A Key Role of the Basal Ganglia in Pain and Analgesia - Insights Gained Through Human Functional Imaging

The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain

Emerging analgesic drugs for Parkinson's disease

Introduction: Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. Areas covered: Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. Expert opinion: Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Rey, María Verónica. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Dellapina, Estelle. Université Toulouse III Paul Sabatier; FranciaFil: Pellaprat, Jean. Université Toulouse III Paul Sabatier; FranciaFil: Brefel Courbon, Christine. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; FranciaFil: Rascol, Olivier. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Franci

Neural mechanisms of orofacial pain - effects of transcranial magnetic stimulation

Neuropathic orofacial pain is challenging to treat. Limited knowledge of the underlying pain-syndrome-specific pathophysiology is one of the reasons for poor response to current pharmacotherapy. Patients with treatment-resistant neuropathic pain are susceptible to concomitant psychiatric and sleep disorders. Psychiatric disorders, sleep problems, and certain personality traits may, in turn, predispose to chronic pain. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been shown to alleviate neuropathic pain, but the mechanisms of its action and optimal treatment parameters are still unclear. We investigated rTMS effects in healthy subjects and chronic neuropathic orofacial pain patients, and compared the analgesic efficacy of stimulation given to different cortical targets. We also evaluated the brain mechanisms involved in rTMS-induced analgesia, especially the dopamine-opioid system. The genetically determined function of the endogenous dopamine system was also investigated regarding thermal and pain perception. We discovered that rTMS targeted to the right secondary somatosensory cortex (S2) alleviated neuropathic orofacial pain (Cohen’s d = 0.60). Pain intensity assessed in numerical rating scale was significantly lower after the S2 stimulation than after the stimulation of the primary somatosensory and motor cortex (S1/M1) (p = 0.007) or placebo (p = 0.019). The analgesic effect of stimulation of the S2 region was not mediated or predicted by comorbid psychiatric or sleep disorders. Orofacial pain patients had more psychiatric and sleep disorders than the general population and there were several associations between these comorbid disorders. The variation caused by single nucleotide polymorphism 957C>T in dopamine receptor D2 (DRD2) gene had an effect on thermal perception and rTMS effects in healthy subjects. rTMS to S1 cortex increased heat pain detection thresholds only in subjects homozygous for the 957T allele (F = 3.78, p = 0.009), whose mean heat pain detection thresholds 6,24 were initially lower than those of 957C allele carriers (p < 0.05). The “pain sensitive” 957TT genotype was overrepresented (50% vs. 27% in general population, p = 0.019) in our unselected group of neuropathic pain patients. In the positron emission tomography (PET) study on healthy subjects, lower μ-opioid receptor availability indicting activation of the endogenous opioid system, was seen in a brain network associated with pain processing after active S1/M1 rTMS compared to sham (p ≤ 0.0001). Our results suggest that the brain dopamine-opioid system is important in the perception and modulation of pain, and in rTMS-induced analgesia. Genetic regulation of striatal DRD2 function may explain some of the individual differences in pain sensitivity and in risk for neuropathic pain.Kasvokivun neuraaliset mekanismit - transkraniaalisen magneettistimulaation vaikutukset Kroonisen neuropaattisen kasvokivun hoito on haasteellista. Neuropaattisen kasvokivun syitä ja sille altistavia tekijöitä ei vielä täysin tunneta, mikä vaikeuttaa tehokkaan hoidon löytämistä. Krooninen hoitoresistentti kipu voi altistaa mielialaongelmille ja univaikeuksille, jotka yhdessä tiettyjen persoonallisuuden piirteiden kanssa taas altistavat kivun pitkittymiselle. Repetitiivinen transkraniaalinen magneettistimulaatio (rTMS) on kajoamaton neuromodulaatiomenetelmä, jonka on osoitettu lievittävän neuropaattista kipua. Magneettistimulaation tarkat vaikutusmekanismit ja parhaat hoitoprotokollat ovat kuitenkin vielä epäselviä. Tässä tutkimuksessa selvitimme rTMS:n vaikutusmekanismeja terveillä vapaaehtoisilla ja kroonisesta neuropaattisesta kasvokivusta kärsivillä potilailla, sekä vertasimme eri aivoalueiden stimulaation vaikutuksia kipupotilaiden kipuun, mielialaan, uneen ja elämänlaatuun. Lisäksi selvitimme rTMS:n aivotason vaikutusmekanismeja, erityisesti aivojen dopamiini-opiodi järjestelmän osalta. Tutkimme myös aivojen sisäsyntyisen dopamiinijärjestelmän geneettisen säätelyn merkitystä kivun kokemisessa ja käsittelyssä sekä sen vaikutusta neuropaattisen kivun riskiin. Totesimme, että oikealle sekundaariselle tuntoaivokuorelle (S2) suunnattu rTMS lievitti neuropaattista kasvokipua. Kivun voimakkuus mitattuna numeerisella arviointiasteikolla oli S2-seudun stimulaation jälkeen merkittävästi matalampi kuin primaarisen tuntoaivokuoren ja liikeaivokuoren (S1/M1) stimulaation (p = 0,007) tai lumestimulaation (p = 0,019) jälkeen. S2-seudun stimulaation hoitovaste oli riippumaton potilaiden mieliala- tai unihäiriöistä. Kasvokipupotilailla oli selvästi enemmän psykiatrisia sairauksia ja uniongelmia kuin väestössä yleensä, ja näiden rinnakkaissairauksien välillä oli riippuvaisuutta. Dopamiini D2-reseptorin (DRD2) perinnöllisellä vaihtelulla oli vaikutusta terveiden koehenkilöiden kylmä-, lämpö- ja kiputuntokynnyksiin. S1-aivokuorelle annettu rTMS nosti kuumakipukynnyksiä vain 957T-genotyypin kantajilla (F = 3,78, p = 0,009), joiden 6,24 kuumakipukynnykset olivat lähtökohtaisesti matalammat kuin 957C-genotyypin kantajien (p < 0,05). Kivulle herkimmän TT-genotyypin kantajia oli enemmän kasvokipupotilaiden ryhmässä kuin väestössä yleensä (50% vs. 27%, p = 0,019). Aivojen positroni-emissiotomografiatutkimuksessa (PET) todettiin, että lumehoitoon verrattuna S1/M1 rTMS laski μ-opioidireseptorien saatavuutta aivoalueilla jotka osallistuvat kiputuntemuksen käsittelyyn (p ≤ 0,000). Löydös viittaa rTMS:n aktivoivan aivojen sisäsyntyistä opioidijärjestelmää. Tulostemme perusteella aivojen dopamiini-opioidisysteemi vaikuttaa kivun kokemiseen ja säätelyyn, sekä rTMS-hoidon tehoon. Tyvitumakkeiden DRD2-tiheyttä säätelevä geneettinen muuntelu saattaa osaltaan selittää yksilöiden välisiä eroja kipuherkkyydessä ja alttiudessa saada neuropaattinen kipu hermovaurion jälkeen.Siirretty Doriast

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

Developing a Brain‐Based, Non‐Invasive Treatment for Pain

Chronic pain cost society more than $500 billion each year and contributes to the ongoing opioid overdose crisis. Substantial risks and low efficacy are associated with opiate usage for chronic pain. This dissertation seeks to fill the urgent need for a new pain treatment using a neural-circuit based approach in healthy controls and chronic pain patients. First, we performed a single-blind study examining the causal effects of transcranial magnetic stimulation (TMS), compared to a well-matched control condition. Using interleaved TMS/fMRI we explored brain activation in response to dorsolateral prefrontal cortex (DLPFC) stimulation in 20 healthy controls. This study tested the hypothesis that the TMS evoked responses would be in frontostriatal locations. Consistent with this hypothesis active TMS, compared to the control, led to significantly greater activity in the caudate, thalamus and anterior cingulate cortex (ACC). Building on these findings, we developed a single-blind, sham-controlled study examining two TMS strategies for analgesia in 45 healthy controls. We completed an fMRI thermal pain paradigm before and after modulatory repetitive TMS at either the DLPFC or the medial prefrontal cortex (MPFC). Despite a role in pain processing, the MPFC has not yet been explored as a target for analgesia. Only MPFC stimulation significantly improved behavioral pain measures. These effects were associated with increased motor and parietal cortex activity during the pain task. We then supplement these findings by testing the hypothesis that chronic pain patients who use opioids (n=14) would have elevated brain responses to thermal pain relative to healthy controls (n=14). Despite indistinguishable self-report measures, we found increased brain activity in the ACC and sensory areas in patients which were positively correlated with opioid dose. We conclude by evaluating the feasibility of these approaches in chronic pain patients, reporting preliminary findings from a pilot study examining the two treatment strategies tested previously in controls. Collectively, our findings support a circuits-first approach to pain treatment. Though MPFC stimulation was effective in reducing pain in healthy controls, further work is required to confirm these results in a chronic pain population, as chronic pain and opioid usage alter how the brain processes the pain experience

Challenges of functional imaging research of pain in children

Functional imaging has revolutionized the neurosciences. In the pain field it has dramatically altered our understanding of how the brain undergoes significant functional, anatomical and chemical changes in patients with chronic pain. However, most studies have been performed in adults. Because functional imaging is non-invasive and can be performed in awake individuals, applications in children have become more prevalent, but only recently in the pain field. Measures of changes in the brains of children have important implications in understanding neural plasticity in response to acute and chronic pain in the developing brain. Such findings may have implications for treatments in children affected by chronic pain and provide novel insights into chronic pain syndromes in adults. In this review we summarize this potential and discuss specific concerns related to the imaging of pain in children

Morphine Attenuates fNIRS Signal Associated With Painful Stimuli in the Medial Frontopolar Cortex (medial BA 10)

Functional near infrared spectroscopy (fNIRS) is a non-invasive optical imaging method that provides continuous measure of cortical brain functions. One application has been its use in the evaluation of pain. Previous studies have delineated a deoxygenation process associated with pain in the medial anterior prefrontal region, more specifically, the medial Brodmann Area 10 (BA 10). Such response to painful stimuli has been consistently observed in awake, sedated and anesthetized patients. In this study, we administered oral morphine (15 mg) or placebo to 14 healthy male volunteers with no history of pain or opioid abuse in a crossover double blind design, and performed fNIRS scans prior to and after the administration to assess the effect of morphine on the medial BA 10 pain signal. Morphine is the gold standard for inhibiting nociceptive processing, most well described for brain effects on sensory and emotional regions including the insula, the somatosensory cortex (the primary somatosensory cortex, S1, and the secondary somatosensory cortex, S2), and the anterior cingulate cortex (ACC). Our results showed an attenuation effect of morphine on the fNIRS-measured pain signal in the medial BA 10, as well as in the contralateral S1 (although observed in a smaller number of subjects). Notably, the extent of signal attenuation corresponded with the temporal profile of the reported plasma concentration for the drug. No clear attenuation by morphine on the medial BA 10 response to innocuous stimuli was observed. These results provide further evidence for the role of medial BA 10 in the processing of pain, and also suggest that fNIRS may be used as an objective measure of drug-brain profiles independent of subjective reports