Most people think of depression as a problem of mood. In long-standing depression, parts of the brain involved in memory, resilience, and long-term cognitive health can actually begin to shrink. One of the most important of these structures is the hippocampus.
This is not a new or controversial idea. For decades, brain imaging studies have shown that people with depression often have smaller hippocampi.
What is the Hippocampus — and Why Should You Care?
You have two hippocampi — one on each side of your brain.
They play a central role in:
- memory formation
- stress regulation
- emotional stability.
In other words, they are critical to how you think, feel, and adapt. Also, the hippocampi are highly sensitive to stress.
(Image generated by Life Science Databases(LSDB)., CC BY-SA 2.1 JP https://creativecommons.org/licenses/by-sa/2.1/jp/deed.en, via Wikimedia Commons)
Depression Brain Shrinkage
In people with chronic or recurrent depression, the hippocampus is often smaller than expected. This is thought to reflect the cumulative effects of prolonged stress on the brain — including reduced neuroplasticity, weaker connections between neurons, and a loss of structural complexity in this region.
This is not speculation. It has been shown repeatedly in MRI studies. (See the list of references at the end of this post.)
The longer depression persists, and the more episodes a person has, the more likely this shrinkage is to occur.
This matters because reduced hippocampal volume is associated with:
In simple terms, depression can begin to “wear down” the very systems needed for recovery.
The Dementia Connection
The hippocampus is also one of the first regions affected in Alzheimer’s disease.
That does not mean depression causes dementia, but it does mean there is overlap in the brain systems involved. Depression is now recognised as a risk factor for later cognitive decline. One of the likely reasons is its effect on hippocampal integrity over time.
The Important Question
If depression can affect the structure of the brain…
Can those changes be reversed?
The Brain is More Adaptable than we Thought
The hippocampus is one of the few regions in the adult brain capable of neurogenesis — the formation of new neurons.
Certain interventions are known to support this process, including:
- exercise
- enriched environments
- some medications
- and forms of brain stimulation
This brings us to something particularly interesting.
New Evidence: Vagus Nerve Stimulation and the Hippocampus
A small clinical MRI study followed patients with treatment-resistant depression who received vagus nerve stimulation (VNS).
Over 6 to 12 months:
- their depressive symptoms improved
- and their hippocampal volume increased
In other words, structural changes in the brain moved in the opposite direction to what we typically see in chronic depression. This is an early finding, based on a small group of patients, and it requires replication. Nonetheless, it is an important signal.
This result suggests that effective treatment may not only relieve symptoms — it may also support recovery in the underlying brain systems affected by depression.
What This Means Clinically
Depression is not just about “feeling low.” It is a disorder of brain regulation — involving stress systems, inflammation, autonomic balance, and neural networks. When those systems remain dysregulated over time, the effects can become more entrenched.
That is why simply cycling through medications is rarely sufficient in treatment-resistant cases — and additional approaches that support brain regulation and neuroplasticity become important.
(If this sounds familiar, it may be worth exploring a different approach. We’re happy to discuss whether VNS could form part of your treatment plan. Please get in touch.)
Where VNS Fits In
Vagus nerve stimulation works by sending signals from the body to the brain, influencing the very systems involved in:
- emotional regulation
- stress response
- neuroplasticity.
It is not intended as a replacement for other treatments. But for many patients — particularly those who have not responded adequately to medication — it offers a different and biologically grounded approach.
Vagus nerve stimulation is a form of bioelectric neuromodulation — a well-established approach in mainstream medicine that directly influences brain regulation through the body’s own neural pathways. It’s been used in clinical medicine for decades, including for epilepsy and treatment-resistant depression.
Vagus nerve stimulation is not fringe or alternative. The surgically implanted form has been used in mainstream medicine for decades and was FDA-approved for treatment-resistant depression in 2005. At Ormond Neuroscience, we use a newer, non-invasive form that targets the same brainstem pathways via a branch of the vagus nerve in the ear, without the need for surgery.
A Different Way of Thinking About Treatment
At Ormond Neuroscience, we understand depression as a disorder of brain regulation — involving stress systems, inflammation, and neural networks.
Effective treatment is not just about symptom control. It is about restoring the brain’s ability to adapt, stabilise, and recover through neuroplasticity.
If This Sounds Familiar
If you or someone you care about:
- has struggled with depression for a long time
- has tried multiple medications without lasting benefit
- or feels stuck despite treatment
it may be time to consider a different approach.
Contact Ormond Neuroscience to discuss whether vagus nerve stimulation could form part of your treatment plan.
Selected References and Evidence Base
Abbott, C. C., Jones, T., Lemke, N. T., Gallegos, P., McClintock, S. M., Mayer, A. R., Bustillo, J., & Calhoun, V. D. (2014). Hippocampal structural and functional changes associated with electroconvulsive therapy response. Translational Psychiatry, 4(11), e483. https://doi.org/10.1038/tp.2014.124
Bajbouj, M., Merkl, A., Schlaepfer, T. E., Frick, C., Zobel, A., Maier, W., O’Keane, V., Corcoran, C., Adolfsson, R., Trimble, M., Rau, H., Hoff, H.-J., Padberg, F., Müller-Siecheneder, F., Audenaert, K., van den Abbeele, D., Matthews, K., Christmas, D., Eljamel, S., & Heuser, I. (2010). Two-year outcome of vagus nerve stimulation in treatment-resistant depression. Journal of Clinical Psychopharmacology, 30(3), 273–281. https://doi.org/10.1097/JCP.0b013e3181db8831
Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G. M. (2004). Lower hippocampal volume in patients suffering from depression: A meta-analysis. American Journal of Psychiatry, 161(4), 598–607. https://doi.org/10.1176/appi.ajp.161.4.598
Frodl, T., Meisenzahl, E. M., Zetzsche, T., Born, C., Jäger, M., Groll, C., Leinsinger, G., Bottlender, R., Hahn, K., & Möller, H. J. (2004). Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. Journal of Clinical Psychiatry, 65(4), 492–499. https://psycnet.apa.org/record/2004-14374-007
Gould, E., Tanapat, P., McEwen, B. S., Flügge, G., & Fuchs, E. (1998). Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences, 95(6), 3168–3171. https://doi.org/10.1073/pnas.95.6.3168
Kempton, M. J., Salvador, Z., Munafò, M. R., Geddes, J. R., Simmons, A., Frangou, S., & Williams, S. C. R. (2011). Structural neuroimaging studies in major depressive disorder: Meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry, 68(7), 675–690. https://doi.org/10.1001/archgenpsychiatry.2011.60
Kraus, C., Kadriu, B., Lanzenberger, R., Zarate, C. A., Jr., & Kasper, S. (2019). Prognosis and improved outcomes in major depression: A review. Translational Psychiatry, 9, 127. https://doi.org/10.1038/s41398-019-0460-3
MacQueen, G., & Frodl, T. (2011). The hippocampus in major depression: Evidence for the convergence of the bench and bedside in psychiatric research? Molecular Psychiatry, 16(3), 252–264. https://doi.org/10.1038/mp.2010.80
McKinnon, M. C., Yucel, K., Nazarov, A., & MacQueen, G. M. (2009). A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. Journal of Psychiatry & Neuroscience, 34(1), 41–54. https://psycnet.apa.org/record/2008-19181-005
Monereo-Sánchez, J., Jansen, J. F. A., van Boxtel, M. P. J., Backes, W. H., Köhler, S., Stehouwer, C. D. A., Linden, D. E. J., & Schram, M. T. (2024). Association of hippocampal subfield volumes with prevalence, course and incidence of depressive symptoms: The Maastricht Study. The British Journal of Psychiatry, 224(2), 54–63. https://doi.org/10.1192/bjp.2023.143
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Weyand, A. M., Cordes, N., Linka, L., Strehlau, S., Tsalouchidou, P.-E., Carl, B., Gjorgjevsky, M., Grote, A., Nimsky, C., Möller, L., Habermehl, L., Zahnert, F., Strzelczyk, A., Rosenow, F., Münchberger, C., Hakel, L., Menzler, K., Immisch, I., Krause, K., & Knake, S. (2026). Long-term effects of invasive and transcutaneous vagus nerve stimulation in patients with epilepsy: A retrospective cohort study. Clinical Epileptology, 39, 145–153. https://doi.org/10.1007/s10309-025-00797-7
