The conditioned expectation or fear of pain often results in disability produced by stimuli related to a painful injury on the job, although the neuroscience of this expectation is unclear. Conditioned expectation in humans can be produced by a protocol that consists of a train of visual conditioning stimuli, some of which are paired (CS+) with a painful laser pulse unconditioned stimulus (US). We now propose to use this protocol to study two domains of this expectation: the experience of pain produced by the laser when it follows the CS+, and the anticipation of pain produced by the CS+. The latter is related to avoidance of future pain and the former is related to escape from current pain instead of approach, e.g. noncompliance with physical therapy which can cause some pain. Increases in either avoidance or escape behaviors are related to occurrence of, and worse outcomes in, chronic pain syndromes from osteoarthritis to fibromyalgia. We propose to study the two domains by recording local field potentials (LFP) directly from anatomic components in the brain involved in these two domains for the expectation of pain. Our Preliminary Data shows LFP activations (ERPs Event Related Potentials & ERS/ERD - increases/ decreases in oscillatory power) in the Amygdala (AMY), Hippocampal formation and parts of the cingulate cortex in response to the unpaired CS+ and US, which may mediate conditioning and produce Conditioned Responses (CRs). CRs for anticipation include increases in: autonomic activity (Skin Conductance Response, SCR), and in ratings of the association between the CS+ and US, and CS unpleasantness and attention produced by a stimulus (salience). The experience of the US was painful, unlike the CS, and was related to conditioning but not to CS unpleasantness or salience, which is consistent with the presence of two separate domains. The CS SCR was related to ERS/ERD and ERC as a function of both frequency bands and components which were different from those related to the CS+ US association which, in turn, were different from those related to CS unpleasantness and CS salience. Model networks for each domain are suggested by these Data, and are supported by the evidence of studies of anatomic projections and fMRI signals. These two models share components including nuclei within the AMY, Anterior and Mid-Cingulate, but differ in components of the Hippocampal formation, Insula, and Lateral Prefrontal Cortex, and in Local networks defined by the presence of of components within one structure or within adjacent structures. Our premise is that components in these models will be involved in pain and conditioning processes, and show activations related to one of the two domains as individual components or as part of Local Network, and will show interactions that define a distributed, Hierarchical network for that domain. This study may suggest sites of interest in drug development and in surgical or stimulation therapies for pain syndromes with significant fear of pain, like studies of neural activity that led to a network model of the basal ganglia, which suggested therapeutic targets and transformed the treatment of Movement Disorders.
The conditioned expectation of pain is an important aspect of pain-related disability produced by environments and stimuli associated with a painful injury on the job, although the neuroscience of this expectation is unclear. We propose to study the neuroscience and mechanisms of expectation of pain by recording electrical signals through electrodes implanted on and in the brain during the surgical treatment or epilepsy, a platform of unrivaled clarity and resolution. The results of this study may lead to testable hypotheses regarding the neural basis of the fear of pain and its treatment by anatomically based surgical or stimulation therapies.
