Beyond respiratory symptoms, SARS-CoV-2 reveals its capacity to invade and disrupt the human nervous system, with implications for both acute illness and long-term health.
When COVID-19 emerged, it was characterized as a respiratory disease. Yet, as case numbers grew, doctors worldwide began noticing something puzzling: patients were reporting lost senses of smell and taste, debilitating headaches, crippling brain fog, and even strokes. The medical community soon realized that SARS-CoV-2, the virus behind the pandemic, was not just attacking lungs—it was invading and affecting the human nervous system 1 .
This discovery opened a new frontier in our understanding of the virus, revealing its ability to impact our most complex organ—the brain. Through this article, we'll explore the fascinating and concerning neurological manifestations of COVID-19, examining both immediate symptoms and the lingering condition known as "long COVID," and delve into the scientific detective work uncovering how the virus affects our nervous system.
During active COVID-19 infection, a diverse array of neurological symptoms can appear, sometimes even before respiratory issues. These acute manifestations represent the body's immediate response to the viral invasion and associated inflammation.
Common acute neurological symptoms include headaches, dizziness, muscle pain, and the distinctive loss of smell (anosmia) or taste (ageusia) 1 6 . These sensory losses often occur early in infection and result from the virus targeting nerve pathways related to smell.
More alarmingly, COVID-19 can cause severe neurological conditions such as strokes, seizures, and inflammation of the brain (encephalitis) , particularly in vulnerable individuals. The virus also appears to increase the risk of Guillain-Barré syndrome, where the immune system attacks the nerves, potentially leading to weakness and paralysis .
For a significant number of people, neurological symptoms persist well beyond the initial infection, sometimes for months or years. This condition, known as "long COVID," presents an ongoing challenge for patients and healthcare systems worldwide 1 .
The symptoms of long COVID are not only diverse but often fluctuate, with patients reporting relapses triggered by physical activity, stress, or mental exertion 4 . This unpredictable pattern complicates both treatment and patients' ability to return to normal daily activities.
Did you know? Up to 56% of severe COVID-19 cases report persistent fatigue at 12 months post-infection, making it the most common neurocognitive complaint in long COVID.
| Symptom | Prevalence Range | Key Characteristics |
|---|---|---|
| Fatigue | Up to 56% (severe cases) | Predominant neurocognitive complaint, often worsened by physical exertion |
| Anxiety | 3.5% - 29% | More prevalent than depression in long COVID |
| Depression | 3.5% - 26% | Persistent low mood affecting quality of life |
| Olfactory Dysfunction | 0.9% - 51% | Partial or complete loss of smell, sometimes persistent |
| Memory Impairment | Variable | "Brain fog," difficulty recalling information |
| Sleep Difficulties | Nearly 50% | Insomnia, disrupted sleep patterns |
SARS-CoV-2 employs several sophisticated pathways to access the nervous system, exploiting natural biological structures to reach the brain 5 .
The virus can infect sustentacular cells in the olfactory mucosa, then travel along the olfactory nerve (cranial nerve I) into the brain 5 . This pathway provides almost direct access from the nose to the brain and explains the high frequency of smell disturbances.
The virus can enter the bloodstream (viremia) and cross protective barriers like the blood-brain barrier (BBB) or blood-cerebrospinal fluid barrier (B-CSFB) 5 . It may infect endothelial cells lining blood vessels or use infected immune cells as a "Trojan horse" to gain entry 9 .
Evidence suggests the virus may use additional cranial nerves, including the trigeminal (CN V) and vagus nerves (CN X), which innervate the respiratory tract and could provide additional entry points 5 .
Once inside the nervous system, SARS-CoV-2 demonstrates both neurotropism (ability to infect nervous system cells) and neurovirulence (capacity to cause disease within the nervous system) 5 .
The virus primarily targets cells expressing ACE2 receptors, including cortical neurons and support cells 3 .
Infection triggers widespread inflammation, oxidative stress, and disruption of normal calcium regulation in brain cells 4 .
These disturbances can lead to the hyperphosphorylation of tau protein, a pathological process also seen in Alzheimer's disease 4 .
The tau protein pathology potentially explains the cognitive deficits observed in many long COVID patients 4 .
To understand exactly how SARS-CoV-2 affects brain function, researchers have conducted innovative experiments using animal models. One particularly illuminating 2025 study published in Communications Biology examined how virus-like particles (VLPs)—non-infectious replicas of SARS-CoV-2—affect neuronal activity in mouse brains 8 .
The research team designed a comprehensive experiment to track brain activity changes before and after VLP exposure:
The results revealed significant, lasting disruptions in brain activity patterns following VLP exposure:
| Activity Metric | Short-Term Effect | Long-Term Effect | Genotype Differences |
|---|---|---|---|
| Stimulus-Evoked Response | Increased by 105-200% | Partially subsided but did not return to baseline | More pronounced in human tau mice |
| Spontaneous Firing | Substantially increased | Remained elevated | Human tau mice showed higher vulnerability |
| Fraction of Tuned Neurons | Increased by 30-80% | Partial recovery | More significant changes in human tau mice |
Understanding COVID-19's effects on the nervous system requires diverse experimental approaches and model systems. Each tool offers unique advantages for answering specific questions about the virus's behavior.
| Research Tool | Primary Function | Key Advantages |
|---|---|---|
| Virus-Like Particles (VLPs) | Study viral protein effects without infectious virus | Enable research outside BSL-3 facilities; isolate protein effects from replication |
| hACE2 Transgenic Mice | Model human-like SARS-CoV-2 infection in rodents | Express human ACE2 receptors, making them susceptible to infection |
| Golden Hamsters | Study transmission, lung effects, and symptoms | Naturally susceptible; display similar symptoms to humans |
| Non-Human Primates | Test vaccine efficacy and protection | Similar immune system to humans; critical for preclinical trials |
| Human Brain Organoids | Model human neuronal infection in 3D cell cultures | Derived from human stem cells; mimic human brain development |
| Two-Photon Microscopy | Monitor neuronal activity in live animals | Enables longitudinal tracking of brain activity in the same subject |
Research Impact: These research tools have been instrumental in advancing our understanding of how SARS-CoV-2 affects the nervous system. For instance, animal models have demonstrated that SARS-CoV-2 can indeed invade the brain via the olfactory nerve and other routes 5 , while human brain organoids have revealed that infection triggers aberrant phosphorylation of tau protein 4 —a finding that connects COVID-19 to known neurodegenerative pathways.
The neurological manifestations of COVID-19, both acute and long-term, represent a significant and ongoing challenge to global health. The virus's ability to invade the nervous system through multiple routes and disrupt normal brain function has resulted in a spectrum of symptoms ranging from temporary sensory disturbances to persistent cognitive impairment. Research has made substantial progress in unraveling how SARS-CoV-2 accesses and affects the nervous system, with studies revealing that even viral proteins alone can significantly disrupt neuronal activity patterns, particularly in vulnerable individuals.
The exploration of COVID-19's impact on the nervous system stands as a powerful reminder of the interconnectedness of our bodily systems and the importance of considering neurological health in pandemic response. While much has been learned, the ongoing research continues to uncover new insights that will hopefully lead to more effective treatments for those suffering from the neurological consequences of this virus.