Using neuroimaging to expose the unconscious influences of priming

In 1996, a group of researchers at NYU conducted an interesting experiment. First, they had NYU students work on unscrambling letters to form words. Unbeknownst to the students, they had been split up into three groups, and each group unscrambled letters that formed slightly different words. One group unscrambled words with a "rude" connotation like aggressively, bold, and interrupt. Another group unscrambled "polite" words like considerate, patiently, and respect. And the third group unscrambled neutral words like watches and normally.

The students were told they should come find the experimenter, who would be waiting in a different room, after they finished the unscrambling task. This, however, was just another part of the experiment. When the students walked up to the experimenter, he was engaged in a conversation with someone else (who was actually in on the experiment). The experimenter stood in such a way that it was clear he knew the student was waiting for him, but he nevertheless continued his conversation and didn't acknowledge the student.

In fact, the experimenter continued talking for 10 minutes unless the student interrupted to draw attention to the fact that he or she was done with the unscrambling task (and being somewhat rudely ignored). What the experiment really had set out to determine was if the type of words the students unscrambled seemed to have an influence on whether or not they interrupted the experimenter. Interestingly, about 80% of students who unscrambled polite words waited a full 10 minutes without interrupting, while only 35% of the students who unscrambled rude words waited that long. On average the rude-word group only waited 5.4 minutes, compared to the polite-word group's 8.7 minutes. The students, of course, were not aware that the words they unscrambled had any effect on their patience, or lack thereof.

Now, think about the implications of this experiment in your daily life. If its findings are valid--and it's worth noting that this particular area of research has been criticized for the publication of studies that others have been unable to replicate--it suggests that information that we are not consciously aware of shapes our thoughts and behavior. Taken a step further, we could begin to question how much of our behavior is even under our own conscious control. For example, you might swear that fight you got into with your significant other was about doing the dishes and it never would have happened if he/she hadn't blatantly disregarded your strong opinions--yet again--about leaving dirty dishes in the sink. But maybe your inclination towards hostility had been influenced by that jerk who cut you off in traffic an hour prior, causing you to overreact negatively and call it quits on an a relationship that was pretty good despite a lack of harmony on the relatively minor issue of timely dish washing.

The influence a previous experience has on our likelihood of responding in a particular way later on is known as priming. It was first discovered in the 1970s through a series of simple experiments exploring response time in tasks like determining if groups of letters represented English words. For example, in one such experiment researchers presented participants with pairs of words. Sometimes the words used were actual English words (e.g. butter), other times they were nonsense words (e.g. nart), and they were presented in different combinations of each. The researchers found that participants were able to identify something as an English word more rapidly if the word presented previous to it had a related meaning (e.g. the first word was nurse and the second was doctor). Since then, a number of experiments have investigated this effect a previous experience can have on a subsequent response, showing that it can influence everything from reaction time to subtleties of behavior like the speed at which someone walks.

Priming and memory

Priming is considered an an example of implicit memory, a term that describes a type of memory that can influence behavior even though we aren't consciously aware of it. We use a form of implicit memory called procedural memory every day when we engage in tasks that we have performed countless other times, like tying our shoes. In these cases we don't consciously think of the process involved in doing the job (often we are thinking of something quite different), but clearly we retain a memory of how to perform the task, and that memory facilitates its execution.

The influence of priming extends much further than shoe-tying, however. Although it may be difficult for us to accept, our implicit memory seems to affect the beliefs we hold and the decisions we make. Because our brains are so good at forming connections between things we see around us and things we have seen or learned in the past, our implicit memory is being accessed on a continuous basis. For example, in another study researchers put participants in two groups: one group filled out a questionnaire in a room that smelled strongly of citrus all-purpose cleaner, while the other filled out a questionnaire in a room with no apparent odor. Then, the researchers had both groups eat a crumbly biscuit. The group that had been exposed to the citrus smell was significantly more likely to clean up the crumbs from their biscuit. Even though they weren't consciously thinking about it, the citrus scent (hypothetically) conjured up implicit associations with cleanliness, which prompted the participants to clean up after themselves.

Priming and the brain

Understanding the neuroscientific correlates of priming has not been simple, in part because it seems to involve a diverse selection of brain areas. One general finding has been that there is a reduction in brain activity during exposure to a primed stimulus (i.e. a stimulus that has been preceded by priming) vs. an unprimed stimulus. For example, if you prime someone by exposing them to words related to transportation, then ask them to unscramble letters that could readily be formed into words like traffic or drive, you will see less activity in their brains than if you hadn't primed them. This should make intuitive sense, as the brain that has been primed is not having to work as hard. It can rely on cues from implicit memory to bring to mind potential words the letters might form.

One reason we tend to see many brain regions involved in priming is that different systems are used to process different types of stimuli--as well as different aspects of the same stimulus. For example, if the primed stimulus involved the meaning of a word, then we would see a decreased response to the primed stimulus in a number of areas of the brain associated with processing different aspects of a word, like meaning, spelling, phonology, and so on. If the primed stimulus involved an odor, we would see a reduction in brain activity in very different regions.  

There are also, however, some commonalities in the neural activity underlying priming across different types of stimuli. For example, regions of the inferior temporal cortex and inferior frontal gyrus have been found to respond to abstract qualities of stimuli, and thus they are activated even when the prime and the primed stimulus are presented in different ways. One study, for instance, saw activity in these areas when the prime involved normally-oriented words and the primed stimulus involved mirror-reversed words. The inferior temporal cortex and inferior frontal gyrus are also activated in response to primed stimuli of different perceptual modalities (e.g. auditory and visual), and they are still activated when the prime and the primed stimulus are each presented in a different modality. Thus, it may be that areas like these mediate the priming of concepts, regardless of how the stimulus is introduced and initially processed.

Neuroimaging evidence also suggests that the prefrontal cortex may play an especially important role in priming, as it is another area where activity is reduced in response to a number of different types of primed stimuli. The prefrontal cortex is frequently associated with executive functions, and as such it is involved in managing the activity of a network of brain areas in retrieving memories and handling other cognitive duties. Having an implicit memory to draw upon, however, may make its job a little easier, allowing the prefrontal cortex to work more efficiently to complete the task at hand. Thus, reduced activity in the prefrontal cortex during exposure to a primed stimulus may generally represent a decreased reliance on the conscious processing of a stimulus due to the contributions of implicit memory.

These are some of the patterns of brain activity that we can associate with priming, but what's really going on still remains somewhat unclear. Regardless, priming seems to be a process that is occurring in our minds all the time. And this feature of the way our brains work is also opportunistically manipulated by others every day, especially those who are trying to sell you something. Take Cinnabon, for example, the baked goods chain known for their American-sized cinnamon rolls. They intentionally place their ovens near the front of their stores so the smell of fresh-baked rolls drifts toward the entrance. Because they strategically put their stores primarily in enclosed buildings like malls and airports, these drifting aromas are more likely to be smelled by those who are passing by. Some of these passersby will then make an impulsive decision to stop in and buy a cinnamon roll. Is this decision free of any priming effects induced by the enticing odors emanating from the store? It's hard to say, but considering that Cinnabon's sales were lower when they tried putting the ovens at the back of stores, it would seem priming is playing a role in many decisions to indulge.

Even your desire to read this article might be able to be traced back to some priming influence that occurred earlier today, last week, or last year. The same could be said for my intention to write it. All of this leads to the inevitable question: with these multitudinous influences on our behavior from unconscious associations with words, sounds, smells, colors, etc., how much of our behavior do we really control? Don't think too hard about trying to answer that question, because you've likely already been primed to respond in a particular way.

Schacter, D., Wig, G., & Stevens, W. (2007). Reductions in cortical activity during priming Current Opinion in Neurobiology, 17 (2), 171-176 DOI: 10.1016/j.conb.2007.02.001

What is the habenula?

Despite the fact that it is present in almost all vertebrate species, very little was known about the habenula until fairly recently. In the past several years, however, the habenula has received a significant amount of attention for its potential role in both cognition (e.g. reward processing) and disorders like depression. Still, the habenula remains a little-known structure whose functions are yet to be fully elucidated.

Where is the habenula?

The habenula is part of the diencephalon and, together with the pineal gland, makes up a structure called the epithalamus. The pineal gland is found on the posterior side of the thalamus and is attached to the diencephalon by a stalk. At the base of that stalk there are two small swellings (one on each side); these are the habenulae. The habenula is traditionally divided into a lateral and medial section.

What is the habenula and what does it do?

The habenula receives information from the limbic system and basal ganglia through a fiber bundle called the stria medullaris. It sends information to areas of the midbrain that are involved in dopamine release, such as the substantia nigra and ventral tegmental area. The habenula also has neurons that project to areas like the raphe nuclei, which are involved in serotonin release. Thus, the habenula is one of the few known structures in the brain that can exert an influence over large populations of both serotonergic and dopaminergic neurons.

The habenula and reward processing

Dopamine and dopamine-rich areas of the brain like the substantia nigra and ventral tegmental area are thought to be important to processing information related to rewards. When we receive a reward--which could be anything from a slice of cheesecake to a line of cocaine--there is corresponding dopamine activity that seems to be associated with how satisfying we expect the reward to be. If the reward is larger than we expected (e.g. a big slice of cheesecake, topped with syrup and with a side of ice cream), our dopamine neurons get excited with activity that seems to help us remember the details of how we obtained the reward. In this way, our dopamine system helps us to recall how to get the reward again. When this encoding of the details associated with a reward becomes hyperactive, it can result in the obsessive reward-seeking we see in addiction.

But when the reward is smaller than we expected (e.g. a few crumbs of cheesecake on an otherwise empty plate), dopamine activity in the substantia nigra and ventral tegmental area is inhibited. Smaller-than-expected rewards, however, cause increased activity in the habenula, while larger rewards lead to an inhibition of activity there.

Thus, it has been hypothesized that the habenula is involved in encoding information about disappointing (or missing) rewards. The habenula has also been found to be activated in response to punishment (e.g. electric shocks) and stimuli that we have previously associated with negative experiences. Based on all of this information, it is thought the habenula plays an important role in learning from aversive experiences and in making decisions so as to avoid such unpleasant experiences in the future.

The habenula and depression

The habenula has been found to be activated in response to stress, and so it may not be surprising--given the strong relationship between chronic stress and depression--that the habenula is suspected to be involved in the pathophysiology of depression. Habenular neurons are hyperactive in depression; some have suggested this activity may correspond with an increased propensity toward pessimism. Structural abnormalities of the habenula have been found in the brains of patients who suffered from major depressive disorder, and in one case a patient who was not responsive to typical treatments for depression did respond to deep-brain stimulation of her lateral habenula. Regardless, although there are some indications of habenular involvement in depression, the association between the habenula and depression is still unclear. More research will be needed to determine if there is a causative link, and if so what the nature of that link is.

The habenula and sleep

The habenula also seems to play a role in sleep. It has mutual connections with the pineal gland, which secretes melatonin--a hormone important for regulating circadian rhythms and promoting sleep. There is also some evidence that the habenula itself produces melatonin. Lesioning the habenula in experimental animals results in a disruption of rapid eye movement (REM) sleep, and thus the habenula may have role in both promoting sleep and sleep quality. Some have suggested the role of the habenula in sleep may also be related to its role in depression, as depressed individuals often suffer from sleep disorders.

The functions of the habenula are just beginning to be understood. Until fairly recently, our neuroimaging techniques were not even powerful enough to visualize the habenula with adequate resolution. Now that this has changed, the tiny structure is becoming recognized as an important part of the brain. The next decade is likely to reveal some interesting new data about just how important this once-obscure brain region really is.

Hikosaka O (2010). The habenula: from stress evasion to value-based decision-making. Nature reviews. Neuroscience, 11 (7), 503-13 PMID: 20559337



Serotonin, depression, neurogenesis, and the beauty of science

If you asked any self-respecting neuroscientist 25 years ago what causes depression, she would likely have only briefly considered the question before responding that depression is caused by a monoamine deficiency. Specifically, she might have added, in many cases it seems to be caused by low levels of serotonin in the brain. The monoamine hypothesis that she would have been referring to was first formulated in the late 1960s, and at that time was centered primarily around norepinephrine. But in the decades following the birth of the monoamine hypothesis, its focus shifted to serotonin, in part due to the putative success of antidepressant drugs that targeted the serotonin transporter (e.g. selective serotonin reuptake inhibitors, or SSRIs). The monoamine/serotonin hypothesis eventually became generally recognized as viable by the scientific community. Interestingly, it also became widely accepted by the public, who were regularly exposed to television commercials for antidepressant drugs like Prozac, Lexapro, and Celexa--drugs whose commercials specifically mentioned a serotonin imbalance as playing a role in depression.

Over the years, however, the scientific method quietly and efficiently went to work. Evidence gradually accumulated that indicated that the serotonin hypothesis does a very inadequate job of explaining depression. For example, although SSRIs increase serotonin levels within hours after drug administration, if their administration leads to beneficial effects--a big if--it usually takes 2-4 weeks of daily administration for those effects to appear. One would assume that if serotonin levels were causally linked to depression, then soon after serotonin levels increased, mood would begin to improve. Also, reducing levels of serotonin in the brain does not cause depression. The list of studies that don't fully support the serotonin hypothesis of depression is actually quite lengthy, and most of the scientific community now agrees that the hypothesis is insufficient as a standalone explanation of depression.

In the 1990s another hypothesis, known as the neurogenic hypothesis, was proposed with the hopes of filling in some of the holes in the etiology of depression that the monoamine hypothesis seemed to be unable to fill. The neurogenic hypothesis suggests that depression is at least partially caused by an impairment of the brain's ability to produce new neurons, a process known as neurogenesis. Specifically, researchers have focused on neurogenesis in the hippocampus, one of the only areas in the brain where neurogenesis has been observed in adulthood (the other being the subventricular zone).

The neurogenic hypothesis was formulated based on several observations. First, depressed patients seem to have smaller hippocampi than the general population, and their hippocampi also appear to be smaller during periods of depression than during periods of remission. Second, glucocorticoids like cortisol are elevated in depression, and glucocorticoids appear to inhibit neurogenesis in the hippocampus in rodents and non-human primates. Finally, there is evidence that the chronic administration of antidepressants increases neurogenesis in the hippocampus in rodents.

The neurogenic hypothesis thus suggests that depression is associated with a reduction in the birth of new neurons in the hippocampus, an area of the brain important to stress regulation, cognition, and mood. According to this hypothesis, when someone takes antidepressants, the drugs do raise levels of monoamines like serotonin, but they also enact long-term processes that increase neurogenesis in the hippocampus. This neurogenesis is hypothesized to be a crucial part of the reason antidepressants work, and the fact that it takes some time for hippocampal neurogenesis to return to normal may help to explain why antidepressants take several weeks to have an effect.

This may all sound logical, but the neurogenic hypothesis has its own share of problems. For example, while stress-related impairment of neurogenesis has been observed in rodents, we don't have definitive evidence it occurs in humans. Human studies thus far have relied on comparing the size of the hippocampi in depressed and non-depressed patients. While smaller hippocampi have been observed in depressed individuals, it is not clear that this is due to reduced neurogenesis rather than some other type of structural changes that might have occurred during depression.

Similarly, while the administration of antidepressants has been associated with increased neurogenesis in rodent models of stress, we don't have clear evidence of this in humans. In humans we again have to rely on looking at things like hippocampal size. Because there could be a number of explanations for changes in the size of the hippocampi, we can't assume neurogenesis is the sole factor involved--or that it is involved at all. Additionally, some studies in rodents have found that antidepressants lead to a reduction in anxiety or depressive symptoms in the absence of increased hippocampal neurogenesis.

Another problem is that when neurogenesis is experimentally decreased in rodents, the animals don't usually display depressive symptoms. Experiments of this type haven't been performed with humans or non-human primates, so we don't know if a reduction in neurogenesis in any species is actually sufficient to cause depression. And no studies have found that increasing neurogenesis alone is enough to alleviate depressive-like symptoms.

Of course none of this means the neurogenic hypothesis is incorrect, but it does suggest there is a long way to go before we can feel confident about incorporating it fully into our understanding of depression. In the reluctance of the scientific community to embrace this hypothesis is where I see the beauty of science. Although it took decades of testing and revising before the monoamine hypothesis became a widely accepted explanation for depression, one could argue (based on its now recognized shortcomings) that we accepted it too readily.

However, it seems that many in the scientific community have learned from that mistake. Although there is no shortage of publications whose authors may be too willing to anoint the neurogenic hypothesis as a new unifying theory of depression, overall the tone when speaking of the neurogenic hypothesis seems to be cautious and/or critical. There is also a great deal of discussion now in the literature about the complexity of mood disorders like depression, and how it is unlikely to be able to explain their manifestation in a diverse population of individuals with just one mechanism, whether it be impaired neurogenesis or a serotonin deficiency.

Thus, the neurogenic hypothesis will require much more testing before we can consider it an important piece in the puzzle of depression. Even if further testing supports it, however, it will likely be considered just that--a piece in the puzzle, instead of an overarching explanation of the disorder. And that circumspect approach to explaining depression represents an important advancement in the way we look at psychiatric disorders.

See also: http://www.neuroscientificallychallenged.com/blog/2008/04/serotonin-hypothesis-and-neurogenesis

Miller, B., & Hen, R. (2015). The current state of the neurogenic theory of depression and anxiety Current Opinion in Neurobiology, 30, 51-58 DOI: 10.1016/j.conb.2014.08.012