Conduct disorder, which is characterized by a repetitive and pervasive pattern of aggressive and rule-breaking antisocial behavior, affects an estimated 3% of all youths. It is one of the most common childhood psychiatric disorders, and is thought to be among several, also including depression and anxiety, that exact the highest “disease burden” in children under age 14. (This term seeks to assess the overall, cumulative consequences of an illness upon those who live with them.)

Yet despite its prevalence and impact, conduct disorder is “one of the least researched psychiatric disorders,” says a large international team that dedicated itself, several years ago, to addressing the relative paucity of research. Organized as the Antisocial Behavior (ASB) working group of the ENIGMA consortium (Enhancing NeuoImaging Genetics Through Meta-Analysis), the team performed a coordinated analysis of structural MRI data from 15 independent cohorts consisting of conduct disorder patients and controls.

The team, consisting of dozens of investigators and co-led by Drs. Yidian Gao and Stephane De Brito from the University of Birmingham, UK, and Drs. Marlene Staginnus and Graeme Fairchild from the University of Bath, UK, recently reported results in Lancet Psychiatry. Six BBRF grant recipients were members of the team, including Paul M. Thompson, Ph.D., 2017 BBRF Distinguished Investigator, and Daniel S. Pine, M.D., BBRF Scientific Council, 2011 BBRF Ruane Prize, 2000 BBRF Independent Investigator.

Prior studies of conduct disorder, though useful, have tended to be small and conducted using a variety of methods and technologies that make results hard to compare. Inconsistency in results has made it difficult to determine whether or to what degree conduct disorder is, like autism spectrum disorder and intellectual disability, “neurodevelopmental” (i.e., the result of biological processes, including those caused by genetic mutations and variations, that occur early in life as the brain is developing), and/or environmental (i.e., stemming from events and factors specific to individuals that reflect, for instance, socioeconomic variables, hardship, interactions between parents and children, etc.).

In hopes of identifying neurobiological correlates of conduct disorder, the ASB working group of the ENIGMA consortium assembled the largest neuroimaging dataset on conduct disorder to date. The 15 cohorts from which MRI data was assembled provided a sample for the current study consisting of 1,185 young people with conduct disorder (28% female) and 1,253 typically developing young people (35% female), with an average age of about 14. The team compared, in those with conduct disorder vs. controls, the thickness and total surface area of the brain’s cerebral cortex, as well as the volumes of “subcortical areas,” focusing on areas of the brain such as the amygdala involved in the processing and regulation of emotions.

Among young people in the study with conduct disorder, they also looked to see if there were differences in brain structure based on age, age of illness onset, and sex, as well as between those youths with high vs. low levels of “callous-unemotional traits,” which help to distinguish conduct disorder patients based on co-occurring personality traits related to empathy, guilt, and concern about others.

“We identified subtle but widespread cortical and subcortical brain structure alterations in young people with conduct disorder,” the team reported. Compared with typically developing young people, those with conduct disorder “had lower surface area across all four cerebral lobes.” In addition to lower total surface area, surface area in specific regions was lower in 26 of 34 of the investigated cortical regions.

Also, compared with controls, young people with conduct disorder showed greater cortical thickness in the caudal anterior cingulate cortex and lower thickness in an area called the banks of the superior temporal sulcus. Importantly, various subcortical structures were reduced in size in patients—they had lower volumes compared with the typically developing youths. These areas included the amygdala, hippocampus, thalamus, and nucleus accumbens (which is involved in reward processing).

In this large sample (which still, however, had a large majority of male participants), no significant differences in brain structure were seen on the basis of sex or age, although those with childhood-onset conduct disorder showed greater cortical thickness in the caudal anterior cingulate cortex, compared to typically developing youths.

“Our finding of widespread alterations in cortical and subcortical structure among young people with conduct disorder, including regions crucial for emotion processing regulation, empathy, and decision-making, provide further evidence of the neurobiological underpinnings of this disorder,” the team said.

“In contrast to previous small-scale studies … our results identify only minor differences in subtypes of the disorder [such as those with high vs. low levels of callous-unemotional traits].” This suggests to the investigators that conduct disorder “is associated with brain structural alterations regardless of subtype.”

Cortical thickness and surface area are associated in different ways with cognitive abilities and disorders. Normally, cortical thickness decreases between ages 1 and 7, and surface area peaks around age 11 or 12. These are the result of various processes in brain development, including neuronal migration and synaptic pruning. “Our findings,” the team said, “suggest that neurodevelopmental processes associated with [cortical] surface area might be more affected in conduct disorder compared with those involved in cortical thickness, and highlight the need for longitudinal studies to investigate neurodevelopmental trajectories in this disorder.”

Another ENIGMA working group that has investigated brain structural changes in young people with ADHD also found reductions in cortical surface area and the volume of subcortical areas. The team controlled for these overlaps and concluded that these phenomena as seen in conduct disorder patients in the current study were not solely driven by ADHD co-morbidity. Rather they speculate, these surface area and volume reductions may be “transdiagnostic markers” of disorders marked by externalizing psychopathology. In such disorders, symptoms, like anger or aggression, are directed outward, toward others, and not primarily inward, as for example rumination or anhedonia are in depression or anxiety.

The team also said that age might play a less important role in brain alterations in conduct disorder than in other disorders such as ADHD, where brain alterations are most pronounced in childhood.

In sum, the team said, evidence of small but widespread brain alterations in young people with conduct disorder extend beyond regions included in neurocognitive models of the illness and appear independent of group differences in IQ, medication use, or comorbidities including ADHD. Future studies should address how the changes in brain structure observed in conduct disorder relate to brain functioning and cognitive processes such as emotion regulation and reward processing, they said.

The research team also included: Gregor Kohls, Ph.D., 2022 BBRF Young Investigator; Luke Wiliamson Hyde, Ph.D., 2017 BBRF Young Investigator; Cindy C. Hagen, Ph.D., 2018 Young Investigator; and Celso Arango, M.D., Ph.D., 2005 BBRF Independent Investigator.