A) Function over Form
Continuing from last time, we can look beyond structures that comprise a system and instead look to the activity of the system. If consciousness is a problem of quality more so than quantity, this would make sense. Or put another way:
We see this in nerves that consist of the same anatomical structure but require histochemical methods to determine which function as afferent and which as efferent. So it makes sense that a disorder like PTSD correlates with decreased metabolism in the hippocampus, but also with hippocampal glutamate specifically. So this seems like a path worth exploring.
B) Perchance to Dream
The basic starting point is to observe differences in function and separate them appropriately. Presumably, one falls asleep or receives anesthesia and that will serve as a proxy showing a general trend towards differentiating conscious and unconscious activity. So one just needs to use a device, eg. EEG, and find the point of not being awake, ie. isoeletric EEG.
But tweaking the bispectral index is not sufficient to find the solution. In the middle of sleep, there is evidence of mental activity whether in “dreams” during REM/NREM or “hallucinations” during hypnogogic/hypnopompic periods. There is also evidence of dreams while under anesthesia, if one takes time to isolate and remove amnestic variables. In short, wakefulness and behavior producing states do not correlate so simply.
So let’s try a finer level of analysis. Let’s instead try to classify and analyze by different stages of sleep and then find the corresponding different types of waves. So periods of REM dreaming are associated with beta waves. But those waves are also associated with our highest points of wakefulness. Likewise, gamma waves are supposed to correlate with alert mental activity, ie. cortical function. But so does meditation, which is supposed to be the least amount of mental activity while awake. So in the end, wave-types don’t reveal much.
So maybe the key is not waveform attributes like amplitude or frequency, but the timing. Looking at this variable, we find that an awake person has desynchronized beta waves while the stages of sleep will show synchronized waves. But looking at just the EEG, seeing synchronized waves does not necessarily mean this is sleep. Maybe it is a seizure. To complicate things further, that reading may be good if the patient is receiving ECT and it may be bad if the patient is on a course of VPA. So don’t look to contemporary clinical attitudes to help because if the simple question of “is this desirable?” is uncertain, than the bigger question of “is this the key element to investigate?” is even more lost.
In short, it looks like neuronal firing patterns per se are insufficient to inform one about the presence or absence of mental phenomena. However, the boundary between being awake and stages of sleep does correlate well with the neurotransmitter acetylcholine. Specifically, in REM sleep there is deactivation of dorsolateral prefrontal cortex by acetylcholine. So if activity levels in the physical sense might not be the best aspect to put mental activity under, it might be better understood in the chemical sense.
C) Better Living Through Chemistry
Ideally, neurochemistry would provide a clear investigatory course in a one-chemical-one-pathway-one-disturbance type of way. This usually doesn’t happen and a chemical will act on multiple pathways, or multiple chemicals may work on the same pathway. The result is that one state can have many different chemical associations. For example, here is depression:
So there are a lot of different candidates and potential functions to assign. For simplicity, let’s look at them one at a time. Let’s start with serotonin.
Serotonin is a good candidate based on its utility as the standard treatment for depression, given out to around 10% of the population, in the form of an SSRI (ie. drugs that make more serotonin available). A lot of this prescription increase stems from findings that suggested a variant of the 5HTTLPR gene is more common in depression. However, Joan Chiao has found that East Asians are more than twice as likely to have those genes but only have half the rate of mood disorders, as shown here:
Besides genes and geography, serotonin also occurs in a variable distribution throughout the body beyond the brain and spinal cord. Platelets have serotonin. So do enterochromaffin cells, from the trachea down through the GI. These cells are less than 1% of the GI but end up being the largest endocrine organ in the body. So to rehash earlier discussions, is the CNS the real target area if the ENS is such a large reservoir of the chemicals being targeted therapeutically? Frenchmen have said that “happiness is the absence of fever”, so why can’t “presence of enteric function” do likewise? After all, 90% of body’s serotonin is made in the gut, and 70% of the immune system is in the gut, so one shouldn’t be surprised to see mood disorders linked to immune system functioning.
Overall, however, the idea of the serotonin hypothesis (that depression is simply a deficit of serotonin) is overly simplistic. The multiple roles of serotonin means that an SNRI like Sibutramine is used as an anorexiant instead of an antidepressant. And on the other hand, serotonin is actually reduced in the antidepressant Wellbutrin. There is also Tianeptine, a TCA antidepressant, which decreases serotonin and instead works on glutamate. And the logic of the serotonin hypothesis was circular to begin with. Antibiotics treat pneumonia, but that doesn’t mean that pneumonia is an antibiotic deficiency. Such thinking has delayed medical progress in insidious ways, as put here:
“Strattera (NRI) and Cymbalta (SNRI), both invented at the same time as Prozac (SSRI), languished in Eli Lilly’s basement because the world of doctors was not ready to hear about drugs that weren’t ‘selective’ or ‘serotonergic’.”
So let’s not be so myopic. Let’s look elsewhere. Dopamine perhaps.
The general teaching is simply that “dopamine = enjoyment”, as if advertised by Coca-Cola. However, “enjoyment” has multiple components. By “enjoy” we may mean pleasure, ie. a subjective reaction. This veers close to qualia and ineffability, so science needs an intervening variable to explore more. When one “enjoys”, one also likes, viz. there is an objective third person observable attribute in the form of facies. I can tell if a fellow mammal likes something based on the facial expressions displayed. However, liking is also produced by opioids and GABAergic neurons, which means that dopamine is not necessary in this case.
Dopaminergic neurons, eg. nucleus accumbens, are actually better correlated with wanting than either pleasure or liking. Wanting is a motivational consequence of reward that makes one aware of the incentives an action will produce. The statement “I want” means “I am motivated to acquire something.” The incentive salience relies on mesolimbic dopaminergic neurons, but require corticolimbic projections for any incentive involving cognitive imagery. This means that you can push all the dopamine into a person that you want, but without the associated cognitive coupling to consequence, you won’t alter behavior.
People can expect that they will like what they want. However, dopamine, as it is salience and not simply pleasure, is not going to do just that. An addict continues to be motivated in drug-seeking even if that person does not like doing so and is trying to recover. Being salient of incentives also is not indicative of whether the incentive is positive or negative, whether is causes desire or aversion. So a dopamine spike while eating a greasy meal may be a combination of current desire and fear for future health effects. Similarly, courting a stranger home brings a recognition of possible reward and possible danger. And so on ad infinitum.
To move from hypothetical delineations, we should find, however imperfect, a correlation between behaviors and dopamine. For instance, we could postulate a direct relationship between libido and dopamine. However, it has been found that Parkinson’s patients on dopamine therapy had reduced libido, and of that women more than men. The gender disparity could be explained by allowing the mind to have a role, instead of pure dopamine chemical transmission. Also, if one permits the mind to enter into one’s calculations then it explains why those who are chemically castrated can have a preserved libido. Remind me again why one would think that something as mentally-laden as libido would ever reduce in the first place? Alas, I digress.
We could also consider that chemicals such as dopamine and serotonin work through secondary effects. After all, both are vasoactive. To that effect, antihypertensives can have mental effects, whether in calming nightmares in PTSD via prazosin or inducing psychosis via propranolol. Need I remind you of the relevance of the heart in mental health?
If this third component is the item we’re interested in, we might as well just target intermediary enzymes while ignoring the specific neurotransmitter that occurs downstream. For example, take monoamine oxidase (MAO). The isozyme MAO-A metabolizes serotonin, dopamine, epinephrine, and tyramine in the CNS and GIT. The form MAO-B metabolizes dopamine and phenylethylamines, but not tyramine, in the CNS and platelets. And so the side effects of MAO inhibitors working on MAO-A, in the form of tyramine crisis, are well understood. But while the adverse effects profile on MAO inhibitors is well understood, this is not true of the direct effects. Consider the following correlation between output (violent behavior) and input (MAO-A), in a complex (realistic) scenario running through a filter (environmental factors):
The combinations show that when MAO-A is high, this prevents maltreatment from developing into antisocial behaviors. Mutatis mutandis, this means low MAO-A is a risk factor for violent antisocial behaviors. However, other studies show that MAO inhibitors are supposed to make people less violent. So which is it?
Another big warning sign concerning antidepressant methodology is the varying time courses required for the same chemicals. The mood boost from MDMA occurs in under an hour, ketamine carries antidepressant effect within days, but an SSRI is supposed to be allowed weeks to work. So what’s the difference?
With all these different, or uncertain, mechanisms at work shouldn’t we be open to many different possibilities?
D) AMS as PFM
Forms of mental disturbance and altered mental status (AMS) are varied in their causes. As far as categorizing varied causes go, a good candidate is an infection. We find OCD associated with Streptococcus, chronic fatigue syndrome correlated with Epstein-Barr, as well as a general tendency for infections to generate encephalitis and the ensuing AMS. As a result, finding Toxoplasma gondii associated with altered behavioral states like schizophrenia or increased rates of car accidents should not be surprising when considered analogously: the analogy is that similarly infected mice draw the parasite toward their host, ie. cats, when a mouse exhibits the “reckless” behavior of no longer being afraid of cat urine. There is a similar motif of behavioral changes across a lot of parasites: Ampulex compressa, Spinochordodes tellinii, Dicrocoelium dendriticum, Glyptapanteles wasp, etc. In general, one should raise their eyebrows when acute changes happen with highly specific and peculiar demands, such as that of Ophiocordyceps unilateralis:
On the other hand, if the association between schizophrenia and Toxoplasma is causal, then how come it affects up to half of the world’s population, and schizophrenia rates are not that high? If we look to only associations, and we make the net wide enough, how many behaviors can we “correlate” with infections? Probably most of them. So we have to return to looking for a chemical explanation instead. So what’s the mechanism for Toxoplasma? Turns out the infectious cysts work on tyrosine hydroxylase allowing an increase in, wait for it, dopamine. Great, we’re back to that again.
Moving right along, beyond infection there are also immune targets leading to AMS, whether encephalitis secondary to targeting NMDA receptors or the basal ganglia in encephalitis lethargica, or myxedema madness or lupus cerebritis. The same effect can also be achieved exogenously whether as chemotherapy fog or a result of treatment with interferon. And let’s not forget the overlap between ENS and CNS as mentioned above, such as nutritional pathologies leading to altered behaviors, from vitamin A metabolism in the liver by mefloquine, deficiency of vitamin B1 in Wernicke-Korsakoff’s or lack of vitamin B3 in hamster infanticide and cannibalism. We can also expand the net outward to incorporate uncertain chemical causation, eg. fibromyalgia fog, and expanding even further we can include the overall environmental stress provokes psychosis and delirium in up to half of ICU patients.
With so many ways to bring about an altered mental state, the treatment options become as varied as the various causes. For problems with pseudobulbar mood lability, a clinician can use a cocktail of malaria prophylaxis and benadryl. For autism, the anti-protozoal suramin. For schizophrenia, the acne drug minocycline. For desensitization, the antibiotic cycloserine.
From all these seemingly disconnected treatment options stemming from so many inciting causes of the initial malady, we can see that the categorization will need to stray far from merely identifying a sole culpatory element. This wandering off leads to the use of empty phrases like “chemical imbalance” as a definite physical state of affairs that we have no clear definite understanding of.
The phrase is basically empty because almost everything that is not structural, ie. anatomical, is going to be a result of balancing chemicals: inflammation, diabetes mellitus, cortisol and stress, proteins transcribed from genes, plaques in myocardial infarcts. Even something like drowning is an “imbalance” of O2 in the lungs. When what we know is that there is an “imbalance” leading to a problem, then all we have for an answer is PFM: pure freaking magic. This is problematic because if everything causes something, this also means nothing causes it. More on that below.
E) Pain is a Many-Splendored Thing
The first task a physician should accomplish, other than healing thyself, is do no harm, ie. treat pain. In the US, there is even an opioid epidemic that is at least partly thought to be linked to the need to treat pain. But medications can lead to tolerance, and after that an insufficient dose will lead to opposite effects. This may be due to a decreased threshold, as is seen in opioid-induced hyperalgesia where patients post abdominal surgery report higher pain severity when receiving high-dose opioids than when receiving low-dose opioids. Similarly, patients on methadone have lower thresholds for cold pressor pain. With opioid use and abuse so widespread, and their decreasing efficacy as well, what will work?
Apparently nothing. I’m not saying that no thing works, but nothingness works. Placebo, ie. a fake treatment, is a classic example of psychology overriding neurology. People such as Irving Kirsch have even developed programs for placebo studies to see how effective it is. Because it definitely is. Daniel Carlat points to meta-analyses of 7 antidepressants on 19,000 patients that showed a 40% drop in depression scores, but placebo alone treated depression by dropping depression scores 30% – this means 75% of your medicine working is just because you think it will work.
This overlap means that the efficacy of the medication is not entirely “in the mind”, as is often disparagingly said. After all, one can chemically (partially) reverse the effects of placebo with naloxone. And the effect of this overlap of placebo might vary, viz. mental development might have parallels with physical development, as evidenced by studies on the placebome that show genetic variants regarding dopamine, opioid, endocannabinoid, and serotonin pathways.
But such findings are clearly evidence that mental states can override physical states. When anxiety and pain have the same neurochemical pathways, this makes it less than surprising that exogenous stress and trauma could trigger depression or chronic pain. We also find greater pain elevations to negative mood stimuli with a central pain state like fibromyalgia than with a peripheral pain state like osteoarthritis.
Pain could also be reduced, not just through neurologic asymbolia, but through having a mindset like that of de Sade. Jouissance may override the pain for some, or the pain may be connected to a factor that replaces pain with pleasure. One need only look to those enjoying BDSM or spicy foods to see examples of this.
Pain can also exist independent of physical input altogether. Pain is not reducible to receptors as there are instances of pain in regions that don’t have pain receptors, such as the thalamus or an amputated limb. Pain is not even necessarily localizable to pain centers, as nocebo causes pain not from anywhere physical but from the mind. This is no minor effect, as nocebo is more and more likely to explain the rhabdomyolysis effect of statins, which are distributed to around 12% of the US population. And the extent of thoughts bearing down on the physical is further shown by the evidence supporting psychotherapy vs. psychopharmacology in treating depression:
If pain required merely receptors or anatomy, than neither placebo nor nocebo would hold any sway. They are a function merely of thoughts. Those thoughts are powerful in other physical dimensions as well. The composition of our tears change depending on our emotional state, just as autonomic responses (eg. sympathetics) are modulated by mental states (eg. fear) instead of merely physical stimuli. Such transformations by mere words and thoughts defies the physical. Consider the following:
“The death of a loved one will alter mood, often dramatically and to an extreme. How is this possible, if no chemicals are introduced into the system? In fact, nothing new is introduced into the brain except, depending on the paradigm, a) information or b) energy (i.e. converted sound waves.) How does the introduction of a new piece of information trigger an alteration of mood? Why would one thought “My family is dead” trigger the release of some chemicals, but another thought “My family is alive” not trigger that same release? And how does a non-physical entity like a thought trigger a physical reaction?”
The person in the scenario, let’s call her Gail, could also have a vasovagal syncopal event. Or she could have been reading a telegram instead of being told. You can alter the variables, but in the end we’re still left pondering how non-physical events can alter physical things. So let’s look at that next.
F) Incommensurability of Intentionality
The reason dopamine is not simply equivalent to enjoyment is because chemicals are not information, and information is not knowledge. Somehow the chemicals transmit information, and that information becomes usable knowledge in our minds, so say neuroscientists like Antonio Damasio. But the current research paradigm has dissenters:
“[Damasio] says the brain creates the mind by making maps… but he gives no reason to suppose that the map, qua map, has any psychological reality at all…When we read words like “image,” “perception,” and “feeling” in his account of maps, we tend naturally to connect them with the conscious formation of images and the experience of perceptions and feelings. But that is not what he means when he talks about the mapping activity of the brain. The problem, to put it in a nutshell, is that he has given us no reason to suppose that these maps have any mental or psychological reality at all.” – John Searle
Chemicals are not information. To ascribe to chemicals the function of information is circular reasoning as it assumes the psychological ability to process it. A person has the apparatus to handle experience when a stimulus comes in, but to ascribe this psychological ability to chemicals is to assume a homunculus already, which is not reductive.
In other words, consider the distinction as follows:
“Consider an obvious example of a map that we are all familiar with, the retinal image inside the eyeball when we see anything. As far as I can see, this map/image has no psychological reality whatever. We do not see it or otherwise experience it. The retinal image is a step from the introduction of optical stimuli to conscious perceptions. But most of these steps, as far as I know, have no psychological reality whatever. They are not the mind, or part of the mind…They are just “momentary patterns.” [Damasio] tells us that they are “of” something and that they “represent” things and events outside the brain. But how do they represent?” – John Searle
The missing element that creates the map or field is intentionality:
“Mental states have the unique property of referring to something else. For example, we are afraid “of” something, we believe “in” something, we know something. Intentionality is the property of being “about” something. “Fearing”, “knowing”, “believing” are intentional states.” – Piero Scaruffi
Information is not knowledge, and it cannot become knowledge by adding more information. Information remains as such until processed further, and for brevity’s sake we’ll call that knowledge. If this were not the case then Gail from the scenario above would not have fainted, changed her mood, or otherwise be altered by benign stimuli such as a combination of phonemes or letters. We take physical stimuli to be information and then construct knowledge by virtue of intentional states since:
“Each part announces more than it contains, and thus this elementary perception is already charged with a sense.” – Maurice Merleau-Ponty
Intentionality is nonphysical, ie. not dependent on external physical objects. I can think of a cat and the cat can cease to be without affecting the intentionality, even though physical acts involving the cat would cease. The current methodology, however, in seeking to create reductionist answers fails to incorporate this intentionality of the mind. As such, it collapses on:
“The idea that [intentionality] creates nothing, since a world of impressions in itself… is shielded from the action of the mind.” – Maurice Merleau-Ponty
To be less theoretcal, IRL this means that mental illness cannot be divorced from subjective phenomenology. The “impressions” and sense data are meaningless markers if not associated with subjective symptoms and mental actions. If the appropriate neurotransmitters are low, but you’re not feeling depressed, then you’re not depressed. The phenomenology, in its intentionality-laden form, needs to be considered first before measuring chemicals and then correcting them, eg. giving an antidepressant.
While it may seem convenient at first glance to reduce the mental down to activities such as the chemical, it also brings about all the above problems. Reductionism is also limited by the fact that, whatever else it can reduce in the sense of accumulated neurocorrelates, it will not do so with intentionality:
“Sooner or later the physicists will complete the catalog they’ve been compiling of the ultimate and irreducible properties of things. When they do, the likes of spin and charm and charge will perhaps appear on their list. But ‘aboutness’ surely won’t; intentionality simply doesn’t go that deep.” – Jerry Fodor
So, to leave intentionality in place, one may be better off considering a science of thought instead of a physical science, as stated here:
“While there is a science of the brain, there is no science of thought…If there is some set of thoughts A, a subset B of which are negative and a subset C of which are positive, then is the introduction of a chemical in the brain able to block only subset C, or does it simply block set A?”
Finding out how that separates seems an admirable goal. Can we build a useful science of thought? This is the matter to be discussed next time.