DELTA-neuroimaging.

BACKGROUND:

Major depressive disorder (MDD) is a highly prevalent and disabling disease, especially because its symptoms tend to return. In general antidepressants reduce the risk of recurrence 2-fold, but after cessation this risk appears to increase again. For prediction of recurrence, the number of previous episodes is amongst the strongest predictors, together with residual symptoms, daily hassles and coping style. Recurrence of MDD has been considered from neuropsychological, brain network dysfunction, neurochemical and psychoneuroendocrine perspectives which have not yet been integrated.
Therefore, despite these perspectives of neurobiological substrates for recurrent depression, the underlying mechanisms of recurrence remain poorly understood, which will be improved by a multimodal approach in which neuroimaging will be combined with neuropsychological and neurobiological/neuroendocrine measurements in patients with recurrent depression.



AIMS:

With this research-protocol we aim to investigate six important issues regarding recurrences of MDD-episodes:

1. The differences between healthy controls and patients with recurrent MDD-episodes with respect to structural (sMRI) and functional (fMRI)-scans;

2. The differences in changes in resting state activations and HPA-axis activity after mood-induction between remitted MDD-patients and controls;

3. The differences in the relations between HPA-axis functioning, fatty acid status and neuroimaging findings between remitted MDD-patients and controls;

4. The predictive value of sMRI/fMRI, changes in resting state activations and HPA-axis activity after mood-induction, fatty acid status and their interactions for the occurrence of new relapse/recurrences;

5. The association between sMRI/fMRI, changes in resting state activations and HPA-axis activity after mood-induction and fatty acid status with the number of previous episodes;

6. What changes occur in brain functions, psychoneuroendocrinological measures and their interaction when patients have a recurrence of their depression;

7. What are the associations of the above neuropsychological, neuroendocrine and fMRI measurements with stress and reward in daily life?



DESIGN:

Prospective and retrospective cohort design, with a healthy control comparison group, and an age and sex matched controlled repeated measurements design in case of future (non-) recurrence in the next 2.5 years.



METHODS:

Patients and controls: Fifty remitted unipolar MDD-patients (35-65 yr, both sexes) with ¡Ý2 MDD episodes, without psychopharmacologic drugs for at least 4 weeks and fifty controls (age, sex and intelligence matched) will be recruited.

Measurements: Two phases (study entry and after recurrence of depressive symptoms) are studied. In Phase I, two blocks of psychological tests will be obtained, followed structural and functional magnetic resonance imaging (MRI). During the scanning, a mood induction will be performed. In Phase II, when patients experience a recurrence during follow-up, we will invite them for new psychological testing and an MRI-scan. At approximately the same moment during follow-up we will invite a matched patient (matched by age ¡À10 years and sex) who has not experienced a recurrence by then, for repeated testing as well.
Neuropsychological tests obtained are the Exogenous cueing task, Face recognition task, Emotional categorization task, Emotional Memory and the Internal Shift Task (both Phases) and the Dutch Adult Reading Test (Phase I only).
MRI scanning will consist of a structural scan, resting state scan, Reinforcement learning task, Magnetic resonance spectroscopy, Diffusion Tensor Imaging, Emotional faces and Cued Emotional Conflict Task (both Phases); in Phase I an Emotion regulation task and a repeated resting-state scan after a sad mood induction will be made.
Neurobiological/Neuroendocrine tests consist of blood collection for polyunsaturated fatty acids and brain derived neurotrophic factor, analysis of genetic polymorphisms and salivary cortisol measurements
Repeated momentary daily assessments will be obtained during 6 days at 10 random timepoints by applying the Experience Sampling Method.

Relative to controls, remitted depressed patients have:

1. Increased negative attentional biases;

2. Decreased functional and effective connectivity between emotion-regulation networks;

3. Increased activations of the cognitive control system when regulating emotions in response to emotionally valenced pictures;

4. Blunted reward-signals in the ventral striatum, and increased activations of dopaminergic neurons in the VTA;

5. Increased glutamate and decreased glutamine/GABA signals in the pgACC and basal ganglia;

6. Increased cortisol and DHEAS levels after mood-induction.



Furthermore we expect that:

1. sMRI/fMRI or change in activations of resting state brain networks after mood-induction are predictive for recurrence (after prospective follow-up of 2.5 years);

2. Changes in cortisol and DHEAS levels after mood-induction predictive for recurrence (after prospective follow-up of 2.5 years);

3. Measures of stress and reward-sensitivity predict future recurrences (after prospective follow-up of 2.5 years);

4. Measures of stress and reward-sensitivity correlate with emotional biases, with reward/aversive learning and specific abnormalities in resting-state brain networks.

1. Baseline;

2. Prospective follow-up every 4 months;

3. Retrospective follow-up for app. 10 years in subjects who participated in a previous study (DELTA).

Apart from mood-induction during assessment no interventions applied.