MULTIMODALE BEELDVORMING VAN NEUROPLASTICITEIT NA ELEKTROCONVULSIE THERAPIE VOOR DEPRESSIE

Introduced in 1938, electroconvulsive therapy (ECT) has been a crucial treatment for severe psychiatric disorders. Although its efficacy is well-established, the exact mechanisms underlying its therapeutic effects remain elusive. The leading hypothesis is that ECT induces neuroplasticity, a theory supported by preclinical studies in rodents. However, translating this evidence to a clinical population has been difficult. The increased gray matter volume (GMV) following ECT has been suggested to reflect structural neuroplasticity. This doctoral thesis examined the neurobiological mechanisms driving GMV increase and aimed to explore possible behavioral and clinical correlates. Chapter 1 comprehensively reviewed the literature on ECT-induced neuroplasticity and categorized these changes into molecular, structural, and functional domains. Molecular neuroplasticity can be seen in the alterations of neurotrophic factors and neurotransmitters following ECT. While there are numerous studies observing molecular markers of neuroplasticity, their clinical relevance remains inconsistent and rarely correlates with therapeutic efficacy. Structural neuroplasticity was evidenced by strong alterations in both gray and white matter in the brain, however, the clinical relevance of these structural changes was inconsistent. Studies on functional neuroplasticity revealed significant but complex modifications in brain network connectivity patterns. The functional neuroplasticity level provided the most compelling evidence for the therapeutic efficacy of ECT. With respect to structural GMV changes following ECT, we investigated the relationship between cortisol and GMV changes in the medial temporal lobe (MTL) following ECT in patients with late-life depression (LLD) in chapter 2. No significant correlations were found between cortisol and pre-treatment MTL volumes or ECT-induced MTL volumetric changes, suggesting a mechanism of ECT-related neuroplasticity independent of the neurotoxicity hypothesis of cortisol. Further, in chapter 3, we investigated ECT-induced hippocampal GMV change and its relation with cognition post-ECT in patients with LLD. We observed that larger right hippocampal GMV change predicted less pronounced improvement in visual memory performance up to six months post-ECT. Interestingly, for verbal and semantic memory, as well as global cognitive function, the predictive value of hippocampal GMV change was only significant in patients who switched from right unilateral to bilateral ECT stimulation. This suggests a nuanced relationship between hippocampal GMV changes and cognitive outcomes, dependent on the specifics of ECT administration. In chapter 4, we investigated long-term GMV patterns following ECT, using data from the GEMRIC consortium. The findings confirmed a significant increase in GMV immediately post-ECT, followed by a consistent decrease within six months, with GMV generally returning to pre-ECT levels. Exceptions were found in both amygdalae, right hippocampus, and pars triangularis, where GMV remained higher than baseline. No consistent relationship was observed between these GMV patterns and clinical depression outcomes during and after ECT, suggesting that the neurobiological effects of ECT as seen with GMV changes might be transient and not directly linked to clinical improvements. The thesis further explored the molecular dynamics of the neurobiological effects of ECT. First, in chapter 5, we performed a scoping review to investigate the role of molecular imaging, particularly PET and SPECT, in understanding ECT's neurobiological effects. The review highlighted two primary research directions in the past four decades: brain activity and neurotransmitter systems. Early research mostly before the year 2000 focused on regional cerebral blood flow and regional glucose metabolism, revealing significant changes during and after ECT. Later studies shifted to the monoamine hypothesis, examining serotonin and dopamine systems. The review pointed out the need to focus on new research targets in PET studies related to the neuroplasticity hypothesis of ECT. This need for novel molecular PET imaging studies investigating the neuroplasticity hypothesis was met in chapter 6. We conducted a pilot study using 3T PET-MRI investigating whether ECT-induced GMV increases corresponded with changes in synaptic density, measured at the molecular level via SV2A. In patients with LLD, post-ECT increases in GMV were observed, but did not correlate with changes in SV2A, as measured by 11C-UCB-J uptake. Interestingly, the post hoc analysis suggested a more nuanced effect, indicating that synaptic plasticity, indicated by changes in SV2A, correlated with the observed GMV changes but only in patients whom achieved clinical remission. However, the small sample size warrants careful interpretation of these post hoc results. Collectively, these studies underscore the complex and multifaceted nature of GMV changes following ECT. Our understanding of the neuroplasticity hypothesis of ECT has improved; however, ongoing scientific advancements are essential to both challenge and validate this theory.