Skip to main content Accessibility help

Structural and functional imaging of the hippocampus in young people at familial risk of depression

  • Z. N. Mannie (a1), N. Filippini (a1), C. Williams (a1), J. Near (a1), C. E. Mackay (a1) and P. J. Cowen (a1)...
  • Please note a correction has been issued for this article.



Major depression is associated with abnormalities in the function and structure of the hippocampus. However, it is unclear whether these abnormalities might also be present in people ‘at risk’ of illness.


We studied 62 young people (mean age 18.8 years) at familial risk of depression (FH+) but who had never been depressed themselves. Participants underwent magnetic resonance imaging to assess hippocampal structure and neural responses to a task designed to activate hippocampal memory networks. Magnetic resonance spectroscopy was used to measure levels of a combination of glutamine and glutamate (Glx) in the right hippocampus. A total of 59 matched controls with no history of mood disorder in a first-degree relative underwent the same investigations.


Hippocampal volume did not differ between FH+ participants and controls; however, relative to controls, during the memory task, FH+ participants showed increased activation in brain regions encompassing the insular cortices, putamen and pallidum as well as the dorsal anterior cingulate cortex (ACC). FH+ participants also had increased hippocampal levels of Glx.


Euthymic individuals with a parental history of depression demonstrate increased activation of hippocampal-related neural networks during a memory task, particularly in brain regions involved in processing the salience of stimuli. Changes in the activity of the ACC replicate previous findings in FH+ participants using different psychological tasks; this suggests that task-related abnormalities in the ACC may be a marker of vulnerability to depression. Increased levels of Glx in the hippocampus might also represent a risk biomarker but follow-up studies will be required to test these various possibilities.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Structural and functional imaging of the hippocampus in young people at familial risk of depression
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Structural and functional imaging of the hippocampus in young people at familial risk of depression
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Structural and functional imaging of the hippocampus in young people at familial risk of depression
      Available formats


The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence .

Corresponding author

* Address for correspondence: P. J. Cowen, M.D., FRCPsych, University of Oxford, Oxford, UK. (Email:


Hide All
Amico, F, Meisenzahl, E, Koutsouleris, N, Resier, M, Moller, HJ, Frodl, T (2011). Structural MRI correlates for vulnerability and resilience to major depressive disorder. Journal of Psychiatry and Neuroscience 36, 1522.
Andreasen, NC, Rice, J, Endicott, J, Reich, T, Coryell, W (1986). The family history approach to diagnosis. How useful is it? Archives of General Psychiatry 43, 421429.
Baaré, WFC, Vinberg, M, Knudsen, GM, Paulson, OB, Langkilde, AR, Jernigan, TL, Kessing, LV (2010). Hippocampal volume changes in healthy subjects at risk of unipolar depression. Journal of Psychiatric Research 44, 655662.
Beardslee, WR, Versage, EM, Gladstone, TR (1998). Children of affectively ill parents: a review of the past 10 years. American Journal of Child Adolescent Psychiatry 37, 11341141.
Block, W, Träber, F, von Widdern, M, Metten, H, Schild, W, Maier, W, Zobel, A, Jessen, F (2008). Proton MR spectroscopy of the hippocampus at 3 T in patients with unipolar major depressive disorder: correlates and predictors of treatment response. International Journal of Neuropsychopharmacology 12, 415422.
Bottomley, PA (1987). Spatial localization in NMR spectroscopy in vivo . Annals of the New York Academy of Sciences 508, 333348.
Bremner, JD, Vythilingam, M, Vermetten, E, Vaccarino, V, Charney, DS (2004). Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. American Journal of Psychiatry 161, 637645.
Campbell, S, Marriott, M, Nahmias, C, MacQueen, GM (2004). Lower hippocampal volume in patients suffering from depression: a meta-analysis. American Journal of Psychiatry 161, 598607.
Carballedo, A, Lisiecka, D, Fagan, A, Saleh, K, Ferguson, Y, Connolley, G, Meaney, J, Frodl, T (2012). Early life adversity is associated with brain changes in subjects at family risk for depression. World Journal of Biological Psychiatry 13, 569578.
Chen, MC, Hamilton, JP, Gotlib, IH (2010). Decreased hippocampal volume in healthy girls at risk of depression. Archives of General Psychiatry 67, 270276.
Cohen, S, Kamarck, T, Mermelstein, R (1983). A global measure of perceived stress. Journal of Health and Social Behaviour 24, 386396.
Cole, J, Costafreda, SG, McGuffin, P, Fu, CHY (2011). Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging studies. Journal of Affective Disorders 134, 483487.
Cole, J, Toga, AW, Hojatkashani, C, Thompson, P, Costafreda, SG, Clear, AJ, Williams, SCR, Bullmore, ET, Scott, JL, Mitterschiffthaler, MT, Walsh, ND, Donaldson, C, Mirza, M, Marquand, A, Nosarti, C, McGuffin, P, Fu, CHY (2010). Subregional hippocampal deformations in major depressive disorder. Journal of Affective Disorders 126, 272277.
de Geus, EJC, van't Ent, D, Wolfenberger, SPA, Heutink, P, Hoogendijk, WJG, Boomsa, DI, Veltman, DJ (2007). Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression Biological Psychiatry 61, 10621071.
di Diego-Adelino, J, Portella, MJ, Gomez-Anson, B, Lopez-Moruelo, O, Serra, BM, Vives, Y, Puigdemont, D, Perez-Egea, R, Alvarez, E, Perez, V (2013). Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness and burden. Journal of Psychiatry and Neuroscience 38, 107116.
Douaud, G, Smith, S, Jenkinson, M, Behrens, T, Johansen-Berg, H, Vickers, J, James, S, Voets, N, Watkins, K, Matthews, PM, James, A (2007). Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain 130, 23752386.
Fairhall, SL, Sharma, S, Magnusson, J, Murphy, B (2010). Memory related dysregulation of hippocampal function in major depressive disorder. Biological Psychiatry 85, 499503.
Filippini, N, Bradley, J, MacIntosh, B J, Hough, MG, Goodwin, GM, Frisoni, GB, Smith, SM, Matthews, PM, Beckmann, CF, Mackay, CE (2009). Distinct patterns of brain activity in young carriers of the APOE-e4 allele. Proceedings of the National Academy of Sciences 106, 72097214.
First, MB, Spitzer, RL, Gibbon, M, Williams, JB (1997). Structured Clinical Interview for DSM-IV Axis I Disorders: Clinical Version. American Psychiatric Association: Washington, DC.
Fleisher, AS, Houston, WS, Eyler, LT, Frye, S, Jenkins, C, Thal, LJ, Bondi, MW (2005). Identification of Alzheimer disease risk by functional magnetic resonance imaging. Archives of Neurology 62, 18811888.
Golby, A, Silverberg, G, Race, E, Gabrieli, S, O'Shea, J, Knierim, K, Stebbins, G, Gabrieli, J (2005). Memory encoding in Alzheimer's disease: an fMRI study of explicit and implicit memory. Brain 128, 773778.
Goodyer, IM, Herbert, J, Tamplin, A, Secher, SM, Pearson, J (1997). Outcome of major depression, II: life events, family dysfunction and friendship difficulties as predictors of persistent disorder. Journal of the American Academy of Child and Adolescent Psychiatry 36, 474480.
Kelly, R, Garrett, A, Cohen, J, Gomez, R, Lembke, A, Keller, J, Reiss, AL, Schatzberg, A (2013). Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression. Psychiatry Research-NeuroImaging 211, 119126.
Kempton, MJ, Salvador, Z, Munafo, MR, Geddes, JR, Simmons, A, Frangou, S, Williams, SCR (2011). Structural neuroimaging studies in major depressive disorder: meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry 68, 675690.
Lisiecka, DM, Carbadello, A, Fagan, AJ, Ferguson, Y, Meaney, J, Frodl, T (2013). Recruitment of the left hemispheric emotional attention neural network in risk for and protection from depression. Journal of Psychiatry and Neuroscience 38, 117128.
MacQueen, G, Frodl, T (2011). The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Molecular Psychiatry 16, 252264.
MacQueen, GM, Campbell, S, McEwen, BS, Macdonald, K, Amano, S, Joffe, RT (2003). Course of illness, hippocampal function, and hippocampal volume in major depression. Proceedings of the National Academy of Sciences USA 100, 13871392.
Mannie, ZN, Barnes, J, Bristow, GC, Harmer, CJ, Cowen, PJ (2009). Memory impairment in young women at increased risk of depression: influence of cortisol and 5-HTT genotype. Psychological Medicine 39, 757762.
Mannie, ZN, Harmer, CJ, Cowen, PJ, Norbury, R (2010). A functional magnetic resonance imaging study of verbal working memory in young people at increased familial risk of depression. Biological Psychiatry 67, 471477.
Mannie, ZN, Norbury, R, Murphy, SE, Inkster, B, Harmer, CJ, Cowen, PJ (2008). Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression. British Journal of Psychiatry 192, 356361.
McCabe, C, Wiffindale, C, Harmer, CJ, Cowen, PJ (2012). Neural processing of reward and punishment in young people at increased familial risk of depression. Biological Psychiatry 72, 588594.
Milne, A, MacQueen, GM, Yucel, K, Soreni, N, Hall, GB (2009). Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: a proton magnetic resonance spectroscopy study. NeuroImage 47, 3641.
Milne, AMB, MacQueen, GM, Hall, GBC (2012). Abnormal hippocampal activation in patients with extensive history of major depression: an FMRI study. Journal of Psychiatry and Neuroscience 37, 2836.
Moylan, S, Maes, M, Wray, NR, Berk, M (2013). The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Molecular Psychiatry 18, 595606.
Near, J, Edden, R, Evans, CJ, Pacquin, R, Harris, A, Jezzard, P (2014). Frequency and phase drift correction of magnetic resonance spectroscopy data by spectral registration in the time domain. Magnetic Resonance in Medicine. Published online 16 January 2014 . doi:10.1002/mrm.25094.
Oertel-Knöchel, V, Reinke, B, Feddern, R, Knake, A, Knöchel, C, Prvulovic, D, Fuβer, F, Karakaya, T, Loellgen, D, Freitag, C, Pantel, J, Linden, DEJ (2013). Verbal episodic memory deficits in remitted bipolar patients: a combined behavioural and fMRI study. Journal of Affective Disorders 150, 430440.
Oldfield, RC (1971). The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9, 97113.
Parker, G (1979). Parental characteristics in relation to depressive disorders. British Journal of Psychiatry 134, 138147.
Patenaude, B, Smith, SM, Kennedy, DN, Jenkinson, M (2011). A Bayesian model of shape and appearance for subcortical brain segmentation. NeuroImage 56, 907922.
Provencher, SW (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance Medicine 30, 672679.
Rao, U, Chen, LA, Bidesi, AS, Shad, MU, Thomas, MA, Hammen, CL (2010). Hippocampal changes associated with early life adversity and vulnerability to depression. Biological Psychiatry 67, 357364.
Rottschy, C, Langer, R, Dogan, I, Reetz, K, Laird, AR, Schultz, JB, Fox, PT, Eickhoff, SB (2012). Modelling neural correlates of working memory: a coordinate-based meta-analysis. NeuroImage 60, 830846.
Smith, S, Jenkinson, M, Woolrich, MW, Beckman, CF, Behrens, TEJ, Johansen-Berg, H, Banister, PR, De Luca, M, Drobnjak, I, Flitney, DE, Niazy, RK, Saunders, J, Vickers, J, Zhang, Y, De Stefano, N, Brady, JM, Matthews, PM (2004). Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23, S208S219.
Taylor, MJ, Mannie, ZN, Norbury, R, Near, J, Cowen, PJ (2011). Elevated cortical glutamate in young people at increased familial risk of depression. International Journal of Neuropsychopharmacology 14, 255259.
Toki, S, Okamoto, Y, Onoda, K, Matsumoto, T, Yoshimura, S, Kunisato, Y, Okada, G, Shishida, K, Kobayakawa, M, Fukomoto, T, Machino, A, Inagaki, M, Yamawaki, S (2014). Hippocampal activation during associative encoding of word pairs and its relation to symptomatic improvement in depression: a functional and volumetric fMRI study. Journal of Affective Disorders 152–154, 462467.
Werner, NS, Meindl, T, Materne, J, Engel, R, Huber, D, Riedel, M, Reiser, M, Hennig-Fast, K (2009). Functional MRI study of memory-related brain regions in patients with depressive disorder. Journal of Affective Disorders 119, 124131.
Woolrich, M (2008). Robust group analysis using outlier inference. NeuroImage 41, 286301.
Woolrich, MW, Behrens, TE, Beckmann, CF, Jenkinson, M, Smith, SM (2004). Multilevel linear modeling for fMRI group analysis using Bayesian inference. NeuroImage 21, 17321747.
Yassa, MA, Stark, CEL (2008). Multiple signals of recognition memory in the medial temporal lobe. Hippocampus 18, 945954.
Yuksel, C, Ongur, D (2010). Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biological Psychiatry 68, 785794.
Zakzanis, KK, Leach, L, Kaplan, E (1998). On the nature and pattern of neurocognitive function in major depressive disorder. Neuropsychiatry, Neuropsychology and Behavioral Neurology 11, 111119.
Zigmond, AS, Snaith, RP (1983). The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica 67, 361370.


Type Description Title
Supplementary materials

Supplementary Material
Supplementary information supplied by authors.

 Word (30 KB)
30 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

A correction has been issued for this article: