cognitive states of the patients, or whether it
remained constant (thus reflecting oscilla-
tory events with an all-or-none behavior). We
computed a peri-ripple wavelet spectrogram
in a time window of–200 to 200 ms relative to
the SWR peak (see methods; see fig. S2, A to D,
for traces of individual SWR events and mean
spectrograms, spectra, and peri-ripple field po-
tential across conditions). A nonparametric
Friedman test comparing SWR amplitude and
peak frequency showed no significant differ-
ences between the main experimental condi-
tions [fig. S2, E and F; mean peak frequency:
88.1 ± 2.1 Hz,c^2 (3) = 2.73,P> 0.43; mean peak
amplitude:9.5±1.5dB,c^2 (3) = 5.00,P>0.17;
n= 15 patients]. Similar spectral characteristics
have been found in sleep SWRs in humans
( 7 , 9 , 49 , 50 ).
Having established that the basic spectral
properties of the SWRs remained constant
throughout the experiment, we next explored
whether the SWR rate may have changed with
the patients’cognitive state. Comparing the mean
SWR rate across the different experimental con-
ditions revealed a significant effect [c^2 (3) = 18.04,
P= 0.0004, Friedman test,n= 15 patients; see
fig. S2G], and post hoc comparisons indicated
that the basal SWR rate was slightly lower during
recall and memory search (i.e., inter-recall inter-
vals) relative to the picture-viewing and rest con-
ditions [P< 0.05, pairwise Friedman tests with
false discovery rate (FDR) correction; median
ripple rate (events/s): 0.45 (rest), 0.47 (viewing),
0.36 (recall), 0.34 (search)].
Content-selective modulation of
SWR rate
To examine whether viewing the pictures during
the encoding phase influenced the SWR rate in
a more transient fashion, we computed in each
patient a peristimulus time histogram (PSTH)
of SWRs, showing the instantaneous SWR rate
in 50-ms time bins starting from–0.5 to 2.25 s
relative to picture onset (Fig. 2A). Averaging
across the different pictures, we found a tran-
sient general increase in SWR rate (peaking at
675 ms poststimulus) that appeared only during
the first presentation of each picture. Repeated
presentations of the same pictures did not
evoke this nonselective time-locked response
(P< 0.01, nonparametric cluster-based permu-
tation test, shuffling condition labels 2000 times
across patients; see fig. S3, A and B, for responses
across individual presentation cycles and indi-
vidual patients’data and fig. S3D for compar-
ison between faces and places). For additional
analysis examining the consistency in ripple
rate across repeated presentations of the same
picture, see fig. S3C.
SWRs elicited during viewing may have been
reactivated later, in a content-specific manner,
during the free-recall period, when patients
recalled the same visual content but in the ab-
sence of any external stimulation. To examine
this possibility, we pooled all items that were
subsequently recalled in each patient (n=252
items in total) and measured the correlation
between the SWR rate evoked by each item
during viewing (throughout the duration of the
picture, from 50 to 1500 ms poststimulus) and
the SWR rate elicited when patients freely re-
called this same item (using a generic time win-
dow of 5 s centered on the onset of the verbal
report of recall; repeated recollections in the
same patient were averaged together). However,
given the significant difference in averaged SWR
rate between novel and repeated presentations
described above, we analyzed the novelty-related
SWRs separately from the SWRs generated during
the repeated presentations.
We found a significant correlation between
the SWR rates elicited by each picture during
viewing and during free recall, but only for the
repeated presentations—that is, when responses
related to novel presentations were excluded
(novel: Spearmanr=0.05,P>0.43;repeated
presentations: Spearmanr=0.18,P= 0.005;
n= 252 successfully recalled items; fig. S4, A
and B).
To investigate the temporal profile of this
content-specific modulation of SWR rate during
recall, we first sorted the pictures in each pa-
tient according to the number of SWRs they
elicited during the repeated presentations (in a
time window of 50 to 1500 ms poststimulus).
We then divided the pictures into two groups:
pictures that elicited a high SWR rate during
viewing (above median), which we termed“high-
RR”images; and pictures that resulted in low
SWR rates (below median), which we termed
“low-RR”images (Fig. 2B, inset).
Figure 2B depicts the average SWR rate when
patients viewed the high-RR and low-RR images
(red and dark contours, respectively). Note that
the difference between these two signals is due
to the selection process and is to be expected
given the variable SWR responses across differ-
ent images during viewing (see fig. S5 for further
characterization of SWR responses across high-
RR and low-RR images). The critical question is
whether this content-specific difference during
viewing reappeared during recall, in the absence
of visual stimuli.
To answer this question, we computed for
each patient a PSTH of SWRs, time-locked to
the onset of verbal report of recall (using time
bins of 200 ms from–5 to 5 s, smoothed with
1000-ms triangular window). Recall events with
separation of less than 5 s from the previous re-
collection were excluded from the analysis. We
first searched for a nonselective signal related to
any recall event. We found a transient increase
in SWR rate that preceded the onset of verbal
report by 1 to 2 s (Fig. 2C). A nonparametric
cluster-based permutation test, which compared
the activation profile to 2000 shuffled PSTHs
produced by circularly jittering SWR timing
in each trial by a random amount, indicated
that the anticipatory increase was highly signif-
icant (P< 0.01; cluster-defining threshold was set
at ±1.96 SD from the mean rate; see also fig. S4D;
significant time bins are marked in orange).
Additional analysis confirmed that SWRs were
not coupled to voice amplitude or instances ofabrupt vocalizations (fig. S6). Movie S1 shows
examples of spontaneous recall events and their
relation to SWRs in three patients.
Next, we examined whether this increase during
recall was content-specific. We compared SWR
rates during recall of high-RR versus low-RR
images (defined by the viewing responses). A
nonparametric permutation test, shuffling high-
RR and low-RR labels 2000 times, revealed that
the SWR rate was significantly higher during
recall of high-RR images (P< 0.05, see Fig. 2D;
for raster plot and individual patients’data, see
fig. S4). Here, too, the content-selective increase
emerged 1 to 2 s prior to the beginning of the
actual verbal report.Ripple rate during picture viewing
predicts memory performance
Could SWR dynamics during picture viewing
be linked to the patients’ability to later recall
these pictures? To examine this possibility, we
computed a PSTH of SWRs time-locked to the
onset of picture presentation, separately for the
first and repeated presentations (120-ms bins
smoothed by a five-point triangular window; see
methods). We then computed in each patient the
normalized difference in SWR rate between pic-
tures that were later remembered or forgotten:
(REM−FOR)/(REM + FOR). A cluster-based
permutation test revealed that the SWR rate
during picture viewing predicted the memo-
rability of items in the subsequent free recall.
Specifically, we found a higher ripple rate for
remembered pictures than for forgotten pictures.
This effect emerged during the poststimulus in-
terval in the first presentation cycle (P<0.05,
one-sided cluster-based permutation test, Fig. 3,
A and B; for individual patients’data, see fig. S7).
To further examine this predictive effect, we
measured in each time bin the correlation be-
tween the difference in ripple rate and the pa-
tients’memory performance during the free-recall
period. We found a significant correlation, peak-
ing during the poststimulus interval and return-
ing back to baseline upon presentation of the next
picture (P< 0.05, FDR correction; peak correla-
tion: Spearmanr= 0.85; Fig. 3C).
Finally, to rule out the possibility that this
correlation resulted from the differences in the
number of trials belonging to each group of
images (remembered and forgotten), we carried
out an additional permutation test, in which we
shuffled the labels of the ripple rate responses
2000 times and randomly resampled the orig-
inal number of remembered and forgotten trials
in each patient. The results of this analysis in-
dicated that the correlation observed in the actual
data during the poststimulus interval was highly
significant and did not arise from differences
in the number of trials (Spearmanr= 0.83,P<
0.001; Fig. 3D).Ripple-triggered cortical activation
A major advantage of iEEG recordings in pa-
tients is that as a result of clinical requirements,
recordings are typically obtained broadly across
several cortical and medial temporal lobe (MTL)Normanet al.,Science 365 , eaax1030 (2019) 16 August 2019 3of14
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