Skip to main content Accessibility help

Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder

  • Michelle T. Kassel (a1) (a2), Julia A. Rao (a1), Sara J. Walker (a2), Emily M. Briceño (a2) (a3), Laura B. Gabriel (a1), Anne L. Weldon (a1), Erich T. Avery (a2), Brennan D. Haase (a2), Marta Peciña (a2), Ciaran M. Considine (a2), Douglas C. Noll (a2), Linas A. Bieliauskas (a2), Monica N. Starkman (a2), Jon-Kar Zubieta (a2), Robert C. Welsh (a2), Bruno Giordani (a2), Sara L. Weisenbach (a1) (a2) (a4) and Scott A. Langenecker (a2)...


Objectives: Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. Methods: Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. Results: MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. Conclusions: Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD. (JINS, 2016, 22, 412–425)


Corresponding author

Correspondence and reprint requests to: Scott A. Langenecker, University of Illinois at Chicago, Department of Psychiatry, 1601 W. Taylor St. M/C 912 Chicago, IL 60612. E-mail:


Hide All
Ai, H., Opmeer, E.M., Veltman, D.J., van der Wee, N.J.A., van Buchem, M.A., Aleman, A., & van Tol, M.-J. (2015). Brain activation during emotional memory processing associated with subsequent course of depression. Neuropsychopharmacology, 40, 24542463.
Army Individual Test Battery. (1944). Manual of Directions and Scoring. Washington, D.C.: War Department, Adjutant General’s Office.
Ashendorf, L., Constantinou, M., & McCaffrey, R.J. (2004). The effect of depression and anxiety on the TOMM in community-dwelling older adults. Archives of Clinical Neuropsychology, 19(1), 125130.
Beason-Held, L.L., Golski, S., Kraut, M.A., Esposito, G., & Resnick, S.M. (2005). Brain activation during encoding and recognition of verbal and figural information in older adults. Neurobiology of Aging, 26(2), 237250.
Bora, E., Harrison, B.J., Davey, C.G., Yücel, M., & Pantelis, C. (2012). Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder. Psychological Medicine, 42, 671681.
Bora, E., Harrison, B.J., Yücel, M., & Pantelis, C. (2013). Cognitive impairment in euthymic major depressive disorder: A meta-analysis. Psychological Medicine, 43, 20172026.
Bradley, M.N., & Lang, P.J. (1999). Affective norms for English words (ANEW). Gainesville, FL: NIMH Center for the Study of Emotion and Attention.
Braskie, M.N., Small, G.W., & Bookheimer, S.Y. (2009). Entorhinal cortex structural and functional MRI response during an associative verbal memory task. Human Brain Mapping, 30, 39813992.
Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., & Charney, D.S. (2000). Hippocampal volume reduction in major depression. The American Journal of Psychiatry, 157(1), 115117.
Bremner, J.D. (2004). Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. The American Journal of Psychiatry, 161(4), 637645.
Brett, M., Anton, J.L., Valabregue, R., & Poline, J.P. (2002). Region of interest analysis using an SPM toolbox. Neuroimage, 16, 497.
Brown, J.A. (1958). Some tests of the decay theory of immediate memory. Quarterly Journal of Experimental Psychology, 10, 1221.
Camara, W.J., Nathan, J.S., & Puente, A.E. (2000). Psychological test usage: Implications in professional psychology. Professional Psychology: Research and Practice, 31, 141154.
Cole, J., Costafreda, S.G., McGuffin, P., & Fu, C.H.Y. (2011). Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies. Journal of Affective Disorders, 134, 483487.
Considine, C.M., Weisenbach, S.L., Walker, S.J., McFadden, E.M., Franti, L.M., Bieliauskas, L.A., & Langenecker, S.A. (2011). Auditory memory decrements, without dissimulation, among patents with major depressive disorder. Archives of Clinical Neuropsychology, 26, 445453.
Delis, D., Kramer, J., Kaplan, E., & Ober, B. (2000). California Verbal Learning Test-II. San Antonio, TX: The Psychological Corporation.
Dietsche, B., Backes, H., Stratmann, M., Konrad, C., Kircher, T., & Krug, A. (2014). Altered neural function during episodic memory encoding and retrieval in major depression. Human Brain Mapping, 35, 42934302.
Elderkin-Thompson, V., Moody, T., Knowlton, B., Hellemann, G., & Kumar, A. (2011). Explicit and implicit memory in late-life depression. The American Journal of Geriatric Psychiatry, 19(4), 364373.
First, M.B., Spitzer, R.L., & Gibbon, M. (1995). Structured clinical interview for DSM-IV axis I disorder. New York: Biometrics Research Department, New York State Psychiatric Institute.
Friston, K., Ashburner, J., Frith, C., Poline, J.-B., Heather, J., & Frackowiak, R. (1995). Spatial registration and normalization of images. Human Brain Mapping, 2, 165189.
Glover, G.H., & Thomason, M.E. (2004). Improved combination of spiral-in/out images for BOLD fMRI. Magnetic Resonance in Medicine, 51(4), 863868.
Grant, D.A., & Berg, E. (1948). A behavioral analysis of degree of reinforcement and ease of shifting to new responses in Weigl-type card-sorting problem. Journal of Experimental Psychology, 38, 404–411.
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, & Psychiatry, 23, 5662.
Hermens, D.F., Naismith, S.L., Redoblado-Hodge, M.A., Scott, E.M., & Hickie, I.B. (2010). Impaired verbal memory in young adults with unipolar and bipolar depression. Early Intervention in Psychiatry, 3, 227233.
Hsu, D.T., Langenecker, S.A., Kennedy, S.E., Zubieta, J.-K., & Heitzeg, M.M. (2010). FMRI BOLD responses to negative stimuli in the prefrontal cortex are dependent on levels of recent negative life stress in major depressive disorder. Psychiatry Research: Neuroimaging, 123(3), 202208.
Kempton, M.J., Salvador, Z., Munafò, M.R., Geddes, J.R., Simmons, A., Frangou, S., & Williams, S.C.R. (2011). Structural neuroimaging studies in major depressive disorder: Meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry, 68(7), 675690.
Kim, H. (2011). Neural activity that predicts subsequent memory and forgetting: A meta-analyses of 74 fMRI studies. Neuroimage, 54, 24462461.
Langenecker, S.A., Caveney, A.F., Persad, C.P., & Giordani, B. (2004). Semantic List Learning Test. Ann Arbor: University of Michigan.
Langenecker, S.A., Kennedy, S.E., Guidotti, L.M., Briceño, E.M., Own, L.S., Hooven, T., & Zubieta, J.-K. (2007). Frontal and limbic activation during inhibitory control predicts treatment response in major depressive disorder. Biological Psychiatry, 62, 12721280.
Langenecker, S.A., Zubieta, J.-K., Young, E.A., Akil, H., & Nielson, K.A. (2007). A task to manipulate attentional load, set-shifting, and inhibitory control: Convergent validity and test-retest reliability of the Parametric Go/No-Go Test. Journal of Clinical and Experimental Neuropsychology, 29, 842853.
Langenecker, S.A., Lee, H.J., & Bieliauskas, L.A. (2009). Neuropsychology of depression and related mood disorders. In I. Grant & K. Adams (Eds.), Neuropsychological assessment of neuropsychiatric and neuromedical disorders (pp. 532559). UK: Oxford University Press.
Langenecker, S.A., Weisenbach, S.L., Giordani, B., Briceño, E.M., Guidotti-Breting, L.M., Schallmo, M.-P., & Starkman, M.N. (2012). Chronic hypercortisolemia and affective dysfunction. Neuropharmacology, 62(1), 217225.
Lee, A.L., Ogle, W.O., & Sapolsky, R.M. (2002). Stress and depression: Possible links to neuron death in the hippocampus. Bipolar Disorders, 4(2), 117128.
Liu, X., Li, L., Xiao, J., Yang, J., & Jiang, X. (2013). Abnormalities of autobiographical memory of patients with depressive disorders: A meta-analysis. Psychology and Psychotherapy: Theory, Research and Practice, 86(4), 353373.
MacQueen, G.M., Yucel, K., Taylor, V.H., Macdonald, K., & Joffe, R. (2008). Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biological Psychiatry, 64, 880883.
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(3), 252264.
Maldjian, J.A., Laurienti, P.J., Burdette, J.B., & Kraft, R.A. (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage, 19, 12331239.
Maldjian, J.A., Laurienti, P.J., & Burdette, J.B. (2004). Precentral gyrus discrepancy in electronic versions of the Talairach Atlas. Neuroimage, 21(1), 450455.
McEwen, B.S., Magariños, A.M., & Reagan, L.P. (2002). Studies of hormone action in the hippocampal formation: Possible relevance to depression and diabetes. Journal of Psychosomatic Research, 53(3), 883890.
Miller, G.A., & Chapman, J.P. (2001). Misunderstanding analysis of covariance. Journal of Abnormal Psychology, 110(1), 4048.
Milne, A.M.B., MacQueen, G.M., & Hall, G.B.C. (2012). Abnormal hippocampal activation in patients with extensive history of major depression: An fMRI study. Journal of Psychiatry and Neuroscience, 31(1), 2836.
Mulligan, N.W. (2011). Implicit memory and depression: Preserved conceptual priming in subclinical depression. Cognition and Emotion, 25(4), 730739.
Papez, J.W. (1937). A proposed mechanism of emotion. Archives of Neurology and Psychiatry, 7, 103112.
Peterson, L.R., & Peterson, M.J. (1959). Short-term retention of individual verbal items. Journal of Experimental Psychology, 58, 193198.
Rabin, L.A., Barr, W.B., & Burton, L.A. (2005). Assessment practices of clinical neuropsychologists in the United States and Canada: A survey of INS, NAN, and APA Division 40 members. Archives of Clinical Neuropsycholoy, 20, 3365.
Rees, L., Tombaugh, T., & Boulay, L. (2001). Depression and the Test of Memory Malingering. Archives of Clinical Neuropsychology, 16, 501–506.
Riggs, E., Carr, A., Bogue, J., & Dooley, B. (2005). Reductions in specific first memories in depression: Influences of distraction, referential set and cue word valence on first memory retrieval. The Irish Journal of Psychology, 26(3-4), 177184.
Roberson-Nay, R., McClure, E.B., Monk, C.S., Nelson, E.E., Guyer, A.E., Fromm, S.J., & Pine, D.S. (2006). Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An fMRI study. Biological Psychiatry, 60(9), 966973.
Rogers, M.A., Kasai, K., Koji, M., Fukuda, R., Iwanami, A., Nakagome, K., & Kato, N. (2004). Executive and prefrontal dysfunction in unipolar depression: A review of neuropsychological and imaging evidence. Neuroscience Research, 50, 111.
Rohling, M.L., & Scogin, F. (1993). Automatic and effortful memory processes in depressed persons. Journal of Gerontology, 48, 87–95.
Sapolsky, R.M. (2000). The possibility of neurotoxicity in the hippocampus in major depression: A primer on neuron death. Biological Psychiatry, 48(8), 755765.
Schallmo, M.-P., Kassel, M.T., Weisenbach, S.L., Walker, S.J., Guidotti-Breting, L.M., Rao, J.A., & Langenecker, S.A. (2015). A new semantic list learning task to parse the functioning of the Papez circuit. Journal of Clinical and Experimental Neuropsychology, 37(8), 816833.
Sheline, Y.I., Gado, M.H., & Kraemer, H.C. (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry, 160(8), 15161518.
Snyder, H. (2013). Major Depressive Disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review. Psychological Bulletin, 139(1), 81–132.
Squire, L.R. (1992). Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychological Review, 99, 195231.
Votruba, K.L., & Langenecker, S.A. (2013). Factor structure, construct validity, and age- and education-based normative data for the Parametric Go/No-Go Test. Journal of Clinical and Experimental Neuropsychology, 35(2), 132–146. doi:10.1080/13803395.2012.758239
Watkins, E., & Brown, R.G. (2002). Rumination and executive function in depression: An experimental study. Journal of Neurology, Neurosurgery, & Psychiatry, 72, 400402.
Weisenbach, S.L., Kassel, M.T., Rao, J.A., Weldon, A.L., Avery, E.T., Briceño, E.M., & Langenecker, S.A. (2014). Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late life depression. International Journal of Geriatric Psychiatry, 29, 11041115.
Weisenbach, S.L., Marshall, D.F., Weldon, A.L., Ryan, K.A., Vederman, A.C., Kamali, M., & Langenecker, S.A. (2014). The double burden of age and disease on cognition and quality of life in bipolar disorder. International Journal of Geriatric Psychiatry, 29(9), 952961.
Werner, N.S., Meindl, T., Materne, J., Engel, R.R., Huber, D., Riedel, M., & Hennig-Fast, K. (2009). Functional MRI study of memory-related brain regions in patients with depressive disorder. Journal of Affective Disorders, 119, 124131.
World Health Organization (2008). The global burden of disease: 2004 update. Geneva: WHO.


Type Description Title
Supplementary materials

Kassel supplementary material
Figure S1A

 PDF (2.4 MB)
2.4 MB
Supplementary materials

Kassel supplementary material
Figure S1B

 PDF (2.2 MB)
2.2 MB
Supplementary materials

Kassel supplementary material
Tables S1-S3

 Word (25 KB)
25 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