Jordi Heemskerk

For my PhD, I am involved in three interconnected research projects examining synaptic function in depression and psychiatric disorders.

The primary project is the SYNABS study, investigating the relationship between SV2A expression and treatment outcomes in patients with treatment-resistant depression receiving non-surgical brain stimulation (rTMS or ECT). SV2A, a synaptic vesicle protein measurable through [18F]SynVesT-1 PET imaging, serves as a biomarker for synapse density. We hypothesize that patients responding to treatment will show increased SV2A binding, while non-responders will not, thereby clarifying the neurobiology of treatment-resistant depression and the mechanisms of action of these brain stimulation modalities.

To contextualize these findings, I am conducting a complementary post-mortem study examining synapse density and SV2A expression in brain tissue from depressed and control donors. Using immunohistochemistry with multiple synaptic markers (SV2A, synaptophysin, bassoon, VGLUT1, VGAT, PSD95, gephyrin) across key depression-implicated regions, we directly investigate changes in density of excitatory and inhibitory synapses in MDD across all six cortical layers. We will also investigate whether changes in SV2A expression correspond to changes in synapse numbers. A subselection of cases undergoes autoradiography with [18F]SynVesT-1, enabling layer-specific binding analyses to validate these findings and link clinical PET observations to underlying synaptic pathology.

The final project focuses on improving the phenotyping and characterization of psychiatric donors in the Netherlands Brain Bank (NBB) Psy-cohort. Currently, there are no severity measures available for the psychiatric donors of the Netherlands Brain Bank. Moreover, we are limited by the absence of confirmatory biological markers — challenges that do not exist for neurological disorders. This heterogeneity significantly reduces statistical power in downstream research. To address this, I am collaborating with fellow clinicians and researchers across multiple workpackages to develop a more rigorous characterization system, automated through the use of LLMs. This includes severity scoring and classification using evidence-based frameworks such as the HiTOP model, which provides dimensional assessment of psychiatric dysfunction beyond traditional categorical diagnostic systems. We hope the outcomes of our project will supply fellow iCNS researchers - and the research community beyond - with the necessary data for state-of-the-art research into psychiatric disorders.