Adolescence a critical period for schizophrenia patients

Researchers at the University of Geneva (UNIGE) have discovered that the development of the hippocampus — the area of the brain responsible for memory and emotions — is severely impacted in adolescence following the onset of the first psychotic symptoms. Published in the journal Molecular Psychiatry, their results open up new avenues for understanding the causes of schizophrenia.

Schizophrenia is a psychiatric illness that affects 0.5% of the general population and may be related to a neurogenetic known as 22q11 deletion syndrome, which targets chromosome 22. However, only around 30% of people affected by the syndrome end up developing psychotic symptoms specific to schizophrenia, such as auditory hallucinations, memory problems, disorders affecting their perception of reality, and difficulties in social interactions characterised by strong paranoia.

“It’s now known that schizophrenia is linked to the hippocampus — a complex area of the brain that carries out a vast amount of processes simultaneously linked to memory, imagination and the emotions,” noted UNIGE Professor Stephan Eliez. Interestingly, recent studies have shown that people suffering from deletion syndrome also have a smaller than average hippocampus.

“That’s why we studied the development of this structure in detail — so we could understand why some people affected by deletion syndrome eventually develop psychotic symptoms, while others don’t.”

For the past 18 years, the UNIGE team has been following 275 patients aged six to 35 years: a control group of 135 individuals and 140 people with deletion syndrome, including 53 with moderate-to-severe psychotic symptoms. As explained by UNIGE researcher Valentina Mancini, “They underwent an MRI every three years so that we could observe their brain development — this has helped us create a statistical model that measures and compares the development of the hippocampus in both groups of patients.”

It was discovered that the hippocampus of the group affected by deletion syndrome, although smaller from the beginning, followed a growth curve identical to that of the control group; this meant the scientists could hypothesise that the smaller size of the hippocampus originates in utero during its development in the womb, Mancini said. They also observed the subfields of the hippocampus in detail, discovering that the subfield CA3 — which plays a crucial role in memorisation – was not affected by the decrease in size.

The researchers then compared the developmental curves of the hippocampus in people with deletion syndrome but no psychotic symptoms with those who developed psychotic symptoms. Mancini stated, “Around the age of 17 or 18, people with schizophrenic symptoms experience a drastic atrophy in the size of their hippocampus, and especially in the CA3 area — despite CA3 had initially managed to develop normally, unlike the other subfields.”

Subfield of the hippocampus in three young adults: (a) healthy control; (b) young male with deletion syndrome but no psychotic symptoms; and (c) young male with deletion syndrome and psychotic symptoms. In the third subject, atrophy of the head of the hippocampus is evident. Image ©UNIGE Stéphan Eliez

The researchers don’t yet have a precise answer that could explain the drastic drop in the development of this vital brain structure. But their hypotheses are geared towards environmental factors, such as stress or neuronal inflammation.

“The hippocampus of individuals with deletion syndrome is smaller; this means it has to compensate for its size through hyperactivity,” Mancini said. “In the event of a huge stress factor, especially during the critical period of adolescence, this hyperactivity might lead to a significant rise in glutamate that ‘poisons’ the hippocampus and causes its atrophy.” The psychotic symptoms may result from this hyper-compensation, which ends up destroying the hippocampus.

The study thus suggests that the small size of the hippocampus in patients with 22q11 deletion syndrome is defined in the mother’s womb, probably due to poor vascularisation. However, a ‘second hit’ later in development might determine the further hippocampal atrophy and the emergence of psychotic symptoms. As the critical period for schizophrenia is adolescence, the researchers are now working on the possibility of preventing the atrophy of the hippocampus in order to preserve its functions.

Top image credit: ©stock.adobe.com/au/andriano_cz

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