Fear extinction as a model for synaptic plasticity in major depressive disorder

Background: The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls. Methods: Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter. Results:After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration. Conclusions: The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder.(VLID)182926

Demographic and clinical characteristics.

<p>Demographic and clinical characteristics.</p

A. Fear-potentiated startle pathway.

<p>The primary acoustic startle pathway comprises only a few synapses involving the cochlear root neurons, neurons in the nucleus reticularis pontis caudalis, and motoneurons in the spinal cord that innervate the musculus orbicularis oculi and illicit the startle response. This pathway is critically modulated by the output of the amygdala. The basolateral amygdala (BLA) receives and integrates sensory information from multiple sources; here, the inputs of the visually presented conditioned stimuli (CS+ and CS−; yellow square, blue circle; assignment counterbalanced across participants) and the unconditioned stimulus (US; electric shock) are represented. The BLA is a locus of sensory convergence and a plausible site for CS-US association in the form of local synaptic plasticity within the amygdala. Intra-amygdaloid circuitry conveys the CS-US association to the central nucleus of the amygdala (CE) that mediates fear responses such as the fear-potentiated acoustic startle. <b>B.</b> <b>Fear conditioning paradigm.</b> The paradigm consists of a startle habituation, acquisition and extinction phase with a previous quiet baseline period. Acquisition consisted of 5 non-reinforced CS+ presentations and 5 CS+ presentations that co-terminated with the electric shock. The CS− was presented 10 times without reinforcement. Extinction was comprised of 10 non-reinforced presentations of each of the CSs. Before and after acquisition, the subjective US expectancy was assessed. Additionally, contingency awareness was assessed after acquisition.</p

Correlation between the strength of conditioning in extinction and the duration of illness.

<p>In the group of MDD patients, the strength of the remaining conditioning in the extinction phase was negatively correlated with the duration of illness, i.e., extinction learning was enhanced in patients with a longer duration of illness, <i>r</i>(35)  = −.40, <i>p</i>  = .014, Pearson correlation.</p