Anxiety Part Three: The Anxious Hardware

VI

Antonio Damasio is a Portuguese neuroscientist who I once saw speak, but found so incomprehensible that I left before his lecture was finished. He’s written a number of popular books about neuroscience but I saw him speak on a book tour around the release of his most recent book, The Strange Order of Things. Neuroscientists are kind of that way - incomprehensible if you’re not used to their particular… idiom.

Damasio puts forward the hypothesis that emotion arises out of the homeostatic imperative that “life is regulated within a range that is not just compatible with survival but also conducive to flourishing, to a projection of life into the future of an organism or a species.” (p 25) That is, the process of evolution led to the homeostatic imperative which gives rise to an emotional response. This isn’t so unique to Damasio - Lazarus also says that the biological imperative of managing external stress to maintain homeostasis is the origin of emotion, citing the history of thinking this way in Stress, Appraisal, and Coping (p3).

He tells stories about how groups of cells seem to behave in ways that seem to indicate something like emotions but he stops short of saying cells experience emotion. He clarifies that subjective experience is the domain of nervous systems.

He describes an orchestra of systems within the body that are involved in the emotive response:

“The actions included in the emotive response include the release of specific chemical molecules in certain sites of the central nervous system or their transport, by neural pathways, to varied regions of the nervous system and of the body [1]. Certain body sites — for instance, the endocrine glands — are brought into play and produce molecules capable of changing body functions on their own [2]. The upshot of all this bustle is a collection of changes in the geometries of viscera — the caliber of blood vessels and tubular organs [3], for example, the distention of muscles [4], the change of respiratory [5] and cardiac rhythms [6]. As a result, in the case of delight, visceral operations are harmonized, by which I mean that the viscera act with no impediment or difficulty and the harmonized state of the body proper is duly signaled to the parts of the nervous system charged with making images of the old interior; metabolism is changed so that the ratio between energy demand and production is reconciled [7]; the operation of the nervous system itself is modified so that our image production is made easier and abundant and our imagination becomes more fluid [8]; positive images are favored over negative ones; one’s mental guard is lowered even as, interestingly, our immune responses are possibly made stronger [9]. It is the ensemble of these actions, as it becomes represented in the mind, that makes way for the pleasant feeling state that one describes as delight and encompasses a minimal amount of stress and considerable relaxation.” (p 109)

I numbered the systems Damasio identifies as acting in symphony to generate emotive response: 1. Neurotransmitters, 2. Hormones, 3. Viscera, 4. Muscle tone, 5. Respiration, 6. Cardiovascular, 7. Metabolism, 8. Cognition, 9. Immune response. He describes emotion as an orchestra of events in the body and naming the emotion as the identification of the genre that is being played.

It took me a while of listening to Damasio and reading about other abstruse neuroscientists like Karl Friston to understand that some neuroscientists are all about broad theories of mind that go beyond the core of their research. It leads in interesting and worthwhile directions and clears ground for potentially interesting new research but is, in general, fantastically confusing. It’s too high-level to tell us all that much about what’s going on as we huddle in our cubicles or crouch behind our screens, riddled with anxiety.

So enough about Damasio and his theory of everything. And god help us try to understand Friston…

VII

In research on emotions, there are others with more focus. For Joseph LeDoux, that singular focus is fear. Joseph LeDoux is an American neuroscientist. He was the #1344th guest on Joe Rogan’s podcast. They talked about chimps, Rogan’s favorite animal. And they talked about rats, LeDoux’s unfortunate subject in his studies on fear.

Looking at the brains of rats, LeDoux has researched the different roles that the cortex and amygdala play. In his view, the subjective experience of fear/anxiety is separate from the underlying neurological and physical process of the anxiety response. He puts it this way:

“mechanisms that detect and respond to threats are not the same as those that give rise to conscious fear. This is an important distinction because symptoms based on conscious and nonconscious processes may be vulnerable to different predisposing factors and may also be treatable with different approaches in people who suffer from uncontrolled fear or anxiety.
…
Although research on the brain mechanisms that detect and respond to threats in animals has important implications for understanding how the human brain feels fear, it is not because the threat detection and defense responses mechanisms are fear mechanisms. It is instead because these nonconscious mechanisms initiate responses in the brain and body that indirectly contribute to conscious fear.” (from Coming to terms with fear)

This leads him to diagram the fear response in a way that shares a lot of commonalities with Lazarus’ model:

In a previous section, I discussed how Lazarus separates the rigid, reflexive response of the body from the flexible, meaning-based response of the mind. Ledoux does the same. They separate the neurological and physiological response (which Ledoux calls “emotion”) from the conscious experience (which Ledoux calls “feeling”). For Lazarus and Ledoux, the feeling that arises is a result of a process that involves a cognitive interpretation of the meaning of the situation and the meaning of the signals coming from the body. Lazarus highlighted how those meanings arise out of events that signal something significant for survival is at stake and LeDoux echoes that sentiment:

“Research on brain mechanisms engaged during confrontations with threats—stimuli with the potential to inflict harm to the organism—has shown high degrees of conservation across mammals, likely reflecting evolutionary advantages of an efficiently functioning threat-processing circuitry.

…

It has long been assumed that an innate “fear system” exists in the mammalian brain and that this system, in the presence of a threat, generates both the conscious feeling of “fear” and the behavioral and physiological responses typical of such experiences (Figure 1A). We propose instead a “two systems” framework, with one set of circuits for generating conscious feelings and a second set for controlling behavioral and physiological responses to threats (Figure 1B). The first system primarily involves cortical areas, and the second mostly involves subcortical regions, such as the amygdala, although certain cortical areas interact with and regulate processing in these regions. While the first system generates conscious feelings, the second largely operates nonconsciously.” (from Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework)

The second part of that paragraph sounds a lot like Lazarus’ ‘secondary appraisal’ and ‘primary appraisal.’ One of the reasons LeDoux makes this separation is as a result of a study where, a small sample of human subjects was provided with a stimulus that provokes a fear response in the amygdala (a brain region which I will discuss more below) but the subject reported no conscious experience of fear. He insists that identifying the activation of the brain’s “survival circuits” as the feeling of fear is a mistake. Rather, he says, “[f]eeling afraid only occurs in organisms that can be conscious that they are in danger,” comparing feelings to a soup made from many ingredients such as the ones Damasio highlighted above. He calls working memory the pot in which these ingredients mix. (from: Feelings: What Are They & How Does the Brain Make Them?)

Earlier, I highlighted that there are competing theories of emotion that divide along the lines of whether emotions should be viewed as governed primarily by physiological, neurological , or cognitive systems. Even after reading various takes, the epistemic status of each of the theories of emotions is unclear - they don’t seem well designed to be falfisiable. Their validity in describing/predicting phenomena seems to vary emotion by emotion. LeDoux is open about the uncertainty he experiences in what feelings are and whether animals other than humans experience them. Lazarus gives a caveat as well by stating, “everyone feels like they know what emotion is until they’re challenged to define it.” I guess people who research emotion feel the same way Mike Tyson did when he said, “everyone has a plan until they get punched in the mouth.”

The general takeaway from theories of emotion is that there is a dynamic relationship between the body, brain and mind. This means we can use relaxation exercises that target the body and reduce an anxious state of mind. It means we can use cognitive exercises that target our thoughts and reduce anxiety we’re experiencing in our body. It means we can reevaluate our beliefs over time and change our relationship to the stressors of life.

Enough about theories of emotion. Let’s see if we can sort any of this out by examining the hardware that gives rise to these phenomena…

VIII

We’re still in the infancy of neuroscience. We hardly understand how even commonly used drugs like SSRIs work. Yet, like a lot of clinical knowledge, we know that they do work even if we don’t exactly understand why. Despite our fancy tools, the brain still mystifies us because it’s incredibly complicated. One theory for why it’s so complicated is the stranger-than-fiction claim that the brain has evolved to be complex in order to thwart behavior-deranging parasites that existed in our evolutionary history. So while we still joke about cat owners being exposed to the notorious behavior-deranging parasite, toxoplasmosis gondii, they should forgive their beloved kitties. The answer to the question, “Is Toxoplasma Gondii Infection Related to Brain and Behavior Impairments in Humans?” follows Betteride’s law of headlines: “probably not.”

As a trained psychotherapist, I have no formal background in neuroscience. I certainly can’t do justice to recent developments in neuroscience but this review is my attempt to figure out some of the few solid pieces of what we do know. In neuroscience, the discussions I’ve been reading about are how brain structure P and neurotransmitter Q are associated with feeling X and behavior Y. The key term is associated because the underlying mechanisms are not well understood. We are only beginning to map out the connections between the territories of our brains. We are still quite far from being able to explain how the brain mechanisms generate thought and behavior. A friend in neuroscience informed me that the recent developments in the field are less about single areas and more about interactions between areas which create networks acting together. He endorsed LeDoux’s take on feeling being an epiphenomenon rather than feeling being the local activation itself.

We are even further from explaining The Hard Problem of how the brain gives rise to the qualitative experiences that make up consciousness. There is a historical schism between knowledge about the brain and the clinical application of psychology. We deal with the “what it’s like” which are like questions about software user interface, rather than the seemingly more basic “what is it” which are like questions about hardware. It’s a difficult gap to close and it’s unclear what we’ll learn about dealing with the user interface as we gain a greater understanding of the hardware.

But let me diverge from the many caveats about neuroscience that keep me from using neuroanatomy to fully explain psychological phenomenae. Let me dive in and discuss what I think we know about neuroanatomy. In my previous article on Anxiety, I mentioned how we feel like we’re the commander of our ship. Well we’re not the only one with responsibilities on the bridge of the ship. There are different characters in the brain with us. The different modules that make up our brain and connect to our bodies are like crew members on the bridge and around the ship.

image from: Gambling disorder

The brain is an incredibly complex organ and naming the regions and subregions will get us into a list with hundreds of entries. The image above lists a number of the big names of “the crew” that is involved in the operations of the ship we call “anxiety.” To further explore the regions of the brain involved in anxiety, I primarily used The Psychotherapist’s Essential Guide to The Brain (PEG-B) and Behavioral Neurobiology of Anxiety and Its Treatment (BNA-T). These seem to be the primary characters associated with anxiety:

The Neocortex - The part of the brain found in higher mammals (especially humans) that is “responsible for the execution of higher-order brain functions, including cognition, sensory perception and sophisticated motor control.” (from: Generating Neuronal Diversity in the Mammalian Cerebral Cortex)

The Prefrontal Cortex (PFC) - Dictates our personality, goals and values. It’s involved in rationality, verbal expressiveness, and keeping our goals aligned with our values. (PEG-B p31)

Left/Right Prefrontal Cortex (L-PFC, R-PFC) - “The left and right sides of the PFC have different biases, with the left side oriented more toward approach, positive goals, and emotions and the right side specialized more in avoidance and negative emotions.” (PEG-B p32)

The Orbitofrontal Cortex (OFC) - “Involved in cognitive processing of decision making; however, because of its close connection with the limbic system, it is particularly associated with our ability to make decisions based on emotional information. The OFC also plays a major role in forming social attachments and regulating emotions.” (PEG-B p33)

The Insular Cortex (Insula)- “[C]entrally placed to receive information about the salience and relative value of the stimulus environment…” the insula senses and processes internal bodily states (a sense called interoception) and relays that information to the rest of the brain. Importantly, it generates an error signal and allocate attentional resources when a discrepancy is detected between the expected and detected state of the body. (from: An Insular View of Anxiety and Keeping the Body in Mind: Insula Functional Organization and Functional Connectivity)

The Limbic System - A collection of brain structures found primarily in mammals that is involved in emotional responsiveness, motivation, memory formation and integration, olfaction, and survival. (PEG-B p.18)

The Amygdala - The “major player in learning, storage, and expression of fear conditioning… [where] both acquisition and retention of fear conditioning occurs…. [it] is critical for the expression of fear conditioning.” (BNA-T p81) “It is most commonly recognized as the emotional processing center that receives incoming sensory information and processes it for an emotional response… The emotional memory learned and utilized by the amygdala is episodic-autobiographical memory that can be notably implicit or unconscious, in contrast with explicit or declarative memory processed by the hippocampus… [It] has an attentional role, focusing our attention on the most important stimuli in the environment.” (PEG-B p20-21)

The Hippocampus - “involved in the formation of declarative memories that are processed and transferred to neocortical areas through the process of memory consolidation… A well-known function of the hippocampus is the capacity to learn and retrieve spatial memory: the what, when and where qualities of an experience.” (PEG-B p22) The hippocampus plays a role in analyzing fear cues and coming to associate fear with places and environments. It may also play a role in generating anxiety during uncertainty and conflict situations that inhibits behavior while increasing the level of arousal and attention. (BNA-T p83-85)

The Hypothalamus - “links the nervous system to the endocrine system via the pituitary gland… It receives sensory inputs that detect changes in both internal and external environments.” (PEG-B p24) It is an integral part of the neural circuit that generates the defensive fight-flight-freeze response. (BNA-T p83)

The Hypothalamic–Pituitary–Adrenal Axis (HPA-Axis) - When a threat is detected by the amygdala, the HPA-Axis mediates physiological response by releasing stress hormones called corticosteroids. (PEG-B p25)

The Anterior Cingulate Cortex (ACC) - between the frontal cortex and the limbic system, the ACC is involved in attention, impulse control, error detection, emotional pain, emotional decision making, and emotional regulation. It has a complex relationship to various anxiety disorders. (PEG-B 65-70) It plays a significant role in mindfulness and the cognitive regulation of emotions like anxiety. (from: Neural correlates of mindfulness meditation-related anxiety relief)

The Nucleus Accumbens (NAcc) - Generally recognized for its role in the processing of reward and learning, “dopamine release in the nucleus accumbens encodes not only reward, but also aversion.” (p1) It is related to fear and anxiety by its role in the acquisition and expression of long-term conditioned fear responses. (from: Temporary inactivation of the nucleus accumbens disrupts acquisition and expression of fear-potentiated startle in rats)

Locus coeruleus (LC) - Part of the brainstem that produces norepinephrine, a hormone and neurotransmitter which the LC releases in high concentration in response to stress and panic. (from: The locus ceruleus norepinephrine system)

Sensory input enters the brain via a “low road,” a fast pathway to the amygdala, and a “high road,” a slower path to the neocortex. The amygdala processes information milliseconds earlier than the neocortex, so in the case where implicit memory matches an incoming stimulus, the amygdala acts before the neocortex can redirect the response. The fast reaction of the amygdala is associated with the physiological activation of the fear response. It signals the LC to release norepinephrine and activates the HPA-axis, releasing corticosteroids. This occurs with rapidity and subtlety - it does not require higher-order thought. The fear response orchestrated by the amygdala begins the experience of being in the grip of anxiety that we feel in our body. (PEG-B p21, 69-70)

The insula is involved in detecting this automatic, visceral response. It picks up on the change inside our body and we become aware of the fear in our gut. The circuit of automatic activation associated with the amygdala and awareness of changes from that activation associated with the insula seems to be heightened in individuals with anxiety. (from: Keeping the Body in Mind: Insula Functional Organization and Functional Connectivity)

The norepinephrine released by the LC can disinhibit the amygdala and lead to a state where the prefrontal cortex is “hijacked” in the form of blood flow being redirected to the limbic system. This leads to a state of arousal, vigilance and distress which leaves us unable to rationalize about the fear and anxiety we are experiencing. (PEG-B p21, 68-69) Non-anxious individuals have an amygdala that are less involved in the active network of the brain. People with anxiety disorders tend to have an amygdala that is differently networked and hyperactive and tend to exhibit greater activation in the insula. This combination leads to paying more attention to threat-related stimuli, interpreting ambiguous cues as threatening, and judging negative outcomes as more likely.

Norepinephrine release is also associated with changes in activity in the PFC. Activity in the L-PFC, associated with biases towards positivity and approach, decreases. Activity in the R-PFC, associated with biases towards negativity and avoidance, increases. This mediates the development of avoidant behavior, a hallmark of anxiety, which is reinforced and entrenched by the reward/salience neurotransmitter, dopamine. (PEG-B 68-69)

The amygdala is associated with the acquisition and expression of fear, the PFC is associated with downregulating that response, and the hippocampus is associated with the modulation and acquisition of the fear response. (from: Neurocognitive mechanisms of anxiety: an integrative account) The automatic and unconscious process Richard Lazarus refers to as “schematic processing” closely matches the role of the amygdala. The conscious and deliberate process that he refers to as “conceptual processing” closely matches the role of the PFC. The role of the hippocampus is as an intermediary, storing memories related to fear that affects both the automatic and deliberate evaluation of stimuli.

Hypothalamus

ACC

OFC

IX

I’ve switched between discussing anxiety and the fear response and I wanted to comment more on why they’re different. The fear response is a normal response to stimulus that are interpreted as being significant to survival and anxiety is a term we use for the ongoing vigilance for threats and anticipation of fear.

In reading to research this piece, I stumbled across an interesting article which proposes distinguishing between “fear” disorders, which are characterized primarily by exaggerated reactivity to fear cues (e.g. social anxiety disorder (SAD), agoraphobia), and “anxious/misery” disorders, which feature a wide-ranging anticipatory anxiety that is not contingent on cue reactivity (e.g. generalized anxiety disorder (GAD)). Disorders such as Post Traumatic Stress Disorder (PTSD) have both fear and anxious/misery components, and disorders such as major depression (MDD) share many anxious/misery features despite being expressed more as a mood disturbance. Obsessive compulsive disorder has been left out of this discussion since neuroimaging studies have shown that it involves circuits distinct from those implicated in the other anxiety disorders, and as such likely will be reclassified in a different category in the next diagnostic manual. (from: Neurobiology of Anxiety: From Neural Circuits to Novel Solutions?)

in the emotional conflict task, we have shown impairments in dorsal and ventral ACC/mPFC in GAD and MDD, along with behavioral evidence of impaired emotional conflict regulation. Collectively, these data implicate ACC/mPFC dysfunction in anxious/misery-type symptoms in anxiety disorders (as well as the related condition of MDD) (from: Neurobiology of Anxiety: From Neural Circuits to Novel Solutions?)

(from: Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior)

X

This was a difficult piece to finish. In researching theories of emotion and the neuroscience of anxiety, I came to notice that these scientific research programmes feel pretty shaky to me. The theories of emotion make few predictions, are difficult to falsify, have a body of research that feels based on questionable interpretations of the evidence. Looking into these topics gave me a lot to think about regarding what we know about emotions and the brain but has not yet help me come to different conclusions about how to approach these emotions. As such, the epistemic status of this piece is that I’m confident that this is what these experts think but relatively uncertain regarding whether these theories correspond to facts about the mind or whether they cohere with what we do know about the mind to produce actionable predictions for clinical practice.

There are multiple routes for intervening in the anxious process including mindfulness, physiological self soothing, changes in cognitive interpretations and attributions, exposure, and changes in unconsciously or implicitly stored information.

It seems to indicate that emotional activation, marked by changes in neurotransmitters and hormones, is required for altering unconsciously or implicitly stored information.

Repeated imaginary exposure affects memory networks which affect both conscious and unconscious evaluation of stimuli

Emotional regulation strategies such as physiological self-soothing (i.e. relaxation exercises such as muscle relaxation and deep breathing) or visualization are also effective methods for reducing the fear response

Reappraisal affects amygdala activation. We know we can make children afraid of a stimulus by telling them a scary story about it. What we must also recognize is that even the stories adults tell themselves affect their appraisal of stimulus, determining what consistently makes them anxious. Abstract fears, such as an imagined situation that has never come to pass, seem to rely on similar neural systems as conditioned fears (from: Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior)