The pursuit of happiness: Why does nothing feel good when you have anhedonia?

By Alessandra Borsini and Amelia St John Wallis


Editors note: Congratulations to Dr. Alessandra Borsini, a neuroscientist in the SPILab, for winning the coveted Pyschonomic Society's Best Article Award 2021, for the systematic review underpinning this post - well done Dr Borsini!

 

Anyone who has experienced anhedonia will know that it is not just inability to feel pleasure, as most commonly defined.


Anhedonia takes away happiness from those small moments that give life meaning, like food, sex, relationships and achievements.


You know what the occasion is, but you just can’t rise to it.


To make this scenario even worse, anhedonia never comes alone.


Anhedonia can occur together with other conditions, particularly depression, but also schizophrenia, Parkinson’s disease, anorexia nervosa and many other disorders.


Anhedonia has received a lot of attention in recent years.


The main reason for this being that it can predict how well someone with depression will respond to treatment. In fact, common antidepressants tend to be less effective for people who have depression with anhedonia, than for those who have depression without anhedonia.


Also, some studies show that anhedonia increases the risk of taking your own life by suicide.


Therefore, the debilitating impact that anhedonia has on quality of life, as well as its resistance to treatment, makes it an important scientific research topic to explore — especially for scientists like us.


I am a senior postdoctoral neuroscientist who has been working in the field of mental health for now more than 10 years, and a member of the Stress, Psychiatry and Immunology Lab, the team who brings you InSPIre the Mind. Together with my student Amelia, a graduate psychologist with a keen interest in clinical psychology, we have recently written a systematic review investigating changes in brain function in patients with anhedonia, as well as the mechanisms underlying such changes.


Considering our interest in studying anhedonia and our recent publication, we are very excited to be writing a blog on this topic.



So, what is happening in the brain when we experience anhedonia?

As with the investigation of any emotional response, the picture is quite complex.

Anhedonia is not simply a reduced appreciation of pleasurable things; the underlying reward processing in the brain is impaired.


Moreover, reward processing is not a single process per se, but rather a series of distinct and overlapping phases, commonly referred to: reward learning, reward wanting and reward liking.


Imagine a mouth-watering chocolate bar in your cupboard: reward learning teaches you that opening the cupboard (and the wrapper!) gets you a chocolatey reward; reward wanting gives you the motivation to go to the cupboard; reward liking allows you to actually enjoy the chocolate bar.


Research has shown that patients with anhedonia often have difficulties in all three reward processes.


This might involve alterations in levels of interest, motivation, anticipation and expectation, all of which are processed by different but interconnected neural circuits.



But, how can we study reward processing in the brain?

One way could be via the use of Functional Magnetic Resonance Imaging (fMRI) techniques, which is a specific type of MRI scan that allows us to record the activity levels of different areas of the human brain, in real-time — or, in other words, how well the brain is functioning.


For example, recording brain activity during a series of reward tasks — such as exposing the person to a favourite food or music stimulus — can easily discriminate specific brain activity changes, as well as the brain areas involved in such changes.


With fMRI, you can also identify differences among different groups of individuals, for example in patients with anhedonia when compared with normal healthy individuals.


Of course, changes in brain activity are often complex and vary across different brain areas, as well as from person to person, but at this stage fMRI measurement can be used to gather valuable clues.


In our recent review article in the scientific journal of Cognitive, Affective and Behavioural Neuroscience, we collected findings from all published fMRI studies investigating changes in brain activity in depressed patients with anhedonia, when compared with healthy individuals, when using tasks assessing reward learning, reward wanting and reward liking.


Combining all of this research together reveals very interesting patterns.


For instance, these patients have lower brain activity in the striatum, an area important for reward processing, and located in the middle of the brain.


And guess what? This is associated with reduced reward learning, reward wanting and reward liking, regardless of the rewards on offer: a bite of some tasty foods, a listen to their favourite music, even winning money!


We came across one study, which in addition to fMRI, used another imaging technique called Positron Emission Tomography (PET), which measures brain metabolism of neurotransmitters, like dopamine. This study found that reduced reward wanting and liking are associated with decreased dopamine signaling in the striatum.


So, lower brain activity in the striatum and a decrease in dopamine signalling are likely to be important changes involved in anhedonia.


But, these findings are not exclusive to the striatum, of course.


Patients also have lower brain activity in an area called the orbito-frontal cortex (OFC), located at the front of the brain — certain regions of the OFC area are involved in the experience of pleasure from rewards. In fact, patients with lower OFC activity also show reduced reward learning, wanting and liking.


We also identified opposite activity patterns in other areas of the brain.


For example, when investigating the medial (mPFC) and dorsolateral prefrontal cortex (DLPFC), areas located very closely to the OFC, the majority of the studies found a higher brain activity, but still reduced reward wanting and liking — as we saw before in studies focussing on the striatum and the OFC.


This result is incredibly interesting and reminds us of how complex the reward processing in our brains is — with closely related brain areas (OFC, mPFC and DLPFC) having opposite brain activity patterns (low activity in OFC versus high activity in mPFC and DLPFC ), but all being involved in reward wanting and liking.


But be aware — further investigations are required as not all studies (although the majority) have confirmed these findings, and so there is still some room for speculation.


Given the brain’s infamous complexity, changes in brain activity associated with anhedonia are likely to be even more complex than what we currently think, and can differ a lot from individual to individual.



So, what do these findings mean for patients?

Understanding alterations in brain activity in patients with anhedonia will allow researchers like us to develop treatments focussed on “rebalancing” these alterations and returning them to a healthy level.


At present there are no treatments able to specifically target anhedonia.


In fact, it is commonly treated alongside the condition that it is part of. For example, individuals with depression and anhedonia often receive antidepressants as treatment.


However, as mentioned above, there is evidence showing that antidepressant treatment is not so effective for anhedonia and, sometimes, it may even worsen the clinical scenario, causing emotional blunting or sexual anhedonia.


This means we have to approach the problem from another angle — a possible therapeutic strategy could be that of targeting other systems.


A working example: we could follow a clue we discussed earlier — that lower brain activity in the striatum is associated with anhedonia in depression via a reduced dopamine system — and develop a treatment that targets such system, ultimately increasing activity in the striatum.


There is already some evidence showing that certain antidepressant-like treatments which target dopamine can reduce anhedonia and normalise brain activity in the striatum of patients with depression.


Also, anesthetic and antidepressant drugs, such as ketamine, are considered for treatment of anhedonia. Trials in rodents show that ketamine decreases anhedonic behaviours and increases the production of glutamate (another neurotransmitter) in the prefrontal cortex of rats.


A more recent study investigated whether ketamine could also have an effect on anhedonia in humans, and the authors concluded that ketamine can reduce anhedonic symptoms, and that this effect is mediated again by the production of glutamate — now added to our list of potential targets for treatment of anhedonia.



What about inflammation?

Not only neurotransmitters, but also other systems may be involved in anhedonia.


One example is inflammation, and particularly inflammatory molecules called cytokines, which are known to cause anhedonia in animal studies, and to be elevated in patients with depression and anhedonia.


I have already discussed in my previous blog about the ability for cytokines to decrease the number of new generated neurons in the brain, and indeed, this may be one of the mechanisms through which inflammation ultimately affects brain structures and circuits involved in anhedonia.


However, the evidence is still in its early stages, and more time and research will tell us whether targeting these neurochemical and molecular systems will become an effective treatment option for anhedonic patients.


But do not despair — tomorrow, or the next day, or the next, something will taste and sound amazing again.


In the meantime, we will continue to relentlessly study new strategies to treat anhedonia in depression, and hopefully, one day, patients will finally regain their ability to enjoy life and to pursue happiness!