Marwan N. Baliki

Scale-free brain functional networks

Functional magnetic resonance imaging is used to extract functional networks connecting correlated human brain sites. Analysis of the resulting networks in different tasks shows that (a) the distribution of functional connections, and the probability of finding a link versus distance are both scale-free, (b) the characteristic path length is small and comparable with those of equivalent random networks, and (c) the clustering coefficient is orders of magnitude larger than those of equivalent random networks. All these properties, typical of scale-free small-world networks, reflect important functional information about brain states.

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.

Corticostriatal functional connectivity predicts transition to chronic back pain

The mechanism of brain reorganization in pain chronification is unknown. In a longitudinal brain imaging study, subacute back pain (SBP) patients were followed over the course of 1 year. When pain persisted (SBPp, in contrast to recovering SBP and healthy controls), brain gray matter density decreased. Initially greater functional connectivity of nucleus accumbens with prefrontal cortex predicted pain persistence, implying that corticostriatal circuitry is causally involved in the transition from acute to chronic pain.

Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain

We review recent advances in brain imaging in humans, concentrating on advances in our understanding of the human brain in clinical chronic pain. Understanding regarding anatomical and functional reorganization of the brain in chronic pain is emphasized. We conclude by proposing a brain model for the transition of the human from acute to chronic pain.

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.

Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits

Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

Brain Morphological Signatures for Chronic Pain

Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical ‘brain signatures’. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain.