Manuscript submitted to eLife
Gamma oscillations during episodic1
memory processing reveal reversal2
of information flow between the3
hippocampus and prefrontal cortex4
Sarah Seger
1
, Michael D. Rugg
2,3,4
, Bradley C. Lega
1*
5
*For correspondence:
bradlega@gmail.com
Present address:
**
B. Lega,
UT-Southwestern, Neurological
Surgery MS 8855, 5323 Harry Hines
Blvd, Dallas, TX 75390
1
Department of Neurological Surgery, University of Texas-Southwestern Medical Center,6
Dallas, Texas 75390;
2
Center for Vital Longevity, University of Texas at Dallas, Dallas, Texas
7
75235;
3
School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas,8
Texas 75080;
4
Department of Psychiatry, University of Texas Southwestern Medical9
Center, Dallas, Texas 7539010
11
Abstract A critical and emerging question in human episodic memory is how the hippocampus12
interacts with the prefrontal cortex during the encoding and retrieval of items and their contexts. In
13
the present study, participants performed an episodic memory task (free recall) while intracranial14
electrodes were simultaneously inserted into the hippocampus and multiple prefrontal locations,15
allowing the quantification of relative onset times of gamma band activity in the cortex and the16
hippocampus in the same individual. We observed that in left anterior ventrolateral prefrontal17
cortex (aVLPFC) gamma band activity onset was significantly later than in the hippocampus during
18
memory encoding, whereas its activity significantly preceded that in the hippocampus during19
memory retrieval. These findings provide direct evidence to support models of20
prefrontal-hippocampal interactions derived from studies of rodents, but suggest that in humans, it
21
is the aVLPFC rather than medial prefrontal cortex that demonstrate these reciprocal interactions.22
23
Introduction24
Prefrontal monitoring and control during episodic memory processing is thought to be critical for
25
contextually mediated memory retrieval (
Miller, 2013
;
Preston and Eichenbaum, 2013
). An influen-
26
tial model characterizing one of the mnemonic roles of the prefrontal cortex (PFC) - termed here
27
the reciprocal flow hypothesis - posits that during memory encoding, contextual information flows
28
from the hippocampus to the PFC while during retrieval, the PFC uses this stored information to
29
guide selection of a contextually appropriate hippocampal memory representation (
Desimone and30
Duncan, 1995
;
Desimone, 1998
;
Miller and Cohen, 2001
;
Preston and Eichenbaum, 2013
). Stated
31
another way, the model posits that information flow between the hippocampus and PFC reverses
32
direction between encoding and retrieval. Evidence supporting this model has come from rodent
33
investigations employing lagged correlation between the hippocampus and PFC in theta band
34
oscillatory power (e.g.
Place et al., 2016
). In humans, noninvasive data have stimulated the hy-
35
pothesis that the VLPFC is necessary for generating retrieval cues during episodic memory search
36
(
Kim, 2019
), consistent with rodent findings, and lesion studies suggest that patients with frontal
37
lobe dysfunction have difficulty recalling items when the context is altered between encoding
38
and subsequent retrieval (
Chao, 1997
;
Fletcher, 2001
). However, to date there is no direct human
39
1 of 12
.CC-BY 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted August 7, 2019. ; https://doi.org/10.1101/728469doi: bioRxiv preprint
Manuscript submitted to eLife
electrophysiological evidence of reversed lags in the timing of hippocampal and PFC activation that
40
would be indicative of differential information flow during encoding and retrieval. fMRI studies lack
41
sufficient temporal resolution to identify such an effect, precise source localization of MEG signals
42
to different mesial temporal structures is problematic, and the absence of direct homology between
43
rodent and human prefrontal cortex means that human intracranial EEG studies are necessary to
44
establish whether this phenomenon is characteristic of human episodic memory and to determine
45
in which brain regions it may occur.46
Encoding Retrieval
CAT
SAND
SAND
TREE
TREE
3
+
7
+
1 = ?
1
+
4
+
5 = ?
6
+
2
+
5 = ?
. . .
.
. .
.
. .
+
1 2
12
Distractor
A
B
HIPP
ACC
MedOrbFront
aVLPFC
pVLPFC
DLPFC
ACC
MedOrbFront
HIPP
DLPFC
pVLPFC
aVLPFC
L
R
Subjects
15
40
2500 500 750
-500-750 -250 0
L. HIPP
L. aVLPFC
L. DLPFC
time (ms) after
word presentation
time (ms) before
vocalization
Encoding Retrieval
t
γ
t
γ
t
γ
t
γ
t
γ
t
γ
Peak Detection Algorithm
100 ms
normalized power
time (ms)
slope of
power
0
maximum
slope =
t
γ
power rises
above threshold
100 ms
100 200 400300
0
1
gamma power
threshold
time of activation (
t
γ
)
normalized power
normalized power
C
D
Figure 1.
(A) Schematic of the experimental paradigm used in this study. Black boxes indicate the encoding and
retrieval epochs. (B) Number of subjects included in each prefrontal and hippocampal region. The colorbar
indicates number of subjects, a minimum of 15 subjects and a maximum of 40 subjects contributed to any
given unilateral region. (C) Example trace from a single electrode contact depicts the activation onset detection
algorithm. The time point of activation (
𝑡
𝛾
) is marked as the time point where the slope is maximized in the 200
msec window centered at the time point where power passes threshold. The 𝑡
𝛾
demonstrates that onset of
activation does not necessarily coincide with the time that power passes the threshold. (D) Example encoding
and retrieval trial show 𝑡
𝛾
for three electrodes.
Figure 1–Figure supplement 1.
Figure 1–Figure supplement 2.
A complicating factor when testing the reciprocal flow hypothesis in humans is that there
47
appear to be multiple oscillations within traditional theta frequency bands, and the dominant theta
48
frequency in the hippocampus may differ that in the neocortex (
Lega et al., 2012
;
Miller, 2013
;
49
Watrous and Ekstrom, 2014
). Furthermore, unlike rodents, human hippocampal recordings do
50
not universally exhibit theta modulation as a function of memory processing (although this might
51
be more prevalent in posterior hippocampal locations) (
Lin et al., 2017
;
Watrous and Ekstrom,52
2014
). By contrast, gamma oscillations exhibit widespread and reproducible power increases in
53
multiple neural regions during episodic memory encoding and retrieval, including in the PFC and
54
hippocampus (Burke et al., 2014; Sederberg et al., 2007).55
Here we sought evidence of reversal of information flow between the hippocampus and pre-
56
frontal cortex during the encoding versus the retrieval of episodic memories. We did this by taking
57
advantage of a unique dataset obtained from 77 human patients implanted with stereo EEG elec-
58
trodes for seizure mapping purposes who performed a verbal free recall paradigm. During the
59
study and recall phases of the task, we identified activation peaks in gamma oscillations from 40 to
60
120 Hz, using the onset of gamma activation as an estimate of the initial timing of activity in a given
61
brain region. As our data set included subjects with electrodes implanted in both the hippocampus
62
and PFC (in addition to other cortical locations), we were able to directly compare the timing of
63
2 of 12
.CC-BY 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted August 7, 2019. ; https://doi.org/10.1101/728469doi: bioRxiv preprint
Manuscript submitted to eLife
memory-related gamma activation in the PFC and hippocampus within-subjects.64
Results65
Behavioral Performance66
Across participants, the average probability of recall for all words was 24.4%. The average percent-
67
age of list intrusions (recall errors) per subject was 12.8%. We derived an estimate of temporal
68
clustering (the tendency for items adjacent to each other in the study list to be recalled sequentially)
69
to determine if temporal contextual factors were operating at retrieval (
Watrous and Ekstrom,70
2014
). The mean clustering factor across all participants was 0.642, robustly higher than the chance
71
value of 0.500 (
𝑡(36) = 8.294
,
𝑝 < 0.001
), indicating that participants incorporated temporal contextual
72
information into encoded representations of the study words (Sederberg et al., 2010).73
sEEG Data74
For our principal analysis, we identified the lag in onset of activation (
Δ𝑡
𝛾
) for five prefrontal locations
75
relative to the hippocampus (positive
Δ𝑡
𝛾
indicating activation following the hippocampus, negative
76
Δ𝑡
𝛾
indicating activation preceding the hippocampus). We divided the PFC into five distinct bilateral
77
regions: dorsal PFC (dorsal to the inferior frontal sulcus, anterior to pre-motor cortex, ventral to
78
the superior frontal gyrus), the posterior VLPFC (posterior to the anterior ascending ramus of the
79
sylvian fissure, anterior to motor cortex), the anterior VLPFC (anterior to that ascending ramus), the
80
medial orbitofrontal cortex and the anterior cingulate cortex. These regions were selected based
81
upon targeting strategies employed for seizure mapping, providing sufficient numbers of electrodes
82
for analysis. Exact timing of activation onset (
𝑡
𝛾
) was estimated on a trial by trial basis for recording
83
sites by calculating a gamma power threshold in the 40-120 Hz range to determine the timing of
84
onset relative to hippocampal contacts in the same individual following established methods (Figure
85
1).86
HIPP
*
Encoding Retrieval
Encoding Retrieval
*
*
Time Lag in Onset of Activation
ACC
MedOrbFront
HIPP
ACC
MedOrbFront
DLPFC
aVLPFC
pVLPFC
aVLPFC
pVLPFC
DLPFC
ACC
MedOrbFront
ACC
MedOrbFront
HIPP
HIPP
DLPFC
pVLPFC
aVLPFC
DLPFC
pVLPFC
aVLPFC
R
L
L
R
Δt
γ
+ 25 ms- 25 ms 0 ms
Cortex Leads Hippocampus Leads
*
*
Figure 2. Mean Δ𝑡
𝛾
across electrodes for all prefrontal cortex regions for the encoding (recalled words only) and retrieval condition. Red colors
indicate that activation in the hippocampus precedes activation in the cortex and blue indicates that the cortical activation precedes hippocampal.
For each memory condition, a black region border indicates that Δ𝑡
𝛾
across all electrode pairs is significantly different than zero (t-test, FDR
corrected 𝑝 < 0.011 for encoding and 𝑝 < 0.007 for retrieval). An asterisk (*) between the encoding and retrieval conditions indicates that the
encoding and retrieval Δ𝑡
𝛾
are significantly different when compared with a paired t-test (FDR corrected 𝑝 < 0.019). The left aVLPFC exhibited a
mean activation lag relative to the hippocampus during successful encoding of +13.4 msec (FDR corrected 𝑝 < 0.001, t-test of activation times
Figure 2 continued on next page.
3 of 12
.CC-BY 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted August 7, 2019. ; https://doi.org/10.1101/728469doi: bioRxiv preprint
Manuscript submitted to eLife
Figure 2. (continued)
compared to hippocampus), and a reversal of this effect during retrieval, such that the region led the hippocampus by -10.4 msec (FDR corrected
𝑝 = 0.0116
). Moreover, the
Δ𝑡
𝛾
distributions for encoding and retrieval were significantly different (FDR corrected
𝑝 < 0.001
) across electrodes when
compared with a paired t-test. Of the remaining PFC regions, only one other region, the right DLPFC, exhibited a
Δ𝑡
𝛾
that was significantly greater
than zero during encoding (FDR corrected 𝑝 = 0.0037); however this region did not exhibit a reversal in Δ𝑡
𝛾
values during retrieval (with the
hippocampus leading during both encoding and retrieval). The left ACC exhibited a significant difference in the distribution of
Δ𝑡
𝛾
during encoding
vs. retrieval (-6.86 msec during encoding, 6.46 msec during retrieval; FDR corrected
𝑝 = 0.0173
); but the
Δ𝑡
𝛾
was not significantly different than zero
during neither encoding (FDR corrected 𝑝 = 0.0700) or retrieval (FDR corrected 𝑝 = 0.0700) indicating onset nearly commensurate with that of the
hippocampus. The pattern of Δ𝑡
𝛾
reversal was evident for the left but not the right aVLPFC. In the latter region, while there was a significant
difference between encoding and retrieval (FDR corrected
𝑝 = 0.0080
), the values indicated that the cortex led the hippocampus during both phases
of the free recall task (lag = -23.5 msec during retrieval, -7.44 msec during encoding).
Figure 2–Figure supplement 1.
Convincing evidence of a reversal in the flow of information consistent with the reciprocal flow87
model would require a PFC region to exhibit 1) a lag in activation onset relative to the hippocampus
88
that is significantly greater than zero during successful item encoding (significant positive
Δ𝑡
𝛾
, hip-
89
pocampus leading), 2) a lag in activation that is significantly less than zero during retrieval (negative
90
Δ𝑡
𝛾
, hippocampus trailing), and finally 3) a significant difference in these
Δ𝑡
𝛾
values when directly
91
compared in a paired test (reversed Δ𝑡
𝛾
). Across all electrodes in our dataset (without any filtering92
of electrodes based upon their functional properties), we observed that the left aVLPFC exhibited
93
the following set of properties: a mean activation lag relative to the hippocampus during successful
94
encoding of 13.4 msec (FDR corrected
𝑝 < 0.001
, t-test of activation times compared to hippocam-
95
pus), and a reversal of this effect during retrieval, such that the region led the hippocampus by -10.4
96
msec (FDR corrected
𝑝 = 0.0116
). Moreover, the
Δ𝑡
𝛾
distributions for encoding and retrieval were
97
significantly different (FDR corrected 𝑝 < 0.001) (Figure 1).98
Time Lag SME
HIPP
ACC
MedOrbFront
aVLPFC
pVLPFC
DLPFC
ACC
MedOrbFront
HIPP
DLPFC
pVLPFC
aVLPFC
L
L
R
R
z-score
> 2.5
≤
0
Δt
γ
vs.
recalled
non
recalled
Δt
γ
Figure 3. Subsequent memory effect in Δ𝑡
𝛾
for all regions. Z-scores were calculated for each region using a
paired t-test between Δ𝑡
𝛾
for recalled words and Δ𝑡
𝛾
for non-recalled words. The subsequent memory effect
for left aVLPFC, left DLPFC, and left ACC was significant (FDR corrected p < 0.007), which is indicated by black
borders for those regions. No regions in the right hemisphere show a significant subsequent memory effect.
Figure 3–Figure supplement 1.
Next, we compared the
Δ𝑡
𝛾
distributions during successful versus unsuccessful encoding, looking
99
for evidence of a subsequent memory effect in this measurement. For the left aVLPFC, this contrast
100
was significant (FDR corrected
𝑝 = 0.0216
), suggesting that
Δ𝑡
𝛾
measurements are sensitive to encod-
101
ing success (Figure 3). Taken together, these findings indicate that the timing of gamma activation102
onset in the left aVLPFC constitute a signal that is sensitive to memory encoding success (exhibiting
103
4 of 12
.CC-BY 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted August 7, 2019. ; https://doi.org/10.1101/728469doi: bioRxiv preprint
Manuscript submitted to eLife
an SME), with a pattern that fits a putative model of the transfer of contextual information to the
104
frontal cortex during successful encoding (significantly positive relative to hippocampal activation)
105
with evidence of a reversal during retrieval (significantly negative relative to the hippocampus).
106
Across all electrode pairs, 38% of aVLPFC electrodes exhibited this pattern of
Δ𝑡
𝛾
reversal, which
107
was significantly greater than the fraction exhibiting this effect in the DLPFC (
𝜒
2
(1, N=630) = 17.160,
108
𝑝 < 0.001
) (Figure 4). Across the subjects who contributed an electrode pair to the left aVLPFC, 59%
109
showed a pattern of Δ𝑡
𝛾
reversal in at least one electrode pair.110
L. aVLPFC
Recalled Retrieval
*
Δt
γ
reversal (direction of mean)
No
Δt
γ
reversal
Δt
γ
reversal (opposite of mean)
38%
52%
10%
# of Electrodes
t
_
γ
(ms)
Retrieval
15
-600 -500
L. HIPP
L. aVLPFC
10
5
Recalled
t
_
γ
(ms)
10
5
250 350
L. HIPP
L. aVLPFC
C
B
# of Electrodes
A
-50 50 100-100 0
Δt
γ
(
m
s
)
Recalled
Non
recalled
Figure 4. The left aVLPFC shows a reversal in the Δ𝑡
𝛾
between encoding and retrieval consistent with the
reciprocal flow information. (A) Distribution of Δ𝑡
𝛾
for all aVLPFC electrodes during the recalled and
non-recalled conditions. The Δ𝑡
𝛾
for non-recalled words is not significantly different than zero (mean
non-recalled lag is +2.91 msec). (B) 38% of aVLPFC electrodes have Δ𝑡
𝛾
reversal between conditions, with the
hippocampus leading in activation during encoding and the cortex leading during retrieval, and 10% show the
opposite pattern of activation, with the cortex leading in activation during encoding and the hippocampus
leading during retrieval. 52% of electrodes show no reversal in lag between conditions. (C) Histograms of the
mean
𝑡
𝛾
during encoding (subsequently recalled only) and retrieval for the 38% of aVLPFC - HIPP electrode pairs
exhibiting the effect depicts the differences in timing of activation onset for hippocampal and aVLPFC
electrodes between memory conditions.
Further, we analyzed prior list intrusions (PLI) to test more directly whether
Δ𝑡
𝛾
reversal is
111
associated with the transmission of contextual information, as hypothesized by the reciprocal
112
flow model. List intrusions represent errors of item–context association (the wrong item for a
113
given context, i.e. the list on which the item was presented, although we discuss caveats to the
114
interpretation of PLI data in the Discussion below). For this analysis, oscillatory activity can be
115
analyzed only during item retrieval. We observed no evidence of information reversal for PLI events,
116
with the onset of left aVLPFC activation not significantly different than for the hippocampus (mean
117
Δ𝑡
𝛾
= -3.5 msec, uncorrected
𝑝 = 0.3861
). In addition, the
Δ𝑡
𝛾
during correct retrieval events was
118
significantly less than that of PLI events (uncorrected 𝑝 = 0.0436).119
In a convergent approach, we looked for evidence of lagged activation using a different method,
120
this time employing the lagged correlation of the gamma power envelope (rather than activation
121
onset), following established methods (
Ossandon et al., 2011
). With this approach, which has a very
122
different rationale and underlying set of assumptions than the lagged activation analysis described
123
above, the results for the left aVLPFC were highly consistent with those observed previously, with a
124
significant positive lag of 14 msec during encoding (uncorrected
𝑝 = 0.0442
) (hippocampus leading)
125
and negative 8 msec lag during retrieval (in the same direction as our initial analysis with the PFC
126
5 of 12
.CC-BY 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted August 7, 2019. ; https://doi.org/10.1101/728469doi: bioRxiv preprint
