Brain scans reveal a bipolar-like link to childhood trauma in some depressed patients

A neuroimaging study in Italy found that patients with bipolar disorder reporting more adverse childhood experiences tended to have worse integrity of brain white matter. This association was present in depressed patients as well, but the effects were less pronounced and structurally different. The research was published in European Neuropsychopharmacology.

Adverse childhood experiences (ACEs) are potentially traumatic events that occur during childhood and can affect a child’s physical, emotional, and psychological development. The concept was popularized by the Adverse Childhood Experiences Study, which examined how early life stress relates to later health outcomes.

ACEs commonly include experiences such as physical abuse, emotional abuse, sexual abuse, neglect, and exposure to domestic violence. They can also involve household dysfunction, such as living with a family member who has substance abuse problems, mental illness, or who has been incarcerated.

These experiences can disrupt a child’s sense of safety and stability and may lead to chronic stress during critical developmental periods. Prolonged exposure to stress in childhood can influence the developing brain and stress-regulation systems in the body. Research has shown that individuals with higher numbers of ACEs have a greater risk of mental health problems such as depression, anxiety, and substance use disorders.

ACEs have also been associated with increased risk of chronic physical health conditions, including cardiovascular disease and diabetes. However, the presence of supportive relationships and protective environments can buffer the negative effects of adverse experiences.

Study author Marco Paolini and his colleagues note that previous studies indicate that adverse childhood experiences might have a detrimental effect on the integrity of brain white matter. However, these effects do not seem to be general, but rather dependent on the mental health diagnosis a person has. They believed that these experiences would have a clear effect in patients with bipolar disorder and a less clear effect in individuals with major depressive disorder.

These researchers conducted a study based on the hypothesis that the effect of adverse childhood experiences on microstructure integrity of brain white matter would be different in individuals suffering from bipolar disorder and in those suffering from major depressive disorder.

Brain white matter integrity refers to the structural quality and organization of the brain’s white matter tracts. The brain white matter consists of bundles of myelinated nerve fibers that connect different brain regions and enable communication between them.

Myelin is the material that insulates nerve fibers, allowing faster nerve impulse transmission and creating the white look. Higher white matter integrity generally indicates more efficient neural connectivity and information transmission in the brain, whereas reduced integrity may reflect developmental abnormalities, aging, injury, or neurological and psychiatric disorders.

Study participants were 260 inpatients admitted to the San Raffaele hospital psychiatric ward during an ongoing depressive episode. 140 of them were diagnosed with major depressive disorder, while 120 were diagnosed with bipolar disorder. Patients’ age ranged between 21 and 69 years.

Patients underwent magnetic resonance imaging scans of their brain structure. A subsample of 162 patients gave blood samples, allowing researchers to conduct genotyping and calculate Polygenic Risk Scores (PRS)—an individualized estimate of a person’s genetic liability for developing major depressive disorder and bipolar disorder. Participants also completed an assessment of adverse childhood experiences (the 28-item Childhood Trauma Questionnaire), including the adversity of their family environment (the Risky Family Questionnaire).

Results showed that patients with bipolar disorder who reported more adverse childhood experiences—specifically physical abuse, emotional abuse, and physical neglect—tended to have widespread, worse white matter integrity. The situation was different in patients with major depressive disorder, where the association was less pronounced and affected different structural metrics of the white matter.

Further analyses revealed that the strength of the association between adverse childhood experiences and the integrity of white matter in the brain depends on the genetic risk for bipolar disorder a person has. Crucially, this genetic moderation was present specifically in patients with major depressive disorder, not those with bipolar disorder. In bipolar patients, childhood trauma negatively impacted white matter regardless of their genetic risk score.

However, in depressed patients, those with a high genetic risk for bipolar disorder showed white matter changes that closely mimicked the bipolar patients. Conversely, depressed patients with a low genetic risk for bipolar disorder showed an opposite biological response to trauma. These findings suggest that major depression is a highly heterogeneous diagnosis, with a subset of depressed patients actually possessing a bipolar-like biological response to trauma.

“In the present study we identified a differential effect of childhood maltreatment on WM [white matter] microstructure between patients suffering from major depression or bipolar disorder, with more pronounced detrimental effects in BD [bipolar disorder] compared to MDD [major depressive disorder]: this may point to distinct pathophysiological routes through which childhood maltreatment, a shared environmental risk factor, affects the development of the two disorders,” the study authors concluded. They added that their findings “give credence to the notion of a shared disease biology with bipolar disorder in a portion of MDD patients, and possibly provide future tools to disentangle MDD heterogeneity.”

The study contributes to the scientific understanding of the neural underpinnings of mental health disorders. However, it should be noted that the design of the study does not allow definitive causal inferences to be derived from the results. Additionally, information on adverse childhood experiences was based on recall of childhood, leaving room for recall bias to have affected the results.

The paper, “Different effect of adverse childhood experiences on white matter microstructure in major depression and bipolar disorder: moderating role of genetic liability,” was authored by Marco Paolini, Laura Raffaelli, Valentina Bettonagli, Cristina Lorenzi, Sara Spadini, Beatrice Bravi, Lidia Fortaner-Uya, Giulia Gulino, Chiara Fabbri, Alessandro Serretti, Raffaella Zanardi, Cristina Colombo, Francesco Benedetti, and Sara Poletti.