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  • Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.

    24 October 2018

    Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.

  • Pain, decisions, and actions: a motivational perspective.

    24 October 2018

    Because pain signals potential harm to the organism, it immediately attracts attention and motivates decisions and action. However, pain is also subject to motivations-an aspect that has led to considerable changes in our understanding of (chronic) pain over the recent years. The relationship between pain and motivational states is therefore clearly bidirectional. This review provides an overview on behavioral and neuroimaging studies investigating motivational aspects of pain. We highlight recent insights into the modulation of pain through fear and social factors, summarize findings on the role of pain in fear conditioning, avoidance learning and goal conflicts and discuss evidence on pain-related cognitive interference and motivational aspects of pain relief.

  • Phantom pain is associated with preserved structure and function in the former hand area.

    24 October 2018

    Phantom pain after arm amputation is widely believed to arise from maladaptive cortical reorganization, triggered by loss of sensory input. We instead propose that chronic phantom pain experience drives plasticity by maintaining local cortical representations and disrupting inter-regional connectivity. Here we show that, while loss of sensory input is generally characterized by structural and functional degeneration in the deprived sensorimotor cortex, the experience of persistent pain is associated with preserved structure and functional organization in the former hand area. Furthermore, consistent with the isolated nature of phantom experience, phantom pain is associated with reduced inter-regional functional connectivity in the primary sensorimotor cortex. We therefore propose that contrary to the maladaptive model, cortical plasticity associated with phantom pain is driven by powerful and long-lasting subjective sensory experience, such as triggered by nociceptive or top-down inputs. Our results prompt a revisiting of the link between phantom pain and brain organization.

  • An fMRI study exploring the overlap and differences between neural representations of physical and recalled pain.

    24 October 2018

    Implementing a recall paradigm without hypnosis, we use functional MRI (fMRI) to explore and compare nociceptive and centrally-driven pain experiences. We posit that a trace of a recent nociceptive event can be used to create sensory-re-experiencing of pain that can be qualified in terms of intensity and vividness. Fifteen healthy volunteers received three levels of thermal stimuli (warm, low pain and high pain) and subsequently were asked to recall and then rate this experience. Neuroimaging results reveal that recalling a previous sensory experience activates an extensive network of classical pain processing structures except the contralateral posterior insular cortex. Nociceptive-specific activation of this structure and the rated intensity difference between physical and recalled pain events allow us to investigate the link between the quality of the original nociceptive stimulus and the mental trace, as well as the differences between the accompanying neural responses. Additionally, by incorporating the behavioural ratings, we explored which brain regions were separately responsible for generating either an accurate or vivid recall of the physical experience. Together, these observations further our understanding of centrally-mediated pain experiences and pain memory as well as the potential relevance of these factors in the maintenance of chronic pain.

  • Relief as a reward: hedonic and neural responses to safety from pain.

    24 October 2018

    Relief fits the definition of a reward. Unlike other reward types the pleasantness of relief depends on the violation of a negative expectation, yet this has not been investigated using neuroimaging approaches. We hypothesized that the degree of negative expectation depends on state (dread) and trait (pessimism) sensitivity. Of the brain regions that are involved in mediating pleasure, the nucleus accumbens also signals unexpected reward and positive prediction error. We hypothesized that accumbens activity reflects the level of negative expectation and subsequent pleasant relief. Using fMRI and two purpose-made tasks, we compared hedonic and BOLD responses to relief with responses during an appetitive reward task in 18 healthy volunteers. We expected some similarities in task responses, reflecting common neural substrates implicated across reward types. However, we also hypothesized that relief responses would differ from appetitive rewards in the nucleus accumbens, since only relief pleasantness depends on negative expectations. The results confirmed these hypotheses. Relief and appetitive reward task activity converged in the ventromedial prefrontal cortex, which also correlated with appetitive reward pleasantness ratings. In contrast, dread and pessimism scores correlated with relief but not with appetitive reward hedonics. Moreover, only relief pleasantness covaried with accumbens activation. Importantly, the accumbens signal appeared to specifically reflect individual differences in anticipation of the adverse event (dread, pessimism) but was uncorrelated to appetitive reward hedonics. In conclusion, relief differs from appetitive rewards due to its reliance on negative expectations, the violation of which is reflected in relief-related accumbens activation.

  • Modeling of regional dynamic CO<inf>2</inf>reactivity in respiratory related brain areas using BOLD fMRI

    24 October 2018

    The cerebrovascular bed is very sensitive to CO2changes, particularly the areas responsible for generation and control of respiratory rhythm. We have used BOLD functional magnetic resonance imaging (fMRI) and externally induced CO2challenges that stimulate respiration, to identify respiratory areas in-vivo in humans and to quantify the dynamic effects of CO2on the BOLD fMRI signal (dynamic CO2reactivity). We sought to identify regional differences in dynamic reactivity within the brainstem and other respiratory related areas (thalamus) by using linear impulse response (IR) and nonlinear Volterra models, as well as experimental measurements obtained during spontaneous breathing and larger externally induced step CO2changes (end-tidal forcing). The results revealed areas in the brainstem and thalamus that responded strongly to the external CO2stimuli, which correspond to respiratory nuclei identified in recent rodent studies, as well as pronounced regional differences in CO2reactivity.