1.1 Prior Research

(a) Describe the state of affairs in the current research field based on the existing body of literature.
Major depressive disorder (MDD) is a chronic disorder associated to reduced well-being and functioning (Hays, Wells, Sherbourne, Rogers, & Spritzer, 1995; Wells et al., 1989), with an average lifetime prevalence of 14,6% in high-income countries and 11,1% in low- to middle income countries (Bromet et al., 2011). According to the World Health Organization (2017) MDD is the leading cause of disability worldwide. A large group of individuals with MDD have Treatment Resistant Depression (TRD), although there is no consensus on the definition of TRD, there is an consensus on the failure to react to at least two dissimilar antidepressants (McIntyre et al., 2014). Recent methods of treatment offer prospect to treating TRD (Dandekar, Fenoy, Carvalho, Soares, & Quevedo, 2018). One of the most promising advances is diminishing overactivity in the Subcallosal Cingulate Gyrus (SCG) including Brodmann area 25 (BA25) with chronic high-frequency Deep Brain Stimulation (DBS) (Mayberg et al., 2005) which is associated to TRD. Despite these findings more recent research(Blumberger, Mulsant, & Daskalakis, 2013; Holtzheimer et al., 2017) shows inconsistent conclusions.

(b) Elaborate on the theoretical framework.
An solution to more optimal DBS treatment of TRD could lie in the localization of electrode contacts in SCG DBS. Hamani et al. (Hamani et al., 2009) compared electrode contacts of patients who responded to DBS and suggested a standardized method to targeting the SCG. Nevertheless the exact location and shape of the SCG is as unique as a fingerprint and therefore a challenging area for parcellating the white matter (WM) of the SCG (McCormick et al., 2006). Despite the crucial role of the morphological characteristics of the SCG for targeting and therefore adequate DBS treatment of TRD. The literature on this topic is minuscule. Nevertheless, research on BA25 suggests sexual dimorphism by demonstrating greater concentration of grey matter (GM) in men compared to women (Garcia-Falgueras et al., 2006). Experiments like this arise questions as, should the SCG in DBS treatment for MDD be adjusted to gender? Another argument is that targeting approaches for the SCG should differ between men and women because of the well-studied gender differences of MDD (Marcus et al., 2005). Furthermore, research showed volumetric reduction of the SCG in women with early-onset MDD (Botteron, Raichle, Drevets, Heath, & Todd, 2002). Although the above described findings altogether suggest the possibility in gender differences of the SCG in MDD and TRD patients.

(c) Clarify how the previous research eventuates into the research questions of the current proposal.
To date no research has been done on gender differences of the SCG in the context of MDD. Because of the importance of the morphological characteristics of the SCG in targeting with DBS, novel research to explore possible differences in WM for the SCG between female and male is suggested.

1.2 Key Questions

(a) Formulate a general relevant research question based on previous research.
Are there gender differences in the morphological characteristics of the SCG in the context of MDD?

(b) Translate the general research question in a clear manner into a specific research question.
Are there gender differences in the white matter characteristics of the SCG?

(c) Translate the specific research questions into testable research hypotheses.
H0. There are no gender differences in the white matter characteristics of the SCG.
H1. There are gender differences in the white matter characteristics of the SCG.

1. METHODOLOGY
   2.1 Sample Characteristics

(a) Indicate how many human/animal participants will be recruited and screened (and on what basis will participants be selected/excluded), or how data will be generated in case of a simulation study.
An existing pool of data will be used consisting of ultra-high resolution in-vivo anatomical imaging from 7T MRI. From this pool a sample of 96 subjects will be taken.

2.2a Operationalization

(a) Operationalize the research questions in a clear manner into a research design/strategy.
To asses if there are gender differences for the SCG manual parcellations according to McCormick et al. (2006) will be done for the left and right hemisphere for 96 subjects.

(b) Describe the procedures for conducting the research and collecting the data.
Before manual parcellations can begin it is crucial to pilot an individual pilot subject. This way the assessor can get accustomed to the procedure described by McCormick et al. (2006) for parcellation of the SCG. Hereafter the randomized manual parcellations for the 96 subjects can begin.
When manual parcellations for the 96 subjects are done it is of importance to see if data is normally distributed.
In addition, it is of importance to asses if there are significant differences in the SCG of the LH and RH.
Based on the results of the above described check there will be determined how the dataset will be treated. If there are differences between de LH and RH, the datasets for each hemisphere will be treated independent of each other. If the datasets of the LH and RH are not independent the dataset can be treated as one dataset.
WM volume of the SCG will be the continues variable. Because of the interest in gender differences of the SCG, the effect of gender will be assessed.
Because of other possible influences in difference of SCG volume the effect of age and assessor will also be assessed.

2.2b Materials

(a) Indicate which tests, stimuli, equipment, etc. will be used; provide sufficiently elaborate escriptions.
For an extensive description of the parcellation method of the SCG see McCormick et al. (2006).

2.3 Data Analyses

(a) Justify the choice of statistical analyses.
See point 2.2a (b)

(b) Indicate how each of the research questions are translated into statistical predictions?
H0. There is no significant effect for gender in the volume of the SCG
H1. There is a significant effect for gender in the volume of the SCG

References
Blumberger, D. M., Mulsant, B. H., & Daskalakis, Z. J. (2013). What Is the Role of Brain Stimulation Therapies in the Treatment of Depression? Current Psychiatry Reports, 15(7), 368. https://doi.org/10.1007/s11920-013-0368-1
Botteron, K. N., Raichle, M. E., Drevets, W. C., Heath, A. C., & Todd, R. D. (2002). Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biological Psychiatry, 51(4), 342–344. https://doi.org/https://doi.org/10.1016/S0006-3223(01)01280-X
Bromet, E., Andrade, L. H., Hwang, I., Sampson, N. A., Alonso, J., de Girolamo, G., … Kessler, R. C. (2011). Cross-national epidemiology of DSM-IV major depressive episode. BMC Medicine. https://doi.org/10.1186/1741-7015-9-90
Dandekar, M. P., Fenoy, A. J., Carvalho, A. F., Soares, J. C., & Quevedo, J. (2018). Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Molecular Psychiatry, 23, 1094. Retrieved from https://doi.org/10.1038/mp.2018.2
Garcia-Falgueras, A., Junque, C., Giménez, M., Caldú, X., Segovia, S., & Guillamon, A. (2006). Sex differences in the human olfactory system. Brain Research, 1116(1), 103–111. https://doi.org/10.1016/J.BRAINRES.2006.07.115
Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., & Lozano, A. M. (2009). Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting. Journal of Neurosurgery JNS, 111(6), 1209–1215. https://doi.org/10.3171/2008.10.JNS08763
Hays, R. D., Wells, K. B., Sherbourne, C. D., Rogers, W., & Spritzer, K. (1995). Functioning and Well-being Outcomes of Patients With Depression Compared With Chronic General Medical Illnesses. JAMA Psychiatry, 52(1), 11–19. https://doi.org/10.1001/archpsyc.1995.03950130011002
Holtzheimer, P. E., Husain, M. M., Lisanby, S. H., Taylor, S. F., Whitworth, L. A., McClintock, S., … Mayberg, H. S. (2017). Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. The Lancet Psychiatry, 4(11), 839–849. https://doi.org/10.1016/S2215-0366(17)30371-1
Marcus, S. M., Young, E. A., Kerber, K. B., Kornstein, S., Farabaugh, A. H., Mitchell, J., … Rush, A. J. (2005). Gender differences in depression: Findings from the STAR*D study. Journal of Affective Disorders, 87(2), 141–150. https://doi.org/https://doi.org/10.1016/j.jad.2004.09.008
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., … Kennedy, S. H. (2005). Deep Brain Stimulation for Treatment-Resistant Depression. Neuron, 45(5), 651–660. https://doi.org/10.1016/J.NEURON.2005.02.014
McCormick, L. M., Ziebell, S., Nopoulos, P., Cassell, M., Andreasen, N. C., & Brumm, M. (2006). Anterior cingulate cortex: An MRI-based parcellation method. NeuroImage, 32(3), 1167–1175. https://doi.org/10.1016/J.NEUROIMAGE.2006.04.227
McIntyre, R. S., Filteau, M.-J., Martin, L., Patry, S., Carvalho, A., Cha, D. S., … Miguelez, M. (2014). Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach. Journal of Affective Disorders, 156, 1–7. https://doi.org/10.1016/J.JAD.2013.10.043
Wells, K. B., Stewart, A., Hays, R. D., Burnam, M. A., Rogers, W., Daniels, M., … Ware, J. (1989). The functioning and well-being of depressed patients: results from the Medical Outcomes Study. Jama, 262(7), 914–919.
World Health Organization. (2017). Depression and Other Common Mental Disorders. Cc By-Nc-Sa 3.0 Igo. https://doi.org/CC BY-NC-SA 3.0 IGO

MODIFIABILITY

1. Is there room for modification of the intended sample characteristics? * yes / no
   (motivate)
   Yes, there is room for modification of the intended sample characteristics. Although the sample of this research is part of a larger project in which a fixed battery of tests is already in use, there is room for modification. If for good reasons such as time management or unreliable data the intended 96 subjects will not be completed there is room for modification.

2a Is there room for modification of the intended operationalization? * yes / no
No, modification of the intended operationalization could possibly change the goal of the research. Therefore, the operationalization methods will be pre-fixed.

2b Is there room for modification of the intended materials? * yes / no
(motivate)
Yes, if the modification of the materials is not too divergent of the materials used by McCormick et al. (2006) there is room for modification. But only after validity and reliability of the materials is justified.

1. Is there room for modification of the intended data analyses? * yes / no
   Yes, there is room to add data analyses but no room for excluding the intended data analyses. The intended data analyses are of great importance to the hypotheses and research questions. Yet, the results of the intended hypothesis leave room for the addition of other explorative analyses that could described effects that are (not) found.
2. INTENDED RESULTS AND FEEDBACK

The results of the intended research will provide the first suggestions in possible differences in morphological characteristics of the SCG between gender. If results suggest differences in the WM of the SCG, the approach in treating MDD and TRD by DBS should be reconsidered. Perhaps an altered approach in targeting the SCG should be considered, specifically and independently for males and females. If the results do not suggest differences in the WM of the SCG an alternated approach should not be suggested yet. Nevertheless, the results of the intended research are to date expected to be novel and therefore not conclusive. Furthermore, the sample of subjects used in this research consists of healthy subjects, thus either way the results of this study will conclude, generalisation to MDD or TRD patients should be treated cautious. Further research on the morphological characteristics of the SCG of subjects with MDD and TRD is suggested independent of the results of this explorative research.

1. WORK PLAN
   3.1 Time schedule
   Intended period for data collection: 09-05-2019 to 24-06-2019
   Intended period for data analysis and writing of thesis: 24-06-2019 to 05-08-2019
   Intended submission date for final thesis: 08-08-2019
   Intended time investment: Monday to Saturday 7 hours a day which makes a total of 42 hours every week.
   If problems arise with time management, additional analyses can be skipped.

3.3 Sample
An existing pool of data will be used, from this pool a sample of 96 subjects will be taken. Because this research will consist out of healthy subjects there is no control group. Access to the data pool will go through an protected VPN server that the University of Amsterdam will provide. Therefore, data is protected and complies with modern privacy regulations.

3.4 Infrastructure
Research will be conducted in the laboratory of the University of Amsterdam. Access is assured through senior researchers in this field such as dr. J.M. (Anneke) Alkemade who will guide me.

1. FURTHER STEPS AND SIGNATURES
   Make sure to submit an Ethics Checklist for your intended research to the Ethics Committee of the Department of Psychology if necessary. Submit the research proposal by e-mail to your supervisor at the proposed deadline.
   To do