Why self-induced pain feels less painful than externally generated pain: distinct brain activation patterns in self- and externally generated pain

Voluntary movement generally inhibits sensory systems. However, it is not clear how such movement influences pain. In the present study, subjects actively or passively experienced mechanical pain or pressure during functional MRI scanning. Pain and pressure were induced using two modified grip strengthener rings, each twined with four crystal bead strings, with polyhedral beads to induce pain, or spherical beads to induce pressure. Subjects held one ring in the left hand and were either asked to squeeze their left hand with their right hand (i.e., active pain or pressure), or to have their left hand squeezed by the experimenter (i.e., passive pain or pressure). Subjects rated the intensity and unpleasantness of the pain sensation lower in the active procedure than in the passive one. Correspondingly, pain-related brain areas were inhibited in the case of self-generated pain, including the primary somatosensory cortex (SI), anterior cingulate cortex (ACC), and the thalamus. These results suggest that active movement behaviorally inhibits concomitant mechanical pain, accompanied by an inhibition of pain response in pain-related brain areas such as the SI cortex. This might be part of the mechanisms underlying the kinesitherapy for pain treatment.     

Towards a fourth spatial dimension of brain activity

Current advances in neurosciences deal with the functional architecture of the central nervous system, paving the way for general theories that improve our understanding of brain activity. From topology, a strong concept comes into play in understanding brain functions, namely, the 4D space of a “hypersphere’s torus”, undetectable by observers living in a 3D world. The torus may be compared with a video game with biplanes in aerial combat: when a biplane flies off one edge of gaming display, it does not crash but rather it comes back from the opposite edge of the screen. Our thoughts exhibit similar behaviour, i.e. the unique ability to connect past, present and future events in a single, coherent picture as if we were allowed to watch the three screens of past-present-future “glued” together in a mental kaleidoscope. Here we hypothesize that brain functions are embedded in a imperceptible fourth spatial dimension and propose a method to empirically assess its presence. Neuroimaging fMRI series can be evaluated, looking for the topological hallmark of the presence of a fourth dimension. Indeed, there is a typical feature which reveal the existence of a functional hypersphere: the simultaneous activation of areas opposite each other on the 3D cortical surface. Our suggestion—substantiated by recent findings—that brain activity takes place on a closed, donut-like trajectory helps to solve long-standing mysteries concerning our psychological activities, such as mind-wandering, memory retrieval, consciousness and dreaming state.     

Genomic expression patterns distinguish long-term from short-term glioblastoma survivors: a preliminary feasibility study

We used microarray analysis to investigate associations between genotypic expression profiles and survival phenotypes in patients with primary glioblastoma (GBM). Tumor samples from 7 long-term glioblastoma survivors (>24 months) and 13 short-term survivors (<9 months) were analyzed to detect differential patterns of gene expression between these groups and to identify genotypic subclasses of glioblastomas that correlate with survival phenotypes. Five unsupervised and three supervised clustering algorithms consistently and accurately grouped the tumors into genotypic subgroups corresponding to the two clinical survival phenotypes. Three unique prospective mathematical classification algorithms were subsequently trained to use expression data to stratify unknown glioblastomas between survival groups and performed this task with 100% accuracy in validation studies. A set of 1478 genes with significant differential expression (p<0.01) between long-term and short-term survivors was identified, and additional mathematical filtering was used to isolate a 43-gene "fingerprint" that distinguished survival phenotypes. Differential regulation of a subset of these genes was confirmed using RT-PCR. Gene ontology analysis of the fingerprint demonstrated pathophysiologic functions for the gene products that are consistent with current models of tumor biology, suggesting that differential expression of these genes may contribute etiologically to the observed differences in survival. These results demonstrate that unique expression profiles characterize genotypic subsets of primary GBMs associated with differential survival phenotypes, and these profiles can be used in a prospective fashion to assign unknown tumors to survival groups. Future efforts will focus on building more robust classifiers and identifying additional subclasses of gliomas with phenotypic significance.     

Arylsulfatase a activity and electrophoretic banding patterns from isolated human blood fractions

Arylsulfatase A (ASA) activity was studied from five blood fractions, leukocytes plus platelets (LKPL), leukocytes (LK), neutrophils (N), lymphocytes (LYM), and platelets (PL). No significant difference was found among the mean ASA specific activity values for the fractions. Electrophoretic examination revealed four distinct activity bands for the LKPL and PL fractions, while the LK, N, and LYM fractions showed only a single, broad peak, which indicates that the four-band pattern is associated with enzyme obtained from platelets. The PL fraction gave a clearer, more distinct banding pattern than the other four fractions. This clearly resolved electrophoretic banding pattern of ASA from pure platelet preparations was demonstrated for variant human ASA as well. These findings may be significant to future work investigating the biochemical genetics of ASA.     

A physiology-based inverse dynamic analysis of human gait using sequential convex programming: a comparative study

This paper presents an enhanced version of the previously proposed physiological inverse approach (PIA) to calculate musculotendon (MT) forces and evaluates the proposed methodology in a comparative study. PIA combines an inverse dynamic analysis with an optimisation approach that imposes muscle physiology and optimises performance over the entire motion. To solve the resulting large-scale, nonlinear optimisation problem, we neglected muscle fibre contraction speed and an approximate quadratic optimisation problem (PIA-QP) was formulated. Conversely, the enhanced version of PIA proposed in this paper takes into account muscle fibre contraction speed. The optimisation problem is solved using a sequential convex programing procedure (PIA-SCP). The comparative study includes PIA-SCP, PIA-QP and two commonly used approaches from the literature: static optimisation (SO) and computed muscle control (CMC). SO and CMC make simplifying assumptions to limit the computational time. Both methods minimise an instantaneous performance criterion. Furthermore, SO does not impose muscle physiology. All methods are applied to a gait cycle of six control subjects. The relative root mean square error averaged over all subjects, ε(RMS), between the joint torques simulated from the optimised activations and the joint torques obtained from the inverse dynamic analysis was about twice as large for SO (ε(RMS) = 86) as compared with CMC (ε(RMS) = 39) and PIA-SCP (ε(RMS) = 50). ε(RMS) was at least twice as large for PIA-QP (ε(RMS) = 197) than for all other methods. As compared with CMC, muscle activation patterns predicted by PIA-SCP better agree with experimental electromyography (EMG). This study shows that imposing muscle physiology as well as globally optimising performance is important to accurately calculate MT forces underlying gait.     

Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging

Functional MRI is a popular tool for investigating central processing of visceral pain in healthy and clinical populations. Despite this, the reproducibility of the neural correlates of visceral sensation by use of functional MRI remains unclear. The aim of the present study was to address this issue. Seven healthy right-handed volunteers participated in the study. Blood oxygen level-dependent contrast images were acquired at 1.5 T while subjects received nonpainful and painful phasic balloon distensions ("on-off" block design, 10 stimuli per "on" period, 0.3 Hz) to the distal esophagus. This procedure was repeated on two further occasions to investigate reproducibility. Painful stimulation resulted in highly reproducible activation over three scanning sessions in the anterior insula, primary somatosensory cortex, and anterior cingulate cortex. A significant decrease in strength of activation occurred from session 1 to session 3 in the anterior cingulate cortex, primary somatosensory cortex, and supplementary motor cortex, which may be explained by an analogous decrease in pain ratings. Nonpainful stimulation activated similar brain regions to painful stimulation, but with greater variability in signal strength and regions of activation between scans. Painful stimulation of the esophagus produces robust activation in many brain regions. A decrease in subjective perception of pain and brain activity from the first to the final scan suggests that serial brain imaging studies may be affected by habituation. These findings indicate that for brain imaging studies that require serial scanning, development of experimental paradigms that control for the effect of habituation is necessary.     

The fractal dimension of EEG as a physical measure of conscious human brain activities

In our previous paper we have given a neuroglia modulated neuronal network model which may display chaotic behaviours under certain parametric values. This work is an attempt to correlate the functions of conscious human brains with the chaotic states shown by the EEG patterns under different physiological conditions. Some of the difficulties and precautions of this kind of work are discussed.     

Towards clinical management of traumatic brain injury: a review of models and mechanisms from a biomechanical perspective

Traumatic brain injury (TBI) is a major worldwide healthcare problem. Despite promising outcomes from many preclinical studies, the failure of several clinical studies to identify effective therapeutic and pharmacological approaches for TBI suggests that methods to improve the translational potential of preclinical studies are highly desirable. Rodent models of TBI are increasingly in demand for preclinical research, particularly for closed head injury (CHI), which mimics the most common type of TBI observed clinically. Although seemingly simple to establish, CHI models are particularly prone to experimental variability. Promisingly, bioengineering-oriented research has advanced our understanding of the nature of the mechanical forces and resulting head and brain motion during TBI. However, many neuroscience-oriented laboratories lack guidance with respect to fundamental biomechanical principles of TBI. Here, we review key historical and current literature that is relevant to the investigation of TBI from clinical, physiological and biomechanical perspectives, and comment on how the current challenges associated with rodent TBI models, particularly those involving CHI, could be improved.     

Purification and characterization of G proteins from human brain: modification of GTPase activity upon phosphorylation

Summary Three G proteins from human brain membranes were purified to near homogeneity by conventional techniques including preparative electrophoresis. These G proteins were characterized by their ability to bind GTP, GDP and GTP analogs. Two of these proteins have molecular weights of 50,000 (G₅₀) and 36,000 (G₃₆), as determined on SDS-gels. G₃₆ was ADP-ribosylated by pertussis toxin. Thus, G₅₀ could represent a G_sα subunit, whereas G₃₆ could be G_iα or G_oα. G₅₀ was phosphorylated by cAMP dependent protein kinase and protein kinase C. G₃₆ was phosphorylated by a protein kinase independent of calcium and phospholipid, a proteolytic product of protein kinase C, analogous to protein kinase M. Phosphorylation of G₃₆ by this protein kinase induced a dramatic decrease in its GTPase activity. The third G protein, of molecular weight 22,000 probably belongs to the group of monomeric G proteins possessing functional similarities withras gene products. The regulation of G proteins involving calcium-dependent and independent pathways is delineated.     

On brain activity mapping: insights and lessons from Brain Decoding Project to map memory patterns in the hippocampus

The BRAIN project recently announced by the president Obama is the reflection of unrelenting human quest for cracking the brain code, the patterns of neuronal activity that define who we are and what we are. While the Brain Activity Mapping proposal has rightly emphasized on the need to develop new technologies for measuring every spike from every neuron, it might be helpful to consider both the theoretical and experimental aspects that would accelerate our search for the organizing principles of the brain code. Here we share several insights and lessons from the similar proposal, namely, Brain Decoding Project that we initiated since 2007. We provide a specific example in our initial mapping of real-time memory traces from one part of the memory circuit, namely, the CA1 region of the mouse hippocampus. We show how innovative behavioral tasks and appropriate mathematical analyses of large datasets can play equally, if not more, important roles in uncovering the specific-to-general feature-coding cell assembly mechanism by which episodic memory, semantic knowledge, and imagination are generated and organized. Our own experiences suggest that the bottleneck of the Brain Project is not only at merely developing additional new technologies, but also the lack of efficient avenues to disseminate cutting edge platforms and decoding expertise to neuroscience community. Therefore, we propose that in order to harness unique insights and extensive knowledge from various investigators working in diverse neuroscience subfields, ranging from perception and emotion to memory and social behaviors, the BRAIN project should create a set of International and National Brain Decoding Centers at which cutting-edge recording technologies and expertise on analyzing large datasets analyses can be made readily available to the entire community of neuroscientists who can apply and schedule to perform cutting-edge research.     

Sparse representation of brain aging: extracting covariance patterns from structural MRI

An enhanced understanding of how normal aging alters brain structure is urgently needed for the early diagnosis and treatment of age-related mental diseases. Structural magnetic resonance imaging (MRI) is a reliable technique used to detect age-related changes in the human brain. Currently, multivariate pattern analysis (MVPA) enables the exploration of subtle and distributed changes of data obtained from structural MRI images. In this study, a new MVPA approach based on sparse representation has been employed to investigate the anatomical covariance patterns of normal aging. Two groups of participants (group 1:290 participants; group 2:56 participants) were evaluated in this study. These two groups were scanned with two 1.5 T MRI machines. In the first group, we obtained the discriminative patterns using a t-test filter and sparse representation step. We were able to distinguish the young from old cohort with a very high accuracy using only a few voxels of the discriminative patterns (group 1:98.4%; group 2:96.4%). The experimental results showed that the selected voxels may be categorized into two components according to the two steps in the proposed method. The first component focuses on the precentral and postcentral gyri, and the caudate nucleus, which play an important role in sensorimotor tasks. The strongest volume reduction with age was observed in these clusters. The second component is mainly distributed over the cerebellum, thalamus, and right inferior frontal gyrus. These regions are not only critical nodes of the sensorimotor circuitry but also the cognitive circuitry although their volume shows a relative resilience against aging. Considering the voxels selection procedure, we suggest that the aging of the sensorimotor and cognitive brain regions identified in this study has a covarying relationship with each other.     

人脑对不同频率穴位电刺激反应的功能性磁共振成像

利用功能性磁共振方法研究人脑对不同频率穴位体表电刺激（transcutaneous electric nerve stimulation,TENS)的反应。实验对11名志愿得进行了22次脑部功能性磁共振成像。成像过程中,每名志愿者分别接受了2和100HzTENS刺激,刺激部位为左腿足三里和三阴交穴,结果为不同频率TENS都激活了初级和次级躯体感觉区,频率特异性的激活信号出现在与运动相关的区域、丘脑、边缘系统和联络皮层。结果显示,在相同穴位给予不同频率的TENS要以在大脑引起不同的反应,提示2和100HzTENS可能激活了不同的神经通路,这些神经通路分别在中枢神经系统起着不同的作用。     

Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study

In a modeling study we show that desynchronization stimulation may have powerful anti-kindling effects. For this, we incorporate spike-timing-dependent plasticity into a generic network of coupled phase oscillators, which serves as a model network of synaptically interacting neurons. Two states may coexist under spontaneous conditions: a state of uncorrelated firing and a state of pathological synchrony. Appropriate stimulation protocols make the network learn or unlearn the pathological synaptic interactions, respectively. Low-frequency periodic pulse train stimulation causes a kindling. Permanent high-frequency stimulation, used as golden standard for deep brain stimulation in medically refractory movement disorders, basically freezes the synaptic weights. In contrast, desynchronization stimulation, e.g., by means of a multi-site coordinated reset, has powerful long-term anti-kindling effects and enables the network to unlearn pathologically strong synaptic interactions. We propose desynchronization stimulation for the therapy of movement disorders and epilepsies.     

The stimulation of normal human melanocyte proliferation in vitro by melanocyte growth factor from bovine brain

Cell culture conditions for the selective growth and serial propagation of normal human melanocytes from epidermal tissue are described. In addition to the presence of 2% fetal bovine serum, the human melanocyte cell culture environment contains the following growth factor supplements: epidermal growth factor (10 ng/ml), triiodothyronine (10(-9) M), hydrocortisone, (5 X 10(-5) M), insulin (10 micrograms/ml), transferrin (10 micrograms/ml), 7S nerve growth factor (100 ng/ml) cholera toxin (10(-10) M), and bovine brain extract (150 micrograms/ml). The ability to establish selectively the human melanocyte in vitro has been attributed to the contrast between human epidermal keratinocytes and melanocytes for attachment to fibronectin, while the growth of the human melanocyte has been attributed to the mitogenic activity of the growth factor-supplemented medium. Human melanocytes can be cultivated for at least 15 cumulative population doublings and are capable of [3H]-Dopa incorporation. The growth factor-supplemented medium contains a neutral extract from bovine brain that is a potent source of a human melanocyte mitogen. The biological activity of melanocyte growth factor is described as a heat and alkaline-labile mitogen with an estimated molecular weight of 30,000 by gel exclusion chromatography and a weakly cationic isoelectric point. The mitogen is capable of stimulating the growth of quiescent populations of human melanocytes in vitro. The ability to isolate and propagate normal human melanocytes in vitro permitted an examination of the expression of fibronectin and tissue plasminogen activator. Human epidermal melanocytes established in culture do not contain either tissue plasminogen activator or fibronectin. In contrast, human melanoma cell lines contain immunologically detectable fibronectin and tissue plasminogen activator. The absence of tissue plasminogen activator and fibronectin in normal human melanocytes also occurs under conditions of co-cultivation with human melanoma cells. These contrasts between normal human melanocytes and human melanoma cells may be relevant to the metastatic capabilities of human melanoma.