Science - 06.03.2020

(Barry) #1

scale(Fig.1C),yetonlysomeofthesecortical
events were also coupled to ripples in the MTL.
Previous evidence has suggested that successful
memory retrieval involves a ripple-mediated
interaction between the cortex and the MTL
( 18 , 25 ). Although each cortical ripple may re-
flect an underlying burst of spiking activity,
only cortical burst events that are coupled to
MTL ripples may be preferentially relevant for
memory retrieval (Fig. 4A). We therefore hy-
pothesized that sequences of spiking activity
that occurred in association with MTL ripples
during retrieval were more similar to encod-
ingsequencesthanburstsofspikingthatwere
not coupled with the MTL. In correct retrieval
trials, we found several examples in which burst
events associated with MTL ripples exhibited
higher average sequence similarity to the en-
coding period than those burst events that oc-
curred in the absence of a MTL ripple (Fig. 4B).
We explicitly quantified replay in the cortex
triggered to the onset of MTL ripples and found
that maximal replay occurred ~100 ms after
MTL ripple onset (significant replay compared
with jittered ~100 to 175 ms) (Fig. 4C). We there-
fore used this temporal relationship to designate
every cortical burst event as coupled or uncou-
pled to a MTL ripple (supplementary materials)
andexaminedthereplaycontentofeachtype
of cortical burst event. In correct retrieval trials
across all participants, burst events coupled to
MTL ripples demonstrated significantly greater
replay of the sequences present during encoding
compared with uncoupled events [n= 6 par-
ticipants,t(5) = 2.85,P= 0.036] (Fig. 4D).
Together, our data demonstrate that ripple
oscillations reflect bursts of spiking activity
in the human cortex and that these bursts
contain item-specific sequences of single-unit


spiking that are established during memory
encoding and replayed during memory retrieval.
Cortical spike replay is enhanced during retrieval
when bursts of spiking in the cortex are coupled
with ripples in the MTL. Our data therefore
suggest that successful memory encoding and
retrievalofindividualitemsinvolvesaspecific
temporal ordering of cortical spiking activity
and provide a link between previous evidence
regarding the role of ripple oscillations in hu-
man memory ( 21 – 26 ) and evidence regarding
the replay of neuronal sequences observed in
rodents ( 7 – 14 ). Studies of spike replay in ro-
dents have largely focused on sequences of
spiking activity that emerge during spatial
navigation and that are replayed during sleep
or during awake periods of rest. These data
have inspired models of memory that posit that
memory formation involves an initial encoding
state, in which the temporal order of spiking
activity is established through sequential expe-
rience, and a subsequent consolidation state,
during which these sequences of spiking ac-
tivity are replayed in a temporally compressed
mannerintheMTL( 17 , 30 ). Our task requires
participants to memorize abstract associations
betweenwordpairsandtoretrievethoseas-
sociations following only a brief distractor pe-
riod. Hence, our data provide direct evidence
that awake human memory retrieval involves
replay of sequences of spiking activity in the
cortex. Whether such cortical spike replay
plays a similar role in longer-term memory
consolidationinthehumanbrainremains
an open question. Moreover, whereas tem-
poral compression and reverse replay may be
common features of spike replay observed in
rodents, their absence here may be related to
our task involving neither sequential experi-

encenor reward. Instead, our data suggest
that spiking sequences may represent indi-
vidual concepts in the human brain through
a temporally stereotyped activation of a neural
ensemble that emerges during the initial ex-
perience of an event and that is replayed when
its memory is retrieved.

REFERENCES AND NOTES


  1. E. Tulving, inOrganization of Memory, E. Tulving, W. Donaldson,
    Eds. (Academic Press, 1972), pp. 381–403.

  2. J. L. McClelland, B. L. McNaughton, R. C. O’Reilly,Psychol. Rev.
    102 , 419–457 (1995).

  3. J. D. Johnson, M. D. Rugg,Cereb. Cortex 17 ,2507–2515 (2007).

  4. B. P. Staresina, R. N. A. Henson, N. Kriegeskorte, A. Alink,
    J. Neurosci. 32 , 18150–18156 (2012).

  5. L. Deukeret al.,J. Neurosci. 33 , 19373–19383 (2013).

  6. R. B. Yaffeet al.,Proc. Natl. Acad. Sci. U.S.A. 111 ,18727–18732 (2014).

  7. W. E. Skaggs, B. L. McNaughton,Science 271 ,1870–1873 (1996).

  8. Z. Nádasdy, H. Hirase, A. Czurkó, J. Csicsvari, G. Buzsáki,
    J. Neurosci. 19 , 9497–9507 (1999).

  9. A. K. Lee, M. A. Wilson,Neuron 36 , 1183–1194 (2002).

  10. D. J. Foster, M. A. Wilson,Nature 440 , 680–683 (2006).

  11. K. Diba, G. Buzsáki,Nat. Neurosci. 10 , 1241–1242 (2007).

  12. D. Ji, M. A. Wilson,Nat. Neurosci. 10 , 100–107 (2007).

  13. M. F. Carr, S. P. Jadhav, L. M. Frank,Nat. Neurosci. 14 ,147–153 (2011).

  14. B. E. Pfeiffer, D. J. Foster,Nature 497 ,74–79 (2013).

  15. G. Girardeau, K. Benchenane, S. I. Wiener, G. Buzsáki,
    M. B. Zugaro,Nat. Neurosci. 12 , 1222–1223 (2009).

  16. S. P. Jadhav, C. Kemere, P. W. German, L. M. Frank,Science
    336 , 1454–1458 (2012).
    17.G.Buzsáki,Hippocampus 25 , 1073–1188 (2015).

  17. D.Khodagholy,J.N.Gelinas,G.Buzsáki,Science 358 ,369–372 (2017).

  18. H. R. Joo, L. M. Frank,Nat. Rev. Neurosci. 19 ,744–757 (2018).

  19. A. Fernández-Ruizet al.,Science 364 , 1082–1086 (2019).

  20. N. Axmacher, C. E. Elger, J. Fell,Brain 131 , 1806–1817 (2008).

  21. B. P. Staresinaet al.,Nat. Neurosci. 18 , 1679–1686 (2015).

  22. H. Zhang, J. Fell, N. Axmacher,Nat. Commun. 9 , 4103 (2018).

  23. Y. Liu, R. J. Dolan, Z. Kurth-Nelson, T. E. J. Behrens,Cell 178 ,
    640 – 652.e14 (2019).

  24. A. P. Vaz, S. K. Inati, N. Brunel, K. A. Zaghloul,Science 363 ,
    975 – 978 (2019).

  25. T. M. Normanet al.,Science 365 , eaax1030 (2019).

  26. A. I. Jang, J. H. Wittig Jr., S. K. Inati, K. A. Zaghloul,Curr. Biol.
    27 , 1700–1705.e5 (2017).

  27. J. H. Wittig Jr., A. I. Jang, J. B. Cocjin, S. K. Inati, K. A. Zaghloul,
    Nat. Neurosci. 21 , 808–810 (2018).

  28. M. Le Van Quyenet al.,J. Neurosci. 28 , 6104–6110 (2008).

  29. G. Buzsáki,Neuroscience 31 , 551–570 (1989).


ACKNOWLEDGMENTS
We thank N. Brunel, A. Sanzeni, A. Zadeh, L. Bachschmid-Romano,
V. Sreekumar, J. Chapeton, and Z. Xie for helpful and insightful
comments on the manuscript. We are indebted to all patients who have
selflessly volunteered their time to participate in this study.Funding:
This work was supported by the Intramural Research Program of the
National Institute for Neurological Disorders and Stroke (NINDS).
This work was also supported by National Institute of General Medical
Sciences grant T32 GM007171 and NINDS grant F31 NS113400 to
A.P.V.Author contributions:A.P.V. and K.A.Z. conceptualized the
study; A.P.V. performed all data analysis, software development, and
visualization; A.P.V., J.H.W., S.K.I., and K.A.Z. curated the data; A.P.V.
and K.A.Z. wrote the original draft; K.A.Z. supervised the study; and
A.P.V., J.H.W., S.K.I., and K.A.Z. reviewed and edited the final
manuscript.Competing interests:The authors declare no competing
interests.Data and materials availability:The data that support
the findings of this study are available for public download at
https://neuroscience.nih.gov/ninds/zaghloul/downloads.html.

SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/367/6482/1131/suppl/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S27
Table S1
References ( 31 – 37 )
View/request a protocol for this paper fromBio-protocol.
1 November 2019; accepted 5 February 2020
10.1126/science.aba0672

Vazet al.,Science 367 , 1131–1134 (2020) 6 March 2020 4of4


A B ***

0

.1
MI

MTL
MTG

-2 -1 0
Time to Retrieval (s)

Units

20
40
60
80
100
120

-250 250
MTL Ripple Onset (ms)

MTL C

D

Uncoupled Coupled

Uncoupled Coupled

0

Cortical Replay

MI (Z)
0

1

Cortical Replay

MI (Z)

0

.5

-.5

TrueJittered

Temp Cortex

*

.5

Fig. 4. MTL ripples precede cortical sequence replay.(A) Schematic of proposed mechanism for se-
quence replay in the cortex. Units are not sequentially organized when cortical bursts occur in isolation
(left), whereas sequence replay occurs when MTL ripplesoccur in coordination with cortical bursts (right).
(B) Example of dynamic coupling between MTL and cortical ripples (top), bursting events (middle), and sequence
replay during successful memory retrieval (bottom). (C) Average cortical replay values relative to onset of MTL
ripples in correct retrieval trials (blue), and the same data when MTL ripple temporal indices were jittered
randomly (gray). Error bars represent SEM across all participants (**P< 0.001, permutation test). (D)Sequence
replay during retrieval after dividing all sequences into those that were uncoupled and those that were coupled
to MTL ripples. Each line indicates a single participant, and bars indicate SEM across all participants. Coupled
sequences exhibited higher replay values than those of uncoupled sequences (
P<0.05).


RESEARCH | REPORT

Free download pdf