Neurobiology of Physical Exercise: Perspectives on Psychophysiological Effects and Opioidergic Neurotransmission

Abstract: Regular physical exercise promotes health and prevents and treats multiple chronic diseases. Despite the well-acknowledged health benefits, many people remain physically inactive. Affective responses induced by exercise are believed to influence future exercise behaviour. Previous studies suggest that pleasurable sensations experienced in response to exercise are regulated by the endogenous opioid system. The opioid system is also involved in the reward processing, and may modulate food reward responses after exercise, possibly contributing to subsequent caloric intake and weight loss outcomes. In this thesis, affective responses to high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) were investigated over a two-week training intervention in untrained healthy subjects and subjects with type 2 diabetes or prediabetes. Positron emission tomography (PET) was used to explore endogenous opioid release after HIIT and MICT in young healthy subjects. The interaction between exercise-induced opioid activation and changes in food reward processing were assessed using functional magnetic resonance imaging (fMRI). HIIT generated a more negative overall affective experience in comparison with MICT; however, this lessened over the training period. Thus, HIIT appears as a tolerable exercise method for sedentary adults with and without diabetes. Furthermore, HIIT induced opioid release in key brain regions implicated in emotion and pain processing and the opioid release correlated with measures of negative emotionality. In contrast, MICT did not result in significant opioid release, although increased opioid activation correlated with increased euphoria after MICT as well as with increased neural responses to palatable foods. These results indicate that the intensity of the exercise regulates endogenous opioid release and concomitant changes in affect and reward processing. Taken together, these findings may have practical implications in developing more tolerable and likeable exercise programs to enhance physical activity participation in different population groups, as well as in optimising the efficient use of exercise in health care, for example in weight loss interventions and in the treatment of various affective disorders.Tiivistelmä: Säännöllinen liikunta ylläpitää terveyttä sekä ennaltaehkäisee ja hoitaa lukuisia sairauksia. Terveyshyödyistä huolimatta moni jää kuitenkin sohvaperunaksi. Liikunnan harrastaminen riippuu osin siitä, miltä liikunta tuntuu. Aikaisempien tutkimusten perusteella aivojen opioidijärjestelmän ajatellaan olevan liikunnasta saatavan mielihyvän taustalla. Opioidijärjestelmä säätelee myös ruuan ja syömisen aiheuttamaa mielihyvää, ja se voi siten muovata liikunnan aikaansaamia muutoksia ruuan palkitsevuudessa vaikuttaen näin syömiskäyttäytymiseen ja painonhallintaan. Tässä väitöskirjatyössä tutkittiin, miltä kovatehoinen intervalliharjoittelu (highintensity interval training, HIIT) ja keskitehoinen kestävyysharjoittelu (moderate- intensity continuous training) tuntuvat kahden viikon liikuntajakson aikana liikunnallisesti passiivisilla terveillä koehenkilöillä, sekä tyypin 2 diabeetikoilla ja esidiabeetikoilla. Lisäksi positroniemissiotomografia (PET) -kuvantamisella selvitettiin aivojen opioidijärjestelmän toimintaa HIIT ja MICT harjoitusten jälkeen terveillä nuorilla miehillä. Toiminnallisen magneettikuvantamisen (fMRI) avulla tutkittiin liikunnan vaikutuksia herkullisten ruokakuvien aikaansaamiin hermostollisiin vasteisiin aivoissa. Lyhytkestoinen HIIT aiheutti huomattavasti negatiivisemman tunnekokemuksen kuin pitkäkestoinen MICT, mikä kuitenkin helpottui jo kahden viikon harjoittelujakson aikana niin terveillä kuin tyypin 2 diabeetikoilla ja esidiabeetikoilla. Näin ollen rankka HIIT voi soveltua liikuntavaihtoehdoksi myös aikaisemmin liikuntaa harrastamattomille. Lisäksi havaittiin, että liikunnan intensiteetti säätelee opioidijärjestelmän toimintaa. HIIT vapautti endogeenisiä opioideja tunteiden ja kivun säätelyyn liittyvillä aivoalueilla. Opioidien vapautuminen oli yhteydessä negatiivisiin tuntemuksiin. Vastaavaa opioidien vapautumista ei havaittu MICT:n jälkeen, joskin suurempi opioidiaktivaatio oli yhteydessä lisääntyneeseen euforisuuden tuntemukseen ja suurempiin hermostollisiin vasteisiin herkullisille ruokakuville pitkäkestoisen liikunnan jälkeen. Tutkimuksista saatuja tuloksia voidaan hyödyntää kehitettäessä uudenlaisia lähestymistapoja paitsi ihmisten liikunnalliseen aktivoimiseen, myös liikunnan tehokkaampaan hyödyntämiseen painonpudotuksessa ja esimerkiksi masennuksen ja riippuvuuksien hoidossa

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms

Neurometabolic correlates of depression and disability in episodic cluster headache

A close association between pain, depression and disability has been shown. However, the neurometabolic correlates of this association have been barely investigated in disease states. Episodic cluster headache is a severe headache syndrome and represents a suitable disease model for the investigation of episodic pain. The aim of this study was to explore the relationship between depression and disability as well as pain scores and brain metabolism in patients with cluster headache during the disease period with repetitive pain attacks, but outside an acute attack. Thirteen patients with cluster headache underwent 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission (FDG-PET) and completed questionnaires on depression and disability as well as a pain visual analogue rating scale (VAS). A positive correlation between the depression scores and glucose metabolism was observed in the insular cortex. A positive correlation between the pain disability scores and brain metabolism was detected in the amygdala. The same applied to the pain visual analogue rating scores. Our data underline the association between severe episodic pain, depression and disability. In addition to this clinical observation, our results stress the importance of the insula and amygdala in pain processing and suffering

Simultaneous brain, brainstem and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans we used simultaneous whole brain-spinal cord pharmacological-fMRI (N=39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity

Update on the pathophysiology of cluster headache: Imaging and neuropeptide studies

Objective: Cluster headache (CH) is the most severe primary headache condition. Its pathophysiology is multifaceted and incompletely understood. This review brings together the latest neuroimaging and neuropeptide evidence on the pathophysiology of CH.Methods: A review of the literature was conducted by searching PubMed and Web of Science. The search was conducted using the following keywords: imaging studies, voxel-based morphometry, diffusion-tensor imaging, diffusion magnetic resonance imaging, tractography, connectivity, cerebral networks, neuromodulation, central modulation, deep brain stimulation, orexin-A, orexin-B, tract-based spatial statistics, single-photon emission computer tomography studies, positron-emission tomography, functional magnetic resonance imaging, magnetic resonance spectroscopy, trigeminovascular system, neuropeptides, calcitonin gene-related peptide, neurokinin A, substance P, nitric oxide synthase, pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide, neuropeptide Y, acetylcholine, noradrenaline, and ATP. “Cluster headache” was combined with each keyword for more relevant results. All irrelevant and duplicated records were excluded. Search dates were from October 1976 to May 2018.Results: Neuroimaging studies support the role of the hypothalamus in CH, as well as other brain areas involved in the pain matrix. Activation of the trigeminovascular system and the release of neuropeptides play an important role in CH pathophysiology. Among neuropeptides, calcitonin gene-related peptide, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating peptide have been reported to be reliable biomarkers for CH attacks, though not specific for CH. Several other neuropeptides are involved in trigeminovascular activation, but the current evidence does not qualify them as reliable biomarkers in CH.Conclusion: CH has a complex pathophysiology and the pain mechanism is not completely understood. Recent neuroimaging studies have provided insight into the functional and structural network bases of CH pathophysiology. Although there has been important progress in neuropeptide studies, a specific biomarker for CH is yet to be found

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms