Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging

Abstract

Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non–rapid eye movement (NREM) sleep and impaired long-term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age-related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep–dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The sleep-dependent episodic word-pair task6,9 used word-nonsense word pairs to maximize the novel episodic and associated hippocampal-dependent demands of the task33 and minimize the semantic, and therefore hippocampal-independent, demands of the task11,12,33.
Figure 2: Age differences in SWA.
Figure 3: Age differences in gray matter volume and associations with SWA and memory.
Figure 4: Age differences in memory retention.
Figure 5: SWA predicts overnight memory change in young and older adults.
Figure 6: Model schematic of mediation findings.
Figure 7: Differences in hippocampal activation and hippocampal-prefrontal task-related functional connectivity are associated with SWA and memory change.

References

  1. 1

    Buckner, R.L. Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 44, 195–208 (2004).

    Article  CAS  Google Scholar 

  2. 2

    Backhaus, J. et al. Midlife decline in declarative memory consolidation is correlated with a decline in slow wave sleep. Learn. Mem. 14, 336–341 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Sowell, E.R. et al. Mapping cortical change across the human life span. Nat. Neurosci. 6, 309–315 (2003).

    Article  CAS  Google Scholar 

  4. 4

    Dijk, D.J., Beersma, D.G. & van den Hoofdakker, R.H. All night spectral analysis of EEG sleep in young adult and middle-aged male subjects. Neurobiol. Aging 10, 677–682 (1989).

    Article  CAS  Google Scholar 

  5. 5

    Van Cauter, E., Leproult, R. & Plat, L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. J. Am. Med. Assoc. 284, 861–868 (2000).

    Article  CAS  Google Scholar 

  6. 6

    Diekelmann, S. & Born, J. The memory function of sleep. Nat. Rev. Neurosci. 11, 114–126 (2010).

    Article  CAS  Google Scholar 

  7. 7

    Walker, M.P. The role of sleep in cognition and emotion. Ann. NY Acad. Sci. 1156, 168–197 (2009).

    Article  Google Scholar 

  8. 8

    Takashima, A. et al. Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study. Proc. Natl. Acad. Sci. USA 103, 756–761 (2006).

    Article  CAS  Google Scholar 

  9. 9

    Marshall, L., Helgadottir, H., Molle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Buzsáki, G. The hippocampo-neocortical dialogue. Cereb. Cortex 6, 81–92 (1996).

    Article  Google Scholar 

  11. 11

    Frankland, P.W. & Bontempi, B. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130 (2005).

    Article  CAS  Google Scholar 

  12. 12

    Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Gais, S. et al. Sleep transforms the cerebral trace of declarative memories. Proc. Natl. Acad. Sci. USA 104, 18778–18783 (2007).

    Article  Google Scholar 

  14. 14

    Westerberg, C.E. et al. Concurrent impairments in sleep and memory in amnestic mild cognitive impairment. J. Int. Neuropsychol. Soc. 18, 490–500 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Vitiello, M.V. Recent advances in understanding sleep and sleep disturbances in older adults: growing older does not mean sleeping poorly. Curr. Dir. Psychol. Sci. 18, 316–320 (2009).

    Article  Google Scholar 

  16. 16

    Murphy, M. et al. Source modeling sleep slow waves. Proc. Natl. Acad. Sci. USA 106, 1608–1613 (2009).

    Article  Google Scholar 

  17. 17

    Marzano, C., Ferrara, M., Curcio, G. & De Gennaro, L. The effects of sleep deprivation in humans: topographical electroencephalogram changes in non-rapid eye movement (NREM) sleep versus REM sleep. J. Sleep Res. 19, 260–268 (2010).

    Article  Google Scholar 

  18. 18

    Nadel, L., Campbell, J. & Ryan, L. Autobiographical memory retrieval and hippocampal activation as a function of repetition and the passage of time. Neural Plast. 2007, 90472 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Dijk, D.J., Hayes, B. & Czeisler, C.A. Dynamics of electroencephalographic sleep spindles and slow wave activity in men: effect of sleep deprivation. Brain Res. 626, 190–199 (1993).

    Article  CAS  Google Scholar 

  20. 20

    MacKinnon, D.P., Warsi, G. & Dwyer, J.H. A simulation study of mediated effect measures. Multivariate Behav. Res. 30, 41–62 (1995).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Mormino, E.C. et al. Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 132, 1310–1323 (2009).

    Article  CAS  Google Scholar 

  22. 22

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B Stat. Methodol. 57, 289–300 (1995).

    Google Scholar 

  23. 23

    Horne, J.A. & Ostberg, O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int. J. Chronobiol. 4, 97–110 (1976).

    CAS  PubMed  Google Scholar 

  24. 24

    Monk, T.H. A visual analogue scale technique to measure global vigor and affect. Psychiatry Res. 27, 89–99 (1989).

    Article  CAS  Google Scholar 

  25. 25

    Johns, M.W. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14, 540–545 (1991).

    Article  CAS  Google Scholar 

  26. 26

    Mander, B.A., Santhanam, S., Saletin, J.M. & Walker, M.P. Wake deterioration and sleep restoration of human learning. Curr. Biol. 21, R183–R184 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Kang, J.E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Albert, M.S. The ageing brain: normal and abnormal memory. Phil. Trans. R. Soc. Lond. B 352, 1703–1709 (1997).

    Article  CAS  Google Scholar 

  29. 29

    Davis, H.P. et al. Acquisition, recall and forgetting of verbal information in long-term memory by young, middle-aged, and elderly individuals. Cortex 39, 1063–1091 (2003).

    Article  Google Scholar 

  30. 30

    Buchmann, A. et al. EEG sleep slow-wave activity as a mirror of cortical maturation. Cereb. Cortex 21, 607–615 (2011).

    Article  Google Scholar 

  31. 31

    Naylor, E. et al. Daily social and physical activity increases slow-wave sleep and daytime neuropsychological performance in the elderly. Sleep 23, 87–95 (2000).

    Article  CAS  Google Scholar 

  32. 32

    Van Cauter, E. et al. Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men. J. Clin. Invest. 100, 745–753 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Otten, L.J., Sveen, J. & Quayle, A.H. Distinct patterns of neural activity during memory formation of nonwords versus words. J. Cogn. Neurosci. 19, 1776–1789 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Nelson, D.L., McEvoy, C.L. & Schreiber, T.A. The University of South Florida free association, rhyme and word fragment norms. Behav. Res. Methods Instrum. Comput. 36, 402–407 (2004).

    Article  Google Scholar 

  35. 35

    Rush, A.J. et al. The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C) and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol. Psychiatry 54, 573–583 (2003).

    Article  Google Scholar 

  36. 36

    Yesavage, J.A. et al. Development and validation of a geriatric depression screening scale: a preliminary report. J. Psychiatr. Res. 17, 37–49 (1982).

    Article  Google Scholar 

  37. 37

    Folstein, M.F., Folstein, S.E. & McHugh, P.R. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198 (1975).

    Article  CAS  Google Scholar 

  38. 38

    Delis, D., Kramer, J., Kaplan, E. & Ober, B. California Verbal Learning Test (The Psychological Corporation, San Antonio, Texas, 2000).

  39. 39

    Wechsler, D. Wechsler Memory Scale-Revised (The Psychological Corporation, San Antonio, Texas, 1987).

  40. 40

    Reitan, R.M. Validity of the trail-making test as an indication of organic brain damage. Percept. Mot. Skills 8, 271–276 (1958).

    Article  Google Scholar 

  41. 41

    Zec, R.F. The stroop color-word test: a paradigm for procedural learning. Arch. Clin. Neuropsychol. 1, 274–275 (1986).

    Article  Google Scholar 

  42. 42

    Young, T., Peppard, P.E. & Gottlieb, D.J. Epidemiology of obstructive sleep apnea: a population health perspective. Am. J. Respir. Crit. Care Med. 165, 1217–1239 (2002).

    Article  Google Scholar 

  43. 43

    Münch, M., Silva, E.J., Ronda, J.M., Czeisler, C.A. & Duffy, J.F. EEG sleep spectra in older adults across all circadian phases during NREM sleep. Sleep 33, 389–401 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Cohen, D.A. & Robertson, E.M. Preventing interference between different memory tasks. Nat. Neurosci. 14, 953–955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Bollinger, J., Rubens, M.T., Masangkay, E., Kalkstein, J. & Gazzaley, A. An expectation-based memory deficit in aging. Neuropsychologia 49, 1466–1475 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Buckner, R.L. et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage 23, 724–738 (2004).

    Article  Google Scholar 

  47. 47

    Daselaar, S.M., Veltman, D.J., Rombouts, S.A., Raaijmakers, J.G. & Jonker, C. Neuroanatomical correlates of episodic encoding and retrieval in young and elderly subjects. Brain 126, 43–56 (2003).

    Article  CAS  Google Scholar 

  48. 48

    Spaniol, J. et al. Event-related fMRI studies of episodic encoding and retrieval: meta-analyses using activation likelihood estimation. Neuropsychologia 47, 1765–1779 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Lieberman, M.D. & Cunningham, W.A. Type I and Type II error concerns in fMRI research: re-balancing the scale. Soc. Cogn. Affect. Neurosci. 4, 423–428 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Friston, K.J. et al. Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6, 218–229 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Gitelman, D.R., Penny, W.D., Ashburner, J. & Friston, K.J. Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution. Neuroimage 19, 200–207 (2003).

    Article  Google Scholar 

  52. 52

    Nieuwenhuis, I.L. & Takashima, A. The role of the ventromedial prefrontal cortex in memory consolidation. Behav. Brain Res. 218, 325–334 (2011).

    Article  Google Scholar 

  53. 53

    Brett, M., Anton, J.L., Valabregue, R. & Poline, J.B. Region of interest analysis using an SPM toolbox [abstract]. in 8th Int. Conf. Funct. Mapp. Hum. Brain 16, 2 (NeuroImage, Sendai, Japan, 2002).

    Google Scholar 

  54. 54

    Ashburner, J. & Friston, K.J. Voxel-based morphometry–the methods. Neuroimage 11, 805–821 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Mak, H.K. et al. Efficacy of voxel-based morphometry with DARTEL and standard registration as imaging biomarkers in Alzheimer's disease patients and cognitively normal older adults at 3.0 Tesla MR imaging. J. Alzheimers Dis. 23, 655–664 (2011).

    Article  Google Scholar 

  56. 56

    Rajapakse, J.C., Giedd, J.N. & Rapoport, J.L. Statistical approach to segmentation of single-channel cerebral MR images. IEEE Trans. Med. Imaging 16, 176–186 (1997).

    Article  CAS  Google Scholar 

  57. 57

    Brodmann, K. Brodmann's Localisation in the Cerebral Cortex: the Principles of Comparative Localisation in the Cerebral Cortex based on Cytoarchitectonics (Springer, New York, 1909).

  58. 58

    Rechtschaffen, A. & Kales, A. A manual of Standardized Terminology, Techniques and Scoring System of Sleep Stages in Human Subjects (UCLA Brain Information Services, Los Angeles, 1968).

  59. 59

    Gasser, T., Bacher, P. & Steinberg, H. Test-retest reliability of spectral parameters of the EEG. Electroencephalogr. Clin. Neurophysiol. 60, 312–319 (1985).

    Article  CAS  Google Scholar 

  60. 60

    Mander, B.A. et al. EEG measures index neural and cognitive recovery from sleep deprivation. J. Neurosci. 30, 2686–2693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Belshe, M. Bhatter, M. Binod, S. Bowditch, C. Dang, A. Hayenga, A. Horn, E. Hur, C. Markeley, E. Mormino, M. Nicholas, L. Zhang and A. Zhu for their assistance, A. Mander for his aid in task design, and M. Rubens and A. Gazzaley for use of their aging template brain. This work was supported by awards R01-AG031164 (M.P.W.), R01-AG034570 (W.J.), R01-AG08415 (S.A.-I.) and F32-AG039170 (B.A.M.) from the US National Institutes of Health.

Author information

Affiliations

Authors

Contributions

B.A.M. designed the study, conducted the experiments, analyzed the data and wrote the manuscript. V.R. aided in data analysis and manuscript preparation. B.L. aided in study screening procedures and manuscript preparation. J.M.S. provided data analytic tools, aided in data analysis and manuscript preparation. J.R.L. aided in conducting the experiment and manuscript preparation. S.A.-I. aided in study design and manuscript preparation. W.J. provided the elderly subject pool and data analytic tools, and aided in study design and manuscript preparation. M.P.W. designed the study, aided data analysis and wrote the manuscript.

Corresponding authors

Correspondence to Bryce A Mander or Matthew P Walker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–3 (PDF 225 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mander, B., Rao, V., Lu, B. et al. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci 16, 357–364 (2013). https://doi.org/10.1038/nn.3324

Download citation

Further reading

Search

Quick links