Altered hypothalamic response to food in smokers.

BACKGROUND: Smoking cessation is often followed by weight gain. Eating behaviors and weight change have been linked to the brain response to food, but it is unknown whether smoking influences this response. OBJECTIVE: We determined the influence of smoking status (smokers compared with nonsmokers) on the brain response to food in regions associated with weight changes in nonsmokers. DESIGN: In study 1, we used functional MRI (fMRI) to identify regions of the brain associated with weight change in nonsmokers. BMI and the brain response to a milk shake, which is a palatable and energy-dense food, were measured in a group of 27 nonsmokers (5 men). Sixteen subjects (3 men) returned 1 y later for BMI reassessment. The change in BMI was regressed against the brain response to isolate regions associated with weight change. In study 2, to determine whether smokers showed altered responses in regions associated with weight change, we assessed the brain response to a milk shake in 11 smokers. The brain response to a milk shake compared with a tasteless control solution was assessed in 11 smokers (5 men) in comparison with a group of age-, sex- and body weight-matched nonsmokers selected from the pool of nonsmokers who participated in study 1. RESULTS: The response in the midbrain, hypothalamus, thalamus, and ventral striatum was positively associated with weight change at the 1-y follow-up in 16 nonsmokers. Compared with nonsmokers, smokers had a greater response to milk shakes in the hypothalamus. CONCLUSION: Smokers display an altered brain response to food in the hypothalamus, which is an area associated with long-term weight change in nonsmokers.

Brain activity for chronic knee osteoarthritis: dissociating evoked pain from spontaneous pain.

Chronic pain is a hallmark of osteoarthritis (OA), yet little is known about its properties and representation in the brain. Here we use fMRI combined with psychophysics to study knee pain in fourteen OA patients and nine healthy controls. Mechanical painful pressure stimuli were applied to the knee in both groups and ratings of evoked pain and related brain activity examined. We observe that psychophysical properties and brain activation patterns of evoked pain are essentially the same between OA patients and healthy subjects, and between worse and better OA knees. In OA patients, stimulus-related brain activity could be distinguished from brain activity associated with spontaneous pain. The former activated brain regions commonly observed for acute painful stimuli in healthy subjects, while the spontaneous pain of OA engaged prefrontal-limbic regions closely corresponding to areas observed for spontaneous pain in other chronic pain conditions, such as chronic back pain and post-herpetic neuralgia. Arthritis-related clinical characteristics of knee OA also mapped to prefrontal-limbic regions. In a subgroup of patients (n=6) we examined brain activity changes for a 2-week, repeat measure, cyclooxygenase-2 inhibitor (valdecoxib) therapy. Treatment decreased spontaneous pain for the worse knee and clinical characteristics of OA, and increased blood and csf levels of the drug which correlated positively with prefrontal-limbic brain activity. These findings indicate dissociation between mechanically induced and spontaneous OA knee pain, the latter engaging brain regions involved in emotional assessment of the self, and challenge the standard clinical view regarding the nature of OA pain.

Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain.

VIDEO ABSTRACT: We compared brain activations in response to acute noxious thermal stimuli in controls and chronic back pain (CBP) patients. Pain perception and related cortical activation patterns were similar in the two groups. However, nucleus accumbens (NAc) activity differentiated the groups at a very high accuracy, exhibiting phasic and tonic responses with distinct properties. Positive phasic NAc activations at stimulus onset and offset tracked stimulus salience and, in normal subjects, predicted reward (pain relief) magnitude at stimulus offset. In CBP, NAc activity correlated with different cortical circuitry from that of normals and phasic activity at stimulus offset was negative in polarity, suggesting that the acute pain relieves the ongoing back pain. The relieving effect was confirmed in a separate psychophysical study in CBP. Therefore, in contrast to somatosensory pathways, which reflect sensory properties of acute noxious stimuli, NAc activity in humans encodes its predicted value and anticipates its analgesic potential on chronic pain.

Towards a theory of chronic pain.

In this review, we integrate recent human and animal studies from the viewpoint of chronic pain. First, we briefly review the impact of chronic pain on society and address current pitfalls of its definition and clinical management. Second, we examine pain mechanisms via nociceptive information transmission cephalad and its impact and interaction with the cortex. Third, we present recent discoveries on the active role of the cortex in chronic pain, with findings indicating that the human cortex continuously reorganizes as it lives in chronic pain. We also introduce data emphasizing that distinct chronic pain conditions impact on the cortex in unique patterns. Fourth, animal studies regarding nociceptive transmission, recent evidence for supraspinal reorganization during pain, the necessity of descending modulation for maintenance of neuropathic behavior, and the impact of cortical manipulations on neuropathic pain is also reviewed. We further expound on the notion that chronic pain can be reformulated within the context of learning and memory, and demonstrate the relevance of the idea in the design of novel pharmacotherapies. Lastly, we integrate the human and animal data into a unified working model outlining the mechanism by which acute pain transitions into a chronic state. It incorporates knowledge of underlying brain structures and their reorganization, and also includes specific variations as a function of pain persistence and injury type, thereby providing mechanistic descriptions of several unique chronic pain conditions within a single model.

The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions.

Chronic complex regional pain syndrome (CRPS) is a debilitating pain condition accompanied by autonomic abnormalities. We investigated gray matter morphometry and white matter anisotropy in CRPS patients and matched controls. Patients exhibited a disrupted relationship between white matter anisotropy and whole-brain gray matter volume; gray matter atrophy in a single cluster encompassing right insula, right ventromedial prefrontal cortex (VMPFC), and right nucleus accumbens; and a decrease in fractional anisotropy in the left cingulum-callosal bundle. Reorganization of white matter connectivity in these regions was characterized by branching pattern alterations, as well as increased (VMPFC to insula) and decreased (VMPFC to basal ganglion) connectivity. While regional atrophy differentially related to pain intensity and duration, the strength of connectivity between specific atrophied regions related to anxiety. These abnormalities encompass emotional, autonomic, and pain perception regions, implying that they likely play a critical role in the global clinical picture of CRPS.

A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis.

The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments.

Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics.

Chronic pain patients suffer from more than just pain; depression and anxiety, sleep disturbances, and decision-making abnormalities (Apkarian et al., 2004a) also significantly diminish their quality of life. Recent studies have demonstrated that chronic pain harms cortical areas unrelated to pain (Apkarian et al., 2004b; Acerra and Moseley, 2005), but whether these structural impairments and behavioral deficits are connected by a single mechanism is as of yet unknown. Here we propose that long-term pain alters the functional connectivity of cortical regions known to be active at rest, i.e., the components of the "default mode network" (DMN). This DMN (Raichle et al., 2001; Greicius et al., 2003; Vincent et al., 2007) is marked by balanced positive and negative correlations between activity in component brain regions. In several disorders, however this balance is disrupted (Fox and Raichle, 2007). Using well validated functional magnetic resonance imaging (fMRI) paradigms to study the DMN (Fox et al., 2005), we investigated whether the impairments of chronic pain patients could be rooted in disturbed DMN dynamics. Studying with fMRI a group of chronic back pain (CBP) patients and healthy controls while executing a simple visual attention task, we discovered that CBP patients, despite performing the task equally well as controls, displayed reduced deactivation in several key DMN regions. These findings demonstrate that chronic pain has a widespread impact on overall brain function, and suggest that disruptions of the DMN may underlie the cognitive and behavioral impairments accompanying chronic pain.

Spontaneous pain and brain activity in neuropathic pain: functional MRI and pharmacologic functional MRI studies.

Functional brain imaging studies in chronic neuropathic pain patients have lagged far behind equivalent studies in acute pain. In the past few years, this trend has begun to shift. This article discusses the novel approach of studying brain activity for spontaneous pain and its modulation by pharmacologic manipulation. We argue that the approach provides a solid methodology for studying clinical (especially neuropathic) pain and patient populations, and moreover, that the latest results using this approach imply that distinct clinical chronic pain conditions seem to involve specific brain circuitry, which is also distinct from the brain activity commonly observed in acute pain.

Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain.

Living with unrelenting pain (chronic pain) is maladaptive and is thought to be associated with physiological and psychological modifications, yet there is a lack of knowledge regarding brain elements involved in such conditions. Here, we identify brain regions involved in spontaneous pain of chronic back pain (CBP) in two separate groups of patients (n = 13 and n = 11), and contrast brain activity between spontaneous pain and thermal pain (CBP and healthy subjects, n = 11 each). Continuous ratings of fluctuations of spontaneous pain during functional magnetic resonance imaging were separated into two components: high sustained pain and increasing pain. Sustained high pain of CBP resulted in increased activity in the medial prefrontal cortex (mPFC; including rostral anterior cingulate). This mPFC activity was strongly related to intensity of CBP, and the region is known to be involved in negative emotions, response conflict, and detection of unfavorable outcomes, especially in relation to the self. In contrast, the increasing phase of CBP transiently activated brain regions commonly observed for acute pain, best exemplified by the insula, which tightly reflected duration of CBP. When spontaneous pain of CBP was contrasted to thermal stimulation, we observe a double-dissociation between mPFC and insula with the former correlating only to intensity of spontaneous pain and the latter correlating only to pain intensity for thermal stimulation. These findings suggest that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self.

Brain imaging findings in neuropathic pain.

The contribution of brain imaging technologies to the understanding of mechanisms underlying clinical neuropathic conditions is discussed in this article. Available technologies, their advantages, and contributions also are presented. The brain regions involved in acute pain are contrasted to chronic pain and the implications of these differences are discussed. Overall, the reasons for the limited contribution of these techniques to the science of chronic pain are presented in this article.