From my own study of mood disorders I generally agree with your valence theory of depression/mania.
However I believe the primary cause (at least for most people today) is disrupted sleep architecture.
To a first order approximation, the brain accumulates batch episodic training data during the day through indexing in the hippocampus (which is similar-ish to upper cortex, but more especially adapted to medium term memory & indexing). The brain’s main episodic replay training then occurs during sleep, with alternation of several key phases (REM and several NREM) with unique functional roles. During NREM (SWS in particular) the hippocampus rehearses sequences to ‘train’ the cortex via episodic replay. (Deepmind’s first atari RL agent is based on directly reverse engineering this mechanism).
But the REM sleep is also vitally important—and it seems to globally downscale/prune synaptic connections, most specifically the weakest and least important. It may also be doing something more complex in subtracting out the distribution of internally generated data ala Hinton’s theories (but maybe not, none of his sleep wake algos actually work well yet).
Regardless the brain does not seem to maintain synaptic strength balance on the hourly timescale. Instead median/average synaptic strength slowly grows without bound during the waking state, and is not correctly renormalized until pruning/renormalization during sleep—and REM sleep most specifically.
This explains many curious facts known of mania and depression:
The oldest known treatment for depression is also completely (but only temporarily) effective: sleep deprivation. Depression generally does not survive sleep deprivation.
Sleep is likewise effective to treat full blown mania, but mania inhibits sleep. One of the early successes in psychiatry was the use of sedatives to treat severe mania.
Red light interferes with the circadian rhythm—specifically serotonin->melatonin conversion, and thereby can disrupt sleep architecture (SAD etc)
SSRIs alter effective serotonin transport quickly but take a week or more to have noticeable effects on mood. Serotonin directly blocks REM—REM sleep is characterized (and probably requires) a near complete absence of monoamine neurotransmitters (histamine, serotonin and norepinephrine).
Lithium—a common treatment for bipolar—is a strong cellular circadian modulator and sleep stabilizer.
So basically the brain does not maintain perfect homeostatic synaptic normalization balance on short timescales. During wake synapses tend to strengthen, and during REM sleep they are pruned/weakened. Balancing this correctly seems to rely on a fairly complex sleep architecture, disruptions to which can cause mood disorders—not immediately, but over weeks/months.
But why does mean synaptic strength imbalance effect mostly mood and not say vision or motor control? Every synapse and brain region has a characteristic plasticity timescale that varies wildly. Peripheral lower regions (closer to sensors/motors) crystallize early and have low learning rate/plasticity in adults, so they aren’t very susceptible. At any one time in life the hippocampal → cortical episodic replay is focusing on particular brain modules, and in adults that focus is mostly on upper regions (PFC etc) that mostly store current plans, consequences, etc that are changing more rapidly.
Thus the upper brain regions that are proposing and computing the valence of various (actual or mental) actions as ‘dopaminergic bids’ with respect to current plans/situations are the most sensitive to synaptic norm imbalance, because they change at higher frequency. Of course if a manic stays awake long enough they do in fact progress to psychosis similar to schizophrenia.
Very interesting, thanks! I hadn’t thought that before, but now I agree with parts of what you said.
One thing is: I think you present some suggestive evidence that REM sleep is an important intervention point that can help mitigate depression / mania. But I think you haven’t presented much evidence that REM sleep abnormalities are (usually) the root cause that led to the depression / mania starting in the first place. Maybe they are, maybe not, I dunno.
Certainly mood disorders like bipolar,depression,mania can have multiple causes—for examle simply doing too much dopaminergic simulants (cocaine, meth etc) can cause mania directly.
But the modern increased prevalence of mood disorders is best explained by a modern divergence from conditions in the ancestral environment, and sleep disorder due to electric lighting disrupting circadian rhythms is a good fit to the evidence.
The evidence for each of my main points is fairly substantial and now mainstream, the only part which isn’t mainstream (yet) is the specific causal mechanism linking synaptic pruning/normalization to imbalance in valence computing upper brain modules (but it’s also fairly straightforward obvious from a DL perspective—we know that training stability is an intrinsic likely failure mode).
Sleep disturbance and psychiatric disorders : “It is argued that insomnia and other mental health conditions not only share common causes but also show a bidirectional relationship, with typically the strongest pathway being disrupted sleep as a causal factor in the occurrence of other psychiatric problems.”
The effectiveness of circadian interventions through the blue light pineal gland serotonin->melatonin pathway is also very well established: daytime bright light therapy has long been known to be effective for depression, nighttime blue light reduction is now also recognized as important/effective, etc.
The interventions required to promote healthy sleep architecture are not especially expensive and are certainly not patentable, so they are in a blindspot for our current partially misaligned drug-product focused healthcare system. Of course there would be a market for a hypothetical drug which could target and fix the specific issues that some people have with sleep quality—but instead we just have hammers like benzos and lithium which cause as many or more problems than they solve.
From my own study of mood disorders I generally agree with your valence theory of depression/mania.
However I believe the primary cause (at least for most people today) is disrupted sleep architecture.
To a first order approximation, the brain accumulates batch episodic training data during the day through indexing in the hippocampus (which is similar-ish to upper cortex, but more especially adapted to medium term memory & indexing). The brain’s main episodic replay training then occurs during sleep, with alternation of several key phases (REM and several NREM) with unique functional roles. During NREM (SWS in particular) the hippocampus rehearses sequences to ‘train’ the cortex via episodic replay. (Deepmind’s first atari RL agent is based on directly reverse engineering this mechanism).
But the REM sleep is also vitally important—and it seems to globally downscale/prune synaptic connections, most specifically the weakest and least important. It may also be doing something more complex in subtracting out the distribution of internally generated data ala Hinton’s theories (but maybe not, none of his sleep wake algos actually work well yet).
Regardless the brain does not seem to maintain synaptic strength balance on the hourly timescale. Instead median/average synaptic strength slowly grows without bound during the waking state, and is not correctly renormalized until pruning/renormalization during sleep—and REM sleep most specifically.
This explains many curious facts known of mania and depression:
The oldest known treatment for depression is also completely (but only temporarily) effective: sleep deprivation. Depression generally does not survive sleep deprivation.
Sleep is likewise effective to treat full blown mania, but mania inhibits sleep. One of the early successes in psychiatry was the use of sedatives to treat severe mania.
Red light interferes with the circadian rhythm—specifically serotonin->melatonin conversion, and thereby can disrupt sleep architecture (SAD etc)
SSRIs alter effective serotonin transport quickly but take a week or more to have noticeable effects on mood. Serotonin directly blocks REM—REM sleep is characterized (and probably requires) a near complete absence of monoamine neurotransmitters (histamine, serotonin and norepinephrine).
Lithium—a common treatment for bipolar—is a strong cellular circadian modulator and sleep stabilizer.
So basically the brain does not maintain perfect homeostatic synaptic normalization balance on short timescales. During wake synapses tend to strengthen, and during REM sleep they are pruned/weakened. Balancing this correctly seems to rely on a fairly complex sleep architecture, disruptions to which can cause mood disorders—not immediately, but over weeks/months.
But why does mean synaptic strength imbalance effect mostly mood and not say vision or motor control? Every synapse and brain region has a characteristic plasticity timescale that varies wildly. Peripheral lower regions (closer to sensors/motors) crystallize early and have low learning rate/plasticity in adults, so they aren’t very susceptible. At any one time in life the hippocampal → cortical episodic replay is focusing on particular brain modules, and in adults that focus is mostly on upper regions (PFC etc) that mostly store current plans, consequences, etc that are changing more rapidly.
Thus the upper brain regions that are proposing and computing the valence of various (actual or mental) actions as ‘dopaminergic bids’ with respect to current plans/situations are the most sensitive to synaptic norm imbalance, because they change at higher frequency. Of course if a manic stays awake long enough they do in fact progress to psychosis similar to schizophrenia.
Very interesting, thanks! I hadn’t thought that before, but now I agree with parts of what you said.
One thing is: I think you present some suggestive evidence that REM sleep is an important intervention point that can help mitigate depression / mania. But I think you haven’t presented much evidence that REM sleep abnormalities are (usually) the root cause that led to the depression / mania starting in the first place. Maybe they are, maybe not, I dunno.
Certainly mood disorders like bipolar,depression,mania can have multiple causes—for examle simply doing too much dopaminergic simulants (cocaine, meth etc) can cause mania directly.
But the modern increased prevalence of mood disorders is best explained by a modern divergence from conditions in the ancestral environment, and sleep disorder due to electric lighting disrupting circadian rhythms is a good fit to the evidence.
The evidence for each of my main points is fairly substantial and now mainstream, the only part which isn’t mainstream (yet) is the specific causal mechanism linking synaptic pruning/normalization to imbalance in valence computing upper brain modules (but it’s also fairly straightforward obvious from a DL perspective—we know that training stability is an intrinsic likely failure mode).
A few random links:
wikipedia page on sleep and bipolar
The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research
REM and synaptic normalization/pruning/homeostasis:
Sleep and synaptic homeostasis
Mechanisms of systems memory consolidation during sleep
Functions and circuits of REM sleep
Plasticity during sleep is linked to specific regulation of cortical circuit activity
Sleep and synaptic down-selection
Sleep promotes downward firing rate homeostasis
REM sleep promotes experience-dependent dendritic spine elimination in the mouse cortex.
REM sleep selectively prunes and maintains new synapses in development and learning
Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation
Remembering and forgetting in sleep: Selective synaptic plasticity during sleep driven by scaling factors Homer1a and Arc
LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice
Sleep and wake cycles dynamically modulate hippocampal inhibitory synaptic plasticity
Sleep and Psychiatric Disorders:
Sleep disturbance and psychiatric disorders : “It is argued that insomnia and other mental health conditions not only share common causes but also show a bidirectional relationship, with typically the strongest pathway being disrupted sleep as a causal factor in the occurrence of other psychiatric problems.”
Improving sleep quality leads to better mental health: A meta-analysis of randomised controlled trials: “For example, people with insomnia are 10 and 17 times more likely than those without insomnia to experience clinically significant levels of depression and anxiety, respectively”
The brain structure and genetic mechanisms underlying the nonlinear association between sleep duration, cognition and mental health
The effectiveness of circadian interventions through the blue light pineal gland serotonin->melatonin pathway is also very well established: daytime bright light therapy has long been known to be effective for depression, nighttime blue light reduction is now also recognized as important/effective, etc.
The interventions required to promote healthy sleep architecture are not especially expensive and are certainly not patentable, so they are in a blindspot for our current partially misaligned drug-product focused healthcare system. Of course there would be a market for a hypothetical drug which could target and fix the specific issues that some people have with sleep quality—but instead we just have hammers like benzos and lithium which cause as many or more problems than they solve.