Childhood brain disorders can lead to adult psychiatric disorders

Brazilian researchers have conducted a comprehensive study of the effects of seizures during development. The findings could lead to new treatments for autism, attention deficit disorder, schizophrenia and epilepsy.

By José Tadeu Arantes  |  Agência FAPESP – The first years of life are crucial for the proper development and maturation of the brain. Brain disorders during this period, such as injury, infection, stress or malnutrition, can have a profound effect on brain function and behavior throughout life. Seizures are the most common neurological event at this age and are significant risk factors for the onset of neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder (ADHD) and intellectual disability, as well as schizophrenia and epilepsy.

A study conducted at the University of São Paulo’s Ribeirão Preto School of Medicine (FMRP-USP) in Brazil, with support from FAPESP, investigated the neurobiology of the behavioral effects of childhood seizures using a rodent animal model.

The study was led by researcher Rafael Naime Ruggiero, under the supervision of Professor João Pereira Leite, and involved scientists from the Federal University of São Paulo (Unifesp) and the Federal University of Minas Gerais (UFMG). It was published in the journal eLife.

“The effects of childhood seizures are not associated with neuronal death, but with molecular, cellular and neural network dysfunction. We found that there’s a persistent increase in inflammation in the brain, which is associated with behavioral changes relevant to autism and schizophrenia,” says Ruggiero.

In addition to neuroinflammation, the researchers observed an unexpected relationship between neuroplasticity (i.e., the brain’s ability to modify itself) and cognition. “Although we expected this relationship, we found that the strengthening of neural connections resulting from childhood seizures is even more exaggerated than we thought, suggesting a high degree of neuroplasticity. It’s worth noting that both too little and too much plasticity lead to cognitive impairment. In addition to attention and memory deficits, this ease in strengthening neural connections may explain the greater risk of developing epilepsy in adulthood for individuals who suffered seizures in childhood,” Ruggiero said.

Another very intriguing finding was that in people who suffered seizures in childhood, brain activity during active waking states is more similar than expected to brain activity during REM sleep. “Since REM sleep is the stage in which the most vivid dreams occur, this similarity could explain the atypical sensory processing that occurs especially in schizophrenia,” says Danilo Benette Marques, co-author of the article. He and his colleagues associate this condition with an excess of dopamine.

“In the clinic, epilepsy has a high rate of psychiatric comorbidities, that is, mental disorders that occur in addition to the neurological disease. There’s a strong association with autism, intellectual disability and attention deficit disorder, as well as with psychiatric conditions that manifest in adulthood, such as schizophrenia and other psychotic disorders. It’s estimated that 30% of people with autism also have epilepsy. This complex intersection between neurology and psychiatry has been one of the main focuses of our research in recent years,” comments Pereira Leite, coordinator of the study in question and researcher in charge of the FAPESP Thematic Project “Drug-resistant epilepsies: diagnostic challenges, study of associated comorbidities and new experimental approaches”. 

“For many years, it was believed that the cognitive and behavioral changes associated with epilepsy were the result of the progressive neuronal death in the brain regions affected by epileptic seizures. However, we found that individuals who experienced seizures in childhood, even without developing epilepsy in adulthood, have a higher incidence of these same psychiatric conditions,” continues Pereira Leite.

Ruggiero adds that, similar to what happens in the clinic, rodents exposed to seizures in the first days of life showed a range of behavioral changes in adulthood. “What intrigued us most was that in both humans and rodents, seizures in early childhood do not cause neuronal death. Therefore, our hypothesis was that the functioning of neural networks might have been affected. It’s important to note that neuronal loss is not a prominent feature in psychiatric disorders. We believe that changes in the functioning of specific neural networks can be identified in different mental disorders and are responsible for a common set of symptoms,” he says.

The researchers examined the behavioral changes in rodents using a series of tests. Among the most striking changes, they found that the affected animals exhibited hyperlocomotion, or persistent spontaneous movement, and difficulties in the sensorimotor filter. This filter is responsible for the brain’s ability to effectively filter sensory information and motor responses, to distinguish between relevant and irrelevant stimuli in a noisy environment, and to regulate exaggerated responses. In the treatment of schizophrenia, antipsychotic medications are used to reduce these behaviors.

“We found that animal models that replicate biological aspects of autism also show marked alterations in the same tests. This set of sensorimotor alterations is strongly associated with perceptual and behavioral changes observed in the clinic, such as hyperactivity in ADHD, hallucinations in psychosis, and hypersensitivity to stimulating environments in autism spectrum disorder [ASD]. At the same time, our study also revealed cognitive impairments in what is known as ‘working memory,’ which we use to temporarily store and then forget information, such as a phone number. This is essential for activities that require attention, planning and reasoning. This type of memory is severely impaired in schizophrenia and neurodevelopmental disorders, resulting in disorganized thinking, learning difficulties and attention deficits,” says Ruggiero.

With the discovery that childhood seizures do not cause neuronal death, the researchers wondered where the brain markers for these behavioral changes were located. “In a previous study, we found that many of the behavioral effects of childhood seizures correspond to cognitive and behavioral functions that depend on the hippocampus [a brain region critical for memory formation and sensorimotor integration], the prefrontal cortex [responsible for planning, attention and emotional control], and communication between them. That’s why we hypothesized that these regions might be good candidates for limiting the neural dysfunction associated with behavioral changes caused by childhood brain disorders,” Ruggiero said.

One of the most striking findings of the study was the presence of inflammation in the brains of animals that had suffered seizures in childhood. The process of neuroinflammation is natural and fundamental for the brain to fight infection and recover from injury. In the nervous system, the main players in this role are glial cells, such as astrocytes, which increase their activity in the face of brain injury, expanding, branching, multiplying and becoming ready to deal with any brain damage. One way to study neuroinflammation in the brain is to label a protein called GFAP, which is present in the cytoskeleton of astrocytes. Its levels are a good indicator of the activation of these cells.

“Although there’s no actual damage to neurons, childhood seizures lead to an increase in the neuroinflammatory process. We observed this increase in all the brain regions examined. In addition, levels of inflammation were significantly correlated with behavioral changes, especially sensorimotor changes, which are more relevant to autism and schizophrenia,” reports Matheus Teixeira Rossignoli, another author of the study.

It is not exactly news that ASD and schizophrenia are associated with neuroinflammation. In 2005, a post-mortem analysis of the brains of individuals with ASD showed various signs of neuroinflammation. In the case of schizophrenia, the relationship with inflammation is even clearer. In 2017, a case was reported of a patient with schizophrenia who showed complete remission of symptoms after a bone marrow transplant – a process that completely replaces the patient’s original immune system. There are also reports of reverse cases, in which patients without schizophrenia developed the disorder after receiving a bone marrow transplant from a person suffering from hallucinations and delusions, as reported in 2015.

In addition to these disorders, cases of autoimmune brain diseases, in which the immune system attacks the brain itself, causing it to become inflamed, often present with typical symptoms of mental confusion, hallucinations and delusions, and are often diagnosed as psychotic disorders but do not respond to conventional treatments.

The present study connects these dots and shows how childhood seizures are an important trigger for dysregulated neuroinflammation that can persist into adulthood. Thus, interventions that interrupt this process could potentially alleviate or prevent the development of long-term behavioral changes. “An optimistic perspective of the findings is that behavioral changes are not necessarily associated with neuronal death, which is irreversible, but rather with neural dysfunction, which may be reversible with treatment. This suggests that even after childhood brain disorders, there are opportunities for intervention that can improve brain and behavioral functioning throughout life. However, the earlier the intervention, the better the chance of promoting healthy development and preventing future complications,” concludes Ruggiero.

The research was also supported by FAPESP through postdoctoral grants awarded to three members of the research team: Ruggiero himself, Matheus Teixeira Rossignoli and Danilo Benette Marques.

The article “Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure” can be found at: elifesciences.org/articles/90997.