New research shows how brain structure and function change in depression and schizophrenia

There is always more to learn about underlying biology in medicine, and this is especially true in psychiatry. The ECNP 2021 hybrid meeting gave the opportunity for early career scientists to present their research, including exciting findings in MDD and schizophrenia from Julia Fietz (Max Planck Research School for Translational Psychiatry, Munich, Germany), Julia Binnewies (Amsterdam University Medical Centers, the Netherlands), and Andrea Perrottelli (University of Campania “Luigi Vanvitelli”, Naples, Italy).

Mental disorders are often categorized based on symptoms, but this can hinder research into the underlying causes. The categories may not be clearly separated, with overlapping symptoms, and different symptoms profiles can sometimes lead to the same diagnosis.1

Unlike other branches of medicine, there is usually not a single cause for a mental disorder, and it may be better to consider transdiagnostic risk factors instead, for instance by using computational models.


Childhood adversity may affect cognitive function

One transdiagnostic risk factor is cognitive dysfunction, which is associated with psychopathology and disease burden, but not a specific diagnosis.2 Julia Fietz and colleagues assessed this in the BeCOME cohort1 of 123 patients with major depressive disorder (MDD), anxiety disorders, or post-traumatic stress disorder (PTSD), using the verbal N-back task with simultaneous pupillometry and functional MRI.

Different pupil responses to cognitive load correlated with different brain regions

They found that pupil size increases with increasing working memory load. However, latent class growth modeling revealed a group of 26 patients with a pupil response profile that was less reactive to the working memory load. A generalized linear model showed the pupil response in this ‘deviant’ group correlated with different brain regions from the ‘typical’ group, specifically the angular gyrus and the inferior parietal gyrus.

Childhood adversity at low levels may be protective for cognitive function

The typical group had higher scores in childhood adversity than the deviant group (p = 0.008 to 0.03), but there was no difference in depression, trait or state anxiety, or anhedonia. One hypothesis is that a lower level of childhood adversity may function as a protective factor in cognitively demanding tasks.3


Clinical, but not subclinical, depression is related to brain structure

It is already known that MDD decreases cortical thickness4 and hippocampal volume,5 and that brain gray matter decreases with age.6 However, the effect of age on the association between MDD and brain structure is unclear.

Julia Binnewies and colleagues used data from 3428 adults in Lifebrain, including general population and patient-control cohorts. Unsurprisingly, mild to severe depression was more common in the patient-control cohorts (62.1%) than the general population (9.5%).

MDD decreases cortical thickness and hippocampal volume, and that brain gray matter decreases with age

As expected, the patient-control cohorts showed associations between depressive symptoms and decreased medial orbitofrontal cortex and rostral anterior cingulate cortex thickness and hippocampal volume. However, the general population did not show these correlations.

The group concluded that clinical, but not subclinical, depression was related to brain structure. There were also no consistent interactions between age and depressive symptoms in any group or brain region.


Functional connectivity in schizophrenia negative symptoms

Negative symptoms of schizophrenia affect functioning and quality of life of patients and have a variety of clinical presentations.7 Neuroimaging studies suggest negative symptoms could result from changes in cerebral networks.8

Andrea Perrottelli and colleagues compared functional connectivity of patients with schizophrenia and healthy controls using MRI. Subjects with schizophrenia showed a reduction in functional connectivity in the limbic network, specifically the rostral region of the left superior temporal gyrus (p = 0.002).

Negative symptoms of schizophrenia correlated with functional connectivity of the dorsal attention network

Negative symptoms in both the experiential and expressive deficit domains were correlated with functional connectivity of the dorsal attention network, in particular the left superior parietal lobule (p = 0.0031 and 0.00044, respectively).

The dorsal attention network controls goal-oriented, top-down deployment of attention.9 The group suggested that dysregulation and disrupted connections of this network could lead to impaired processing of the environment.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


  1. Brückl et al. The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes. BMC Psychiatry. 2020;20(1):213
  2. Abramovitch et al. The C Factor: Cognitive dysfunction as a transdiagnostic dimension in psychopathology. Clin Psychol Rev. 2021;86:102007
  3. Seery et al. Whatever does not kill us: cumulative lifetime adversity, vulnerability, and resilience. J Pers Soc Psychol. 2010;99(6):1025-41
  4. Schmaal et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22(6):900-9
  5. Schmaal et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Mol Psychiatry. 2016;21(6):808-12
  6. Pomponio et al. Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan. Neuroimage. 2020;208:116450.
  7. Galderisi et al. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5(8):664-77
  8. Uscătescu et al. Effective connectivity of the hippocampus can differentiate patients with schizophrenia from healthy controls: a spectral DCM approach. Brain Topogr. 2021. doi: 10.1007/s10548-021-00868-8
  9. Vossel et al. Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. Neuroscientist. 2014;20(2):150-9