The brain and behavioral correlates of motor-related analgesia (MRA).

The human motor system has the capacity to act as an internal form of analgesia. Since the discovery of the potential influence of motor systems on analgesia in rodent models, clinical applications of targeting the motor system for analgesia have been implemented. However, a neurobiological basis for motor activation's effects on analgesia is not well defined. Motor-related analgesia (MRA) is a phenomenon wherein a decrease in pain symptoms can be achieved through either indirect or direct activation of the motor axis. To date, research has focused on (a) evaluating the pain-motor interaction as one focused on the acute protection from painful stimuli; (b) motor cortex stimulation for chronic pain; or (c) exercise as a method of improving chronic pain in animal and human models. This review evaluates (1) current knowledge surrounding how pain interferes with canonical neurological performance throughout the motor axis; and (2) the physiological basis for motor-related analgesia as a means to reduce pain symptom loads for patients. A proposal for future research directions is provided.

Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas.

A number of drugs, including triptans, promote migraine chronification in susceptible individuals. In rats, a period of triptan administration over 7 days can produce "latent sensitization" (14 days after discontinuation of drug) demonstrated as enhanced sensitivity to presumed migraine triggers such as environmental stress and lowered threshold for electrically induced cortical spreading depression (CSD). Here we have used fMRI to evaluate the early changes in brain networks at day 7 of sumatriptan administration that may induce latent sensitization as well as the potential response to stress. After continuous infusion of sumatriptan, rats were scanned to measure changes in resting state networks and the response to bright light environmental stress. Rats receiving sumatriptan, but not saline infusion, showed significant differences in default mode, autonomic, basal ganglia, salience, and sensorimotor networks. Bright light stress produced CSD-like responses in sumatriptan-treated but not control rats. Our data show the first brain-related changes in a rat model of medication overuse headache and suggest that this approach could be used to evaluate the multiple brain networks involved that may promote this condition.

Sex and the migraine brain.

The brain responds differently to environmental and internal signals that relate to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

Analogous responses in the nucleus accumbens and cingulate cortex to pain onset (aversion) and offset (relief) in rats and humans.

In humans, functional magnetic resonance imaging (fMRI) activity in the anterior cingulate cortex (ACC) and the nucleus accumbens (NAc) appears to reflect affective and motivational aspects of pain. The responses of this reward-aversion circuit to relief of pain, however, have not been investigated in detail. Moreover, it is not clear whether brain processing of the affective qualities of pain in animals parallels the mechanisms observed in humans. In the present study, we analyzed fMRI blood oxygen level-dependent (BOLD) activity separately in response to an onset (aversion) and offset (reward) of a noxious heat stimulus to a dorsal part of a limb in both humans and rats. We show that pain onset results in negative activity change in the NAc and pain offset produces positive activity change in the ACC and NAc. These changes were analogous in humans and rats, suggesting that translational studies of brain circuits modulated by pain are plausible and may offer an opportunity for mechanistic investigation of pain and pain relief.

Mapping pain activation and connectivity of the human habenula.

The habenula, located in the posterior thalamus, is implicated in a wide array of functions. Animal anatomical studies have indicated that the structure receives inputs from a number of brain regions (e.g., frontal areas, hypothalamic, basal ganglia) and sends efferent connections predominantly to the brain stem (e.g., periaqueductal gray, raphe, interpeduncular nucleus). The role of the habenula in pain and its anatomical connectivity are well-documented in animals but not in humans. In this study, for the first time, we show how high-field magnetic resonance imaging can be used to detect habenula activation to noxious heat. Functional maps revealed significant, localized, and bilateral habenula responses. During pain processing, functional connectivity analysis demonstrated significant functional correlations between the habenula and the periaqueductal gray and putamen. Probabilistic tractography was used to assess connectivity of afferent (e.g., putamen) and efferent (e.g., periaqueductal gray) pathways previously reported in animals. We believe that this study is the first report of habenula activation by experimental pain in humans. Since the habenula connects forebrain structures with brain stem structures, we suggest that the findings have important implications for understanding sensory and emotional processing in the brain during both acute and chronic pain.

The enigma of the dorsolateral pons as a migraine generator.

In this editorial, we integrate improved understanding of functional and structural brain stem anatomy with lessons learned from other disciplines on brainstem function to provide an alternative interpretation to the data used to support the brainstem migraine generator theory.

Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine States.

During migraine attacks, alterations in sensation accompanying headache may manifest as allodynia and enhanced sensitivity to light, sound, and odors. Our objective was to identify physiological changes in cortical regions in migraine patients using painful heat and functional magnetic resonance imaging (fMRI) and the structural basis for such changes using diffusion tensor imaging (DTI). In 11 interictal patients, painful heat threshold + 1°C was applied unilaterally to the forehead during fMRI scanning. Significantly greater activation was identified in the medial temporal lobe in patients relative to healthy subjects, specifically in the anterior temporal pole (TP). In patients, TP showed significantly increased functional connectivity in several brain regions relative to controls, suggesting that TP hyperexcitability may contribute to functional abnormalities in migraine. In 9 healthy subjects, DTI identified white matter connectivity between TP and pulvinar nucleus, which has been related to migraine. In 8 patients, fMRI activation in TP with painful heat was exacerbated during migraine, suggesting that repeated migraines may sensitize TP. This article investigates a nonclassical role of TP in migraineurs. Observed temporal lobe abnormalities may provide a basis for many of the perceptual changes in migraineurs and may serve as a potential interictal biomarker for drug efficacy.

CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw.

Imaging pain pathways in rats offers a tool to investigate CNS systems in acute and chronic rodent models of pain, neural plasticity associated with the latter, and the opportunity to evaluate pharmacological effects of analgesics on these systems. Furthermore, the evaluation of CNS circuits (e.g., sensory, emotional, endogenous analgesic) offers the potential for defining the complexity of circuit-based behaviors that are difficult to evaluate in current preclinical behavioral models of pain. In these studies, we performed functional MRI in trained, acclimated, awake rats to define neural systems activated by noxious thermal stimuli. Analysis revealed activation in response to a 48°C stimuli in cortical, subcortical and brainstem areas, known to be substrates of the pain pathways. Our results demonstrate the ability to characterize CNS patterns of activation in response to pain in rodents while avoiding the potential complicating effects of anesthesia.

Biological and behavioral markers of pain following nerve injury in humans.

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system.

fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children.

Complex regional pain syndrome (CRPS) in paediatric patients is clinically distinct from the adult condition in which there is often complete resolution of its signs and symptoms within several months to a few years. The ability to compare the symptomatic and asymptomatic condition in the same individuals makes this population interesting for the investigation of mechanisms underlying pain and other symptoms of CRPS. We used fMRI to evaluate CNS activation in paediatric patients (9-18 years) with CRPS affecting the lower extremity. Each patient underwent two scanning sessions: once during an active period of pain (CRPS(+)), and once after symptomatic recovery (CRPS(-)). In each session, mechanical (brush) and thermal (cold) stimuli were applied to the affected region of the involved limb and the corresponding mirror region of the unaffected limb. Two fundamental fMRI analyses were performed: (i) within-group analysis for CRPS(+) state and CRPS(-) state for brush and cold for the affected and unaffected limbs in each case; (ii) between-group (contrast) analysis for activations in affected and unaffected limbs in CRPS or post-CRPS states. We found: (i) in the CRPS(+) state, stimuli that evoked mechanical or cold allodynia produced patterns of CNS activation similar to those reported in adult CRPS; (ii) in the CRPS(+) state, stimuli that evoked mechanical or cold allodynia produced significant decreases in BOLD signal, suggesting pain-induced activation of endogenous pain modulatory systems; (iii) cold- or brush-induced activations in regions such as the basal ganglia and parietal lobe may explain some CNS-related symptoms in CRPS, including movement disorders and hemineglect/inattention; (iv) in the CRPS(-) state, significant activation differences persisted despite nearly complete elimination of evoked pain; (v) although non-noxious stimuli to the unaffected limb were perceived as equivalent in CRPS(+) and CRPS(-) states, the same stimulus produced different patterns of activation in the two states, suggesting that the 'CRPS brain' responds differently to normal stimuli applied to unaffected regions. Our results suggest significant changes in CNS circuitry in patients with CRPS.

Reward circuitry activation by noxious thermal stimuli.

Using functional magnetic resonance imaging (fMRI), we observed that noxious thermal stimuli (46 degrees C) produce significant signal change in putative reward circuitry as well as in classic pain circuitry. Increases in signal were observed in the sublenticular extended amygdala of the basal forebrain (SLEA) and the ventral tegmentum/periaqueductal gray (VT/PAG), while foci of increased signal and decreased signal were observed in the ventral striatum and nucleus accumbens (NAc). Early and late phases were observed for signals in most brain regions, with early activation in reward related regions such as the SLEA, VT/PAG, and ventral striatum. In contrast, structures associated with somatosensory perception, including SI somatosensory cortex, thalamus, and insula, showed delayed activation. These data support the notion that there may be a shared neural system for evaluation of aversive and rewarding stimuli.

Human cerebellar responses to brush and heat stimuli in healthy and neuropathic pain subjects.

Though human pain imaging studies almost always demonstrate activation in the cerebellum, the role of the cerebellum in pain function is not well understood. Here we present results from two studies on the effects of noxious thermal heat and brush applied to the right side of the face in a group of healthy subjects (Group I) and a group of patients with neuropathic pain (Group II) who are more sensitive to both thermal and mechanical stimuli. Statistically significant activations and volumes of activations were defined in the cerebellum. Activated cerebellar structures were identified by colocalization of fMRI activation with the 'MRI Atlas of the Human Cerebellum'. Functional data (obtained using a 3T magnet) were defined in terms of maximum voxels and volume of activation in the cerebellum. Volume maps were then mapped onto two millimeter serial slices taken through the cerebellum in order to identify activation within regions defined by the activation volume. The data indicate that different regions of the cerebellum are involved in acute and chronic pain processing. Heat produces greater contralateral activation compared with brush, while brush resulted in more ipsilateral/bilateral cerebellar activation. Further, innocuous brush stimuli in healthy subjects produced decreased cerebellar activation in lobules concerned with somatosensory processing. The data also suggest a dichotomy of innocuous stimuli/sensorimotor cerebellum activation versus noxious experience/cognitive/limbic cerebellum activation. These results lead us to propose that the cerebellum may modulate the emotional and cognitive experience that distinguishes the perception of pain from the appreciation of innocuous sensory stimulation.

Cumulative effects of multiple pain sites in youth with chronic pain.

BACKGROUND: The experience of persistent pain in multiple locations is common in youth. Based on current literature, youth with multiple pain sites (MPS) are at risk of experiencing poorer emotional outcomes and a spread of symptoms into late adolescence and adulthood. Little is known regarding the association between MPS with physical and school functioning domains, particularly after initiation of multidisciplinary pain treatment. Therefore, the objective of this study was to examine the association of MPS with disability and school functioning among youth with chronic pain. METHODS: A total of 195 patients with chronic pain, aged 8-17, and their parents completed measures assessing patient distress and functioning at a multidisciplinary pain clinic evaluation and at 4-month follow-up. RESULTS: At evaluation, 63% of patients presented with MPS; 25% reporting MPS endorsed pain in five or more locations. When controlling for relevant demographic and emotional distress factors, MPS were associated with lower school functioning at evaluation with a persistent trend at follow-up. Although MPS were not a significant predictor of pain-related disability at evaluation, it emerged as significant at follow-up. CONCLUSIONS: Potentially due to the MPS load and the inverse effects that such a pain state has on function, such patients may be at risk for poorer health and school-related outcomes. The mechanisms influencing these relationships appear to extend beyond psychological/emotional factors and warrant further investigation in order to aid in our understanding of youth with MPS. SIGNIFICANCE: Youth with MPS may be at risk for experiencing poorer physical and school functioning in comparison with single-site peers, despite treatment initiation. Further research is warranted to inform assessment and treatment approaches for this subgroup of patients.

Basal ganglia dysfunction in complex regional pain syndrome - A valid hypothesis?

Complex regional pain syndrome (CRPS) is a poorly understood pain disorder of the limbs. Maladaptive cortical plasticity has been shown to play a major role in its pathophysiological presentation. Recently, there is increasing interest in the role of the basal ganglia (BG), since clinical findings and neuroimaging studies point to possible BG involvement in CRPS. CRPS symptoms are often characterized by movement disorders associated with BG dysfunction. Very frequently, dystonia and tremor are reported and, to a lesser extent, myoclonus. Neuroimaging studies present inconsistent findings concerning altered brain networks and mainly focus on cortical areas. Subcortical contribution to this disorder has so far been neglected. Clinical data presenting BG dysfunction-related movement disorders in CRPS patients raise the hypothesis of BG dysfunction in this syndrome. Moreover, several neuroimaging studies documented abnormalities in the BG and in the frontal, parietal and limbic cortical areas. These regions are functionally and anatomically connected in motor, pain and working memory networks. Put together, these findings call for further characterization of the dynamic cortical and subcortical interactions in CRPS. SIGNIFICANCE: This paper presents an overview of our current knowledge about BG pathology in CRPS. A better understanding of the involvement of the BG in the CRPS pathology holds the potential for developing and improving efficacious, mechanism-based treatment modalities.

Noxious heat induces fMRI activation in two anatomically distinct clusters within the nucleus accumbens.

Using functional magnetic resonance imaging (fMRI) we found that a noxious thermal stimulus (46 degrees C) to the hand activates the nucleus accumbens (NAc) in humans, while a non-noxious warm stimulus (41 degrees C) does not. Following the noxious stimulus, two distinct foci of decreased activation were observed showing distinct time course profiles. One focus was anterior, superior, and lateral and the second that was more posterior, inferior, and medial. The anatomical segregation may correlate with the functional components of the NAc, i.e., shell and core. The results support heterogeneity of function within the NAc and have implications for the understanding the contribution of NAc function to processing of pain and analgesia.

Pain in an era of armed conflicts: Prevention and treatment for warfighters and civilian casualties.

Chronic pain is a common squealae of military- and terror-related injuries. While its pathophysiology has not yet been fully elucidated, it may be potentially related to premorbid neuropsychobiological status, as well as to the type of injury and to the neural alterations that it may evoke. Accordingly, optimized approaches for wounded individuals should integrate primary, secondary and tertiary prevention in the form of thorough evaluation of risk factors along with specific interventions to contravene and mitigate the ensuing chronicity. Thus, Premorbid Events phase may encompass assessments of psychological and neurobiological vulnerability factors in conjunction with fostering preparedness and resilience in both military and civilian populations at risk. Injuries per se phase calls for immediate treatment of acute pain in the field by pharmacological agents that spare and even enhance coping and adaptive capabilities. The key objective of the Post Injury Events is to prevent and/or reverse maladaptive peripheral- and central neural system's processes that mediate transformation of acute to chronic pain and to incorporate timely interventions for concomitant mental health problems including post-traumatic stress disorder and addiction We suggest that the proposed continuum of care may avert more disability and suffering than the currently employed less integrated strategies. While the requirements of the armed forces present a pressing need for this integrated continuum and a framework in which it can be most readily implemented, this approach may be also instrumental for the care of civilian casualties.

Reward deficiency and anti-reward in pain chronification.

Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification).

A 'complex' of brain metabolites distinguish altered chemistry in the cingulate cortex of episodic migraine patients.

Despite the prevalence of migraine, the pathophysiology of the disease remains unclear. Current understanding of migraine has alluded to the possibility of a hyperexcitable brain. The aim of the current study is to investigate human brain metabolite differences in the anterior cingulate cortex (ACC) during the interictal phase in migraine patients. We hypothesized that there may be differences in levels of excitatory neurotransmitters and/or their derivatives in the migraine cohort in support of the theory of hyperexcitability in migraine. 2D J-resolved proton magnetic resonance spectroscopy ((1)H-MRS) data were acquired on a 3 Tesla (3 T) MRI from a voxel placed over the ACC of 32 migraine patients (MP; 23 females, 9 males, age 33 ± 9.6 years) and 33 healthy controls (HC; 25 females, 8 males, age 32 ± 9.6 years). Amplitude correlation matrices were constructed for each subject to evaluate metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal to assess subject differences. The initial analysis of variance (ANOVA) was performed to test for group differences for all metabolites/creatine (Cre) ratios between healthy controls and migraineurs but showed no statistically significant differences. In addition, we used a multivariate approach to distinguish migraineurs from healthy subjects based on the metabolite/Cre ratio. A quadratic discriminant analysis (QDA) model was used to identify 3 metabolite ratios sufficient to minimize minimum classification error (MCE). The 3 selected metabolite ratios were aspartate (Asp)/Cre, N-acetyl aspartate (NAA)/Cre, and glutamine (Gln)/Cre. These findings are in support of a 'complex' of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain. Furthermore, the parallel changes in the three-metabolite 'complex' may confer more subtle but biological processes that are ongoing. The data also support the current theory that the migraine brain is hyperexcitable even in the interictal state.

Molecular mechanisms of stress-induced proenkephalin gene regulation: CREB interacts with the proenkephalin gene in the mouse hypothalamus and is phosphorylated in response to hyperosmolar stress.

We have established a transgenic model to facilitate the study of stress-induced gene regulation in the hypothalamus. This model, which uses a human proenkephalin-beta-galactosidase fusion gene, readily permits anatomic and cellular colocalization of stress-regulated immediate early gene products (e.g. Fos) and other transcription factors [e.g. cAMP response element-binding protein (CREB)] with the product of a potential target gene. Moreover, Fos provides a marker of cellular activation that is independent of the transgene. Hypertonic saline stress induced Fos in almost all cells in the PVN that exhibited basal expression of the proenkephalin transgene; however, all cells in which the transgene was activated by stress also expressed Fos. CREB was found in essentially all neurons. Gel shift analysis with and without antisera to Fos and CREB showed that AP-1 binding activity, containing Fos protein, was induced by hyperosmotic stress. However, Fos was not detected binding to the proenkephalin second messenger-inducible enhancer even in hypothalamic cell extracts from stressed animals. In contrast, CREB formed specific complexes with both the proenkephalin enhancer and a cAMP- and calcium-regulated element (CaRE) within the c-fos gene. Moreover, we found that hypertonic saline induced CREB phosphorylation in cells that express the transgene within the paraventricular nucleus and supraoptic nucleus. These results suggest a model in which proenkephalin gene expression in the paraventricular nucleus is regulated by CREB in response to hypertonic stress.