Linda Steinholtz: On inhibitory neurotransmission in depression

Abstract

This thesis investigates the function of inhibitory neurotransmission in depression. Gamma-aminobutyric acid (GABA) serves as the primary inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of depression. Furthermore, GABA is thought to play a role in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS). GABA levels in depression measured with magnetic resonance spectroscopy seem to be reduced, while changes following rTMS appear more inconsistent. Additionally, the availability of GABAA-receptors in depression and following rTMS remains largely unexplored. Cortical excitability also seems to be altered during depression, though results are heterogeneous, while research on excitability changes following prefrontal rTMS is limited.

Depression can present with a wide range of symptoms, leading to the identification of clinical subtypes, which may have distinct neurobiological mechanisms. GABA dysfunction might hold particular relevance in specific symptom profiles of depression, such as melancholic features. 

Study I found that the rTMS protocol intermittent theta-burst stimulation (iTBS) did not affect average GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) or GABAA-receptor availability as measured by positron emission tomography. However, a decrease in GABA levels was associated with symptom improvement, and lower baseline GABAA-receptor availability in the nucleus accumbens was related to the antidepressant effect following iTBS.

Study II found no changes in motor cortical excitability in depression or schizophrenia following iTBS, as measured using transcranial magnetic stimulation paired with electromyography (TMS-EMG). Furthermore, baseline TMS-EMG could not predict the effect of iTBS on negative symptoms in depression. Participants with schizophrenia exhibited higher GABAB-receptor-mediated activity than depressed and healthy controls, with this activity also correlating with the dose of antipsychotic medication. 

Study III examined the relationship between GABAA-receptor availability and TMS-EMG indices. In participants with depression, changes in GABAA-receptor availability in the hand motor cortex were inversely related to changes in the resting motor threshold.

Study IV could not establish that melancholic features, specifically psychomotor retardation and vegetative symptoms, are related to GABA levels in the dACC or GABAA-receptor availability in the dACC, basal ganglia, and hypothalamus. 

These findings contribute to the understanding of the pathophysiology of depression and the mechanisms of iTBS.