Human brain mechanisms of pain perception and regulation in health and disease

Denne beskriver det meste rundt hvordan forskjellige områder av hjernen aktiveres i smertetilstander.

http://www.sigurdmikkelsen.no/admin/dokumenter/NP%20-%20Apkarian%20-%202005%20-%20Human%20brain%20mechanisms%20of%20pain%20perception.pdf

 

Both primary somatosensory cortex (S1) and secondary somatosensory cortex (S2) are commonly activated in heat pain studies. Evidence suggests that the nociceptive input into these regions at least partially underlies the perception of sensory fea- tures of pain (Coghill et al., 1999; Peyron et al., 1999; Bushnell et al., 1999; Chen et al., 2002). Anterior cingu- late (ACC) and insular (IC) cortices, both components of the limbic system, are activated during the majority of PET or fMRI studies of heat pain, and these regions have been implicated in the affective processing of pain (Rainville et al., 1997; Tolle et al., 1999; Fulbright et al., 2001). Prefrontal cortical areas, as well as parietal association areas, are also sometimes activated by heat pain and may be related to cognitive variables, such as memory or stimulus evaluation (Coghill et al., 1999; Strigo et al., 2003). Motor and pre-motor cortical areas are on occasion activated by heat pain, but these activa- tions are less reliable, suggesting they may be related to pain epiphenomena, such as suppression of movement or actual pain-evoked movements themselves.

Subcortical activations are also observed, most notably in thalamus (Th), basal ganglia, and cerebellum (eTable 1). Fig. 1 illustrates the brain regions most com- monly reported activated in pain studies.

Utilizing similar methodology, rCBF responses to a l-opioid agonist, remifentanil, were com- pared to that elicited by a placebo (Petrovic et al., 2002a). The two effects overlapped in terms of rCBF increases in dorsal ACC, suggesting that this brain region may be in- volved in placebo effects. Perhaps more notably, placebo responders showed responses to remifentanil that were more prominent than non-responders. These data suggest that the placebo effect on pain responses may be mediated by inter-individual variations in the ability to activate this neurotransmitter system, as hypothesized by others (Amanzio and Benedetti, 1999).

Another recent study demonstrated that thermal stimulation in com- plex regional pain syndrome (CRPS) patients gives rise to activity that closely matches that observed in normal subjects. However, this pattern changes dramatically when the ongoing pain of CRPS is isolated, by com- paring brain activity before and after sympathetic blocks that reduce the ongoing CRPS pain but do not change the thermal stimulus pain (Apkarian et al., 2001). Thus, there is no compelling evidence that examining brain responses to experimental painful stimuli can predict the pattern of brain responses in chronic clinical pain states.

Thus, we can assert that brain activity for pain in chronic clinical conditions is different from brain activity for acute painful stimuli in normal subjects. We add the caution that this does not imply that all clinical pain conditions have a homo- geneous underlying brain activity pattern. On the con- trary, most likely the patterns involving different clinical conditions are unique but with the current avail- able data we cannot test this at a meta-analysis level.

The brain imaging studies reviewed here indicate the cortical and sub-cortical substrate that underlies pain perception. Instead of locating a singular ‘‘pain center’’ in the brain, neuroimaging studies identify a network of somatosensory (S1, S2, IC), limbic (IC, ACC) and asso- ciative (PFC) structures receiving parallel inputs from multiple nociceptive pathways (Fig. 1). In contrast to touch, pain invokes an early activation of S2 and IC that may play a prominent role in sensory-discriminative functions of pain. The strong affective-motivational character of pain is exemplified by the participation of regions of the cingulate gyrus. The intensity and affec- tive quality of perceived pain is the net result of the interaction between ascending nociceptive inputs and antinociceptive controls. Dysregulations in the function of these networks may underlie vulnerability factors for the development of chronic pain and comorbid conditions.

Our analysis, in- stead, suggests that chronic pain conditions may be a reflection of decreased sensory processing and enhanced emotional/cognitive processing.

 

David Butler forklarer «smudging»

David Butler er en av våre største inspirasjonskilder når det gjelder å forstå hvordan smerte fungerer, og hva vi kan gjøre med det.

Her forklarer han hvordan hjernens opplevelse av kroppen endres ved langvarig smerte. Han kaller det «smudging». Hjernens kart over kroppen blir utydelig. Han forklarer også hvordan dette kan trenes opp igjen.

Hjernen er ekstremt plastisk, foranderlig og tilpasningsdyktig. På Verkstedet gjør vi alt vi kan for å gi hjernen og nervesystemet bedre vilkår å tilpasse seg til: The Founder, ernæring, pust og god behandling.

Motor Imagery in People With a History of Back Pain, Current Back Pain, Both, or Neither

Nevner at for mennesker med ryggsmerte er hjernens opplevelse av kroppen og dens bevegelser dårligere. Hjernens kart over kroppen blir utydelig. Dette kartet er noe av det første vi vil gjenopprette. Det er en viktig del av behandling, og en av de viktigste årsakene til at vi anbefaler daglige øvelser, som f.eks. Foundation trening.

http://www.ncbi.nlm.nih.gov/pubmed/24535054

Introduction:

There is mounting evidence that cortical maps are disrupted in chronic limb pain and that these disruptions may contribute to the problem and be a viable target for treatment. Little is known as to whether this is also the case for the most common and costly chronic pain—back pain.

Objectives:

To investigate the effects of back pain characteristics on the performance of left/right trunk judgment tasks, a method of testing the integrity of cortical maps.

Methods:

A total of 1008 volunteers completed an online left/right trunk judgment task in which they judged whether a model was rotated or laterally flexed to the left or right in a series of images.

Results:

Participants who had back pain at the time of testing were less accurate than pain-free controls (P=0.027), as were participants who were pain free but had a history of back pain (P<0.01). However, these results were driven by an interaction such that those with current back pain and a history of back pain were less accurate (mean [95% CI]=76% [74%-78%]) than all other groups (>84% [83%-85%]).

Discussion:

Trunk motor imagery performance is reduced in people with a history of back pain when they are in a current episode. This is consistent with disruption of cortical proprioceptive representation of the trunk in this group. On the basis of this result, we propose a conceptual model speculating a role of this measure in understanding the development of chronic back pain, a model that can be tested in future studies.

Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries

Denne viser hvordan CO2-responsen er litt forskjellige i forskjellige blodkar. Den er sterkere i blodkar inni hjernen enn i blodkar i kraniet, ansiktet og ryggraden. Blodkar i ryggraden har større respons enn blodkar i ansiktet, men mindre respons enn blodkar i hjernen.

http://jp.physoc.org/content/590/14/3277.long

Because of methodological limitations, almost all previous studies have evaluated the response of mean blood flow velocity (Vmean) in the middle cerebral artery (MCA) to changes in CO2 as a measure of CO2 reactivity across the whole brain (Aaslid et al. 1989Ainslie & Duffin, 2009Ainslie & Ogoh, 2009).

 

ICA, VA and BA CO2 reactivity was significantly higher during hypercapnia than during hypocapnia (ICA, P < 0.01; VA, P < 0.05; BA, P < 0.05), but ECA and MCA were not significantly different.

The major finding from the present study was that cerebral CO2 reactivity was significantly lower in the VA and its distal artery (BA) than in the ICA and its distal artery (MCA). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation. Our second major finding was that ECA blood flow was unresponsive to hypocapnia and hypercapnia, suggesting that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation. These findings suggest that different CO2 reactivity may explain differences in CBF responses to physiological conditions (i.e. dynamic exercise and orthostatic stress) across areas in the brain and/or head.

Hypercapnic cerebral CO2 reactivity in global CBF was greater than the hypocapnic reactivity (Ide et al. 2003) (Table 3). The mechanisms underlying this greater reactivity to hypercapnia compared with hypocapnia may be related to a greater influence of vasodilator mediators on intracranial vascular tone compared with vasoconstrictive mediators (Toda & Okamura, 1998Ainslie & Duffin, 2009). In humans, Peebles et al.(2008) recently reported that, during hypercapnia, there is a large release of nitric oxide (NO) from the brain, whereas this response was absent during hypocapnia.

The difference in CO2 reactivity between vertebro-basilar territories (VA and BA) and the cerebral cortex (ICA and MCA) may be due to diverse characteristics of vasculature, e.g. regional microvascular density (Sato et al. 1984), basal vascular tone (Ackerman, 1973Haubrich et al. 2004Reinhard et al. 2008), autonomic innervation (Edvinsson et al. 1976Hamel et al. 1988) and regional heterogeneity in ion channels or production of NO (Iadecola & Zhang, 1994Gotoh et al. 2001).

Interestingly, the response of the ECA to changes in CO2 may be similar to other peripheral arteries. It has long been appreciated that the vasodilatory effect of hypercapnia is much more profound in cerebral than in peripheral vasculature, particularly leg (Lennox & Gibbs, 1932Ainslie et al. 2005) and brachial arteries (Miyazaki, 1973). These findings suggest that control of CO2 is particularly important in the cerebral circulation. The high resting metabolic requirements of the brain, compared with that of other vasculature, might be one reason why this circulatory arrangement is desirable (Ainslie et al. 2005). Specifically, high CO2 reactivity may be a way for the brain to match metabolism with flow (Ainslie et al. 2005).

Lower CO2reactivity in the vertebro-basilar system may be important for maintaining central respiratory function because Graphic in central chemoreceptors is regulated by Graphic and blood flow to maintain breathing stability.

In summary, our study shows that cerebral CO2 reactivity in the vertebro-basilar circulation is lower than that in the internal carotid circulation, while CO2 reactivity in the external carotid circulation is much lower compared with two other cerebral arteries. These findings indicate a difference in cerebral CO2 reactivity between different circulatory areas in the brain and head, which may explain different CBF responses to physiological stress. Lower CO2 reactivity in the vertebro-basilar system may be beneficial for preserving blood flow to the medulla oblongata to maintain vital systemic functions, while higher CO2 reactivity in the internal carotid system may imply a larger tolerance for varied blood flow in the cerebral cortex.

Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2

Denne beskriver hvordan blodkarenes respons på CO2 er dårligere om morgenen, og det er derfor det skjer flere slag og slikt om morgenen. Den nevner mange interessante prinsipper. Bl.a. at lavere vasomotor respons (på CO2) gir mindre oksygen til hjernen. Og at i opptil 20 sekunder etter en 20 sekunder holdning av pust (etter utpust) øker fortsatt oksygenmengden og blodgjennomstrømningen i hjernen. Nevner også at siden blodkarene i hjernen reagerer dårligere på CO2 om morgenen blir det lett at pusten over- eller underkompenserer, så pustemønsteret blir uregelmessig om morgenen. Spesielt om man har underliggende faremomenter som hjerte/karsykdommer.

http://jap.physiology.org/content/102/5/1891

 

Furthermore, our results suggest that morning cerebral tissue oxygenation might be reduced as a result of a decreased cerebrovascular responsiveness to CO2 or other factors, leading to a higher level of desaturation.

Our data indicate that the cerebrovascular reactivity to CO2 in healthy subjects is significantly reduced in the morning and is strongly associated with an augmented ventilatory response to CO2. It is likely that this reduction in MCAV CO2 reactivity, by reducing blood flow through medullary respiratory control centers, increases both the arterial-brain tissue PCO2 difference and the H+ concentration presented to the central chemoreceptor(s) (1144). In effect, it appears the brain tissue is more susceptible in the morning to changes in arterial PCO2, which could increase the likelihood of ventilatory overshoots and undershoots.

However, as was the case with the hypercapnic challenge, subjects holding their breath in the morning experienced a significantly blunted increase in MCAV compared with evening, likely a result of a reduced cerebrovascular responsiveness to CO2.

In conclusion, our results suggest that early morning reductions in cerebrovascular CO2 reactivity strongly influence the magnitude of the ventilatory response to CO2. This may have significant implications for breathing stability, increasing the chances of periodic breathing in the morning in patients with additional risk factors. The early morning reduction in cerebral oxygenation with hypercapnic challenge, mild hypoxemia, or during apnea may be a contributing factor in the high prevalence of early morning stroke. Whether differences in the responses of CBF, oxygenation, or V̇E to CO2challenge are associated with other risk factors for stroke, such as gender or age, remains to be elucidated.

Is recovery driven by central or peripheral factors? A role for the brain in recovery following intermittent-sprint exercise

Nevner svært mye spennende om stølhet (DOMS). Spesielt om hvor mye central sensitering har å si, og mye om hydrering (vann). Samt alt om betennelser og andre faktorer knyttet til DOMS. Sier bl.a. at glucogenlagre normaliseres etter 24 timer uavhengig av hva man spiser, men glykogen omsetningen i kroppen er begrenset i 2-3 dager etter. Nevner også at det er alle de perifere faktorene, sammen med de sentrale, som tilsammen skaper DOMS tilstanden.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909945/

Abstract

Prolonged intermittent-sprint exercise (i.e., team sports) induce disturbances in skeletal muscle structure and function that are associated with reduced contractile function, a cascade of inflammatory responses, perceptual soreness, and a delayed return to optimal physical performance. In this context, recovery from exercise-induced fatigue is traditionally treated from a peripheral viewpoint, with the regeneration of muscle physiology and other peripheral factors the target of recovery strategies. The direction of this research narrative on post-exercise recovery differs to the increasing emphasis on the complex interaction between both central and peripheral factors regulating exercise intensity during exercise performance. Given the role of the central nervous system (CNS) in motor-unit recruitment during exercise, it too may have an integral role in post-exercise recovery. Indeed, this hypothesis is indirectly supported by an apparent disconnect in time-course changes in physiological and biochemical markers resultant from exercise and the ensuing recovery of exercise performance. Equally, improvements in perceptual recovery, even withstanding the physiological state of recovery, may interact with both feed-forward/feed-back mechanisms to influence subsequent efforts. Considering the research interest afforded to recovery methodologies designed to hasten the return of homeostasis within the muscle, the limited focus on contributors to post-exercise recovery from CNS origins is somewhat surprising. Based on this context, the current review aims to outline the potential contributions of the brain to performance recovery after strenuous exercise.

recovery strategies might be broadly differentiated as being either physiological (e.g., cryotherapy, hydrotherapy, massage, compression, sleep), pharmacological (e.g., non-steroidal anti-inflammatory medications) or nutritional (e.g., dietary supplements), all mean to limit continued post-exercise disturbances and inflammatory events within the exercised muscle cells. This peripheral focus emphasizes the importance of an accelerated return of structural integrity and functional capacity from below the neuromuscular junction.

Conceptually, if the brain is held as central to the process of performance declines (i.e., fatigue), it stands to reason that it would also have some role in post-exercise recovery (De Pauw et al., 2013).

Classically defined as an exercise-induced reduction in force generating capacity of the muscle, fatigue may be attributed to peripheral contractile failure, sub-optimal motor cortical output (supraspinal fatigue) and/or altered afferent inputs (spinal fatigue) innervating the active musculature (Gandevia, 2001).

Alternatively, concepts of residual fatigue remain predominately within the domain of peripherally driven mechanisms, such as blood flow, muscle glycogen repletion and clearance of metabolic wastes (Bangsbo et al., 2006).

The physical and biochemical changes observed during intermittent-sprint exercise have traditionally been interpreted in terms of metabolic capacity (Glaister, 2005). Indeed, lowered phosphocreatine concentrations (Dawson et al., 1997), reduced glycolytic regeneration of ATP (Gaitanos et al., 1993) and increasing H+ accumulation (Bishop et al., 2003) have all been associated with declining intermittent-sprint performance.

While reductions in muscle excitability after intermittent-sprint exercise have also been observed (Bishop, 2012), metabolic perturbations are rapidly recovered within minutes (Glaister, 2005).

The ultimate indicator of post-exercise recovery is the ability of the muscle to produce force i.e., performance outcomes.

Reductions in skeletal muscle function after intermittent-sprint exercise are often proposed to be caused by a range of peripherally-induced factors, including: intra-muscular glycogen depletion; increased muscle and blood metabolites concentrations; altered Ca++ or Na+-K+ pump function; increased skeletal muscle damage; excessive increases in endogenous muscle and core temperatures; and the reduction in circulatory function via reduced blood volume and hypohydration (Duffield and Coutts, 2011; Bishop, 2012; Nédélec et al., 2012).

Conversely, Krustrup et al. (2006) reported declines in intramuscular glycogen of 42 ± 6% in soccer players, with depleted or almost depleted glycogen stores in ~55% of type I fibers and ~25–45% of type II fibers reasoned to explain acute declines in sprint speed post-match. Importantly, muscle glycogen resynthesis after team sport activity is slow and may remain attenuated for 2–3 days (Nédélec et al., 2012). Such findings highlight the importance of nutrition in post-exercise recovery (Burke et al., 2006); yet it is noteworthy that muscle glycogen stores remain impaired 24 h after a soccer match, irrespective of carbohydrate intake and should be recognized as a factor in sustained post-match suppression of force (Bangsbo et al., 2006; Krustrup et al., 2011).

Mechanical disruptions to the muscle fiber are task dependant, though likely relate to the volume of acceleration, deceleration, directional change and inter-player contact completed (i.e., tackling or collisions) (McLellan et al., 2011; Duffield et al., 2012). Importantly, EIMD manifests in reduced voluntary force production that has been associated with the elevated expression of intracellular proteins (e.g., creatine kinase and C-reactive protein), swelling, restricted range of motion and muscle soreness (Cheung et al., 2003). Whilst it is generally accepted that lowering blood-based muscle damage profiles may hasten athletic recovery, mechanisms explaining the return of skeletal muscle function are somewhat ambiguous (Howatson and Van Someren, 2008).

Interestingly, markers of EIMD are also not closely associated with muscle soreness (Nosaka et al., 2002; Prasartwuth et al., 2005), though perceptual recovery is reportedly related with the recovery of maximal sprint speed (Cook and Beaven, 2013). While this raises questions in terms of the physiological underpinnings of muscle soreness, weaker relationships between EIMD and neuromuscular performance may suggest the potential for other drivers of recovery outside of peripheral (muscle damage or metabolic) factors alone.

Finally, while the relationship between hydration status and intermittent-sprint performance remains contentious (Edwards and Noakes, 2009), fluid deficits of 2–4% are common following team-sport exercise (Duffield and Coutts, 2011). Mild hypohydration reportedly demonstrates limited effects on anaerobic power and vertical jump performance (Hoffman et al., 1995; Cheuvront et al., 2006); however, some caution is required in interpreting these data as these testing protocols reflect only select components of team sport performance.

Nevertheless, the role of hydration in recovery should not be overlooked as changes in extracellular osmolarity are suggested to influence glucose and leucine kinetics (Keller et al., 2003). Further, the negative psychological associations (conscious or otherwise) derived from a greater perceptual effort incurred in a hypohydrated state may impact mental fatigue (Devlin et al., 2001; Mohr et al., 2010).

Rather, that the integrative regulation of whole body disturbances based on these peripheral factors, alongside central regulation may be relevant.