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Neuropsychiatric Manifestations in Bartonella spp. and Borrelia burgdorferi sensu lato Infections: Hypotheses for Behavioral Dysregulation, Immune-Mediated Neuroinflammatory Pathology and the Cultural Phenomenon of Aggressive Zombie Imagery
Introduction
Infections caused by the intracellular bacteria Bartonella spp. and the Borrelia burgdorferi sensu lato complex are attracting increasing scientific interest due to their ability to induce a complex neuroinflammatory reaction, which can lead to significant alterations in mental functioning. Within recent decades, accumulating clinical observations and research in the field of neuroimmunology demonstrate that certain chronically persisting infectious agents are capable of modifying cognitive processes, affective regulation, and behavioral patterns. This trend lays the foundation for a serious scientific discussion regarding the mechanisms through which infectious diseases can contribute to the etiopathogenesis of impulsivity, irritability, aggressive disinhibition, and other impairments of emotional control.
Bacteria of the genus Bartonella are Gram-negative, intracellular pathogens with a pronounced tropism for endothelial cells and erythrocytes, which enables the formation of persistent infectious foci within the vascular system. From a neurobiological perspective, the greatest interest is aroused by the ability of Bartonella spp. to induce a cascade of immune reactions leading to microvascular damage, impaired cerebral perfusion, and activation of microglia. Microglial cells, as the primary regulators of immune activity in the central nervous system, produce a broad spectrum of inflammatory mediators, including interleukin-1β, interleukin-6, and tumor necrosis factor-alpha (TNF-α). These molecules possess the ability to influence neuronal excitability, alter the metabolism of serotonin and dopamine, and modify the activity of neural networks responsible for emotional regulation. At the clinical level, such alterations can manifest as heightened irritability, sudden episodes of anger, a diminished capacity for impulse control, and significant affective lability. These phenomena are sometimes described in the English-language literature with the informal term "Bartonella Rage," which denotes severe behavioral destabilization in the context of infection with Bartonella spp. The term does not represent an official nosological entity, but the described clinical characteristics merit serious attention from the standpoint of the neuroimmune mechanisms underlying them.
Borrelia burgdorferi sensu lato, the causative agent of Lyme disease, is another pathogen that is frequently associated with neurological and psychiatric manifestations. Neuroborreliosis is an established clinical condition and can affect both the peripheral and central nervous systems. Increasing evidence indicates that prolonged infection can lead to dysregulation of limbic structures and prefrontal cortical areas. These zones are crucial for the integration of emotional stimuli, decision-making, and social behavior. When their function is impaired as a result of immunological stress, inflammatory activity, or dysregulation of neurotransmitters, symptoms such as anxiety, affective instability, irritability, and episodes of anger dysregulation can appear. Some clinicians and researchers use the popular term "Lyme Rage" to denote precisely these episodes of acute anger and behavioral disinhibition in patients with Lyme disease. Although the term lacks official status in medical nomenclature, the interest in it stems from the need to explain certain clinical observations that cannot be reduced solely to psychological factors and require an integrative neuroimmunological approach.
The Behavioral Modification Paradigm: From Pathogens in Nature to the Zombie Archetype
When examining the phenomena of aggression and behavioral destabilization, one cannot overlook the fact that numerous infectious agents in nature possess the ability to alter the behavior of their hosts. A classic example is the rabies virus, which in the terminal phase of the disease leads to hyperactivity, aggressiveness, disturbances in consciousness, and disorganized behavior. Another well-studied example is Toxoplasma gondii, which in animal models alters the response to risk stimuli and modifies fear and impulsivity. These biological examples demonstrate that pathogens can have a strong impact on the nervous system and consequently influence behavior.
It is precisely this line of reasoning that leads to the interesting cultural parallel between infectious-induced behavioral change and the image of the aggressive zombie in popular culture. Zombies are a fictional construct, but their behavioral characteristics often include loss of cognitive control, the destruction of social behavior, and strongly expressed aggressiveness. These elements have their scientific equivalent in certain clinical conditions, including severe encephalitis, infection-induced psychotic episodes, and immune-mediated impairments of limbic regulatory networks. Of course, the artistic image is hyperbolic and does not reflect the real pathophysiological mechanisms, but the idea that infectious agents can modify behavior is deeply rooted in scientific literature long before the emergence of the modern zombie genre.
Core Neuroimmunological Mechanisms: Chronic Microglial Activation and Its Impact on Key Brain Structures
The neuroimmunological mechanisms through which infections with Bartonella spp. and Borrelia burgdorferi sensu lato can lead to significant behavioral changes represent one of the most intensively studied aspects of contemporary infectious neurobiology. In recent years, it has been established that the interaction between pathogens and the immune system of the central nervous system is a multi-layered process, encompassing both direct impact on nervous tissue and indirect effects mediated by inflammatory mediators. At the foundation of this pathophysiology lies prolonged microglial activation. Microglia constitute a vital component of neuroimmune integration and, under normal conditions, perform the role of a sensory system that detects pathogenic signals, damaged neurotissue, and imbalances in neurochemistry. When a pathogen, be it Bartonella or Borrelia, persists in the organism for a prolonged period, microglia transition into a chronically activated state. This leads to the release of inflammatory cytokines, which can remodel synaptic connections, increase neuronal excitability, and disrupt fine neurotransmitter regulation.
This process affects primarily the limbic structures, among which the amygdala and hippocampus are particularly sensitive to inflammatory mediators. The amygdala, as a center for threat processing and a generator of emotional reactions, can become hyperactive under prolonged cytokine exposure. This, in clinical terms, is associated with heightened irritability, easier provocation of angry outbursts, and intensified impulsivity. The hippocampus, which participates in the regulation of memory, emotional stability, and control of the stress response, can also be affected by inflammatory processes, leading to impairments in emotional integration and worsened cognitive judgment. In some patients, a combination of these mechanisms is observed, which explains the emergence of episodes popularly described as Bartonella Rage and Lyme Rage, even though these terms remain informal.
The Role of Prefrontal Cortex Dysfunction: Impairment of Top-Down Control
Dysfunction of the prefrontal cortex, which under normal conditions performs the task of moderating and suppressing impulsive reactions, can also be a result of prolonged neuroinflammatory activity. The prefrontal cortex is exceptionally rich in receptors for inflammatory mediators, and under conditions of chronic immune stress, its regulatory functions weaken. The clinical consequences include a diminished ability to inhibit anger, impaired social behavior, a sharp decline in stress tolerance, and an inability to maintain emotional homeostasis. This explains why some patients with Lyme disease or bartonellosis describe a sudden change in their character, the emergence of uncharacteristic aggressiveness, or a lack of their usual self-control. Such manifestations are often mistakenly viewed as purely psychological phenomena, but accumulating neurobiological data show that they are frequently the result of real pathophysiological dysfunction.
Phenomenological Validity: The Analytical Utility of "Lyme Rage" and "Bartonella Rage"
In this context, it is important to analyze the question of the validity of the terms Lyme Rage and Bartonella Rage. Although they do not represent official medical diagnoses, they emerge as phenomenological descriptions of real clinical conditions observed by physicians, patients, and researchers. The use of these terms is an attempt to designate a specific behavioral phenotype characterized by acute emotional lability, sudden outbursts of anger, severely reduced frustration tolerance, and diverse impulsive reactions. The scientific validity of these terms should not be sought in their officialization, but in their ability to create a starting point for investigating the neuroimmune processes that stand at the foundation of the described behavioral phenomena. This allows for structuring hypotheses, formulating diagnostic criteria, and developing methods for therapeutic intervention that address not only the symptoms but also the underlying biological mechanism.
Differential Diagnosis and Integrative Assessment
From the perspective of differential diagnosis, these behavioral changes must be examined with pronounced care. Numerous psychiatric conditions, including bipolar disorder, post-traumatic stress disorder, schizoaffective states, and impulse control disorders, present a similar clinical picture. This necessitates a comprehensive approach that integrates infectious history, neuroimaging methods, laboratory markers for neuroinflammation, and psychometric measurements. Neuroimaging, including magnetic resonance spectroscopy, functional magnetic resonance imaging, and positron emission tomography, provides the opportunity to visualize the alterations in brain activity characteristic of chronic microglial activation and to trace the correlation between the burden of neuroinflammation and clinical symptomatology. Data from such studies support the idea that infections with Borrelia and Bartonella can lead to structural and functional changes in brain regions involved in emotional regulation and social behavior.
The Zombie Motif: Between Pop Culture and Scientific Precedent
Against this backdrop, the parallel with the pop-cultural image of the aggressive zombie acquires an unexpected scientific dimension. Although artistic interpretations exaggerate and hyperbolize real biological processes, the idea of an infection that changes the behavior of its host has deep roots in biology and medicine. The aggressive zombie in cinema is often characterized by loss of cognitive control, the collapse of moral and social norms, and dominant, destructive behavior. This triad, in its artistic form, is reminiscent of the clinical manifestations of certain neuroinfections, albeit in a significantly more dramatized form. The rabies virus, for example, demonstrates that it is biologically possible for a pathogen to induce a state of hyperaggressiveness, motor hyperactivity, and behavioral disorganization. In this sense, the zombie motif, though artistic, draws inspiration from real biological phenomena observed in nature.
Epidemiological Considerations and the Challenge of Subclinical Infection
From an epidemiological aspect, it is important to emphasize that the early recognition of infectious diseases associated with neurodevelopmental disorders depends to a significant degree on knowledge of the seasonality, distribution, and specific characteristics of each causative agent. Viral agents, such as cytomegalovirus, affect a significant portion of pregnant women, often without clinical manifestations, yet they can still cause severe damage to the fetus. Similar subclinical progression is observed with several bacterial infections, including chlamydial and mycoplasmal diseases, which frequently remain undiagnosed or are mistaken for banal respiratory conditions. It is precisely this invisible presence of pathogens in the population that creates the preconditions for chronic, persistent processes which mark the beginning of long-term neuroimmune disturbances.
Manifestations in Pediatric Populations: A Multifaceted and Deceptive Clinical Picture
The clinical manifestation of these diseases in children is multifaceted and often misleading. In early childhood, symptoms may be limited to non-specific manifestations such as easy irritability, sleep disturbances, episodic regression of skills, or short-term behavioral changes, the infectious origin of which parents do not suspect. Concurrently, discrete neurological symptoms such as tremor, hypotonia, or disturbances in the sucking and swallowing reflex may remain unnoticed or be misinterpreted as variations of normal development. As age advances, the neurodevelopmental pathology manifests more distinctly, but the link to the primary infection is already difficult to trace, especially when early diagnostic data are lacking.
Immunological Basis for Long-Term Neurodevelopmental Impact
From an immunological standpoint, the chronic persistence of infectious agents creates conditions for prolonged activation of the innate and adaptive mechanisms of the immune system. In many children, this leads to a phenomenon of low-grade but constant systemic inflammation, which impacts brain tissue, creating a background for impaired synaptic plasticity, delayed myelination, and dysregulation of neurotransmitter systems. Microglial cells, which play a key role in the normal maturation of brain networks, are particularly sensitive. When they are maintained in an activated state due to the prolonged presence of microbial antigens, their function changes from supportive to destructive, which contributes to the formation of pathological neural connections and persistent behavioral manifestations.
Conclusion: Infectious Diseases as Modulators of Neurological Development
In this context, it becomes clear that infectious diseases are not merely episodic events in a child's life, but potential modulators of their neurological development. The consequences of these infections can manifest years after the acute infection has subsided, often in the form of impairments in social communication, delayed language development, stereotypical behavior, or deficits in executive functions. This mandates an integrated approach to diagnosis and treatment, in which pediatricians, infectious disease specialists, neurologists, and child development specialists work collaboratively for the early recognition of risk factors and timely intervention.
Diagnostic Challenges and the Search for a Biological Footprint
The diagnostic process when infection-induced neurodevelopmental disorders are suspected requires particular precision, as it is often necessary to search for traces of past or chronically persisting infections that no longer manifest clinically. Serological studies play an important role, but their interpretation is not always unambiguous. The presence of specific IgG antibodies may indicate a past infection, but does not provide information on whether the microorganism continues to be present in the organism or has caused structural damage during critical phases of neuronal development. Greater informativeness is provided by tests aimed at detecting active viral replication or bacterial persistence, including PCR analyses and determination of antigen presence in blood, cerebrospinal fluid, or other biological materials. However, a negative result can never completely rule out an infectious etiology, especially with pathogens that hide within tissues or enter a latent state.
Synthesis: Infectious Agents as Underestimated Etiopathogenic Factors
In conclusion, it becomes clear that infectious agents such as Borrelia burgdorferi sensu lato, Bartonella henselae, Bartonella quintana, and several intracellular pathogens represent an underestimated factor in the etiopathogenesis of certain mental, cognitive, and behavioral disorders. Although classical neuroinfections are typically associated with acute neuropathology, contemporary data outline a significantly more complex picture, in which chronically persisting microorganisms can sustain low-intensity inflammatory cycles in nervous tissue or the immune system. This type of covert yet prolonged impact is often not recognized promptly, and its subclinical manifestations are sometimes interpreted as purely psychiatric phenomena, disconnected from the biological basis that generates them. When aggressive episodes, impulsivity, or dissociative states are viewed solely through the prism of psychiatric nomenclature, this not only hinders accurate diagnosis but also limits opportunities for etiological treatment.
"Lyme Rage" and "Bartonella Rage": From Informal Terms to Analytical Frameworks
The concepts of Lyme rage and Bartonella rage, although still not part of formalized nosological systems, are gradually transforming into analytical frameworks through which clinicians and researchers can discuss observed neuro-aggressive phenotypes arising against a background of systemic infections. These terms function not as sensational descriptions, but as designations for a complex of neurobiological alterations in which inflammatory mediators, microangiopathic damage, and glial dysfunctions intertwine into a clinically visible behavioral expression. It is precisely in this context that the idea of zombification, dominant in popular culture, acquires metaphorical value. The aggressive, disorganized, impulsive, and sometimes hyperaroused model prominent in cinema is not a literal parallel, but it reflects an intuitive judgment of human societies regarding how certain pathological processes can disrupt the integrity of the personality and control over behavior. Although artistically exaggerated, these motifs often find roots in real biological phenomena, including infection-influenced changes in limbic networks and prefrontal regulation of affect.
Clinical and Therapeutic Implications: Towards an Interdisciplinary Paradigm
From a clinical standpoint, this necessitates a reevaluation of the traditional boundaries between infectious, immunological, and psychiatric disciplines. Modern neuroscience shows that mental health cannot be considered a separate domain, independent of somatic pathology. The body and brain function as an integrated biological system in which persistent pathogens or chronic inflammatory processes can cause dysfunction of neural networks regulating behavior. Herein, an infectious etiology does not negate the psychiatric dimension but places it within its biological context, allowing for the development of more complex and multi-layered therapeutic strategies that combine anti-infective agents, immunomodulatory approaches, and psychotherapeutic intervention.
The final and most important conclusion is that the scientific and clinical community must perceive infectious factors not as isolated medical curiosities, but as potentially substantial elements in understanding psychopathology. This requires expanding diagnostic algorithms, more active use of molecular methods, attention to subclinical symptomatic clusters, and flexibility in interpreting clinical phenomena. Only through such an interdisciplinary approach can adequate recognition and treatment of conditions be achieved, in which infectious biology, immune regulation, and mental function intertwine in a complex pathophysiological network.
Future Research Directions and Ethical Considerations
The prospects for future research in the field of infection-determined psychopathology require a significant expansion of the methodological arsenal. A primary necessity is the development of highly sensitive techniques for detecting low-level persistent pathogens, especially those with intracellular tropism like Borrelia and Bartonella. A new generation of molecular analyses, including metagenomic sequencing, single-cell transcriptomic profiling, and spatial molecular cartography methods, allows for more precise mapping of the interactions between microorganisms and neuroglial components. These technologies can reveal not only the presence of pathogens but also their functional activity and their influence on neuroimmune axes, including the role of microglia, astrocytic reactivity, and dysregulated synaptic plasticity. In such a context, it becomes possible to trace how individual infectious micro-events integrate into a long-term pathological trajectory leading to alterations in behavior and cognitive function.
The public health implications of this type of knowledge are significant. If the broader role of chronic infections in the etiology of certain mental and behavioral disorders is confirmed, this would require the adaptation of national and international protocols for screening, early diagnosis, and prevention. Such an approach could transform the way children are monitored in high-risk areas with substantial vector activity, as well as stimulate earlier and more aggressive treatment of diagnostically uncertain conditions with inflammatory or neurological characteristics. From a public health perspective, this creates an opportunity to reduce the long-term burden of chronic cognitive and behavioral problems, which are currently often interpreted as idiopathic or entirely psychogenic.
Significant, too, is the ethical aspect related to the possibility of infectious biology being misused as an explanatory model for stigmatizing or pathologizing individuals with certain mental symptoms. Here, a clear distinction is necessary between the scientific understanding of biological mechanisms and the socio-cultural interpretations that may accompany them. A scientifically accurate framework for infectious influences on the psyche must be formulated so as not to undermine human dignity and autonomy. Instead, it should serve as a means of reducing stigma by emphasizing the biological, treatable, and potentially reversible aspects of these conditions.
When such knowledge is integrated into clinical practice, it opens possibilities for developing personalized therapeutic strategies. The concept of precision medicine acquires new meaning in the context of infection-associated mental disorders, where the presence or absence of a given pathogen may determine the most effective therapeutic combination. In the future, comprehensive clinical protocols will likely become necessary, assessing microbiological status, immunological profile, neuroimaging markers, and behavioral characteristics as interconnected elements in a holistic diagnosis. Such a model would replace reductionist approaches that isolate psychiatric symptoms from their biological determinants.
Ultimately, the endeavor to integrate infectious factors into the understanding of mental disorders does not represent a rejection of existing knowledge, but rather its expansion. This is a movement towards a more complete, comprehensive, and scientifically consistent description of the human mind as a product of complex interactions between biology, environment, and external pathogenic influences. This movement requires the courage to ask questions that until recently were considered marginal, and the scientific discipline to formulate answers based on rigorous methodology and interdisciplinary collaboration.
Sources
- Neuropsychiatric Manifestations of Lyme Disease: A Literature Review of Psychiatric and Cognitive Impacts, doi: 10.15388/Amed.2025.32.1.17
- Neuropsychiatric Manifestations and Cognitive Decline in Patients With Long-Standing Lyme Disease: A Scoping Review, doi: 10.7759/cureus.58308
- Neurobartonelloses: emerging from obscurity!, doi: 10.1186/s13071-024-06491-3
- Bartonella henselae and Borrelia burgdorferi infections of the central nervous system, doi: 10.1111/j.1749-6632.2003.tb07400.x.
- Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioural, Psychiatric, Autoimmune and Fatiguing Illnesses, Garth L. Nicolson and Jörg Haier, BJMP 2010;3(1):301
- Bartonella species bacteremia in association with adult psychosis, doi: 10.3389/fpsyt.2024.1388442
- Concurrent infection of the central nervous system by Borrelia burgdorferi and Bartonella henselae: evidence for a novel tick-borne disease complex, doi: 10.1001/archneur.58.9.1357
- Do Bartonella Infections Cause Agitation, Panic Disorder, and Treatment-Resistant Depression?, PMCID: PMC2100128 PMID: 18092060
- Bartonella sp. Bacteremia in Patients with Neurological and Neurocognitive Dysfunction, doi: 10.1128/jcm.00832-08
- The FGF/FGFR system in the microglial neuroinflammation with Borrelia burgdorferi: likely intersectionality with other neurological conditions, doi: 10.1186/s12974-022-02681-x
- A key protein from Borrelia burgdorferi could stimulate cytokines in human microglial cells and inhibitory effects of Cucurbitacin IIa, doi: 10.1016/j.ibneur.2023.11.004