The neural basis of Fear & Anxiety Disorders and Reward System

Question 1

What’s fear?

Answer 1

Behavioral neuroscientists use the term “fear” or “fear responses” to refer to the combined behavioral and physiological responses elicited in animals by an overt threat or signal of potential threat

Fear, according to LeDoux is the behavioral adaptation that allows organisms to detect and respond to danger

By convention, the brain system mediating these capacities is called the fear system.

With reference to human emotions, fear is used interchangeably to refer to subjective
experience (“feeling”) and to response (behavior and physiology) elicited when
threatening stimuli are processed by the fear system→ possible confusion

Maybe a more appropriate terminology would be:
“defensive survival circuit”: the brain network that detects and responds to danger
“defensive motivational state”: result of the activation of the defensive survival circuit
“fearful feelings”: the conscious experience of fear

Question 2

Which are the two types of fear responses?

Answer 2

“innate” or unconditioned fear responses: activated by intrinsically threatening stimuli; e.g., the
presence of a predator, footshocks, loud noises

“learned” fear: elicited by neutral stimuli that have been associated with innate threats; e.g.,
exposure to a cue or context associated with predator exposure

Question 3

What’s Pavlovian contribute to fear conditioning?

Answer 3

Research using Pavlovian fear conditioning tasks in rodents and other small mammals has led to a
detailed description of the neuroanatomy of the fear system, in which the amygdala is a central
neural node

Question 4

Findings about fear through neuroimaging

Answer 4

Findings from human research converge with findings in experimental animals, highlighting the role of the amygdala in human fear/threat-related response

Question 5

The role of the amygdala in human defensive activation

Answer 5

(1) threat stimuli should activate the amygdala
(2) amygdala activation should be rapid and not require conscious recognition of the eliciting stimulus
(3) activation of the amygdala should be independent of focal attention to the eliciting stimulus
(4) activation of the amygdala should not require cortical activation
(5) the amygdala should be directly activated by visual stimuli via a subcortical route that includes the superior colliculus of the midbrain and the pulvinar nucleus of the dorsal thalamus

Question 6

What happens when exposure to fearful stimuli allows only for incomplete visual processing?

Answer 6

the amygdala responds to anything that might turn out to have important consequences for
safety and for survival (bias toward false positive responses rather than to false negative ones)

Question 7

Evidence of amygdala activation without focal attention

Answer 7

Amygdala activation by fearful expressions was similar when subjects selectively processed faces at relevant locations or, instead, judged concurrent neutral (house) stimuli while the faces appeared at task-irrelevant location

Question 8

What’s the effect of patient G.Y. who suffered right hemianopia (blindness to right hemifield) ?

Answer 8

Throughout testing, G.Y. denied any perception of faces presented in his blind (right)
hemifield.

However, blind hemifield presentation of fearful faces evoked increased responses of the bilateral amygdala

Amygdala responses to fearful and fear-conditioned faces in GY’s blind hemifield co-varied with activity in the posterior thalamus and superior colliculus → the residual ability might depend on the colliculo-thalamo-amygdala neural pathway, that can process fear-related stimuli independently of both the striate cortex and visual awareness

Activity in these regions to undetected fear signals suggests a crude relay of stimulus information
from the retina to the superior colliculus, which conveys stimulus information to the pulvinar in the
posterior thalamus

The pulvinar is functionally connected with the amygdala, which may facilitate rapid processing
of threat signals

Such signals may initiate the fight/flight mechanisms of the brainstem, including the
locus coeruleus from which noradrenergic pathways are triggered to provide rapid and
diffuse excitatory innervation of the cortex, that facilitates an increase in alertness

Question 9

Flexibility in the fear system

Answer 9

Learning fear allows organisms to quickly use cues in the environment to predict the imminent upcoming of aversive events, even after 1 learning trial. But ever-changing environments pose a challenge: the need to flexibly readjust fear learning to track ongoing changes in circumstances and adapt behavior accordingly

Question 10

Which are the 3 to modify learned fear?

Answer 10

• Extinction: a process by which learned fear responses are no longer expressed after repeated exposure to the conditioned stimulus with no aversive consequences
• Reversal: a procedure in which fear responses are switched between two stimuli following a reversal of reinforcement contingencies
• Regulation: a set of processes involving the use of strategies aimed at attenuating a conditioned fear
  respons

Question 11

Do different fear modulation strategies share a common neural circuit specialized for changing learned fear?

Answer 11

• The striatum shows increased activation to the CS+ in the acquisition phase;
activation decreases when the CS+ is extinguished or regulated, and switches to the “new CS+” following reversal
• By contrast, the vmPFC shows decreased activation to the CS+ during acquisition; activation increases with extinction or regulation, and switches to the “new CS-” following reversal

Question 12

The intra-connectivity between the vmPFC, the amygdala and the striatum would subserve different functions:

Answer 12

• inhibitory control over fear responses via vmPFC-amygdala connections
• learn stimulus-response associations and initiate instrumental responses to actively cope with conditioned fear → output to motor systems via amygdala–striatum connections

Question 13

Which are the Anxiety Disorders (DSM-5)?

Answer 13

• Separation Anxiety disorder
• Selective mutism
• Specific phobia
• Social anxiety disorder (Social phobia)
• Panic Disorder
• Agoraphobia
• Generalized Anxiety Disorder

Although they differ from one another in the types of objects or situations that induce fear, anxiety, or avoidance behavior, and the content of the associated thoughts or beliefs, the common feature is persistent and excessive fear/anxiety in response to imminent or anticipated danger

Question 14

Combined lifetime prevalence of common and disabling disorders

Answer 14

> 30%

Question 15

Anxiety is often comorbid with Depression:

Answer 15

• about 50% of patients with depression have an anxiety disorder; about ¼ of patients with anxiety
disorders have depression;
• highly overlapping symptoms (e.g., insomnia, irritability, difficulty concentrating);
• the neural circuits involved in both disorders can be difficult to distinguish;
• some treatments are effective for both disorders, including antidepressants such as SSRIs and
cognitive-behavioral therapy

Question 16

Which are the brain areas most reproducibly found to show functional alterations in anxiety?

Answer 16

The PFC and the ACC, which are involved in cognitive control, decoding the reward/punishment value of stimuli, conflict monitoring, anticipation, emotion experience and regulation, integration of
visceral/emotional information

The hippocampus and the amygdala, which are involved in fear learning and expression,
emotional memory formation and retrieval

Question 17

From non-pathological to pathological fear/anxiety

Answer 17

In non-pathological fear/anxiety, bottom-up and top- down processes interact adaptively to shape behavior in a given situation

In anxiety (and mood) disorders, the interaction between bottom-up and top-down processes is
hypothesized to be impaired, as reflected in a dysfunctional crosstalk between cortical (PFC)
and subcortical (amygdala) structures

Question 18

Amygdala and mPFC circuit

Answer 18

The dynamic interactions between the amygdala and the mPFC can be usefully conceptualized
as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as
well as regulate these reactions when the situation calls for it

Question 19

What’s the distinction between two classes of anxiety disorders:

Answer 19

• Disorders involving intense fear (specific phobias, social phobia, panic disorder, [PTSD]) seem to be characterized by hypoactivity of distinct prefrontal cortex areas, thus failing to inhibit the amygdala
• Disorders which mainly involve worry and rumination (repetitive patterns of thoughts that involve engaging in mental problem-solving on an issue whose outcome is uncertain but contains the possibility of one or more negative outcomes, or focus an individual’s attention on his/her symptoms of distress and their implications), such as GAD or [OCD], seem to be characterized by
hyperactivity of some prefrontal cortex areas

Question 20

Specific Phobia (animal type)

Answer 20

When animal phobics watch fear-relevant but nonphobic stimuli, there is a negative functional connectivity (negative co-variation) between the ACC and the amygdala (inhibitory influence, emotional control). When watching phobia-related stimuli, functional connectivity between PFC
and amygdala is absent →disruption of the negative feedback loop that results in phobic fear

Question 21

Specific Phobia (blood-injection-injury type)

Answer 21

During the viewing of phobia-related pictures, but not fear-related pictures, blood phobics show hypoactivation of the mPFC, suggesting a deficit in the automatic (vm) and controlled (dm) regulation of emotional responses to phobic stimuli

Question 22

Social Anxiety Disorder

Answer 22

During the anticipation of a public speech, participants with social phobia showed greater
neural activity in subcortical regions (including the amygdala) and less cortical activity
in prefrontal regions compared with healthy controls.

Patients with Social Anxiety Disorder exhibit less connectivity between amygdala and ACC/DLPFC during viewing of fearful faces. Patients with Social Anxiety Disorder also show less amygdala to
ACC connectivity at rest → Reduced capacity for emotion regulation when a threatening
social cue is present (i.e., during viewing of fearful faces) and increased vigilance for threatening information in the absence of threat cues (i.e., at rest)

Question 23

Generalized Anxiety Disorder

Answer 23

In both healthy participants and participants with GAD, worry triggered by worry-inducing sentences activates the medial PFC and ACC (mentalization and introspective thinking) However, GAD patients show a persistent activation of these areas even during the resting state that
follows the worrying phase. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying

Question 24

What’s the worry in GAD?

Answer 24

Worry arise in GAD patients as a pathological strategy of cognitive avoidance and an attempt to down-regulate autonomic arousal. But as emotion regulation by the vlPFC and ACC is impaired in these patients, the worries seem to be uncontrollable on a subjective level and autonomic hyperactivity and cortisol secretion become chronic on a biological level. Furthermore, increased cortisol secretion seems to decrease functional connectivity between amygdala and PFC as well as hippocampal volume, again increasing anxiety and diminishing emotion regulation abilities

Question 25

Fear and anxiety are supported by partially different neural circuits

Answer 25

Threats that are spatially or temporally close, immediate, and predictable, provoke short-term, phasic fear and are mediated by the amygdala Threats that are spatially and temporally distant, or diffuse and unpredictable, provoke sustained, long-lasting anxiety and are mediated by the BNST

Question 26

What’s the bed nucleus of the stria terminalis ?

Answer 26

The bed nucleus of the stria terminalis is a cluster of about 12 nuclei located superior, medial, and rostral to the amygdala, that receives heavy projections from, among other areas, the basolateral amygdala The bed nucleus of the stria terminalis projects to hypothalamic and brainstem target areas that mediate many of the autonomic and behavioral responses to aversive or threatening stimuli

Question 27

Anxiety-provoking task

Answer 27

fluctuation in the height of the line dynamically represents increasing future environmental threat level with increasing proximity to the shock threshold → subjects have to continuously monitor the environment for cues signaling risk for a forthcoming aversive event In individuals with greater trait anxiety, a region consistent with the BNST demonstrates a linear increase in response as a function of line height (→ tracking of threat proximity) → vigilant threat-monitoring behavior characteristic of anxious individuals is mediated by exaggerated responding in the BNST

Question 28

What is reward?

Answer 28

It lies in a set of active processes of the brain and mind in response to a stimulus, rather than the stimulus itself. It includes several psychological components that correspond to distinguishable neurobiological mechanisms It is not a sensation It is not something desired for its pleasant qualities, or because it produces subjective pleasure It is not a unitary process

Question 29

Which are the specific psychological components of reward?

Answer 29

• Wanting (the motivational component, attribution of incentive salience to a percept or representation) • Learning (knowledge based on past experience - associative conditioning and cognitions - that allow cues to raise expectations of future reward, and to guide goal-directed behavior) • Liking (the affective quality of experience, pleasure, or hedonic impact of reward)

Question 30

How to measure reward components?

Answer 30

Each process includes both explicit (consciously experienced) and implicit (operating at a level not always directly accessible to consciousness) components, and can be evaluated by appropriate measurements or behavioral procedures

Question 31

What led to the idea of an identifiable anatomical reward circuit ?

Answer 31

Demonstration by Olds & Milner (1950’s) Animals will work to obtain electrical stimulation in specific brain regions, including: • lateral hypothalamus, • medial forebrain bundle (from ventral tegmental area to nucleus accumbens through lateral hypothalamus) • septal area (set of nuclei below the anterior part of the corpus callosum) led to the idea that there is an anatomically identifiable reward circuit

Question 32

human imaging work on reward-related activity

Answer 32

Whereas the basic anatomy of the structure and pathways of the reward circuit are now well established in animals (including primates), human imaging work on reward-related activity is relatively new→ fMRI has too low spatial resolution (size, endogenous motion, inhomogeneity) to visualize activation in midbrain structures, thus anatomical landmarks have to be used for reference (e.g., substantia nigra, brain midline)

Question 33

The neural basis of reward: the meso-cortico-limbic circuit

Answer 33

• Meso-limbic pathway: dopaminergic neurons in the VTA project to the striatum (dorsal, i.e., caudate nucleus + putamen, and ventral striatum, i.e., nucleus accumbens) • Meso-cortical pathway: dopaminergic projections from the VTA to dorsal and ventral PFC, OFC, ACC The network includes connections with • Amygdala • Hippocampus • Ventral pallidum • Mediodorsal thalamus with glutamatergic, GABAergic, opioid, cholinergic, and serotonergic neurotransmission

Question 34

The Ventral Pallidum

Answer 34

Ventral pallidum receives major afferents from cortex, accumbens shell (AcbSh) and core (AcbC), paraventricular thalamus (PVT), subthalamic nucleus (STN), basolateral amygdala (BLA), and ventral tegmental area (VTA). In turn, ventral pallidum projects to subthalamic nucleus (STN), lateral hypothalamus (LH), basolateral amygdala (BLA), and ventral tegmental area (VTA)

Question 35

Activation of human midbrain regions by different rewards:

Answer 35

- Food - Drug - Sexual orgasm - Romantic love - Music - Humor - Sportscar - Mooney - Good social reputation (also receiving likes on social media)

Question 36

What’s the difference between primary and secondary rewards?

Answer 36

- Primary rewards (e.g., food, sex) are innate, and are essential for the maintenance of homeostasis and reproduction - Secondary rewards (e.g., money, power) are acquired; they are not directly related to survival and only gain value through learned associations with lower-level rewards Both primary and secondary rewards engage a core “reward system” (including the ventromedial prefrontal cortex, ventral striatum, amygdala, anterior insula and mediodorsal thalamus), although with some variations in the intensity and location of peak activity Music - with other aesthetic stimuli - is neither a primary reward in the sense of being strictly necessary for survival or to achieve physiological homeostasis, nor is its value related to an association with a primary reward. Music is essentially its own reward, intrinsically valuable, yet of course very much dependent on learning. As such it presents a remarkable opportunity to learn more about how the cognitive systems interact with the reward network

Question 37

How do we map wanting, learning and liking onto the reward circuit?

Answer 37

• All psychological components of reward are intertwined and normally operate together as part of a coordinated network integrating motivational, learning and emotional processes in reward • It is often only after manipulation of specific brain circuits and/or using appropriate experimental paradigms that reward dissociates into psychological components, revealing the identity of distinct components of reward

Question 38

Reinforcement learning and reward

Answer 38

As any living organism, humans are faced with the need to make decisions about how to act in response to a multitude of environmental cues every day. Often, we encounter similar situations repeatedly, which enables us to use past experiences (i.e., to learn) to predict future outcomes. Learning from trial and error, or reinforcement learning, can be explained in terms of a reward prediction error, i.e., a mismatch between predicted and actual rewards. On a neural level, it has been shown that dopaminergic midbrain neurons, with their massive projections to the ventral striatum (VS), represent this reward prediction error and play a central role in reward-based learning

Question 39

The role of the ventral striatum in reinforcement learning

Answer 39

The ventral striatum is a key structure in reinforcement learning. During the expectation of increasing reward probabilities (expectation phase), ventral striatal activity increases with probability following a linear trend. Activation in the Nac during the outcome phase (upon receipt of reward) tracks linearly the prediction error as coded by reward probability, i.e., the Nac signal is highest with the most positive prediction error (subject expects to win at a probability of only 25% and wins), and lowest with the most negative prediction error (subject expects to win at probability of 75% but does not win) However, in ecologically valid settings, organisms may have to make more complex decisions that do not (or cannot) rely on trial-and- error learning, e.g., which objects in the environment to categorize as nutrition, which partner to choose, or, in the human case, what career path to follow, or how to provide for retirement For many of these decisions, feedback from the environment is sparse and delayed, learning from errors is costly, and errors can be avoided. In these situations, we have to additionally rely on other mechanisms than learning from trial and error, such as building abstract representations, mental models of the environment, or learning from others The ventral striatum is activated not only when learning from explicit rewards, but also from cognitive information, or when observing other’s actions and other’s feedback, indicating that in human learning ’’reinforcement’’ has to be considered a very broad term

Question 40

Where in the brain are sensations transformed into pleasure? (the encoding of “liking” in brain activity)

Answer 40

Only few circumscribed brain locations and neurochemical systems have been found so far to be able to apply a “pleasure gloss” to ordinary sensations. They have been called “hedonic hotspots”, because they are capable of generating increases in “liking” reactions, and by inference, pleasure The brain’s “rose-tinted glasses” are found in the nucleus accumbens and the ventral pallidum (… but note that some uniquely human abstract pleasures have cognitive qualities too, that depend on cortical areas, such as OFC, ACC, insula)

Question 41

“liking” and “disliking” facial expressions elicited in different species

Answer 41

Affective “liking” and “disliking” facial expressions elicited by the hedonic impact of sweet and bitter tastes are similar in humans, orangutans, chimpanzees, monkeys, rats and mice • Liking: lip licking, tongue protrusion, elevation of mouth corners, paw-licking • Disliking: gaping, headshaking, lip retraction, nose “wrinkle”, mouth wiping In experimental animals, it is possible to probe hedonic coding mechanisms directly by recording of neuronal firing patterns in temporal synchrony with video-recording animals’ facial affective liking and disliking reactions to pleasant and unpleasant tastes

Question 42

Isolating the pleasure code in the Ventral Pallidum

Answer 42

When the (un)pleasantness of salty taste is selectively manipulated by sodium depletion (mineralocorticoid hormone and diuretic administration), that induces a physiological salt appetite, salty taste becomes “liked” as much as sucrose→ neurons in VP begin to fire as strongly and fast to salt as to sucrose→ the change in the firing pattern of VP neurons encodes hedonic “liking” for the sensation, rather than simple sensory feature

Question 43

Neurotransmitter systems important for generating pleasurable reactions?

Answer 43

Endogenous opioid peptides, endocannabinoid and GABA systems are important for generating pleasurable reactions

Question 44

Nucleus Accumbens and Ventral Pallidum hedonic hotspots

Answer 44

The “liking” system comprises a collection of interactive hedonic hotspots embedded in the nucleus accumbens and ventral pallidum The NAc medial shell (rostral half) and the posterior half of VP contain a hedonic hotspot, where opioid and related stimulation increases “liking” reactions to sucrose taste Hotspots in NAcc and Ventral Pallidum act as a functional unit for mediating pleasure enhancements Each hotspot seems to be able to recruit the other to unanimously generate amplification of ‘liking’: - opioid microinjection into the NAcc hotspot enhances also the firing patterns of the Ventral Pallidum hotspot neurons elicited by a sweet taste; - blocking either hotspot with an opioid-antagonist microinjection completely prevents opioid stimulation of the other hotspot from producing any ‘liking’ enhancement The hedonic hotspot located in the ventral pallidum may be especially crucial to the normal capacity for pleasure. The ventral pallidal hotspot is the only known site in the brain where a small lesion eliminates normal pleasure, and reverses the hedonic impact of sweet sensation from “liked” to “disgust”(so that after the lesion sucrose elicits gapes and related negative expressions)

Question 45

Patient with selective bilateral lesion of the globus pallidus shows…

Answer 45

severe anhedonia

Question 46

Parkinson’s patients with pallidotomies show…

Answer 46

flattened affect

Question 47

Stimulation of the globus pallidus…

Answer 47

alleviates depressive symptoms

Question 48

anterior orbitofrontal cortex and posterior insula hedonic hotspost

Answer 48

Hedonic hotspots have been found in anterior orbitofrontal cortex, and in posterior insula in the rat’s brain (Castro & Berridge, 2017): opioid or orexin stimulations causally enhance hedonic “liking” reactions to sweetness

Question 49

Attempts to translate pre-clinical literature to humans have been mixed

Answer 49

1. Human neuroimaging and PET studies have shown that the same set of regions are commonly activated by diverse rewards, with involvement of endogenous opioids, but the functional homology of the reward network in humans and circuits identified in rodents is contested — particularly in prefrontal cortex and insula 2. The nature of pleasurable stimuli accessible for study in animal models does not extend to many important modalities of human pleasure, such as music and humor, therefore the generalizability of rodent models for understanding the full complement of human pleasures is uncertain 3. The size and spatial configuration of affective circuitry in subcortical structures, as well as the limitations of conventional imaging approaches have limited efforts to characterize hedonic brain systems in humans, making it difficult to isolate neural substrates involved in different components of reward

Question 50

Liking and Wanting

Answer 50

Reward in the full sense requires both “liking” and “wanting” together The brain substrates of “wanting” are more widely distributed and more easily activated than substrates for “liking” (that is probably why we often want a reward without equally liking it)

Question 51

Dopamine and Wanting/Liking

Answer 51

The manipulation of dopamine systems powerfully changes “wanting”-related motivated behavior (as measured by instrumental performance and consumption of rewards) without affecting “liking” (as measured by affective facial expressions). Rats depleted of dopamine in the NAcc and striatum by intracranial application of a dopamine-selective neurotoxin (6-hydroxydopamine;6-OH) become aphagic and adipsic even though food may be available, and will starve to death unless nourished artificially→ wanting is abolished However, they show normal hedonic reaction patterns to sucrose vs. quinine → liking is preserved Berridge & Robinson, 1998 Oral administration of d-amphetamine induces an increase in extracellular dopamine in bilateral NAcc → correlates significantly with self-reported “Want Drug”, but not with self-reported “Like Drug” and mood elevation→ wanting is enhanced, liking is not affected

Question 52

Why did brains evolve separate “wanting” and “liking” mechanisms for the same reward?

Answer 52

• “Wanting” might have evolved as an elementary form of goal directedness to pursue particular innate incentives even before experience of their hedonic effects • Later, as hedonic and associative mechanisms evolved, “wanting” came to work with them in extending “wanting” to learned stimuli associated with “liked” rewards • Also, a distinct mechanism for “wanting” might be useful for comparing (and deciding) between competing “liked” stimuli (e.g., food, sex, shelter, and others) with a common neural currency (i.e., incentive salience dopamine signalling in the ventral striatum and vmPFC) • The “dissociation” of “wanting” and “liking” might explain “irrational desires” that could underlie reward-related psychopathologies

Question 53

Disorders of desire and pleasure: compulsive gambling/buying/internet use, eating disorders, substance abuse & addiction, mood disorders…

Answer 53

Could derive from different alterations: - Hyper/Hypoactivation of hedonic hotspots in NAcc and VP (food “liked” too much or too little)? Neural sensitization of incentive salience systems (too much “wanting” to eat that is neither cognitively wanted, nor “liked”)? - Hypoactivation of hedonic hotspots in NAcc and VP and/or hypoactivation of dopamine “wanting” systems (anhedonia, loss of pleasure and motivation)? - Neural sensitization of mesocorticolimbic systems (compulsive and long-lasting “wanting” addictive substances/activities without deriving much pleasure)?