“I am really very, very tired of everything – more than tired.” Friedrich Nietzsche
“There are wounds that never show on the body that are deeper and more hurtful than anything that bleeds.” Laurell K. Hamilton
Anhedonia and Parkinson’s: Anhedonia is a non-motor-related problem in Parkinson’s. It is a core symptom of depression in Parkinson’s patients. Furthermore, it is typically under-diagnosed, which is a cause for concern. Anhedonia describes a diminished ability to experience joy and pleasure, and is thought to affect 5–46% of patients with Parkinson’s. It is not only found in those with Parkinson’s but also in other disorders like schizophrenia and other neurological and psychological conditions. Thus, anhedonia is an essential component of depression that is poorly understood, not easily treated, and remains an important unsolved mystery. Â
“I think I’m afraid of being happy because whenever I get too happy something bad always happens.” Charles M. Schulz
The Current Research Article to Understand the Neurological Pattern of Anhedonia: The paper reported here is a tour de force work of scientific genius and cutting-edge use of modern technology and science. The citation for the paper is: Xia F, Fascianelli V, Vishwakarma N, Ghinger FG, Kwon A, Gergues MM, Lalani LK, Fusi S, Kheirbek MA. Understanding the neural code of stress to control anhedonia. Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08241-y. Epub ahead of print. PMID: 39633053. Here is a link to the paper: https://rdcu.be/d2E0X. The paper is over 30 pages in length, and most figures have 5-7 inserted parts of the figure, which partly indicates the depth and thoroughness of the work presented.
“I’m tired of pretending that everything’s fine just so I can please everyone else.” Spencer Tracy
The Brain Signature of Stress that Leads to Anhedonia: In collaboration with Dr. Mazen Kheirbek, scientists studied how the brain promotes anhedonia using a model system with mice. It is well known that mice prefer sugar water over plain water when given a choice. The overall aim was to study mice under a stressful situation by exposing them to larger and more aggressive mice. Interestingly, some of the test mice preferred plain water. The researchers interpreted this as a mouse version of anhedonia. The researchers also found that some mice still preferred the sugar water, and they decided that these mice were resilient to the stress. Next, the researchers studied the neurons in the amygdala and hippocampus, which are important brain regions for our emotions, using the mice deciding to drink either plain water or sugar water.
“Depression isn’t just being a bit sad. It’s feeling nothing. It’s not wanting to be alive anymore.” J. K. Rowling
Processing the Reward of Sugar Water in the Resilient Brain: The researchers found that the resilient mice showed strong communication processes between the hippocampus and amygdala. By contrast, the mice assumed to have anhedonia revealed a more fragmented or disconnected link between these two brain regions. They then injected the susceptible mice with substances that caused neurons to fire more frequently to improve the communication link. The technique used by these researchers is called chemogenetics, where they used artificial molecules to make the hippocampus and amygdala fire more often. Following this procedure, these susceptible mice opted for sugar water over plain water. This experiment showed that the response to stress shown in the susceptible mice could be rescued and their behavior reversed by manipulating the link between the amygdala and hippocampus. Ultimately, the brain signatures of these susceptible mice treated with chemogenetic stimulation now show brain activity similar to those of the resistant mice. Â
“I am really very, very tired of everything – more than tired.” Friedrich Nietzsche
Amygdala and Hippocampus: The results of this study revealed distinct neural signatures in the resilient mice and those mice susceptible to stress. In an important step forward, they successfully altered and modified the signature profile of the mice identified to have anhedonia by targeted modulation of the neurons firing in the amygdala and hippocampus. The results of this study showed that resilient mice process information about rewards differently than the mice that were susceptible to stress-induced anhedonia. These results also demonstrate that the same stored material for reward is intact in the stressed mice. There may be different steps in deciphering how the mice retain the ability to seek the reward (sugar water) and the other direction by the stress-susceptible mice following the pathway to plain water and anhedonia. Remarkably, stimulating the neurons in the amygdala and hippocampus disrupted this dominant intention in the stressed mice and allowed them to seek the reward of sugar water.
“You don’t have to control your thoughts; you just have to stop letting them control you.” Dan Millman
Where Does Dopamine Come Into This Story? The brain is a complex and intricate organ, which suggests that multiple regions of the brain share the burden of dealing with the response to stress. The results here contribute a new avenue to explore for understanding and treating anhedonia and depression. Previous work has implicated a dysfunction in dopaminergic neuron systems in chronic stress and depression and is highlighted by the following study. Again, in a mouse model of “social-defeat stress-induced depression,” the resilient mice showed regular dopaminergic neuronal activity in the ventral tegmental area (thought to be a critical brain region involved in depression). When the susceptible mice (i.e., the depressed mice) were challenged experimentally into hyper-polarization, the changes in dopaminergic neurons were able to reverse the depression-related actions. These studies highlighted in this blog post broaden the complexity of brain circuits needed to navigate an ocean of challenges. The current work highlights a new target for neuromodulation, specifically the amygdala and hippocampus, in the future of treating stress-induced disorders like anhedonia.
“Every day begins with an act of courage and hope: getting out of bed.” Mason Cooley
Importance of this Study: The results of this study showed that resistance to stress is partly dependent on the signals transmitted between the hippocampus and amygdala. The results showed that stimulating the neuronal activity reversed the stress-induced effect in the susceptible mice. If this type of response could be studied and verified in humans, it opens up the notion that we could be treating depression by targeting the circuits of the brain. Translational research is focused on bridging the laboratory bench to the clinic setting dealing with and treating human patients. The researchers are now exploring ways to change brain patterns as a way to treat anhedonia. Thus, this is truly an exciting new avenue of hope in treating and understanding how the brain reacts to stress and our attempt to find effective treatment procedures that can reverse the detrimental effects of anhedonia and depression.
“If you know someone who’s depressed, please resolve never to ask them why. Depression isn’t a straightforward response to a bad situation; depression just is, like the weather. Try to understand the blackness, lethargy, hopelessness, and loneliness they’re going through. Be there for them when they come through the other side. It’s hard to be a friend to someone who’s depressed, but it is one of the kindest, noblest, and best things you will ever do.” Stephen Fry
Helpful References:
Loas, Gwenolé, Cécile Duru, Olivier Godefroy, and Pierre Krystkowiak. “Hedonic deficits in Parkinson’s disease: is consummatory anhedonia specific?.” Frontiers in neurology 5 (2014): 24.
Loas, Gwenolé, Pierre Krystkowiak, and Olivier Godefroy. “Anhedonia in Parkinson’s disease: an overview.” The Journal of neuropsychiatry and clinical neurosciences 24, no. 4 (2012): 444-451.
El-Mansoury, Bilal, Abdelaati El Khiat, Ayyoub Skaou, Omar El Hiba, Arumugam R. Jayakumar, Youssef Ait Hamdan, Abdelali Bitar, and Abdesslam Ferssiwi. “Non-motor symptoms of Parkinson’s disease.” In Essential Guide to Neurodegenerative Disorders, pp. 269-280. Academic Press, 2025.
Tiwari, Vishnu, and Feras Alkharboush. “Management of Apathy in Parkinson’s Disease: A Scoping Review.” The American Journal of Geriatric Psychiatry 32, no. 4 (2024): S69.
Houeto, Jean-Luc, Robin Magnard, Jeffrey W. Dalley, David Belin, and Sebastien Carnicella. “Trait impulsivity and anhedonia: two gateways for the development of impulse control disorders in Parkinson’s disease?.” Frontiers in psychiatry 7 (2016): 91.
Pizzagalli, Diego A. “Depression, stress, and anhedonia: toward a synthesis and integrated model.” Annual review of clinical psychology 10, no. 1 (2014): 393-423.
Chaudhury, Dipesh, Jessica J. Walsh, Allyson K. Friedman, Barbara Juarez, Stacy M. Ku, Ja Wook Koo, Deveroux Ferguson et al. “Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.” Nature 493, no. 7433 (2013): 532-536.
Friedman, Allyson K., Jessica J. Walsh, Barbara Juarez, Stacy M. Ku, Dipesh Chaudhury, Jing Wang, Xianting Li et al. “Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience.” Science 344, no. 6181 (2014): 313-319.
Cover Photo Image by holgerheinze0 from Pixabay
Journey with Parkinson's 