Toward a Unified Model of the Brain Action of Psychedelics

By: R. L. Carhart-Harris and K. J. Friston

In: Pharmacological Reviews

Date: July 2019

Key Takeaways:

• Brains make models to reduce uncertainty: guess, test and revise.
  • Guess: best-guess statistical approximations of causes of experiences.
  • Update: empirically informed belief updating.
• Psychedelics relax the brain’s models.
  • Relaxation of the (top-down) grip of prior beliefs.
  • Increased (bottom-up) signals and prediction errors alter firmly held beliefs.
  • Different connectivity patterns emerge and potentially endure.
• Serotonin flow promotes adaptation when faced with environmental uncertainty:
  • Putting the brain in a “hot state” of cognitive flexibility and neuroplasticity.
  • The brain is more suggestibele to influences from the environment (“critical slowing”: pebbles cause more ripples than normal).
• Insight: exploring and reducing uncertainty.
  • Exploring uncertainty: curious, novelty seeking behavior.
    • Expectation of uncertainty: relaxation of priors, inquiring state of mind.
    • Exploring novelty for the sake of knowledge gain and opportunity to learn.
    • Reduces as confidence grows.
  • Reducing uncertainty: eureka, aha moments.
    • Make existing beliefs / models simpler by removing redundant parameters, revealing the underlying core structure.
    • Typically emerge spontaneously, out of the blue.
    • Redundant model parameters have been unconsciously stripped away.
• Normal consciousness biases order over disorder.
  • Preservation over adaptation.
  • Biases high-level models, prior beliefs over data.
  • May become less efficient in high change environment, uncertainty.

Key Concepts:

REBUS

• Relaxed beliefs under psychedelics (REBUS)
  • Unified model of the brain mechanisms of psychedelics.
• Free-energy principle (FEP).
  • Description of the behavior of living (i.e., self-producing and maintaining) systems.
  • Based on inherent tendency to resist disorder and minimize uncertainty.
  • Hierarchical predictive coding.
    • Free-energy minimization in the brain.
    • [Minimize errors: mismatch between prediction and environment].
    • Approximate reality through invoking, testing, revising, and optimizing models.
• Entropic brain hypothesis (EBH).
  • “Measuring” the richness of subjective experience within any given state of consciousness.
    • Diversity and vividness.
    • Psychedelics acutely increase both.
  • Psychedelics increase the entropy of spontaneous brain activity.
    • Effect mirrored at the subjective level by an increase in the richness of conscious experience.
    • Assumes that the brain and mind are flip sides of the same coin.
    • “Dual aspect monism”
• Entropy.
  • Dimensionless measure of uncertainty about a dynamical phenomenon.
    • EBH: Uncertainty of neuronal fluctuations across time.
    • FEP: Uncertainty of beliefs encoded by neuronal fluctuations.
• Central thesis:
  • Hierarchical predictive coding in the brain …
    • Predominant neurobiological and computational framework for describing psychological phenomena in health and disease.
    • Sensory input arrives (bottom-up) and is compared with (top-down) predictions.
  • … generates models …
    • Best-guess statistical approximations of causes of experiences.
    • Based on Bayesian principles: empirically informed belief updating.
  • … to minimize prediction errors.
    • Update predictions.
    • Furnish best explanation for sensory inputs.
    • At multiple levels of hierarchical abstraction
  • The process depends on:
    • Salience: the precision afforded to the ascending prediction errors (surprise).
    • Confidence: the precision of posterior beliefs.
  • The hierarchy “compresses” consciousness.
    • The brain’s highest levels naturally envelope the content of levels below.
    • Effectively compress the content of levels below.
      • Informationally efficient.
      • High level beliefs function to route or canalize thought and behavior.
      • Compress more elemental information held and processed below them.
      • May restrict self-awareness and obstruct new learning.
  • Causing some content to disappear or at least not be heard.
  • Breaking down the compressive model (psychedelics, etc.):
    • Could have an expansive influence:
    • Liberates suppressed information.
    • Enables this information to travel more freely up through the hierarchy.
    • Relaxing prior beliefs.
    • Potentially generating new insights.

Potential belief-revising effects of psychedelics

• Effect takes place at the top end of the brain’s functional architecture.
  • Top layers that constrain and compress perception, cognition, and emotion.
  • Although “something” is also going on at lower (sensory, vision) levels.
• Psychedelics disinhibit the higher levels of the brain hierarchy.
  • Lightening the precision of higher-level expectations .
  • Becoming more sensitive to ascending prediction errors (surprise/ascending information).
• Reducing the precision (felt confidence) of higher-level prior beliefs.
  • In network speak:
    • Flattening of local minima.
    • Enabling neuronal dynamics to escape their basins of attraction.
    • Express long-range correlations and desynchronized activity.
• Creating a state in which these priors are imbued with less confidence.
  • Felt at levels that instantiate particularly high-level models:
    • Narrative selfhood, identity, or ego.
    • Belief that one has a particular personality, set of characteristics, views
• Deregulating and “flattening” the brain.
  • Subverting the brain’s ability to narrow emotion and perception down to a central narrative.
  • Lightening the top heaviness of human cognition.
    • Temporarily flattening the hierarchical organization that supports it.
    • Rendering the brain/mind’s energy landscape flattened or opened up.
• Allowing for ascendance of more prediction errors from lower levels of the system.
  • Ordinarily unable to update beliefs due to the top-down suppressive influence of heavily-weighted priors.
  • Find freer register in conscious experience, by reaching and impressing on higher levels of the hierarchy.
  • Enable bottom-up information intrinsic to the system, to travel up the hierarchy with greater latitude.
• Allowing for a process of belief relaxation and revision.
  • Recalibration of the relevant beliefs.
  • Better align or harmonize with:
    • Other levels of the system.
    • Bottom-up information (from within, lower-level intrinsic systems or outside the individual, sensory inputs).
• Psychedelics and the “anarchic brain”.
  • Psychedelics create a transient, “hot state” flattened landscape.
  • Brain / mind states encoding beliefs are less stable and influential.
  • “Interstate” transitions can occur more freely.
  • Rather than being constrained to a small number of dominant attractors, the mind and brain spontaneously transition between states with greater freedom—and in a less predictable way.
  • These altered dynamics may be felt as an enriched or broadened global state of consciousness.
  • State of the mind opening up.
  • Small perturbations to the system can have large repercussions in such a flattened energy landscape.
• Analogous to the phenomenon of simulated annealing in computer science / metallurgy.
  • System is heated, heightened plasticity, new minima become more accessible.
  • System cools down, stabilizes and attractor basins begin to steepen again.
  • Emergence of a new energy landscape with revised properties.
• This model can account for the full breadth of subjective phenomena associated with the psychedelic experience.
  • Ego dissolution, the unitive peak experience, near-death-like experiences, a sense of anxiety and uncertainty, heightened suggestibility, a sense, etc.
• In short:
  • Relaxation of the (top-down) grip of prior beliefs.
  • Allows increased (bottom-up) signals and prediction errors to alter firmly held beliefs.
  • Different connectivity patterns emerge and potentially endure (anarchic brain).

Psychedelics neuroscience

• Psychedelics act by stimulating 5-HT2ARs.
  • Cells within the visual cortex as well as at higher levels of the cortical hierarchy.
  • Thought to encode posterior expectations, priors, or beliefs.
• 5-HT2AR.
  • Specific serotonin receptor subtype activated by psychedelics.
  • Expressed most densely in the cortex, including areas such as:
    • High-level association regions, such as the DMN.
      • DMN:
        • A high-level brain network associated with high level behaviors.
        • Perspective taking, metacognition, mental time travel, moral decision making and self-consciousness.
        • Can be considered to sit at the top of the brain’s hierarchical system.
        • The self is perhaps the most central high level prior instantiated by the DMN.
    • Primary visual cortex.
      • Hallucinations
    • Pyramidal cells in layer V.
      • Modulating cognitive processes, working memory and attention.
• Psychedelics increases activation of 5-HT2AR.
  • Rendering them selectively more sensitive to ascending input (e.g., prediction errors).
  • Reduces the precision weighting of the expectations they encode.
  • The physiologic mechanism that destroys sharp minima and weakens prior expectations.
• Alpha rhythm and Beta rhythm brain waves.
  • Range of functions, including top-down inhibition.
  • Silencing silence more granular information processed by lower-level of the brain.
    • Positively correlated with DMN activity.
  • Psychedelics has been associated with reduced alpha rhythm expression.
• The influence of the high levels runs deep.
  • Affecting them has particularly large or general implications.
  • More removed from the (anchoring and entraining influence of) statistical regularities within the sensorium.
  • More able to change or undergo revision.
• Serotonin transmission plays an important role in enhancing adaptability in the face of uncertainty.
  • Facilitates adaptability to environmental volatility.
  • Cognitive flexibility (creativity, associative thinking).
• Brain is in a “hot state” as neuroplasticity increases.
  • Environment can exert higher influence in systems that are near a “critical state”.
  • More suggestible (“critical slowing”: pebble causing more ripples than normal).

Psychopathologies.

• Most mental illnesses reflect issues in mechanics of hierarchical predictive coding.
  • Precision weighing of both high-level priors and prediction error.
• Gradual entrenchment of pathologic thoughts and behaviors, beliefs held at a high level.
  • Negative self-perception, fearful, pessimistic, paranoid outlooks.
  • These pathologic beliefs are ascribed excessive precision or influence.
• Forms of “altered states”.
  • (Early) psychosis.
    • Weak high-level priors, heavily weighted prediction errors.
    • Leads to formulation of (stable) delusional high-level priors.
    • Somewhat similar to psychedelics, but in psychedelics:
      • Effects are short and mostly temporary.
      • Start with and return to stable high-level priors.
  • Autism.
    • Also characterized by aberrant high-level priors.
      • Bias towards lower (i.e. sensory) hierarchical levels.
      • Deficient in higher level priors (cognition linked to complex emotion, social awareness).
  • Meditation.
    • Similar deactivation of the DMN.
    • Relaxation of self-consciousness.
• Psychedelic therapy:
  • Target the high-levels of the brain’s functional hierarchy.
  • Relax the precision weighting of high-level priors.
  • Increase sensitivity to (previously suppressed) bottom-up information flow.
  • Revise of priors: shifts in perspective, insight.
• Insights may or may not be “real”.
  • But they serve to close an explanatory gap.
  • May have short-term beneficial therapeutic outcome.
    • Provide some level of “harmony” in brain’s functional hierarchy.
    • [Perhaps useful initially and immediately to break unproductive patterns, but to become longer term useful, insight have to be adaptively useful? Ie, reliable and replicable over time? This issue comes up in the Pollan’s book as well, see below: issue of increase in delusional beliefs].
• Ideal outcome:
  • Updated priors resonate more harmoniously with previously silenced information.

Psychedelics and insight.

• According to psychoanalysts in the 50s and 60s, psychedelics:
  • Relax the ego and its various defenses.
  • Allow unconscious material to emerge into consciousness.
  • But, hard to measure what actually happens.
• Component of insight:
  • Curious behavior, explorative search, novelty seeking, and epistemic learning.
  • Structure and fact-free learning, abductive reasoning, Bayesian model selection (BMS), “Aha” or “eureka” moment.
• Curious behavior: starts with an expectation of uncertainty, relaxation of priors:
  • Relax one’s confidence in one’s prior assumptions (i.e., high-level priors).
  • Promote an open, inquiring state of mind.
  • Sampling: in areas where this is an opportunity to resolve uncertainty.
    • e., where there is a lot to be learnt.
  • Exploring novelty for the sake of significant knowledge gain.
    • Dominates early in life, reduces later on.
    • As confidence grows, less explorative search.
  • May be enhanced by psychedelics.
  • Implies that insight-related processes operate implicitly:
    • Without conscious awareness.
    • Can be made more effective if executive function is suspended.
• Structure learning and fact-free learning.
  • Structure: identification of high-level structure or patterns (“bigger picture”).
  • Fact-free: without accumulating new facts.
    • Fresh perspective or frame of reference, rather than more data.
  • Refine high-level models or narratives:
    • Make them simpler by removing redundant parameters.
    • Thereby revealing the underlying core structures and manifolds.
    • Perhaps this happens while you sleep.
  • Optimizing breadth (comprehension) and accuracy (precision).
  • Aha, Eureka:
    • Elegant solutions typically emerge spontaneously, out of the blue.
    • Redundant model parameters have been unconsciously stripped away.
  • Psychedelics may also catalyze the processes of refinement.
    • Relaxed high-level priors allow information to travel up the hierarchy.
    • Fresh opportunity to cultivate changes to the relevant assumptions.
• Criticality versus optimality:
  • When a system nears a transition point between order and disorder.
    • Complex dynamics may occur.
  • A critical system can exhibit complex emergent phenomena.
    • A “critical brain”: neuronal activity may be poised at criticality.
  • Normal consciousness biases order over disorder.
    • Preservation over adaptation.
  • In some cases, system may sub-optimal, too top-heavy.
    • Biases high-level models, priors (such as the ego and its various beliefs and defenses) over data.
    • Especially exaggerated in certain psychopathologies (depression, etc.)
  • Psychedelics can bring the brain closer to a critical point.
    • Weakening priors (reduced strength of the DMN).
    • Enhanced sensitivity to data (increased amygdala responsiveness).
• Once insight is discovered, the newly appreciated awareness cannot easily be forgotten.
  • Similar to the (negative) effects of trauma…
• Psychedelic use could have broader social and political implications.
  • Poorly integrated experiences can lead to increased uncertainty.
  • Increase in delusional beliefs as stop-gap to close the uncertainty gap.