Most drugs that alter mental function, whether for recreational purposes or to treat mental disorders, affect synaptic transmission. Some drugs remodel the action potential by altering neurotransmitter release; others antagonize or potentiate the effect of a neurotransmitter on the synaptic receptor protein.
Other drugs inhibit the reuptake of the neurotransmitter from the extracellular space, which prolongs its action at the synapse. This naturally leads to the idea that disorders of thought, attention and mood are fundamentally disorders of the synapse. Furthermore, it presents a rationale for treating mental disorders through synapse pharmacotherapy.
The raison d’être remains the venerable model of physiological regulation, homeostasis , where each parameter is supposed to maintain a certain fixed and stable value . A higher or lower value is considered "inappropriate" (a deviation or defect) and therefore potentially a cause of disorder and a logical target for therapeutic readjustment.
Normal functioning supposedly requires various synaptic parameters to maintain their set values, while mental disorders supposedly result from “inappropriate” values of these variables.
Certain neurons may release too much neurotransmitter; others may release very little. The action of a neurotransmitter may be too weak or too strong; or it may be too short or too long. Such are the hypothetical "inappropriate" values that drugs must correct.
Proponents of this theory often analogize the mental disorder with type 1 diabetes, in which "inappropriate" blood glucose is caused by insulin deficiency and that disorder is controlled by administering the exogenous hormone.
For cognitive disorders there is no evidence of an "inappropriate" value of any synaptic parameter
But the analogy does not hold .
For cognitive disorders there is no evidence of an “inappropriate” value of any synaptic parameter. The search continues within individual synapses, local circuits and large areas of the brain, and eventually genetic analysis will associate certain mental disorders with molecular variants of a particular ion channel or a receptor for a certain neurotransmitter. But this probably explains only a small fraction of the common disorders, and until then there is nothing specific to correct by pharmacotherapy.
Homeostasis vs Allostasis
However, there is a deeper flaw in the homeostasis model. Efficient physiological regulation does not attempt to maintain a parameter at an established fixed point. On the contrary, demand is constantly flowing, so a fixed value would often be too low for what is needed or, conversely, it would be too high. Furthermore, a strategy to regulate the change of the created set point would introduce delays: the value of the parameter would often be different and the adjustment would arrive when the demand had already passed.
The predictive regulation strategy has been called allostasis , meaning "stability" through change
A more efficient strategy is for the brain to continually monitor many parameters and use its stored knowledge to predict which values will be most needed; then it establishes them rapidly by controlling the neuroendocrine and autonomic systems. This predictive regulatory strategy has been termed allostasis , which means “stability through change” 1,2 .
While homeostasis waits for errors and then corrects them (reactive), allostasis uses prior knowledge, both innate and learned, to prevent errors and minimize them (predictive).
Parameter values vary widely above and below the mean, but not because they are "inappropriate." Rather, it is because the brain predicts changes in need and retune the parameters to maintain them correctly.
Rethink glucose vs. insulin: When you’re sitting at the computer, the brain predicts a modest need for glucose uptake by muscle and a modest need for insulin, allowing for that uptake. The brain then controls the neuroendocrine and autonomic systems to set the levels low.
When the brain decides to play tennis, it predicts a greater metabolic demand. It then increases blood glucose and insulin through neuroendocrine and autonomic mechanisms. In anticipation of intense athletic competition, the brain may momentarily raise glucose to diabetic levels that are spilled into the urine (glycosuria).
A diabetic patient learns to mimic the brain’s “natural” predictive regulation by self-administering a dose of insulin just before tennis and before a meal, and this works to some extent.
However, the brain does much better because it continually monitors the levels of all key metabolites and hormones. Neural circuits integrate this data in real time along with body and brain temperature, ambient temperature, humidity, and estimates of the opponent’s skill.
Effector circuits continuously coordinate and control multiple outputs. Consequently, when parameter values fluctuate above or below the mean, they reflect the brain’s best predictions of what the body is about to need at all levels. From this example, we take 3 points.
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In this way, the settings could reflect all normal calculations on the normal time scale. Although this is impossible for diabetes, it works well as the primary therapy for a neurological disorder, Parkinson’s syndrome.
As neurons specialized to release the transmitter dopamine gradually die, their synapses are lost in many brain regions, including the frontal cortex, striatum, and retina. The loss of dopamine release at critical sites at a critical time clearly causes them to have parkinsonian symptoms.
The therapy delivers a molecular precursor that neurons convert into dopamine and then release into remaining synapses. Neurons continue to modulate dopamine release through their established circuits with their natural timing. Because this therapy uses existing mechanisms of predictive regulation , it can be substantially effective as long as sufficient dopaminergic neurons are maintained.
Lessons to treat mental disorders
First , since normal physiology requires that all parameters vary, it will be difficult to identify the causes of psychopathology at the synaptic level. Will synapses or circuits fluctuate differently when generating benign or evil thoughts? Is there some synaptic parameter that is deficient when attention switches easily and excessive when it persists?
It seems just as likely that the attention-controlling system simply responds appropriately to instructions from other brain regions. Although drugs may provide some symptomatic relief, until specific synaptic deficits are shown to cause significant mental disorders, pharmacotherapy will lack a rational basis.
Second , any treatment that attempts to clamp a key parameter to an average level across the entire brain on a single time scale will tend to reduce synaptic variations essential for normal thought, attention , and mood. Such dullness can make things worse. In fact, this explains certain common effects of synaptic pharmacotherapies (emotional flattening).
These are not "side effects" as they are commonly called; rather, they are exactly what the model predicts for allostasis and the loss of its adaptive and predictive function with treatment.
Third , the allostasis model suggests a principled definition of mental health: as the responsiveness of the conscious and unconscious mind to the full range of signals from many sources: current thoughts, personal and family memories, memories, and innate appetites.
| Mental health is the ability to choose between thoughts and flexibly switch between them; It is the ability to link the mood and emotional expression to the immediate situation. |
Mental disorder is the opposite: it is the reduced ability to respond to demands. The patient is being caught in a thought: a compelling voice; or a fear of contamination; or a mood such as depression. This suggests a therapeutic goal in accordance with those principles: restoring responsiveness to the full range of cues that constitute the adaptive demand of “normal” life.
Restoring responsiveness
To exploit, as in Parkinson’s therapy, the natural functioning of synaptic mechanisms, therapies based on these principles must use natural mechanisms for predictive regulation.
These involve the continuous updating of sources of knowledge of the external and internal environment (signals); that is, continuous learning that involves the permanent remodeling of neuronal circuits. The adult brain continues to generate new synapses. Therefore, the response to mental health involves both learning and forgetting. 3
To learn a new behavior we must repeat it, and to cause repetition, the brain uses a special circuit. If the behavior provides a greater reward than predicted, this circuit delivers a pulse of dopamine plus other neurochemicals, including endogenous opioids, to the striatum and frontal cortex. 4
With this pulse we experience a brief pleasure, and to obtain another pulse, we repeat the behavior. That is, we practice. To learn, however, practice alone is insufficient.
Remodeling a circuit also requires a state of plasticity where synapses are sensitive to chemical signals such as brain-derived growth factor, which allows them to grow or shrink. Plasticity is enhanced by various activities, including physical exercise 5 and this suggests a first-principles approach to improving a mental disorder.
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Conclusions
The “Practice + Plasticity” strategy may not repair a variant molecule that contributes to a mental disorder. On the other hand, neuronal circuits, in restructuring to improve their predictions, constantly change their gene expression patterns and constantly modify the structures of synaptic proteins, for example, by altering phosphorylation levels.
So the practice + plasticity strategy offers infinite opportunities to improve mental health by restructuring the circuit at the molecular level to expand the range of adaptive responsiveness to the environment.
