Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

The neurobiology of interoception in health and disease

Interoception is the sensing of internal bodily sensations. Interoception is an umbrella term that encompasses (1) the afferent (body‐to‐brain) signaling through distinct neural and humoral (including immune and endocrine) channels; (2) the neural encoding, representation, and integration of this information concerning internal bodily state; (3) the influence of such information on other perceptions, cognitions, and behaviors; (4) and the psychological expression of these representations as consciously accessible physical sensations and feelings. Interoceptive mechanisms ensure physiological health through the cerebral coordination of homeostatic reflexes and allostatic responses that include motivational behaviors and associated affective and emotional feelings. Furthermore, the conscious, unitary sense of self in time and space may be grounded in the primacy and lifelong continuity of interoception. Body‐to‐brain interactions influence physical and mental well‐being. Consequently, we show that systematic investigation of how individual differences, and within‐individual changes, in interoceptive processing can contribute to the mechanistic understanding of physical and psychological disorders. We present a neurobiological overview of interoception and describe how interoceptive impairments at different levels relate to specific physical and mental health conditions, including sickness behaviors and fatigue, depression, eating disorders, autism, and anxiety. We frame these findings in an interoceptive predictive processing framework and highlight potential new avenues for treatments

Interoception and inflammation in psychiatric disorders

Despite a historical focus on neurally-mediated interoceptive signaling mechanisms, humoral (and even cellular) signals also play an important role in communicating bodily physiological state to the brain. These signaling pathways can perturb neuronal structure, chemistry and function leading to discrete changes in behavior. They are also increasingly implicated in the pathophysiology of psychiatric disorders. The importance of these humoral signaling pathways is perhaps most powerfully illustrated in the context of infection and inflammation. Here we provide an overview of how immune activation of neural and humoral interoceptive mechanisms interact to mediate discrete changes in brain and behavior and highlight how activation of these pathways at specific points in neural development may predispose to psychiatric disorder. As our mechanistic understanding of these interoceptive pathways continues to emerge it is revealing novel therapeutic targets, potentially heralding an exciting new era of immunotherapies in psychiatry

Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art

Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins – and how these lead to neurodegeneration – remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression

The Sensitivity of Endpoint Forces Produced by the Extrinsic Muscles of the Thumb to Posture

This study utilizes a biomechanical model of the thumb to estimate the force produced at the thumb-tip by each of the four extrinsic muscles. We used the principle of virtual work to relate joint torques produced by a given muscle force to the resulting endpoint force and compared the results to two separate cadaveric studies. When we calculated thumb-tip forces using the muscle forces and thumb postures described in the experimental studies, we observed large errors. When relatively small deviations from experimentally reported thumb joint angles were allowed, errors in force direction decreased substantially. For example, when thumb posture was constrained to fall within +15 degrees of reported joint angles, simulated force directions fell within experimental variability in the proximal-palmar plane for all four muscles. Increasing the solution space from +1 degrees to an unbounded space produced a sigmoidal decrease in error in force direction. Changes in thumb posture remained consistent with a lateral pinch posture, and were generally consistent with each muscle\u27s function. Altering thumb posture alters both the components of the Jacobian and muscle moment arms in a nonlinear fashion, yielding a nonlinear change in thumb-tip force relative to muscle force. These results explain experimental data that suggest endpoint force is a nonlinear function of muscle force for the thumb, support the continued use of methods that implement linear transformations between muscle force and thumb-tip force for a specific posture, and suggest the feasibility of accurate prediction of lateral pinch force in situations where joint angles can be measured accurately. Published by Elsevier Ltd

Computational Development of Jacobian Matrices for Complex Spatial Manipulators

Current methods for developing manipulator Jacobian matrices are based on traditional kinematic descriptions such as Denavit and Hartenberg parameters. The resulting symbolic equations for these matrices become cumbersome and computationally inefficient when dealing with more complex spatial manipulators, such as those seen in the field of biomechanics. This paper develops a modified method for Jacobian development based on generalized kinematic equations that incorporates partial derivatives of matrices with Leibniz\u27s Law (the product rule). It is shown that a set of symbolic matrix functions can be derived that improve computational efficiency when used in MATLAB (R) M-Files and are applicable to any spatial manipulator. An articulated arm subassembly and a musculoskeletal model of the hand are used as examples. (C) 2012 Elsevier Ltd. All rights reserved