Paul Geha

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.

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.

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.

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.

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.

Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy

Abstract Postherpetic neuralgia (PHN) is a debilitating chronic pain condition, yet there is a lack of knowledge regarding underlying brain activity. Here we identify brain regions involved in spontaneous pain of PHN (n = 11) and determine its modulation with Lidoderm therapy (patches of 5% lidocaine applied to the PHN affected body part). Continuous ratings of fluctuations of spontaneous pain during fMRI were contrasted to ratings of fluctuations of a bar observed during scanning, at three sessions: (1) pre‐treatment baseline, (2) after 6 h of Lidoderm treatment, and (3) after 2 weeks of Lidoderm use. Overall brain activity for spontaneous pain of PHN involved affective and sensory‐discriminative areas: thalamus, primary and secondary somatosensory, insula and anterior cingulate cortices, as well as areas involved in emotion, hedonics, reward, and punishment: ventral striatum, amygdala, orbital frontal cortex, and ventral tegmental area. Generally, these activations decreased at sessions 2 and 3, except right anterior insular activity which increased with treatment. The sensory and affective activations only responded to the short‐term treatment (6 h of Lidoderm); while the ventral striatum and amygdala (reward‐related regions) decreased mainly with longer‐term treatment (2 weeks of Lidoderm). Pain properties: average magnitude of spontaneous pain, and responses on Neuropathic Pain Scale (NPS), decreased with treatment. The ventral striatal and amygdala activity best reflected changes in NPS, which was modulated only with longer‐term treatment. The results show a specific brain activity pattern for PHN spontaneous pain, and implicate areas involved in emotions and reward as best reflecting changes in pain with treatment.

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.

Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia

&NA; Postherpetic neuralgia (PHN) is a debilitating chronic pain condition often accompanied by a sensation of pain when the affected region is touched (tactile allodynia). Here we identify brain regions involved in stimulus‐induced touch‐evoked pain (dynamical mechanical allodynia, DMA), compare brain activity between DMA and spontaneous pain (described earlier for the same patients in [Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV. Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 2007;128:88–100]), delineate regions that specifically code the magnitude of perceived allodynia, and show the transformation of allodynia‐related information in the brain as a time‐evolving network. Eleven PHN patients were studied for DMA and its modulation with Lidoderm therapy (patches of 5% lidocaine applied to the PHN affected body part). Continuous ratings of pain while the affected body part was brushed during fMRI were contrasted with non‐painful touch when brushing was applied to an equivalent opposite body site, and with fluctuations of a bar observed during scanning, at three sessions relative to Lidoderm treatment. Lidoderm treatment did not decrease DMA ratings but did decrease spontaneous pain. Multiple brain areas showed preferential activity for allodynia. However, mainly responses in the bilateral putamen and left medial temporal gyrus were related to the magnitude of allodynia. Both DMA and spontaneous pain perceptions were best represented within the same sub‐cortical structures but with minimal overlap, implying that PHN pain modulates behavioral learning and hedonics. These results have important clinical implications regarding adequate therapy.

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.

Ketamine Treatment and Global Brain Connectivity in Major Depression

Capitalizing on recent advances in resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24 h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected α<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants’ development.