ECT-induced connectivity mechanisms in treatment resistant depression

Depression is one of the most prevalent psychiatric disorders with a highly
recurrent course leading to a large socioeconomic burden not only for the
patients but also for those who care for them. Despite 50 years of intensive
research into treatment options, 1/3 of the patients will not respond to
psychotherapy and pharmacotherapy. For these treatment resistant depression
(TRD) patients electroconvulsive therapy (ECT) is the last resort. However, the
neurobiological effects of ECT at the human system level remain unclear,
possibly because animal guided research has mainly focused on specific
neurotrophic effects such as for example adult neurogenesis. Here, we propose
an exploratory two staged model investigating the effects of ECT on a
cortico-limbic network related to the pathophysiology of depression. In a first
step we will identify depression related changes in the default mode network,
the emotional salience network and the cognitive control network. We will
longitudinally assess the changes in the connectivity as a function of ECT
treatment and therapeutic response. In the next stage we want to augment these
dynamic changes in brain function with changes in structural brain measures
that were identified in previous studies (cortical thickness and hippocampus
and amygdala volumes). By these means we aim generating a coherent
network-based mechanistic explanations for the treatment effects, which can be
used for future approaches that are less invasive and have less side effects.

Dopaminergic dysfunction - Amendment 28-4-2021
Another potential mechanisms of action of ECT will be additionally
investigated. It has been suggested that dopaminergic dysfunction plays an
important role in the pathophysiology of TRD, the main indication of ECT. We
will investigate changes of dopamine dysfunction via dopamine neuron activity
in the habenula-Ventral Tegmental Area (VTA) network during a
reward/punishment-related learning task before and after ECT treatment.
Moreover, we will also investigate the association between change in dopamine
dysfunction and treatment response.

Primary objectives:
1.) Investigate changes in functional connectivity between different resting
state networks as a function of ECT treatment and therapeutic response.
2.) Investigate changes in VTA-related BOLD-signals coding for Temporal
Difference Errors in reward/punishment-related learning, as a function of ECT
treatment and therapeutic response

Secondary objectives:
1.) Correlate changes in functional connectivity and GABA with changes in
structural brain measures (cortical thickness, amygdala and hippocampal
volume).
2.) Investigate potential neural markers that will discriminate between
patients who relapse and patients who don*t after successful ECT treatment
during a follow-up period of one year.

A longitudinal study with 50 patients suffering from TRD and eligible for ECT
treatment will be concluded. Patients will receive care as usual and undergo
fMRI at four time points during and after treatment (before start or ECT, after
6 sessions, after treatment is discontinued and at 3 months after treatment). A
control group of 50 healthy controls matched for sex and age will undergo fMRI
during a similar timecourse as the ECT-treated patients to distinguish changes
specific to MDD.

All psychiatric measurements are administered routinely at our out- and
inpatient depression unit. The (f)MRI measurements will require a maximum of
75-90 minutes of the patients time at four time points during and after
treatment. Risks associated with the measurements used in this study are
negligible.