Innovations In Clinical Neuroscience

MAY-JUN 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 5 – 6 , M A Y – J U N E 2 0 1 7 ] 14 more superficial regions of the dorsal horn ( e.g., laminae I and II) and become receptive to nociceptive input. 21 OVERVIEW OF BRAIN PROCESSING OF SENSORY STIMULI The manner in which chronic sensation develops was previously thought to mainly affect the somatosensory system, but now is thought to mainly affect emotional, cognitive, and modulatory areas of the brain. Defining these effects is imperative to understanding how they can modulate these sensations. Perhaps the most simple effect to understand is somatosensory information, which involves the evaluation of stimulus intensity, (i.e., duration, intensity, frequency) and the somatotopic representation of the stimulus. The cognitive aspects of processing sensory information involves increased "vigilance" toward this sensation and other sensation- related information. Finally, emotional aspects involved with the processing of sensory stimuli include the unpleasant mood that might result from different sensations. 20 Another negative cognitive and mood effect that impacts pain is catastrophizing. This construct incorporates magnification of pain-related symptoms, rumination about pain, feelings of helplessness, and pessimism about pain-related outcomes, and it is defined as a set of negative emotional and cognitive processes. 22 Thus, sensorimotor (SM), emotional/affective (EA), cognitive/integrative and modulatory regions of the brain are involved in the complex processing of sensory information, with some areas being involved in more than one domain. Overall, meta-analyses show that chronic sensory experiences produce activation in the primary and secondary somatosensory cortex (SM), insular cortex (SM/EA), anterior cingulate cortex (EA/CI), orbitofrontal cortex (EA/CI) and dorsolateral prefrontal cortex (CI). 20 BRAIN PROCESSING OF PAIN The rostral anterior cingulate cortex (rACC) connects to the hippocampus, and extends into the periaqueductal grey (PAG) area of the brainstem. It is well known that descending inhibitory pathways in the b rain that involve the rACC and PAG play a crucial role in pain modulation. 23 The PAG receives direct projections from regions within the limbic forebrain (i.e., rACC and the amygdala) and can modulate pain p erception through brainstem structures (i.e., rostral ventromedial medulla (RVM)), that directly communicate with nociceptive neurons in the dorsal horn of the spinal cord. 23 The ACC might be divided in subregions that serve different aspects of pain processing. Therefore, one region might be associated with increased or decreased response to pain depending on the exact anatomical location. While primary (S1) and secondary somatosensory cortices (S2) are involved in coding pain stimulus intensity and location, rACC appears to participate in both the affective and attentional concomitants of pain sensation, as well as response selection. 25 Recently published animal studies found augmented synaptic transmission in the ACC in response to long-term exposure to peripheral pain, and there is evidence suggesting that the rACC is required for the reward associated with pain relief. 2 3 Activation of the rACC in humans has been demonstrated during inhibition of pain, whereas activation of the more posterior parts of the ACC has been associated with increased pain and negative affect in humans. 2 3 The role of the hippocampus in pain modulation is likely related to the aversive drive and motivational dimension of pain. Similar to the posited role of the hippocampus, the activation of amygdala in relation to pain is proposed to represent a defensive mechanism that contributes to the recruitment of descending inhibition. Thus, the reduced connectivity between the rACC and hippocampus/amygdala in patients with chronic pain might indicate a weakened defensive response to pain stimuli. 23 The orbitofrontal cortex (OFC) is involved in sensory integration, reward processing, decision-making, and expectation. 23 A meta-analysis of previously published imaging data revealed that the medial part of the OFC is related to reward whereas the lateral areas are more associated with evaluation of noxious events and motivation to respond. 24 In a recent pain study, the OFC activity was a ssociated with reduction in pain unpleasantness after meditation training, which supports OFC involvement in the processing of incoming pain signals. Moreover the lateral OFC is central for p lacebo analgesia (compared to opioid analgesia) and for anticipation of pain relief, thus furthering the notion that the OFC plays an essential role in evaluation and inhibition of pain. 24 Finally, the insular cortex has a primary role in interoception, or the sense of the physiological condition of the body. The interoceptive pathway overlaps with the traditional pain pathways in several areas and additionally relays distinct painful sensory information with homeostatic properties. The parallel and imminent effect is increased pain sensitivity, as the insula is at the core of "the pain matrix" and relays sensory information to the limbic system as well as has a role in autonomic regulation. 26,27 In summary, pain-related brain areas have different patterns of activity with distinct characteristics during the processing of pain. Related to the affective aspects of pain processing, areas such as the insula, inferior frontal gyrus, orbitofrontal cortex, ventrolateral and dorsolateral prefrontal cortex, posterior cingulate cortex (PCC), and ACC show discriminative activity. The S1 and S2 areas as well as the insula are reportedly essential in the sensory processing of pain, with S2 also important for affective processing. Pain processing related to attention has been associated with significantly altered activity in the thalamus, insula, hippocampus, ACC, OFC, dorsolateral prefrontal cortex, and posterior parietal cortex. Finally, it is important to note that among these areas, the insula has been continually reported to be significantly active during the entirety of pain processing. Knowledge of these anatomic areas might be essential for treating chronic pain patients without distinct symptoms, as summarized in Table 1. 28 BRAIN PROCESSING OF PRURITIS The complexity of itch processing in the brain is consistent with the sensation's multidimensional nature. Cerebral neuropathic pruritus is induced

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