Stikkordarkiv: Nervesystemet

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Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

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Denne beskriver endocannabinoider(eCB) og hvordan man kan øke produksjonen av dem og reseptorene for dem. eCB er et kroppens viktigste naturlige smertstillende stoffer som kan produseres og påvirker alle nerver i kroppen. Spesielt viktig i hjernen, men også i det perifere nervesystem.

Massasje, kiropraktikk og hard trening (f.eks. runners high) utløser eCB i kroppen. Det gjør også omegabalanse (mer n-3), probiotica, NSAIDs, m.m. Også yoga, meditasjon, pust og andre stressreduserende påvirker eCB. Og trening, men kun om man gjør det jevnlig over tid.

Den nevner at langvarig stress reduserer eCB i kroppen siden det er koblet til kortisol. Men den nevner også at noen tilstander kan ha forhøyet eCB i kroppen, f.eks. overvekt.

Med høyt nivå av n-6 relativt til n-3 blir det en overvekt av AA (arakidonsyre) som produserer en overvekt av eCB, som dermed fører til en reduksjon av eCB reseptorer. Dette gjør at smertestillende medikamenter fungerer dårligere, og at det blir lettere kronisk smerte. Tilskudd av n-3 gjør at eCB reseptorene øker. Studiene er gjort på mus og innebærer 17 g/kg.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089566

The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. Metaphorically the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine. Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with particularly dense expression in (rank order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala [1]. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous [2], [3].

The eCB system’s salient homeostatic roles have been summarized as, “relax, eat, sleep, forget, and protect” [5]. It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism. Obese individuals seem to display an increased eCB tone, driving CB1activation in a chronic, feed-forward dysfunction (reviewed by [6]).

Other diseases are associated with suboptimal functioning of the eCB system. Russo [8]proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride [9] speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka [10] hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia [11], migraine [12], multiple sclerosis [13], Huntington’s [14],[15], uncompensated Parkinson’s [16], irritable bowel syndrome [17], uncompensated anorexia[18], and chronic motion sickness [19].

NSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine [27]. SeeFigure 2. A binding site for some NSAIDs on FAAH has also been identified [28]. NSAID inhibition of COX2 blocks the metabolism of AEA and 2-AG into prostaglandin ethanolamides (PG-EAs) and prostaglandin glycerol esters (PG-GEs), respectively [29].

Combining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects. A sub-effective dose of WIN55,212-2 became fully antinociceptive following administration of indomethacin in rats [36].

In summary, preclinical studies indicate that some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Combinational effects may be particularly relevant at peripheral sites, such as the peripheral terminals of nociceptors.

The distribution of glucocorticoid receptors (GRs) and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoid-mediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects.

The acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain.

Chronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus [59] and mouse hippocampus and amygdala [61]. Chronic corticosterone administration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [62].

Polyunsaturated fatty acids (PUFAs) play fundamental roles in many cellular and multicellular processes, including inflammation, immunity, and neurotransmission. They must be obtained through diet, and a proper balance between omega-6 (ω-6) PUFAs and ω-3 PUFAs is essential. The typical Western diet contains a surfeit of ω-6s and a deficiency of ω-3s [130].

The inflammatory metabolites of AA are countered by dietary ω-3s. The two best-known ω-3s are eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 22:6ω-3).

eCBs are derived from AA (see Figure 2). Several preclinical studies showed that dietary supplementation with AA increased serum levels of AEA and 2-AG, summarized in Table 1. Although we clearly need AA to biosynthesize eCBs, excessive levels of AA, administered chronically, may lead to excessive levels of eCBs. This in turn may lead to desensitized and downregulated CB1 and CB2 receptors.

Dietary supplementation with ω-3s predictably increased the concentration of EPA and/or DHA in tissues, cells, and plasma, and decreased the relative concentration of AA in tissues, cells, and plasma [132], [133]. ω-3 supplementation also decreased AEA and 2-AG in tissues, cells, and plasma (Table 1).

Adequate levels of dietary ω-3s are required for proper eCB signaling. Mice supplemented with ω-3s, compared to mice on a control diet, expressed greater levels of CB1 and CB2 mRNA.

n summary, dietary ω-3s seem to act as homeostatic regulators of the eCB system. In obese rodents fed a high-AA diet, ω-3s significantly decrease eCBs, especially 2-AG, particularly in tissues that become dysregulated, such as adipose and liver tissues. Plasma eCB levels are reduced by krill oil also in obese humans. Little change in eCB levels are seen in normo-weight individuals not fed a high ω-6 diet, and dietary ω-3s are required for proper eCB signaling.

Human intestinal epithelial cells incubated with L. acidophilus produced more CB2 mRNA [145]. Feeding L. acidophilus to mice and rats increased the expression of CB2 mRNA in colonic epithelial cells. Lastly, mice fed L. acidophilus showed less pain behavior following colonic distension with butyrate than control mice, an effect reversed by the CB2 antagonist AM630[145].

Chronic or repeated stress results in a chronic elevation of endogenous corticosterone via the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic stress (repeated restraint) reduced AEA levels throughout the corticolimbic stress circuit in rodents [99], [196], [197].

In summary, chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG. Changes in CB1 expression are more labile. Stress management may reverse the effects of chronic stress on eCB signaling, although few studies exploring this possibility have been performed to date. Clinical anecdotes suggests that stress-reduction techniques, such as meditation, yoga, and deep breathing exercises impart mild cannabimimetic effects [218].

Massage and osteopathic manipulation of asymptomatic participants increased serum AEA 168% over pretreatment levels; mean OEA levels decreased 27%, and no changes occurred in 2-AG. Participants receiving sham manipulation showed no changes [218].

Upregulation of the eCB system in obese humans seems to be driven by excessive production of eCBs in several peripheral tissues such as visceral adipose tissue, liver, pancreas, and skeletal muscle.

In summary, increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.

Although both types of exercise regimens increased eCB ligand concentrations, only long-term-forced exercise led to sustained elevations of eCBs, and predictable CB1 downregulation.

In whole animals, however, caffeine’s effects are biphasic and vary by dosage and acute versus chronic administration. In humans, the acute administration of caffeine decreases headache pain, but exposure to chronic high doses, ≥300 mg/day, may exacerbate chronic pain [275].

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Structure and Biomechanics of Peripheral Nerves: Nerve Responses to Physical Stresses and Implications for Physical Therapist Practice

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Denne sier mye om nervenes blodgjennomstrømmning. Spesielt interessant er avnittet om hvor lite trykk som skal til før blodgjennomstrømningen stopper. Om trykket opprettholdes i 8 timer vil det skje en skade i nerven. Så lite som 20 mm Hg er nok til at blodsirkluasjonen blir dårligere.

http://ptjournal.apta.org/content/86/1/92.full

Simply placing the hand on a computer mouse was shown to increase the tunnel pressure from the resting 5 mm Hg to 16 to 21 mm Hg,79 and actively using the mouse to point and click increased the tunnel pressure to 28 to 33 mm Hg, a pressure high enough to reduce nerve blood flow.

In subjects with carpal tunnel syndrome, pressure in the carpal tunnel was 32 mm Hg with the wrist in a neutral position and rose to a mean of 110 mm Hg with full wrist extension in subjects with carpal tunnel syndrome.76 These tunnel pressures exceed the threshold of 20 to 30 mm Hg for vascular perfusion even at rest. Taken together, these findings suggest that even functional positions, such as the use of a computer keyboard and mouse, place the wrist in a position of increased carpal tunnel pressure, compromising nerve blood flow and placing people at risk for median nerve injury.

Arterial and endoneurial capillary blood flows were stopped at pressures of 50 to 70 mm Hg67 and 80 mm Hg,75 respectively. Interestingly, in humans, intraneural blood flow and sensory responses are blocked at extraneural tissue pressures 45 mm Hg below the mean arterial pressure.82 A compressive stress of only 30 mm Hg, if maintained for 2 hours, results in endoneurial edema,83 and, if maintained for 8 hours, results in endoneurial pressure high enough to subsequently impair blood flow.84 The endoneurial edema is thought to result from ischemic damage to endoneurial capillary endothelial cells and an alteration in the blood-nerve barrier. The same compressive stress of 30 mm Hg applied for 8 hours is sufficient to impair both anterograde axonal transport and retrograde axonal transport.85,86Increasing pressure results in greater tissue damage, as a compressive force of 150 mm Hg maintained for 30 minutes was shown to induce a degeneration of 30% of the distal fibers,48 and compressive forces of 200 and 400 mm Hg maintained for 2 hours were shown to block axonal transport for 1 and 3 days, respectively.87

The pathological consequences of prolonged compression include subperineurial edema; inflammation; deposition of fibrin; activation of endoneurial fibroblasts, mast cells, and macrophages; demyelination; axon degeneration; and fibrosis.83 Compression of a very long duration has been modeled in animals with loose ligatures,88 Silastic* tubes,89,90and pressure balloons placed within an anatomical tunnel.91 The pathological findings are thought to result from both inflammatory and cellular phenomena and include changes in the blood-nerve barrier, thickening of the perineurium and epineurium, thinning of myelin, demyelination and degeneration of axons in the fascicle periphery, and slowed nerve conduction velocity.

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

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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.

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The Mechanisms of Manual Therapy in the Treatment of Musculoskeletal Pain: A Comprehensive Model

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Nevner det meste rundt behandling av muskel og skjelett problemer, både usikkerheter, manglende diagnostisk spesifisitet, dårlig forhold mellom forklaringsmodelle og realitet, og foreslår nevrosentriske forklaringsmodeller. Viser til at spesifikk behandling ikke har bedre effekt enn uspesifikk behandling. Og til at den mekaniske teknikken setter igang en kaskade av nevrologiske effekter som resulterer i en behandlingeffekt.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775050/

Abstract

Prior studies suggest manual therapy (MT) as effective in the treatment of musculoskeletal pain; however, the mechanisms through which MT exerts its effects are not established. In this paper we present a comprehensive model to direct future studies in MT. This model provides visualization of potential individual mechanisms of MT that the current literature suggests as pertinent and provides a framework for the consideration of the potential interaction between these individual mechanisms. Specifically, this model suggests that a mechanical force from MT initiates a cascade of neurophysiological responses from the peripheral and central nervous system which are then responsible for the clinical outcomes. This model provides clear direction so that future studies may provide appropriate methodology to account for multiple potential pertinent mechanisms.

Mechanical Stimulus 

First, only transient biomechanical effects are supported by studies which quantify motion (Colloca et al., 2006;Gal et al., 1997;Coppieters & Butler, 2007;Coppieters & Alshami, 2007) but not a lasting positional change (Tullberg et al., 1998;Hsieh et al., 2002). Second, biomechanical assessment is not reliable. Palpation for position and movement faults has demonstrated poor reliability (Seffinger et al., 2004;Troyanovich et al., 1998) suggesting an inability to accurately determine a specific area requiring MT.  Third, MT techniques lack precision as nerve biased techniques are not specific to a single nerve (Kleinrensink et al., 2000) and joint biased technique forces are dissipated over a large area (Herzog et al., 2001;Ross et al., 2004).

Finally, studies have reported improvements in signs and symptoms away from the site of application such as treating cervical pain with MT directed to the thoracic spine (Cleland et al., 2005;Cleland et al., 2007) and lateral epicondylitis with MT directed to the cervical spine (Vicenzino et al., 1996).

Subsequently, we suggest, that as illustrated by the model, a mechanical force is necessary to initiate a chain of neurophysiological responses which produce the outcomes associated with MT. 

Neurophysiological Mechanism 

Studies have measured associated responses of hypoalgesia and sympathetic activity following MT to suggest a mechanism of action mediated by the periaquaductal gray (Wright, 1995) and lessening of temporal summation following MT to suggest a mechanism mediated by the dorsal horn of the spinal cord (George et al., 2006) The model makes use of directly measurable associated responses to imply specific neurophysiological mechanisms when direct observations are not possible. The model categorizes neurophysiological mechanisms as those likely originating from a peripheral mechanism, spinal cord mechanisms, and/or supraspinal mechanisms.

Peripheral mechanism 

Musculoskeletal injuries induce an inflammatory response in the periphery which initiates the healing process and influences pain processing. Inflammatory mediators and peripheral nociceptors interact in response to injury and MT may directly affect this process. For example, (Teodorczyk-Injeyan et al., 2006) observed a significant reduction of blood and serum level cytokines in individuals receiving joint biased MT which was not observed in those receiving sham MT or in a control group. Additionally, changes of blood levels of β-endorphin, anandamide, N-palmitoylethanolamide, serotonin, (Degenhardt et al., 2007) and endogenous cannabinoids (McPartland et al., 2005) have been observed following MT. Finally, soft tissue biased MT has been shown to alter acute inflammation in response to exercise (Smith et al., 1994) and substance P levels in individuals with fibromyalgia (Field et al., 2002). Collectively, these studies suggest a potential mechanism of action of MT on musculoskeletal pain mediated by the peripheral nervous system for which mechanistic studies may wish to account. 

Spinal mechanisms 

MT may exert an effect on the spinal cord. For example, MT has been suggested to act as a counter irritant to modulate pain (Boal & Gillette, 2004) and joint biased MT is speculated to “bombard the central nervous system with sensory input from the muscle proprioceptors (Pickar & Wheeler, 2001).”Subsequently, a spinal cord mediated mechanism of MT must be considered and is accounted for in the model. Direct evidence for such an effect comes from a study (Malisza et al., 2003b) in which joint biased MT was applied to the lower extremity of rats following capsaicin injection. A spinal cord response was quantified by functional MRI during light touch to the hind paw. A trend was noted towards decreased activation of the dorsal horn of the spinal cord following the MT. The model uses associated neuromuscular responses following MT to provide indirect evidence for a spinal cord mediated mechanism. For example, MT is associated with hypoalgesia (George et al., 2006;Mohammadian et al., 2004;Vicenzino et al., 2001), afferent discharge (Colloca et al., 2000;Colloca et al., 2003), motoneuron pool activity (Bulbulian et al., 2002;Dishman & Burke, 2003), and changes in muscle activity (Herzog et al., 1999;Symons et al., 2000) all of which may indirectly implicate a spinal cord mediated effect.

Supraspinal mechanisms 

Finally, the pain literature suggests the influence of specific supraspinal structures in response to pain. Structures such as the anterior cingular cortex (ACC), amygdala, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) are considered instrumental in the pain experience.(Peyron et al., 2000;Vogt et al., 1996;Derbyshire et al., 1997;Iadarola et al., 1998;Hsieh et al., 1995;Oshiro et al., 2007;Moulton et al., 2005;Staud et al., 2007;Bee & Dickenson, 2007;Guo et al., 2006). Subsequently, the model considers potential supraspinal mechanisms of MT. Direct support for a supraspinal mechanism of action of MT comes from (Malisza et al., 2003a) who applied joint biased MT to the lower extremity of rats following capsaicin injection. Functional MRI of the supraspinal region quantified the response of the hind paw to light touch following the injection. A trend was noted towards decreased activation of the supraspinal regions responsible for central pain processing. The model accounts for direct measures of supraspinal activity along with associated responses such as autonomic responses (Moulson & Watson, 2006;Sterling et al., 2001;Vicenzino et al., 1998) (Delaney et al., 2002;Zhang et al., 2006), and opiod responses (Vernon et al., 1986) (Kaada & Torsteinbo, 1989) to indirectly imply a supraspinal mechanism. Additionally, variables such as placebo, expectation, and psychosocial factors may be pertinent in the mechanisms of MT (Ernst, 2000;Kaptchuk, 2002). For example expectation for the effectiveness of MT is associated with functional outcomes (Kalauokalani et al., 2001) and a recent systematic review of the literature has noted that joint biased MT is associated with improved psychological outcomes (Williams et al., 2007). For this paper we categorize such factors as neurophysiological effects related to supraspinal descending inhibition due to associated changes in the opioid system (Sauro & Greenberg, 2005), dopamine production (Fuente-Fernandez et al., 2006), and central nervous system (Petrovic et al., 2002;Wager et al., 2004;Matre et al., 2006) which have been observed in studies unrelated to MT.

Figure 3 Pathway considering both a spinal cord and supraspinal mediated effect from Bialosky et al (2008)

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Understanding the rhythm of breathing: so near yet so far

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Nevner mange interessante prinsipper om pusten og hvordan dens rytmiske egenskaper regulerer kroppsfunksjoner.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671763/

Abstract
Understanding the mechanisms leading from DNA to molecules to neurons to networks to behavior is a major goal for neuroscience, but largely out of reach for many fundamental and interesting behaviors. The neural control of breathing may be a rare exception, presenting a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to rapidly and slowly changing conditions, and how particular dysfunctions result in disease. Why can we assert this? First and foremost, the functions of breathing are clearly definable, starting with its regulatory job of maintaining blood (and brain) O2, CO2 and pH; failure is not an option. Breathing is also an essential component of many vocal and emotive behaviors including, e.g., crying, laughing, singing, and sniffing, and must be coordinated with such vital behaviors as suckling and swallowing, even at birth. Second, the regulated variables, O2, CO2 and pH (and temperature in non-primate mammals), are continuous and are readily and precisely quantifiable, as is ventilation itself along with the underlying rhythmic motor activity, i.e., respiratory muscle EMGs. Third, we breathe all the time, except for short breaks as during breath-holding (which can be especially long in diving or hibernating mammals) or sleep apnea. Mammals (including humans) breathe in all behavioral states, e.g., sleep-wake, rest, exercise, panic, or fear, during anesthesia and even following decerebration. Moreover, essential aspects of the neural mechanisms driving breathing, including rhythmicity, are present at levels of reduction down to a medullary slice. Fourth, the relevant circuits exhibit a remarkable combination of extraordinary reliability, starting ex utero with the first air breath – intermittent breathing movements actually start in utero during the third trimester – and continuing for as many as ~109 breaths, as well as considerable lability, responding rapidly (in less than one second) and with considerable precision, over an order of magnitude in metabolic demand for O2 (~0.25 to ~5 liters of O2/min). Breathing does indeed persist! Finally, breathing is genetically determined to work at birth, with a well-defined developmental program underlying a neuroanatomical organization with apparent segregation of function, i.e., rhythmogenesis is separate from motor pattern (burst shape and coordination) generation. Importantly, single human gene mutations can affect breathing, and several neurodegenerative disorders compromise breathing by direct effects on brainstem respiratory circuits (See below).

 

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Vagal tone and the inflammatory reflex

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En studie som beskriver mekanismene bak hvordan vagus nerven henger sammen med immunsystemet. Med en sterk vagusnerve (høy HRV) kan betennelser dempes.

http://www.ccjm.org/content/76/Suppl_2/S23.long

Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate inflammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data suggest an association between heart rate variability and inflammation that may support the concept of a cholinergic anti-inflammatory pathway.

The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

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The inflammatory reflex: the role of the vagus nerve in regulation of immune functions

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Nevner mekanismene bak hvordan vagus nerven demper betennelsesreaksjoner og kan bidra i autoimmune sykdommer.

http://www.ncbi.nlm.nih.gov/pubmed/22263327

Abstract

Experimental studies published in past years have shown an important role of the vagus nerve in regulating immune functions. Afferent pathways of this cranial nerve transmit signals related to tissue damage and immune reactions to the brain stem. After central processing of these signals, activated efferent vagal pathways modulate inflammatory reactions through inhibiting the synthesis and secretion of pro-inflammatory cytokines by immune cells. Therefore, pathways localized in the vagus nerve constitute the afferent and efferent arms of the so-called «inflammatory reflex» that participates in negative feedback regulation of inflammation in peripheral tissues. Activation of efferent pathways of the vagus nerve significantly reduces tissue damage in several models of diseases in experimental animals. Clinical studies also indicate the importance of the vagus nerve in regulating inflammatory reactions in humans. It is suggested that alteration of the inflammatory reflex underlies the etiopathogenesis of diseases characterized by exaggerated production of pro-inflammatory mediators. Therefore, research into the inflammatory reflex may create the basis for developing new approaches in the treatment of diseases with inflammatory components.

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Neurobiologic basis of craving for carbohydrates.

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Denne studen nevner 5 systemer som bidrar til at vi føler behov for karbohydrater. Den viktigste er at serotonin øker i hjernen, noe som over tid kan gi en avhengighet. De nevner også at evnen til å skille sult fra andre interne følelser kan bli dårligere, og at det gir behov for mat når andre ting i kropp og sinn er i ulage.

http://www.ncbi.nlm.nih.gov/pubmed/24139726

Serotonergic:  Increased brain serotonin improves mood. Brain serotonin levels depend on the availability of its Trp precursor. Dietary carbohydrates increase the passage of Trp through the blood–brain barrier, unlike proteins, which alter LNAA.  Faced with anxiety, an individual eats carbohydrates, which increase brain serotonin, thus improving mood.

Palatability and hedonic response: The pleasurable experience of eating food with high palatability immediately improves mood. This occurs in individuals with greater genetic sensitivity to sweet taste through the activation of the endogenous opioid system. Faced with anxiety, an individual eats a food with high palatability, activating the hedonic mechanism, which improvesmood.

Motivational system:  Carbohydrates act in the motivational system in the same manner as abused substances. This increases dopamine and endogenous opioids, which are associated with a known pleasurable effect, improving mood. If this behavior is repeated over time, structural changes in the brain are produced that generate dependence on highly palatable foods.

Stress response: Faced with anxiety associated with stress, the HPA axis activates. Highly palatable foods activate the motivational system and reduce the HPA axis, thus regulating the stress system. Therefore, when faced with anxiety, highly palatable food produces a hedonic reward as well as reducing the state of anxiety.

Gene–environment:  Eating is a coping tool to relieve negative emotions. The behavior is learned through inadequate parenting and environment. It also stems from an inability to distinguish hunger from other aversive internal states. There is greater susceptibility in carriers of the A1 allele of the DRD2 dopamine receptor and carriers of the short allele of the serotonin transporter gene.

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PHASE RELATIONSHIP BETWEEN NORMAL HUMAN RESPIRATION AND BAROREFLEX RESPONSIVENESS

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Nevner hvordan forskjellige pustefrekvenser påvirker det autonome nervesystemet.

http://jp.physoc.org/content/304/1/489.full.pdf+html

1. We studied the influences of phase of respiration and breathing frequency upon human sinus node responses to arterial baroreceptor stimulation.

2. Carotid baroreceptors were stimulated with brief (0.6 sec), moderate (30 mmHg) neck suction during early, mid, and late inspiration or expiratin at usual breathing rates, or, during early inspiration and expiration at breathing rates of 3, 6, 12, and 24 breaths/min.

3. Baroreceptor stimuli applied during early and mid inspiration and late expiration provoked only minor sinus node inhibition; stimuli begun during late inspiration and early expiration provoked maximum sinus node inhibition.

4. At breathing rates of 3, 6 and 12 breaths/min, expiratory baroreflex responses were significantly greater than inspiratory responses; at 24 breaths/min, however, inspiratory and expiratory baroreceptor stimuli produced comparable degrees of sinus node inhibition.

5. Our results delineate an important central biological rhythm in normal man: human baroreflex responsiveness oscillates continuously during normal, quiet respiration. The phase shift of baroreflex responsiveness on respiration suggests that this interaction cannot be ascribed simply to gating synchronous with central inspiratory neurone activity. Regularization of heart rate during rapid breathing is associated with loss of the differential inspiratory-expiratory baroreflex responsiveness which is present at usual breathing rates.