Increasing consistency of disease biomarker prediction across datasets

Microarray studies with human subjects often have limited sample sizes which hampers the ability to detect reliable biomarkers associated with disease and motivates the need to aggregate data across studies. However, human gene expression measurements may be influenced by many non-random factors such as genetics, sample preparations, and tissue heterogeneity. These factors can contribute to a lack of agreement among related studies, limiting the utility of their aggregation. We show that it is feasible to carry out an automatic correction of individual datasets to reduce the effect of such 'latent variables' (without prior knowledge of the variables) in such a way that datasets addressing the same condition show better agreement once each is corrected. We build our approach on the method of surrogate variable analysis but we demonstrate that the original algorithm is unsuitable for the analysis of human tissue samples that are mixtures of different cell types. We propose a modification to SVA that is crucial to obtaining the improvement in agreement that we observe. We develop our method on a compendium of multiple sclerosis data and verify it on an independent compendium of Parkinson's disease datasets. In both cases, we show that our method is able to improve agreement across varying study designs, platforms, and tissues. This approach has the potential for wide applicability to any field where lack of inter-study agreement has been a concern. © 2014 Chikina, Sealfon

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative "pain matrix" that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a "pain matrix" and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience

Influence of Body Position on Cortical Pain-Related Somatosensory Processing: An ERP Study

Background: Despite the consistent information available on the physiological changes induced by head down bed rest, a condition which simulates space microgravity, our knowledge on the possible perceptual-cortical alterations is still poor. The present study investigated the effects of 2-h head-down bed rest on subjective and cortical responses elicited by electrical, pain-related somatosensory stimulation. Methodology/Principal Findings: Twenty male subjects were randomly assigned to two groups, head-down bed rest (BR) or sitting control condition. Starting from individual electrical thresholds, Somatosensory Evoked Potentials were elicited by electrical stimuli administered randomly to the left wrist and divided into four conditions: control painless condition, electrical pain threshold, 30 % above pain threshold, 30 % below pain threshold. Subjective pain ratings collected during the EEG session showed significantly reduced pain perception in BR compared to Control group. Statistical analysis on four electrode clusters and sLORETA source analysis revealed, in sitting controls, a P1 component (40–50 ms) in the right somatosensory cortex, whereas it was bilateral and differently located in BR group. Controls ’ N1 (80–90 ms) had widespread right hemisphere activation, involving also anterior cingulate, whereas BR group showed primary somatosensory cortex activation. The P2 (190–220 ms) was larger in left-central locations of Controls compared with BR group. Conclusions/Significance: Head-down bed rest was associated to an overall decrease of pain sensitivity and an altered pai

A Functional Architecture of Optic Flow in the Inferior Parietal Lobule of the Behaving Monkey

The representation of navigational optic flow across the inferior parietal lobule was assessed using optical imaging of intrinsic signals in behaving monkeys. The exposed cortex, corresponding to the dorsal-most portion of areas 7a and dorsal prelunate (DP), was imaged in two hemispheres of two rhesus monkeys. The monkeys actively attended to changes in motion stimuli while fixating. Radial expansion and contraction, and rotation clockwise and counter-clockwise optic flow stimuli were presented concentric to the fixation point at two angles of gaze to assess the interrelationship between the eye position and optic flow signal. The cortical response depended upon the type of flow and was modulated by eye position. The optic flow selectivity was embedded in a patchy architecture within the gain field architecture. All four optic flow stimuli tested were represented in areas 7a and DP. The location of the patches varied across days. However the spatial periodicity of the patches remained constant across days at ∼950 and 1100 µm for the two animals examined. These optical recordings agree with previous electrophysiological studies of area 7a, and provide new evidence for flow selectivity in DP and a fine scale description of its cortical topography. That the functional architectures for optic flow can change over time was unexpected. These and earlier results also from inferior parietal lobule support the inclusion of both static and dynamic functional architectures that define association cortical areas and ultimately support complex cognitive function

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania

The Human Operculo-Insular Cortex Is Pain-Preferentially but Not Pain-Exclusively Activated by Trigeminal and Olfactory Stimuli

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful

Viewing the body modulates both pain sensations and pain responses

Viewing the body can influence pain perception, even when vision is non-informative about the noxious stimulus. Prior studies used either continuous pain rating scales or pain detection thresholds, which cannot distinguish whether viewing the body changes the discriminability of noxious heat intensities or merely shifts reported pain levels. In Experiment 1, participants discriminated two intensities of heat-pain stimulation. Noxious stimuli were delivered to the hand in darkness immediately after participants viewed either their own hand or a non-body object appearing in the same location. The visual condition varied randomly between trials. Discriminability of the noxious heat intensities (d?) was lower after viewing the hand than after viewing the object, indicating that viewing the hand reduced the information about stimulus intensity available within the nociceptive system. In Experiment 2, the hand and the object were presented in separate blocks of trials. Viewing the hand shifted perceived pain levels irrespective of actual stimulus intensity, biasing responses toward ‘high pain’ judgments. In Experiment 3, participants saw the noxious stimulus as it approached and touched their hand or the object. Seeing the pain-inducing event counteracted the reduction in discriminability found when viewing the hand alone. These findings show that viewing the body can affect both perceptual processing of pain and responses to pain, depending on the visual context. Many factors modulate pain; our study highlights the importance of distinguishing modulations of perceptual processing from modulations of response bias

Thermal perception thresholds recorded using method of limits change over brief time intervals

This paper raises methodological issues concerning Quantitative Sensory Testing assessments used to investigate short term efficacy of analgesic interventions. Thermal perception thresholds were demonstrated to change over time even in the absence of an analgesic. Hence such assessments cannot reliably be used to make judgements about individual responses to interventions