RESEARCH ARTICLE
◥NEUROSCIENCE
Hippocampal sharp-wave ripples
linked to visual episodic recollection
in humans
Yitzhak Norman^1 , Erin M. Yeagle^2 , Simon Khuvis^2 , Michal Harel^1 ,
Ashesh D. Mehta^2 , Rafael Malach^1 *
Hippocampal sharp-wave ripples (SWRs) constitute one of the most synchronized
activation events in the brain and play a critical role in offline memory consolidation. Yet
their cognitive content and function during awake, conscious behavior remains unclear. We
directly examined this question using intracranial recordings in human patients engaged in
episodic free recall of previously viewed photographs. Our results reveal a content-
selective increase in hippocampal ripple rate emerging 1 to 2 seconds prior to recall events.
During recollection, high-order visual areas showed pronounced SWR-coupled
reemergence of activation patterns associated with recalled content. Finally, the SWR rate
during encoding predicted subsequent free-recall performance. These results point to a
role for hippocampal SWRs in triggering spontaneous recollections and orchestrating the
reinstatement of cortical representations during free episodic memory retrieval.
H
ippocampal ripples ( 1 , 2 )arebrief(<150ms)
high-frequency oscillatory events, in the
range of 140 to 200 Hz in rodents ( 3 – 6 )
and 80 to 140 Hz in primates and humans
( 7 – 11 ), that appear in the local field poten-
tial (LFP) of the hippocampal CA1 pyramidal
layer ( 3 , 5 ). Conserved across a variety of species,
these short-lived network oscillations constitute
instances of highly synchronized neuronal ac-
tivity in the brain. During a ripple, 10 to 15% of
pyramidal neurons in the hippocampal-entorhinal
output pathway discharge synchronously ( 12 , 13 ),
orchestrating a network activation that has a
potent impact on several cortical and subcortical
targets ( 10 , 14 ). Because these ripples commonly
co-occur with large-amplitude sharp waves ap-
pearing in CA1 stratum radiatum ( 3 , 15 ), it is
customary to refer to them as sharp-wave ripple
(SWR) complexes ( 16 ). SWRs occur most fre-
quently during non–rapid eye movement sleep
and quiescent wakefulness ( 14 , 16 ). In primates,
SWRs can also be seen during attentive visual
search, especially before the gaze is being di-
rected toward a familiar target location ( 17 , 18 ).
Electrophysiological studies of humans and
rodents have demonstrated different forms of
coupling between hippocampal SWRs and cor-
tical LFP ( 9 , 11 , 19 – 22 ). Extrahippocampal neuronal
activations linked to previous awake experiences
are reexpressed in the brief time window of the
hippocampal ripple ( 14 , 23 – 29 ). The temporal
relationship between SWRs and cortical reac-
tivation during sleep suggests a coordinated
bidirectional interaction whereby spontaneously
generated patterns in the cortex bias the activity
in the hippocampus, which then broadcasts,
during the ripple, an integrated memory rep-
resentation back to the cortex ( 24 , 27 ). Such
hippocampal-cortical interplay has been hypoth-
esized as an orchestration mechanism that
governs the reactivation of mnemonic repre-
sentations across distributed cortical networks
( 24 , 27 , 30 , 31 ).
Examination of the representational content
of SWR events during ongoing awake behavior
has revealed a structured, temporally compressed
replay of hippocampal multicell sequences repre-
senting previous navigation-related experiences,
as well as“preplay”ofpossiblefuturepaths( 32 – 38 ).
Awake replay/preplay points to a potential role
for SWRs in reactivating mnemonic informa-
tion not only during offline consolidation, but
also during ongoing awake behavior that in-
volves recall or imagination of nonpresent sce-
narios ( 14 , 39 – 41 ). However, the exact cognitive
content and function of SWRs during awake
behavior remains unclear. This is largely be-
cause of the difficulty of assessing detailed
cognitive content in animal models. Here, we
addressed this challenge by using a free-recall
paradigm to examine the cognitive role of SWRs
in intracranial recordings of human epileptic
patients.
Free recall is a cognitive process by which
previously stored items are recalled spontane-
ously, without externally presented cueing in-
formation. It allows the dissociation between
any external stimuli and the internally drivenmemory process. We previously showed that
hippocampal and ventral-temporal neurons re-
activate in a content-specific manner during free
recall ( 42 , 43 ). Furthermore, we were able to
demonstrate a putative top-down biasing mech-
anism that constrains free recall to a particular
category by modulating the ongoing baseline
excitation of category-selective visual areas in
the cortex ( 44 ).
One unique advantage of intracranial electro-
encephalography (iEEG) recordings conducted
in patients is that the diagnostic procedure calls
for multiple simultaneous recording sites in
each patient. This allowed us to record LFP and
SWR activity in the hippocampus simultaneously
with high-frequency broadband (HFB; 60 to
160 Hz) signals reflecting local neuronal popu-
lation activity ( 45 – 47 )intask-relevant,content-
specific, cortical sites.
SWR events were recorded in patients during
a resting state and during a visual free-recall
task (Fig. 1A). The task consisted of two runs,
each beginning with a resting-state period of
200 s. Patients were then presented with vivid,
full-color photographs of famous faces and places.
After viewing each picture four times in pseudo-
random order and completing a short interfer-
ence task, patients were instructed to freely recall
the pictures, targeting each category in separate
blocks. To ensure reinstatement of visual content
during recall, we instructed patients to describe
each recalled item with two or three prominent
visual features. Verbal responses during the recall
phase were recorded, and the onset and offset of
each verbal recall event were carefully extracted
in an offline analysis. Patients were blindfolded
throughout the free-recall period to completely
block external visual input.
On average, patients recalled 8.8 ± 2.7 (SD)
items per run; when including repeated re-
collections, they had 12.4 ± 5.7“recall events”
per run. There was no significant difference in
recall performance between the two runs (P>
0.22, Wilcoxon signed-rank test). Recall events
were defined as any verbal utterance in which
patients began to describe a specific picture (see
methods). The average duration of verbal recall
events was 8.08 ± 6.27 s. Recall performance
was similar between the two categories (average
number of recalled items per run: 4.43 faces,
4.37 places;P> 0.9, Wilcoxon signed-rank test).Sharp-wave ripple detection
A multicontact depth electrode implanted in the
hippocampus was used for detection of SWR
events. We used pre- and postoperative computed
tomography (CT) and magnetic resonance imag-
ing (MRI) scans to identify in each patient a
hippocampal recording site located in or adjacent
to the CA1/CA2 subfields, where SWR events are
known to occur most prominently ( 48 ). The LFP
in the selected site was then filtered between
70 and 180 Hz, rectified, squared, smoothed, and
transformed into z-scores. Transient events that
exceeded 4 SD and survived the exclusion criteria
were selected as candidate SWR events (Fig. 1D;
see methods).RESEARCH
Normanet al.,Science 365 , eaax1030 (2019) 16 August 2019 1of14
(^1) Department of Neurobiology, Weizmann Institute of Science,
Rehovot 76100, Israel.^2 Department of Neurosurgery,
Donald and Barbara Zucker School of Medicine at Hofstra/
Northwell, and Feinstein Institute for Medical Research,
Manhasset, NY 11030, USA.
*Corresponding author. Email: [email protected]