The Balanced Brain

By Herb Wiggins, M.D.; Clinical Neurosciences; Discoverer/Creator of the Comparison Process/CP Theory/Model; 14 Mar. 2014
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There are a few basic concepts to understand more completely the complexities of neurochemistry. First of all, dopamine is the oldest and most central neurochemical of primate brains. It has upwards of 15-20 receptors with which it interacts, and thus must likely be very ancient to have so many. The D1 and D2 receptors, which largely, respectively mediate Motion and Emotion. In addition, DA is the parent compound of the catecholamines, the precursor of both norepinephrine and adrenaline, from which the former is directly derived.  DA interacts with both NE and Adrenalin receptors as well, and shares many of their alerting, activating, and stimulant qualities.
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Also, it must be understood that it’s the comparative activity of neurochemicals, not just only their absolute levels which determine these activities’ outputs. This is because there are down regulators of DA, such as GABA and Serotonin (5-HT), as well as other catecholamine up regulators. So a modest DA level, but with decline in inhibitory neurochemicals such as serotonin and GABA can produce overexcitation, well past what the actual DA levels would produce. For instance, a GABA setting protein in brain reduces effective GABA inhibition of DA, and may create psychosis or mania, while the DA level really has not changed that much.
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Next, in order to generate information, at least two events must be compared to generate information, just as comparing a length of an object to a measuring scale creates data, so comparing the known major effects of DA with other neurochemicals will create the relationships and information about most all the other neurochemicals, which both share effects of and interact with DA in some ways. Thus we use DA as the major descriptor, the least energy comparison by which we interpret and more completely can understand, in a general framework sort of way, more comprehension of brain neurophysiology and neurochemistries.
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Dopamine (DA) has these multiplicit capabilities as manifested by its many receptors sites, showing its complex systems’ essential nature.
It creates pleasure, and this is well established. DA in too high activity/levels can create an imbalance which creates psychosis and/or mania, which in the “Emotional Continuum” :
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shows how essential it is to understanding emotion. Talking to those who’ve experience such events, they state it was a rich and wonderfully joyous thing. Then did NOT want to lose the mania or psychosis, because it was a highly euphoric state. This observation also explains why taking meds to suppress such states is often resisted by patients as they lose that feeling of “Freude” and pleasure. It’s highly rewarding effect to have high DA activities and levels.
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In addition, high DA levels/activities are associated with increased speed and depths of memory lay downs. The most exciting events we experience, those mountaintop experiences, the dangers and major events of our lives are enshrouded in a high DA state, and we thus rarely forget them, Wild, wonderful, dangerous, or very exciting. DA enhances long term memory, possibly by enhancing synaptic creation by protein synthesis.
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Also, high DA, or indeed high adrenaline as well, creates a euphoria, which can be imitated by opiates, cocaine, amphetamine, endorphines, nicotine, and even the dimethylxanthines, such as Caffeine, theobromine, theophylline, tho the latter three are not as strong as the former.
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Also, each those substances may be quite addictive, in various levels, and when levels decline, also result in addictive withdrawal effects, from mild in caffeine and its congeners, to moderate in nicotine, and rather severe in opiates, cocaine, etc. These withdrawals also reinforce the addiction because getting “high” again will ablate the highly unpleasant withdrawal states of nausea, illness, headaches, etc., as well as restore that euphoric feeling.

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Often those with high DA activity are anorexic, and lose appetite, as it’s a potent anorexic agent, as are nicotine, amphetamines, etc. The implications of this for anorexia nervosa treatment is significant, because if that DA activity is high, it can be blocked with DA inhibitors, such as the haloperidols, and so forth.  Orexin effects can also be a source of this condition, but operates via the older, deeper DA systems creating appetite suppression and satiety.

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Inhibiting DA will also create drowsiness, which is commonly seen with most all DA blockers, as well. Thus DA is a very well described alerting agent in brain among the neurochemicals, as are the other catecholamines and those agents which release them.
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In addition, DA is known to be addictive as well, as giving large doses of L-dopa, will create problems with addictive withdrawals upon stopping higher L-dopa use in Parkinson’s patients. In addition, fava beans have a moderate amount of L-dopa in them and thus can be addictive in themselves, perhaps accounting for some of the popularity of fava beans and humus.
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DA can create nausea and vomiting, as anyone has seen with a flight or fight response of bilateral adrenal discharges released in dangerous, threatening, or modest to severe injuries. Strength, performance and speeds enhancement occur with this survival response, as well. & many of the opiates create serious nausea, too. although the anandamide receptors (via, for instance,THC)which can create euphorias also, creating increased appetite, pain control, and control nausea to some extent. Thus we learn by those chemicals which create & modulate DA effects, more of the entire aspects of DA, itself. We learn by comparison, and create knowledge and information by these fruitful comparisons.
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Those persons often will throw up with high DA effects, and in addition, are highly resistant to pain. PCP users are notable for this pain resistance, and nothing but a strong taser will slow them down. Thus DA has significant pain relieving activity, and notably modest with dimethyl xanthines, nicotine, but more pronounced with opiates (both exogenous and endogenous), and cocaine, as well.
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The association of euphoria producing drugs with pain control is well known, and this is yet again another DA effect, centrally.
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The association of DA with higher creativity is well known. And if the DA gets too high it can also create madness. Thus, the well known association between madness and genius of this type. And the creativity of many highly talented persons is associated with a DA profile very much like that of a schizophrenic, though those affective characteristics are controlled in some way, so they do not come out as mania or madness of frank psychoses. Creativity and inspiration are thus DA characteristics as well. And those drugs associated with this kind of DA stimulation can also promote creativity, though with a cost, as is well known with such stimulant drugs: addiction, death, psychosis, and so forth. Heart attacks with overstimulating effects of the catecholamines are well known. For this reason very little coffee or even chocolate are allowed patients in coronary care units.

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The well known “roid rages” seen in males who use huge amounts of androgenic steroids, show how very widely originating DA stimulation effects can be. And in estrogen usages, or menapausal withdrawal of estrogen, psychoses and related mental disorders can also, clearly be observed. And “roid rage” and those menopausal disorder ARE successfully, confirmably and repeatedly treated with major tranquilizers, as more confirmation of this wide range of substances whose multiplicit effects, show the complex systems at work. Thus, the balanced, brain.

In addition, testosterone can create an aggressiveness often seen in younger men, shortly after puberty, which may persist unless socially better controlled. Almost all of those males who “burn rubber” creating the squealing tires effect are young. Few women do that, either.
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Recently a “Y” chromosome of a highly specific type was reported in 50% of the men in Europe, having a common male ancestor. For that much growth and spread of the few genes on the Y, it must have been potent indeed, creating substantial advantages, Least energy effects, which created its stupendous growth. Y chromosome is uniformly associate with 4-5 fold higher androgen levels after puberty in most all males compared to women. Thus the complex system effects of sex hormones in creating advantage of enough of a value to perpetuate itself and grow to this degree, is likely a possible reason for its growth and success.
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Let us take a number of clinical states, such as sleep/wake cycles, migraine headaches, and in a later article, on the pain complex system of DA, opiates and endorphins, and the neurokinins. This will explain the bases of pain control as a complex system strategy, rather than just taking a single medication, & instead of the usual, linear, and too limited approaches to DA disorders and related conditions.
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During wakefulness, DA levels and activities are rather high. However, as the day wears on, esp. with hard physical labor, a certain amount of sleepiness can occur. Because the DA and 5HT interact in a balanced way, as DA activity declines, the person normally becomes more drowsy and tired, & very often a nap will restore normal wakefulness. Thus, the 5HT effects will rise when DA activity declines. And alertness will rise, as DA effects are enhanced, as caused also with nicotine, dimethyl xanthines, and so forth. This also is another case of the “balanced brain” where effects are activities levels modulated by other neurochemicals, being stimulants or sedatives.
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IN fact, it’s rather interesting that humans have what are termed nicotinic receptor sites, when nicotine is NOT found in the brain at all!! This indicates that there is something in the brain, normally, which activates those receptor sites, and in doing so, creates similar effects as do nicotine, including withdrawal and addictive effects, as well as with higher doses (as with Strychnine), delusional, manic states, and often seizures. Thus, since DA is the major stimulant widely employed endogenously,(it will awaken some comatose patients when given IV to raise BP) the primary nicotinic neurochemicals must be the catecholamines. There is NO endogenous nicotine found in human brain.
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Why then are nicotinic receptors sites discussed? What do those receptor site ACTUALLY bind to? And why is this question never really addressed? But it does strongly imply a relationship between muscle activity and acetylcholine and dopamine. We know that the strength of those who are in high DA states is far, far greater than normally seen. PCP and other manias are seen to do this. Stories of flight and fight responses from Adrenal release are well known. The increased aggressiveness of those with high DA activity/levels is also well known. Thus, the secondary neurochemical in muscle activation is likely DA as well as ACh. The evidence has been there for years, tho and hasn’t really been well understood, either. But these are extreme cases, but nonethless real, observed, and repeatedly seen events showing almost supernormal strength. DA is likely behind this as well as adrenaline.
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For this reason, as we know that stimulants necessarily mimic DA, and that DA creates addiction if in high levels/activities, then the so called nicotinic receptors are in fact, partial DA receptor sites.  External nicotine when administered, activates these sites to produce addictions, some euphoria, appetite suppression, and can create withdrawal effects, as well. Thus the DA spectrum is partially, again, mimicked by nicotine. And that’s the whole key.
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In terms of pain control, euphoria is found with elevated DA levels/activities, as with amphetamines, cocaine, PCP, and even with THC, which is the anandamide receptor, tho that is endogenously produced and often released with stress and flight or fight responses, but short lived. Where DA activity is imitated, or mimicked, then we have found, as with opiates, a cross reactivity with the DA primary sites, in most cases. Thus the nicotine receptors Are NOT actually such sites, but ALSO cross reactive with where DA is also active, either primarily or as a moderator.
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This fact is also strongly reinforced by this observation, clinically, that DA can create nausea, as can any of the catecholamines in high doses, but that they also create pain control as well. This explains why the nicotinic agonists, epibatidine and its analogue nicotinic agonist tebenacline both are powerful pain reducers, too,  200 and 50 times as effective, mg./mg. as morphine sulfate, the baseline pain control drug we use to measure pain reduction (again, comparison process!!). They act as DA analogues, and kill pain as well, but without the addictive side effects, tolerance, although they do create nausea, as do opiates and DA.
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We see partial DA spectral effects with many other meds as well, thus showing the overlaps with DA effects of stimulation. We also begin to understand why the aspirin in some compound drugs, are given with caffeine (Anacin)to enhance pain control, as well, This, too is no accident, but complex system effects acting, which we can see, once we detail the full DA effects of stimulation, pain control, appetite suppression, nausea, increased BP and heart rate, etc. When we measure by comparison other drugs against the DA profile of multiplicit effects, we begin to see more deeply into the neurochemical systems in our brain & how they interact and act.
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Thus we can see why DA operates in the nicotinic receptor sites, when there is NO nicotine in brain to activate them!!
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We see depressions with beta blockers, but why does no one ask how this happens? Because beta blockers block catecholamine effects, the DA is also affected in some cases and thus depression occurs, as partial spectrum of DA effects. Thus the alpha and beta adrenergic receptor sites are ALSO DA receptor sites. This adds about 4-5 more receptor sites to the DA family as well. Plus the nicotinic sites, too.
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Then when we discuss sleep, we must make a model of DA and 5HT and how they interact. The drowsiness which occurs is when the lowering DA level/activity occurs, unmasking the 5HT (and GABA) sedating effects. When GABA is low in activity/levels, mania and psychosis can be produced.
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So when drowsiness occurs, the 5HT may then increase in activity as well as in levels, & the person sleeps for a while. Then awakens when the DA returns more towards normal activities, too. And we can dream during naps as well.
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And that is interesting, because as we awaken partially during normal sleep, the 5HT activity is high and we cannot awaken fully. But the cortex is activated and normal activity during dreaming is seen there. Thus dreaming is a state of heightened DA activity while 5HT is high and one cannot fully move, nor get up.l
How does one explain hypnosis? DA activity stays high enough to be able to hear the hypnotist, but a sort of dream state occurs, and can encode suggestions which act as post hypnotic states. This is largely what’s happening as we know that memory encoding is enhanced during sleep, too. So we dream due to higher DA activities plus heightened 5HT levels, which maintain sleep long enough to get enough rest and not to increase muscle activity. The combinations of Da and 5HT are more than just a few, but also multiplicit as their receptors sites show.
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The facts are, when we are asleep, we are NOT comatose nor fully asleep. This is easily shown by nocturnal bladder and bowel control, and the fact that we do NOT roll out of bed!! Even when we are asleep, parts of our brains are wakeful enough to do these unconscious acts, preventing bed wetting, and falling out of bed, too. Children often do not have these systems fully matured until after 5-6 years old and are often at risk of falling out of bed, too. But few adults do, either.
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Nor are we in total paralysis during sleep, because we move around in the bed at night as time lapse photography has shown, confirmably and repeatedly in sleeping people. Why does this happen? So the body does not get pressure palsies, or bed sores due to too much lying in one position. These ARE seen with paralysis total as well as drug and often Ethanol induced comatose states, as most clinicians quite well know by multiple, confirming observations.
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Thus while asleep, apparently we move, the sleep paralysis is temporarily lifted to allow some movement, & sleep paralysis recurs. But bladder/bowel control are not lost, and neither do we fall out of bed!! These observations which are fairly straight forward and clear, put to rest the belief that sleep is a simple, not complex system state. And it also explains rather well hypnogogic states, as well. It’s more complicated than that, but it provides insights into how the other brain states change and highly influence our behaviors via DA and 5HT, among others.
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Brain is in a balanced state with the core pillar of brain activity being DA for both motion and Emotion. It’s balanced with GABA to maintain sanity and decreased delusional states. It’s balanced with 5HT to create wakefulness and drowsiness, signaling to us via yawning that we need to sleep. Thus yawning is a declining DA level/activity associated with a normal to rising 5HT activity. It often precedes sleep, very likely. Simple, simplifying and highly problem solving. Comparing the KNOWN effects of DA to the other neurochemicals to gain deeper and greater understanding and knowledge about how the brain works.
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Thus, the balanced brain.
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All of this suggests the root of anorexia nervosa, as a high DA activity level, with the delusion states of “being fat” when the person is not. The appetite suppressant effect is very apparent by the extreme weight loss. Thus simple, effective DA blockers currently available will suppress the anorexia, and begin to ablate the delusions of being fat as well. Anorexia is a too high DA activity/level brain disorder, and should be approached as such. No doubt this insight will result in much better understanding of AN, how to treat it and by T&E show more of its complex neurochemical bases, rooted in DA over-activity, at least.
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Sleep disorders are often seen with manias, depressions and related conditions. This should not be surprising. A normal sleep pattern in the circadian rhythms of cycling DA levels/activities, modulated by serotonin. The interesting fact that raising 5HT levels in depressions using SSRI’s shows this codependency of normal sleep with 5HT upon DA, as well. Getting better sleep allows the DA levels to be more normally repleted over night, and thus helps one side of the neurochemical balance equation to return to normal, thus pulling the person out of depression better. Depression IS a complex system disorder, thus neatly explaining the whole spectra of presentations and seemingly unlimited ways of presenting itself. PLUS showing that simply elevating DA activity via a MAO anti-depressant will NOT fully cure/treat the condition. Nor will SSRI’s, either. Thus the stage is set to more fully understand migraine headaches and How those must be treated more successfully using the complex system neurochemical approach, which we use to treat depressions in their fullest variations and nearly unlimited forms.
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Migraines are complex system neurochemical disorders. There are a huge variety of kinds of this, as well, thus complex system traits being apparent. What seems to occur in migraines is that the 5HT level drops, thus releasing the stimulatory effects of the visual scotomata and the other positive effects of DA being unbound and over active.
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In addition, the visual cortex in migraineurs has a peculiarly low threshold to magnetic stimulation causing visual scotomata, when so stimulated. Normals do NOT have this. Thus the migraineur has a 5HT neurochemical variant, which from time to time, will drop the 5HT level/activity and in some cases, create, guess what? The fingerprint spectra of DA being released from inhibition. There will be nausea, which must be treated. There will be pain from vasodilation, the usual throbbing ha’s. There is the spreading depression of Leao seen over the cortex, which ignores and passes over the arterial supply, thus showing an inhibition of normal cortical activity,quite independent of blood supply patterns. There can be seizures about 10% of the time, showing that normal cortical inhibition is gone, and DA activation has occurred as well. The migraineur in an acute attack is NOT interested in eating, either, not just because of nausea, but because of the DA effects increased by decreased 5HT, unmasking DA signs!!
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In addition, many migraineurs will take coffee, and caffeine is often added to ergots to enhance their activities against a migraine. The inflammation which occurs with migraines is often seen. Thus migraines are complex system, neurochemical effects, whose effects are better detailed when compared to DA effects, enhanced or so forth.
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MIgraineurs may be highly perfectionistic persons, because the DA is unmasked in part by lowered 5HT activity. This also goes along with the syndrome of DA hyperactivity as well, but migraines may well enhance inspiration as well as creativity, even intelligence. How else to explain why the gene is present in about 20% of many women, although in males much less expressed. Understanding that it’s a complex system also explains why a single drug approach so often fails to fully control the migraine.
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It used to be we used ergots to control it, to some extent, tho there were side effects, and a tolerance developed, often. Just like tolerance to addictive drugs. Also rebound HA’s came about in tandem. Ergots were largely thought to create more vasoconstriction to control the pounding arterial HA’s like nitrate HA’s which can imitate migraine’s pounding, throbbing pain. BUT, and this is the point, the universe is subtle. The ergots do NOT fully control migraine, and ergots ARE 5HT agonists as well.
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Even the strokes we seen occ. with migraines are a result of the complex system biology, because the platelets contain a LOT of 5HT, and if they discharge will raise 5HT levels & technically could partly treat migraines. But that causes clotting and thus the strokes seen with migraines to some extent, with or without the use of ergots or much else.
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For instance, even if we used the newer tryptans which now exist in a wide variety from slow onset but prolonged action, to fast onset but shorter activity, we see only about 2/3 of migraines responding well. This again, shows that even though the 5HT agonists work, they do not work much more than 2/3 of the time, which means complex system neurochemistry in going on in the brain. 5-HT agonists are NOT the whole story of migraines!!
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The key to understanding this is to understand the full panoply of drug treatments for migraines: the tryptans, the DA blockers, the anti-inflammatories AND the muscle relaxants, plus an anti-nauseant, AND the amitriptyline antidepressants as preventatives when taken largely at bedtime, to sleep.
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Does this complex spectrum at All sound familiar? Nausea AND appetite suppression. The DA activity is unmasked and enhanced by the 5HT plus effects. Thus using a potent anti-nauseant, which is oral, and very fast acting, with the 5HT agonists, or by itself in more mature migraineurs, we can get a close to a 90-100% control rate of migraines.
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When we consider that there are sleep disorders with migraines, helping the person sleep better and more regularizing in the normal diurnal cycles, (NO night shift work!), we can better control them, too. Now this will not ignore Orexin and other neurochemicals, but simply how those too will fit into the DA/5-HT balanced brain model to help control migraines.
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We’ve known for years that chlorpromazine with its massive DA blocking capacity blocks both the nausea and directly the migraine HA’s too. The sleep it induces of itself will substantially treat a migraine. But because of its side effects, we choose not to use it except when, if the migraine goes on too long without effective RX & a migraine rescue is needed, then the whole panoply of the complex system migraine effects are shown.
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Thus the domperidona plus tryptans methodologies. Those, by themselves, block most all migraines, which is not generally known. But we must recall the neurokinins that get going as well, which create pain, directly, create vasodilation and the throbbing pains. Thus Anacin may work pretty well partly, but only 50-60% or so, too. Showing once again, even those there is caffeine with Aspirin, only partial treatment works, in this case, also.
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So here we have the major components: the dropping of the 5HT, which creates the DA effects, occasionally seizures as well, and the scotomata. Then we have the inability to sleep because the migraine is too strong, due to DA overstimulation and activity. & unless the person can sleep, the migraine will be longer lasting. Thus sleep has an effect to restore the balanced brain by raising 5HT levels. & we do this with sedatives such as Fiorinal (APAP plus Butalbital), using a barbiturate to induce sleep, as well as sedate & suppress the overactive DA effects.
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Thus we see very clearly, using the comparison process via comparing with DA, the 5HT effects, the entire spectrum of migraine HA’s in all those full panoplies of presentations, symptoms and signs.
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I had a patient who did well with domperidona alone, but noted if he took an Aleve, the HA went totally away. He had more neurokinin effects than most, and if THOSE get going, then the HA is very resistant to drug alleviation, too, with only the Tryptans. Thus fast treatment at onset of migraines is essential to control. Once the migraine train of events gets going too much, it’s hard to control it from getting worse. & multiple meds are usually needed to block the HA.
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So we have 5HT withdrawal effects, and unmasking of DA effects of nausea, anorexia, decreased pain control because DA is overbalanced, and so forth. Then the neurokinin effects of throbbing HA’s plus the inflammatory effects, locally in brain, best treated with whatever is effect and safe for the patient to use, aspirins, NSAID’s or whatever works best. Then the muscle spasms and pain effects as well, best Rx’ed with sedation, sleep and acetaminophen is some form or combination.
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Most migraineurs except in familial forms, are different. They present in the full complexity of the system in a wide range of forms. All the myriad ways of complex systems. And understanding that it’s NOT a linear condition, but complex system, allows us to not only better understand the wide range of migraines, but also how to best treat it NOT as a linear, single condition, but 5HT declines in actvities/levels, causing DA interactivity, and then neurokinin release, & a sleep disorder, and the muscle tension aspects of it as well, PLUS the nausea from DA unmasking by lowered 5HT activity/levels, etc.
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Extending this model to most other disease states, ignoring the linear models which ignore the complex system nature of most all medical conditions, will result in much more successful prevention, treatment and avoidances of the many, many complications of migraine, such as loss of work time, handicapping otherwise productive persons, strokes, seizures, and long term chronicity, as well. Because if the system simply gets used to having migraines and these recurrent behaviors become ingrained & learned, then those are ever harder to treat, as well. HA’s can be behaviorally learned, indulged, and self-promoted to occur. It’s complex system!!!
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These are the benefits in the long run of considering the “Balanced Brain” approaches to a more mature, more effective and better treatment using the CP, complex systems, and DA as the parent neurochemical in the brain, with whose effects, by comparison with the other neurochemicals, we can far more easily understand much, much more the complex neurochemistry/neurophysiology of brain.
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Will not go into the sleep disorders, too, although those are largely associated with depressions, mood disorders, and many other conditions. But those too, are amenable to the complex system, comparison process approaches for improved understanding and treatment.
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