Chemical approaches to study metabolic networks

One of the more provocative realizations that have come out of the genome sequencing projects is that organisms possess a large number of uncharacterized or poorly characterized enzymes. This finding belies the commonly held notion that our knowledge of cell metabolism is nearly complete, underscoring the vast landscape of unannotated metabolic and signaling networks that operate under normal physiological conditions, let alone in disease states where metabolic networks may be rewired, dysregulated, or altered to drive disease progression. Consequently, the functional annotation of enzymatic pathways represents a grand challenge for researchers in the post-genomic era. This review will highlight the chemical technologies that have been successfully used to characterize metabolism, and put forth some of the challenges we face as we expand our map of metabolic pathways.     

New approaches to the delivery of drugs to the brain

The Human Immunodeficiency Virus (HIV) is the causative agent of AIDS and this has been found to be neurotropic. For this reason the development of an effective strategy for the delivery of antiviral drugs across the blood-brain barrier is of paramount importance in the treatment of HIV infection. There are insulin receptors on the capillary endothelial cells making up the blood-brain barrier (BBB) and it is proposed that these may play a role, along with exogenously administered insulin, in enhancing the transport of drug molecules across the BBB. Evidence is presented showing that insulin may be used as a pharmacologic adjunct in the therapy of HIV infection by allowing for higher concentrations of antiviral drugs to be obtained within the CNS using lower total doses of drug. This would enhance the drug's therapeutic effectiveness while simultaneously obviating potential dose-related side-effects.     

Comparative genetic approaches to the evolution of human brain and behavior

With advances in genomic technologies, the amount of genetic data available to scientists today is vast. Genomes are now available or planned for 14 different primate species and complete resequencing of numerous human individuals from numerous populations is underway. Moreover, high‐throughput deep sequencing is quickly making whole genome efforts within the reach of single laboratories allowing for unprecedented studies. Comparative genetic approaches to the identification of the underlying basis of human brain, behavior, and cognitive ability are moving to the forefront. Two approaches predominate: inter‐species divergence comparisons and intra‐species polymorphism studies. These methodological differences are useful for different time scales of evolution and necessarily focus on different evolutionary events in the history of primate and hominin evolution. Inter‐species divergence is more useful in studying large scale primate, or hominoid, evolution whereas intra‐species polymorphism can be more illuminating of recent hominin evolution. These differences in methodological utility also extend to studies of differing genetic substrates; current divergence studies focus primarily on protein evolution whereas polymorphism studies are substrate ambivalent. Some of the issues inherent in these studies can be ameliorated by current sequencing capabilities whereas others remain intractable. New avenues are also being opened that allow for the incorporation of novel substrates and approaches. In the post‐genomic era, the study of human evolution, specifically as it relates to the brain, is becoming more complete focusing increasingly on the totality of the system and better conceptualizing the entirety of the genetic changes that have lead to the human phenotype today. Am. J. Hum. Biol., 2011. © 2010 Wiley‐Liss, Inc.     

Multimodal mechanisms of attention related to rates of spatial shifting in vision and touch

Covert attention can be directed spatially in several different sensory modalities (e.g. vision and touch). Recent psychological experiments indicate the existence of crossmodal links in spatial attention, but their neural basis in humans remains underspecified. We used positron emission tomography (PET) to assess the role of stimulus modality in the activity of brain regions involved in different rates of spatial attention shifting. A 2×2 factorial design manipulated the rate (high versus low) of spatial attention shifts between left and right hemifields, plus the sensory modality (vision versus touch) of stimulation. Two brain regions showed activations related to attentional shift-rate, independent of the stimulated modality: these were the right frontopolar gyrus, and the right posterior superior temporal sulcus (STS). The anterior area showed higher blood flow with the high rate of shifts in spatial attention, while the posterior area showed higher flow during the low rate conditions, where attention was sustained for longer on one side. No area showed a significant rate effect in one modality without an effect in the second modality. These results demonstrate multimodal roles for the activated brain regions in relation to the rate of spatial attention shifting, plus right-hemisphere dominance for this. They also suggest that anterior and posterior regions of the spatial-attention network play different roles in attention shifting. Electronic Publication     

An event-related brain potential study of cross-modal links in spatial attention between vision and touch

Event-related potential (ERP) evidence for the existence of cross-modal links in endogenous spatial attention between vision and touch was obtained in an experiment where participants had to detect tactile or visual targets on the attended side and to ignore the irrelevant modality and stimuli on the unattended side. For visual ERPs, attentional modulations of occipital P1 and N1 components were present when attention was directed both within vision and within touch, indicating that links in spatial attention from touch to vision can affect early stages of visual processing. For somatosensory ERPs, attentional negativities starting around 140 ms poststimulus were present at midline and lateral central electrodes when touch was relevant. No attentional somatosensory ERP modulations were present when vision was relevant and tactile stimuli could be entirely ignored. However, in another task condition where responses were also required to infrequent tactile targets regardless of their location, visual-spatial attention modulated somatosensory ERPs. Unlike vision, touch apparently can be decoupled from attentional orienting within another modality unless it is potentially relevant.     

Time-varying cortical activations related to visual-tactile cross-modal links in spatial selective attention

The neural mechanisms underlying unimodal spatial attention have long been studied, but the cortical processes underlying cross-modal links remain a matter of debate. To reveal the cortical processes underlying the cross-modal links between vision and touch in spatial attention, we recorded magnetoencephalographic (MEG) responses to electrocutaneous stimuli when subjects directed attention to an electrocutaneous or visual stimulus presented randomly in the left or right space. Neural responses recorded around the bilateral sylvian fissures at 85 and 100 ms after the electrocutaneous stimulus were significantly enhanced by spatial attention in both the touch-irrelevant and -relevant modalities. Source analysis revealed that the sylvian responses were generated in the secondary somatosensory cortex (SII). An early response, M50c, generated in the contralateral primary somatosensory cortex (SI), was not modulated by attention. There were no significant attentional changes in the source location or magnetic field distribution, suggesting attentional facilitation of the neural activity in SII itself, rather than a tonic bias effect or overlapping of separate neuronal populations. The results show that spatial attention enhances responses to tactile inputs in SII, independent of sensory modality attended. The underlying mechanism remains to be determined, but may be an increase in gain.     

New approaches to modelling the disabled human operator

Tracking tasks are increasingly used to quantify eye/limb co-ordination and control, especially in patients with neurological disorders. However, the usual measures of a patient’s performance take no account of the movement strategy employed. Two new approaches to the characterisation of tracking by disabled patients are therefore developed: one based on probabilistic modelling techniques, the other on the theory of fuzzy sets. Although applied here to hemiplegic stroke patients, the work is of potential interest for a wide range of human movement studies.     

An ERP study of sustained spatial attention to stimulus eccentricity

Effects of attention on event-related brain potentials (ERPs) were measured when subjects kept sustained attention focused on ring-shaped regions of visual space to detect infrequently presented targets at a given eccentricity. In line with a previous study that employed a trial-by-trial cueing paradigm, no modulations of sensory-evoked P1 and N1 components were found. This suggests that attentional selectivity in complex spatial selection tasks is primarily located at post-perceptual processing levels. Enhanced negativities for attended as compared to unattended stimuli were present between 220 and 380 ms post-stimulus and were followed by an enlarged positivity for attended stimuli in the P3 time range. These effects reflected the distribution of attention in visual space, in part consistent with 'attentional gradient' and 'zoom-lens' models. However, ERPs also suggested the presence of selective mechanisms that exclude irrelevant stimuli located between two simultaneously attended areas.     

Tracking the voluntary control of auditory spatial attention with event-related brain potentials

A lateralized event-related potential (ERP) component elicited by attention-directing cues (ADAN) has been linked to frontal-lobe control but is often absent when spatial attention is deployed in the auditory modality. Here, we tested the hypothesis that ERP activity associated with frontal-lobe control of auditory spatial attention is distributed bilaterally by comparing ERPs elicited by attention-directing cues and neutral cues in a unimodal auditory task. This revealed an initial ERP positivity over the anterior scalp and a later ERP negativity over the parietal scalp. Distributed source analysis indicated that the anterior positivity was generated primarily in bilateral prefrontal cortices, whereas the more posterior negativity was generated in parietal and temporal cortices. The anterior ERP positivity likely reflects frontal-lobe attentional control, whereas the subsequent ERP negativity likely reflects anticipatory biasing of activity in auditory cortex.     

Systems approaches to the networks of aging

The aging of an organism is the result of complex changes in structure and function of molecules, cells, tissues, and whole body systems. To increase our understanding of how aging works, we have to analyze and integrate quantitative evidence from multiple levels of biological organization. Here, we define a broader conceptual framework for a quantitative, computational systems biology approach to aging. Initially, we consider fractal supply networks that give rise to scaling laws relating body mass, metabolism and lifespan. This approach provides a top-down view of constrained cellular processes. Concomitantly, multi-omics data generation build such a framework from the bottom-up, using modeling strategies to identify key pathways and their physiological capacity. Multiscale spatio-temporal representations finally connect molecular processes with structural organization. As aging manifests on a systems level, it emerges as a highly networked process regulated through feedback loops between levels of biological organization.     

Enhanced visual spatial attention ipsilateral to rTMS-induced 'virtual lesions' of human parietal cortex

The breakdown of attentional mechanisms after brain damage can have drastic behavioral consequences, as in patients suffering from spatial neglect. While much research has concentrated on impaired attention to targets contralateral to sites of brain damage, here we report the ipsilateral enhancement of visual attention after repetitive transcranial magnetic stimulation (rTMS) of parietal cortex at parameters known to reduce cortical excitability. Normal healthy subjects received rTMS (1 Hz, 10 mins) over right or left parietal cortex. Subsequently, detection of visual stimuli contralateral to the stimulated hemisphere was consistently impaired when stimuli were also present in the opposite hemifield, mirroring the extinction phenomenon commonly observed in neglect patients. Additionally, subjects' attention to ipsilateral targets improved significantly over normal levels. These results underline the potential of focal brain dysfunction to produce behavioral improvement and give experimental support to models of interhemispheric competition in the distributed brain network for spatial attention.     

New approaches to the treatment of human herpesvirus 8-associated disease

Human herpesvirus 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus or KSHV) is the etiologic agent of Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), as well as many cases of Castleman disease. Despite significant advances in understanding the biology and natural history of these diseases, current treatment options have important limitations, and strategies to prevent their development in high-risk individuals are lacking. This article reviews the scope of HHV-8-associated disease, as well as the efficacy of current treatment options. Finally, novel approaches to treatment and prevention are described, including antiviral agents, targeted molecular therapy and a combination of these modalities. Copyright (c) 2008 John Wiley & Sons, Ltd.     

Frontoparietal control of spatial attention and motor intention in human EEG

Relations between spatial attention and motor intention were investigated by means of an EEG potential elicited by shifting attention to a location in space as well as by the selection of a hand for responding. High-density recordings traced this potential to a common frontoparietal network activated by attentional orienting and by response selection. Within this network, parietal and frontal cortex were activated sequentially, followed by an anterior-to-posterior migration of activity culminating in the lateral occipital cortex. Based on temporal and polarity information provided by EEG, we hypothesize that the frontoparietal activation, evoked by directional information, updates a task-defined preparatory state by deselecting or inhibiting the behavioral option competing with the cued response side or the cued direction of attention. These results from human EEG demonstrate a direct EEG manifestation of the frontoparietal attention network previously identified in functional imaging. EEG reveals the time-course of activation within this network and elucidates the generation and function of associated directing-attention EEG potentials. The results emphasize transient activation and a decision-related function of the frontoparietal attention network, contrasting with the sustained preparatory activation that is commonly inferred from neuroimaging.     

A magnetoencephalographic study of brain activity related to recognition memory in healthy young human subjects

Neural activity associated with recognition memory was investigated using magnetencephalography (MEG) in healthy young subjects. At sensor sites overlying frontal and temporoparietal cortices, magnetic evoked fields (MEFs) revealed a difference between studied and unstudied stimuli, which onset about 400 ms following stimulus onset and lasted about 600 ms. MEG yielded reliable source information revealing the activity of three independent dipoles, located in the right medial temporal lobe (MTL), the right inferior frontal and the left inferior parietal cortices. Our findings suggest that neural activity underlying recognition memory from both superficial and deep brain structures can be monitored by MEG.     

Subcortical gating in the human visual system during spatial selective attention

The question of whether subcortical gating occurs as a function of spatial selective attention remains unsettled. This issue was investigated, using the paradigm of Eason et al. (1969) wherein subjects are instructed to attend to a specified location in a given visual field while attempting to ignore stimuli presented in the opposite field. Visual evoked responses falling within the 40-70 ms range were found to be significantly more negative when the location at which the evoking stimulus appeared was being attended to than when it was not. Also, later deflections (100-200 ms) were enhanced in amplitude and negatively biased. The very early effect provides further evidence for spatial attention-induced precortical gating. The later effects provide additional evidence for the amplitude enhancement of 'exogenous' components, along with the possible involvement of glial cell activity in the generation of slow wave negativity.     

Topographic maps of visual spatial attention in human parietal cortex

Functional magnetic resonance imaging (fMRI) was used to measure activity in human parietal cortex during performance of a visual detection task in which the focus of attention systematically traversed the visual field. Critically, the stimuli were identical on all trials (except for slight contrast changes in a fully randomized selection of the target locations) whereas only the cued location varied. Traveling waves of activity were observed in posterior parietal cortex consistent with shifts in covert attention in the absence of eye movements. The temporal phase of the fMRI signal in each voxel indicated the corresponding visual field location. Visualization of the distribution of temporal phases on a flattened representation of parietal cortex revealed at least two distinct topographically organized cortical areas within the intraparietal sulcus (IPS), each representing the contralateral visual field. Two cortical areas were proposed based on this topographic organization, which we refer to as IPS1 and IPS2 to indicate their locations within the IPS. This nomenclature is neutral with respect to possible homologies with well-established cortical areas in the monkey brain. The two proposed cortical areas exhibited relatively little response to passive visual stimulation in comparison with early visual areas. These results provide evidence for multiple topographic maps in human parietal cortex.     

Visual spatial attention to stimuli presented on the vertical and horizontal meridian: An ERP study

In the first experiment, 48 subjects carried out a visual spatial attention task. Stimuli were presented at the vertical meridian, either above or below a fixation dot, and the subjects were instructed to attend to one of these stimulus positions and ignore the other position. In three different conditions, the distances between stimulus positions and fixation were 0.5°, 0.9°, and 1.3°. Subjects searched for the presence of prememorized target letters at the attended location: memory load was one or four items in different conditions. The P1/N1 enhancement typically found on the horizontal dimension was not observed on the vertical dimension. Instead, a positive shift of the attended compared with the unattended stimuli was found, which was most prominent at anterior electrodes. This positivity showed effects of the distance manipulation. The N2b-P3a effect of attention and the effect of memory load (search negativity) normally present in this kind of selective search task were also found. Reaction times were faster when attention was directed above fixation than when it was directed below fixation. The event-related potential data suggested that this difference could be attributed to a more efficient neglecting of irrelevant stimuli presented below fixation. In Experiment 2, we examined whether the absence of the P1/N1 enhancement as the result of spatial attention in Experiment 1 could be attributed to (a) the presentation of stimuli along the vertical meridian instead of along the horizontal meridian, (b) the use of midline electrodes instead of lateralized electrodes, and (c) the relatively small spatial separation between the relevant and irrelevant stimuli. Twelve subjects searched for the presence of a single target letter at an attended position in three different conditions. In two of the conditions the letters were presented to the left or right of fixation. The distance between fixation and the stimulus positions was 1.3° in one of these conditions and 3° in the other condition. In the third condition, the stimuli were presented at 3° above or below fixation. In all three conditions effects similar to those in Experiment 1 were observed. In addition, in all three conditions an enhancement of the P1 and N1 components was found at two lateral occipitotemporal electrodes.