**9. Decoding pain representation in the brain**

Recent progress has expanded the current view of pain representation and encoding in the brain by utilizing functional magnetic resonance imaging (fMRI), MR spectroscopy, MR morphometry, and diffusion tensor MRI. In a comprehensive review, Apkarian and colleagues summarize this recent progress and propose a model that includes a temporal, as well as a spatial, cerebral representation of pain [53]. They've suggested that in the context of acute thermal pain activity in the anterior insula, nucleus accumbens (NAc), and mid-cingulum peak prior to the conscious perception of pain, the "anticipation", while perception is distinctly correlated with peak activity in the anterior cingulate, mid- and posterior insula, and portions of the dorsal striatum. Lastly, as the stimulus is extinguished bringing about "relief" regions of the brainstem, in particular the periaqueductal grey (PAG), become active [53].

Two neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) are normally exclusively expressed by Aδ and C fibers in the periphery. Following nerve injury, however, Aβ fibers begin to manufacture these neuropeptides [43]. Additionally, there is evidence to suggest that remodeling of Aβ dendritic arbors can create novel circuitry [44]. These changes

10 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

In contrast to the gain-of-function changes that take place in Aβ fibers following injury, inhibitory descending and interneurons experience a sharp loss-of-function. This loss of inhibitory input releases the brake on neurotransmission and increases the excitatory current in the superficial dorsal horn [45]. Although there is evidence that excitotoxicity contributes to apoptotic loss of gamma-amino butyric acid (GABA)-ergic interneurons and descending inhibitory neurons of the rostroventral medulla [46, 47], it has been argued that injury-induced disinhibition is the result of attenuated efficacy of intact GABAergic interneurons that occurs independent of cell death [48-50]. Activation of microglia, resident macrophages of the nervous system, is a pathological hallmark of nervous system damage [51]. Release of brain-derived neurotrophic factor (BDNF) from activated microglia is necessary and sufficient to shift the anion reversal potential in lamina I projection neurons, reducing the effect of GABA in these neurons [52]. Specifically targeting BDNF or activated microglia may be a viable treatment for

Activation of peripheral nociceptors elicits a complex behavioral response that allows an organism to avoid the noxious stimulus immediately (by moving away from the source) and in the future (by enhanced learning and memory). To carry out the sum of these behaviors the pain circuit recruits a large number of cortical and subcortical regions that manage a variety of aspects of cognition and perception. Prominent examples include areas of the brain associated with motivation/reward, learning/memory, and somatosensation (reviewed in [53]). Classically, pain in the brain has been described in terms of a particular pattern of activation referred to as the "pain matrix". Areas of the matrix can be classified as belonging to one of two parallel pathways that control distinct aspects of pain: sensory discrimination (e.g. location, duration, and intensity) or affective/motivational (e.g. feelings of suffering and avoidance behaviors) [54, 55]. Increasing evidence gathered from rapidly evolving technology has suggested this description to be an oversimplification, however, as it applies uniquely to healthy individuals with experimentally induced acute pain [53]. Although useful, it is important for the future of pain research and treatment that we continue evaluate the current

Recent progress has expanded the current view of pain representation and encoding in the brain by utilizing functional magnetic resonance imaging (fMRI), MR spectroscopy, MR

all manifest as dynamic mechanical allodynia.

**8. Supraspinal nuclei interpret the signal**

schematic, employing new technologies as they develop.

**9. Decoding pain representation in the brain**

neuropathic pain.

Another significant finding led to the disentanglement of the neural coding for two distinct dimensions of a stimulus: the objective magnitude of an applied stimulus and an individual's subjective perception of stimulus intensity. Again using fMRI in the context of acute thermal pain, Baliki et. al. suggest that actual stimulus intensity is encoded by large portions of the cingulate and insular cortices while specific subsections of each, namely the anterior portion of the cingulate and the posterior insula, correlate strongly with subjective perception [56]. Thus it appears that pain perception follows a similar processing stream as other sensory modalities (e.g. vision, hearing, olfaction) wherein information about subjective magnitude is extracted by specific regions of the insular cortex [53]. These findings are beginning to lay the foundation for a clear and accurate representation of spatiotemporal coding of pain in the brain, with the ultimate goal of correlating neural activity with distinct cognitive and behav‐ ioral functions.
