Science - 16.08.2019

events. Critically, this coupled cortical activity
was content-specific; that is, it occurred only
when the patients recalled images from the
electrodes’preferred category (preference that
was revealed during viewing). In some cases,
recalling the nonpreferred category led to a
decrease in HFB amplitude. Thus, cortical activity
coupled to hippocampal SWRs appeared most
prominently when contrasting the preferred ver-
sus the nonpreferred images in each recording site.
To examine whether this peri-ripple ampli-
tude modulation was a general phenomenon
across the entire group of category-selective vi-
sual electrodes, we computed a multitaper spec-
trogram for each recording site during a time
window of–750 to 750 ms relative to SWR onset
(see methods). When patients recalled the elec-
trodes’preferred images (i.e., top 10 images that
elicited the strongest response during viewing),
there was a small but highly consistent HFB
activation centered around the onset of hippo-
campal SWRs (Fig. 5, A to C,PFDR<0.001,n=
57, Wilcoxon signed-rank test; peak normalized
amplitude, 0.24 dB; SE, ±0.04). This peri-ripple
cortical response involved a broadband power
increase in frequencies between 50 and 180 Hz

(High-Gamma), a signal known to reflect a local

increase in population firing rate ( 47 , 51 ). This

peri-ripple visual activation was significantly

higher when patients recalled the electrodes’

preferred images (top 10 images) as compared

to the nonpreferred ones (bottom 10 images that

least activated the electrodes during viewing)

(P< 0.01, cluster-based nonparametric permu-

tation test, shuffling preferred/nonpreferred

labels 2000 times over electrodes;n=57re-

cording sites in 13 patients, after excluding re-

cording sites with fewer than five peri-ripple

responses in each condition). Lower frequencies

(1 to 30 Hz) did not exhibit content-selective

power changes (no significant differences; pre-

ferred versus nonpreferred images, cluster-based

permutation test; fig. S8A).

Was the SWR-triggered effect specific to

overtly reported recall events? We performed

the same analysis on SWRs that occurred while

patients attempted to recall the electrode’s pre-

ferred and nonpreferred categories but did not

overtly report any recalled item (i.e., the“memory

search”period). There was no content-selective

peri-ripple activation during these inter-recall

periods (no significant differences; fig. S8, B to

D); this finding suggested that the effect was

specific to conscious, reportable recall events

(further comparisons among recall, memory

search, and resting-state SWRs are depicted

in fig. S8F). Finally, using a bootstrap sampling

procedure with 2000 resamples, we estimated

the latency of the maximal difference between

the preferred and nonpreferred spectrograms

during a [–300, 300] ms time window centered

on SWR onset. The analysis showed a slight

trend of an advance cortical activation [mean

peak latency:–18 ms, 95% CI (–65, 29); fre-

quency: 102.1 Hz, 95% CI (85, 118)]; however,

this effect was not statistically significant.

We next examined how content-selective peri-

ripple activation was distributed across the en-

tire set of visually responsive electrodes. Figure 5D

depicts the distribution of all recording sites in

our dataset presented on an average cortical

template. Recording sites that showed a signif-

icant visual response during the picture-viewing

condition were color-coded according to their

peri-ripple reactivation effect during recall. To

obtain this map, we first identified the 10 im-

ages that produced the strongest and weakest

responses during viewing individually in each

Normanet al.,Science 365 , eaax1030 (2019) 16 August 2019 5of14

0123 Number of items recalled

-0.5

0

0.5

1

0123

0.2

0.4

0.6

0.8

1

-0.5 0 0.5 1

Ripple rate difference

(REM-FOR)/(REM+FOR)

7

14

21

28

post-stimulus interval

[1500-2250 ms]

Correlation coef. ()

95% CI

resampling test

-1 0 1

0

100

200

Iterations p<10-3

=0.83, p<0.001

Ripple rate (events/sec)

AB

C correlation to recall performance:

first presentation: repeated presentations:

Time from picture onset (s)

PFDR<0.05

Correlation coef. (

D

Time from picture onset (s)

Ripple rate (events/sec)

Time from picture onset (s)

0123

0.2

0.4

0.6

0.8

1

p<0.04

remembered (n=756)

forgotten (n=588)

image on

remembered (n=252)

forgotten (n=196)

image on

Fig. 3. Ripple rate during picture viewing predicts subsequent
free-recall performance.(A) SWRs PSTH time-locked to onset of the first
presentation of each picture shows a significantly higher ripple rate
for remembered versus forgotten pictures during the poststimulus interval
(P= 0.02, cluster-based permutation test;n= 15 patients). (B)No
significant differences were observed during repeated presentations.
(C) The difference in ripple rate between remembered and forgotten items
significantly predicts subsequent recall performance across patients
(PFDR< 0.05; peak correlation: Spearmanr= 0.85). Note how the
correlation returns to baseline upon presentation of the next picture,

attesting to the temporal specificity of this effect. (D) Left: Scatterplot

showing the correlation between the poststimulus ripple rate difference

(1500 to 2250 ms) and the subsequent recall performance (each dot

represents an individual subject; gray line represents the least-squares fit).

Right: Resampling test indicating that the correlation obtained in the

actual data was highly significant (2000 iterations,P< 0.001) and did

not arise from differences in the number of items in each group

(remembered/forgotten). In (A) to (C), shaded area represents ±1

bootstrap SE computed over pooled trials [(A) and (B)] or patients (C);

black horizontal bars on thexaxis represent stimulus-on periods.

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