Narrowing Down the Choices: Neurobiology to Subtype

This post is Part 4 in a five-part series entitled "Narrowing Down the Choices." Part 1 can be found here, Part 2 here; Part 3 here.

The neuro-cognitive model of addictions frames addictions as being secondary to alterations in one or more of three domains—negative emotionality, executive function, and incentive salience. Aberrant functioning in one of these three domains forms the core functional elements of an addiction. Function in these domains can be measured with genetic and neuroimaging technology. Neuropsychological and clinical information may also be used.

More on negative emotionality, executive function, and incentive salience in addictions

Negative emotionality: Many people use a substance for the relief it gives from negative emotions. “I use because it makes me feel better when I’m anxious, irritable, or down.” Someone with susceptibility in this domain may be more affected by stress and adversity, or have a tendency towards depression and anxiety, and may have more reactive brain emotional circuits.

Executive function: Someone who has problems with executive function may use because they tend to have trouble controlling their impulses. “No matter how many times I quit, or no matter how convinced I am I’ll never go back, I always seem to relapse.” They may have difficulty with attention, and staying on-task.

Incentive salience: Someone who has a strong tendency to seek pleasurable experiences, or sensitive to their conditioning effects, may use for reward. “I use because I love how it makes me feel.” This person may be especially attached to the positive emotions they get from use.

What do vulnerabilities in these domains look like neurobiologically?

Negative emotionality: Abnormal function in the brain’s stress response and emotional-processing circuits (like hyperactivity in the amygdala and other regions of the limbic system, or excess release of corticotrophin releasing factor and noradrenaline) can increase proneness to anxiety, depression, irritability. A person with relief motivations will use because the substance gives them an emotional reprieve. Improving mood, and stabilizing emotional reactivity could support recovery.

Executive function: An under-functioning prefrontal cortex can contribute to impulse control problems. Alterations in dopamine and norepinephrine function can also contribute. The synchronicity of neuronal firing patterns, otherwise known as brain connectivity, may also be disrupted in people with poor executive function. Restoring dopamine function and enhancing executive function brain network connectivity (connectivity is a measure of synchronicity of firing between distinct brain regions) could improve executive function and support recovery, studies imply.

Incentive salience: Incentive salience is a cognitive process that imbues a stimuli with significance for a person. The sight of another smoker or the smell of cigarette smoke (these are examples of stimuli, cues) can, in an instant, convince someone with a nicotine addiction who recently quit to return to smoking. Humans learn to engage in certain behaviors, or habits, through the psychological process of conditioned learning. The more rewarding use of a substance is, the more likely the person will repeat the original behavior that lead to procurement of the substance, especially upon exposure to familiar, or related, stimuli or cues. Altering conditioning and reward processes, which depend on dopamine, glutamate, and opioid function, might help improve treatment outcomes in addictions too.

Can we use these three domains to subtype people with addictions?

Are aberrant functions in emotional circuits, executive control circuits, and reward circuits common to all people with addictions, or is there variability between individuals? We aren't totally sure, but clinical experience says there is significant variability. So does some new research.

A recent study in 593 individuals, 173 with substance use disorders, found that there were three distinct subtypes in their group: a “reward type” with higher approach-related behavior (N = 69); a “cognitive type” with lower executive function (N = 70); and a “relief type” with high negative emotionality (N = 34). They did brain imaging and found that this method of subgrouping mapped onto unique brain function profiles, using a kind of neuro-imaging measure that looked at connectivity within and between brain networks (circuits).

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So yes, these three domains can be used to subtype people with addictions. Some people use for reward, others because they are deficient in impulse control, and others because they tend towards negative emotional states.

Could this approach to subtyping be used to help match treatment recommendations to the individual?

If someone uses for relief, treatments that target depression, anxiety, dysphoria, and irritability (such as antidepressants, non-habit-forming anti-anxiety medications, buprenorphine for people with opioid use disorder, physical exercise, or psychotherapy) may be first-line. If impulse control is the primary issue (for example, if they also have a diagnosis of attention-deficit disorder), treatment that enhances executive function (such as long-acting stimulants, bupropion, atomoxetine, or physical exercise) might be most important. For someone with reward motivations—vulnerability in the incentive salience domain—a treatment that blocks the attention-grabbing-effect of cues or rewarding effects of the substance might be most effective (such as relapse prevention psychotherapy, topiramate, medication-assisted treatment for opioid use disorder, naltrexone).

We already have a proof of concept in a series of studies of naltrexone for alcohol use disorder. Researchers have shown that naltrexone works best in people whose ventral stratia are most reactive to alcohol cues (replicated in two samples). Previous work indicates that naltrexone dampens activation in this brain region. Taken together these series of studies show that ventral striatal reactivity to alcohol cues might be a reliable biological marker of vulnerability in the incentive salience domain, and that naltrexone is a first-line treatment for those that have it.

Beyond this work in naltrexone though, the science still doesn't yet say what the best measures to subtype and predict are. So although this is an exciting theoretical model, it is not yet a practical approach, nor are clinicians regularly (yet) obtaining genetic, neuroimaging, and neuropsychological information from their patients to treatment plan.

Conclusion

More research on how existing medications work in the brain, and whether brain function can predict who will respond to what medications (and other treatments, such as psychotherapy and exercise) is needed. Larger studies, replication studies, and cost-benefit analyses will need to be done too (since genetic testing and neuroimaging can be expensive). In the meantime, we can still listen to our patients and ask them which of the three cognitive domains they think they might need the most help in.