encountered during processing and storage.