Article

Encoding of Target Detection during Visual Search

by Single Neurons in the Human Brain
Highlights Authors
d A new class of neurons in the human MTL signal target Shuo Wang, Adam N. Mamelak,
detection during visual search Ralph Adolphs, Ueli Rutishauser

d Response of target neurons is invariant to visual category Correspondence

d MFC target neurons precede MTL target neurons by 200ms shuo.wang@mail.wvu.edu (S.W.),
radolphs@hss.caltech.edu (R.A.),
d Target neurons do not depend on explicitly defined targets ueli.rutishauser@cshs.org (U.R.)

In Brief
Wang et al. reveal a new class of neurons
in the human medial temporal lobe that
signals target detection during visual
search. These neurons have invariant
response to visual category, predict
detected or missed targets, do not
depend on explicitly defined targets, and
likely have a frontal origin.

Wang et al., 2018, Current Biology 28, 1–12

July 9, 2018 ª 2018 Elsevier Ltd.
https://doi.org/10.1016/j.cub.2018.04.092
 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

Current Biology

Article

Encoding of Target Detection during Visual Search

by Single Neurons in the Human Brain
Shuo Wang,1,2,* Adam N. Mamelak,3 Ralph Adolphs,2,5,6,* and Ueli Rutishauser3,4,5,*
1Department of Chemical and Biomedical Engineering, and Rockefeller Neuroscience Institute, West Virginia University, 1 Medical Center Dr,

Morgantown, WV 26506, USA

2Computation and Neural Systems, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA
3Departments of Neurosurgery and Neurology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
4Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles,

CA 90048, USA
5Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA
6Lead Contact

*Correspondence: shuo.wang@mail.wvu.edu (S.W.), radolphs@hss.caltech.edu (R.A.), ueli.rutishauser@cshs.org (U.R.)

https://doi.org/10.1016/j.cub.2018.04.092

SUMMARY actions to reach the goal [1–4]. Search depends on top-down

Neurons in the primate medial temporal lobe (MTL)
respond selectively to visual categories such as
faces, contributing to how the brain represents stim-
ulus meaning. However, it remains unknown whether
MTL neurons continue to encode stimulus meaning
when it changes flexibly as a function of variable
task demands imposed by goal-directed behavior.
While classically associated with long-term memory,
recent lesion and neuroimaging studies show that
the MTL also contributes critically to the online guid-
ance of goal-directed behaviors such as visual
search. Do such tasks modulate responses of neu-
rons in the MTL, and if so, do their responses mirror
bottom-up input from visual cortices or do they reflect
more abstract goal-directed properties? To answer
these questions, we performed concurrent record-
ings of eye movements and single neurons in the
MTL and medial frontal cortex (MFC) in human neuro-
surgical patients performing a memory-guided visual
search task. We identified a distinct population of
target-selective neurons in both the MTL and MFC
whose response signaled whether the currently
fixated stimulus was a target or distractor. This
target-selective response was invariant to visual cate-
gory and predicted whether a target was detected or
missed behaviorally during a given fixation. The
response latencies, relative to fixation onset, of MFC
target-selective neurons preceded those in the MTL
by
200 ms, suggesting a frontal origin for the target
signal. The human MTL thus represents not only fixed
stimulus identity, but also task-specified stimulus
relevance due to top-down goal relevance.
INTRODUCTION
Goal-directed behaviors such as visual search depend on hold-
ing in mind a desired outcome while deploying sequences of
modulation of bottom-up visual processes to detect whether
the current location contains the target [2, 5–12]. While classi-
cally investigated for its role in long-term memory [13], the MTL
is also involved in mediating ongoing behaviors by facilitating vi-
sual and spatial working memory and scene integration pro-
cesses [14–18]. For example, patients with MTL lesions are
impaired in visual search due to an inability to organize explora-
tion patterns and properly maintain a representation of the
search target [17, 18]. Similarly, such patients are impaired in
oddity-judgment tasks that require the inspection of complex
scenes [19]. A key contribution of the MTL to ongoing behavior
is through its support of visual and spatial working memory
[15, 16, 20, 21], which is essential in visual search to maintain
the representation of the target and to organize an efficient
search without revisits. In the presence of distractors (which in
our task are fixations on non-targets), patients without a func-
tional MTL are impaired in some working memory tasks
[14, 16, 22–24]. During search, this manifests in more revisits
of the target [17]. Similarly, evidence from neuroimaging
[20, 25] and intracranial recordings [21, 26] indicates that persis-
tent activity within the MTL supports visual working memory
in such tasks. Together, this body of work shows that the
MTL—and in particular, the hippocampus—supports goal-
directed behavior. However, it remains largely unknown how
such modulation by behaviorally relevant goals is implemented.
In higher-order visual cortex, the response of neurons is
modulated by whether the preferred stimulus of a neuron is
currently a target of a search [9, 12, 27]. This modulation in visual
cortex is in addition to a neuron’s visual tuning, such that a cell’s
response is informative about the presence or absence of only a
specific target [2, 11, 12, 28]. Furthermore, this neuronal target
response predicts whether a search target will be missed
[2, 28]. The origins of such modulation are thought to be primarily
the frontal cortex [4, 29–34]. However, higher-level visual re-
sponses in macaques are in addition also modulated by the
MTL in tasks requiring memory [35, 36]. Despite this observation,
the role of the MTL in search has remained unclear because no
previous study has obtained single-neuron recordings from
this region during memory-guided visual search.
We used simultaneous single-neuron recordings and eye
tracking performed in neurosurgical patients to investigate how

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 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

A B C D
7 500

Fixation Duration (ms)

6 450

5 400
Target

RT (s)
Search Cue Present ? Absent
1 sec 4 350
Correct
RT 3 300
Up to 14 sec +
2 250
1 sec
ITI 1
1-2 sec TP TA T D

Figure 1. Task and Behavior

(A) Task structure. The search cue is shown for 1 s, immediately followed by the search array. Subjects are instructed to indicate by button press whether the
target is present or absent (timeout 14 s). Trial-by-trial feedback is given immediately after button press (‘‘correct,’’ ‘‘incorrect,’’ or ‘‘time out’’), followed by a blank
screen for 1–2 s.
(B and C) Example visual search arrays with fixations indicated. (B) Sample stimuli. Each circle represents a fixation. Green circle: first fixation. Magenta circle: last
fixation. Yellow line: saccades. Blue dot: raw gaze position. Red box: target. (C) Boxplot of reaction time. TP: target-present; TA: target-absent.
(D) Boxplot of fixation duration. T: fixations on targets; D: fixations on distractors. On each box, the central mark is the median, the edges of the box are the 25th
and 75th percentiles, the whiskers extend to the most extreme data points the algorithm considers to be not outliers, and the outliers are plotted individually.

signals related to target detection interact with visual sensory
signals in the human MTL during active search. Subjects were in-
structed to locate a visual target shown among 23 other stimuli in
an array during instructed visual search. The target changed trial
by trial, requiring rapid implementation of changing goals. We
used a range of stimuli, including objects and faces, as search
targets [37]. This approach enabled us to identify category-tuned
neurons [38–40] and to test whether the response of these neu-
rons was modulated by target relevance.
RESULTS
Task and Behavior
Patients (n = 8, 11 sessions; Table S1) performed a visual search
task. In each trial, subjects reported by button press whether the
search target was present or absent (Figures 1A and 1B; 80% of
all trials contained the target). The search target (cue) changed
for every trial and was displayed for 1 s immediately preceding
the search array. Therefore, patients had to keep the target item
in working memory throughout the search. Patients performed
well with an average reporting accuracy of 92.0% ± 7.52%
(mean ± SD across sessions; 91.4% ± 8.47% for target-present tri-
als and 94.5% ± 6.02% for target-absent trials, two-tailed paired t
test, p = 0.18). Considering only correct trials, the average reaction
time (RT, relative to search array onset) for target-present trials
was significantly faster compared to target-absent trials
(1.92 s ± 0.76 s versus 3.96 s ± 1.56 s, two-tailed paired t test,
p < 104; Figure 1C). The accuracy and RT of the patients was
comparable to that of healthy participants who had performed
the same task in a previous study [37], confirming that our patients’
behavioral performance was not impaired (two-tailed two-sample
t test, p values = 0.17 and 0.11 for accuracy and RT, respectively).
Consistent with prior reports [41], dwell times of fixations on tar-
gets (384 ± 88.4 ms) were significantly longer than those on dis-
tractors (302 ± 63.0 ms; paired two-tailed t test, t[10] = 2.72, p =
0.022; Figure 1D; see STAR Methods for more fixation analysis).
Electrophysiology
We recorded in total 317 single neurons in the human amygdala
and hippocampus. 228 neurons had an average firing rate >
0.2 Hz, and we restricted our analysis to this subset. In the ana-
lyses below, we pool neurons from both areas and commonly
refer to them as ‘‘MTL neurons.’’ The words ‘‘cell’’ and ‘‘neuron’’
are used interchangeably.
Target-Selective Neurons in the MTL
To investigate the neural substrates of target detection, we
aligned neuronal responses at fixation onset and compared
the response of each neuron between fixations on distractors
and targets. We first analyzed responses to all fixations onto
targets, whether or not they were detected. As the response,
we used the mean firing rate in a time window starting
200 ms before fixation onset and ending 200 ms after fixation
offset (next saccade onset). The duration of this window was
on average 690 ms ± 45.0 ms (mean ± SD across sessions).
50 cells (21.9%; binomial p < 1020; 19 and 31 from the amyg-
dala and hippocampus, respectively) had a response that
differed significantly between fixations on targets versus dis-
tractors in target-present trials (two-tailed t test, p < 0.05).
We identified two types of such ‘‘target-selective’’ (TS) neu-
rons: one type had a greater response to targets relative to
distractors (target-preferring; 27/50 cells, Figures 2A–2C),
and the second had a greater response to distractors relative
to targets (distractor-preferring; 23/50, Figures 2D and 2E;
note that these distractor-preferring cells still carried informa-
tion about targets; see STAR Methods). The proportion of TS
cells identified was highly significant (permutation test, p <
0.001): a control permutation test shuffling the labels of targets
and distractors revealed 11.43 ± 3.34 neurons expected
by chance (mean ± SD; 6.44 ± 2.51 target-preferring and
5.00 ± 2.17 distractor-preferring). This result demonstrates
that a subset of MTL neurons encode whether the present fix-
ation landed on a target (see Figure S3 for example neuronal
responses aligned at button-press).
To assess whether the response of TS cells could be attributed
to target detection alone, or in addition also encoded visual stim-
ulus category, we next compared their response between fixa-
tions on identical objects as a function of whether the fixated
object was a target or a distractor in that trial. This comparison
revealed that the TS neurons that increased their activity for

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 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
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A B C D E

F G H I J K

Figure 2. TS Cells Signal Top-Down Goal Relevance but Are Not Visually Tuned
(A–C) Neurons that increase their firing rate when fixating on targets, but not distractors (selection by two-tailed t test in a time window of 200 ms before fixation
onset to 200 ms after fixation offset: all p values < 1011).
(D and E) Neurons that decrease their firing rate when fixating on targets but not distractors (all p values < 103). Fixations are sorted by fixation duration (black line
shows start of the next saccade). t = 0 is fixation onset. Asterisk (*) indicates a significant difference between fixations on targets and distractors in that bin (p <
0.05, two-tailed t test, Bonferroni-corrected; bin size = 50 ms).
(F and G) Mean response to fixations on each visual object as a function of whether the object is currently a target or a distractor (two example neurons are shown).
Each data point is a different object. Gray bars (upper right) show the number of data points above and below the diagonal. In these two examples, the response to
most objects was stronger when the object was a target (sign-test: [F] p = 1.40 3 105; [G] p = 5.35 3 104), indicating that the response was predominantly
modulated trial-by-trial by target relevance rather than visual identity. Note that these two example neurons are the same as in (B) and (C).
(H–K) Single-fixation analysis using the TSI. (H) Shown is the cumulative distribution of the single-fixation response of fixation-aligned target- and distractor-
preferring neurons for fixations on targets and distractors (n = 50 neurons). (I) TSI summary. TS: target-selective cells; NTS: non-TS cells. Error bars denote one
SEM across cells. Chance performance was calculated by permutation tests by shuffling the label of target and distractor. Error bars denote one SD across
permutations. KS test was used to compare TS cells with non-TS cells and permutation test was used to compare against chance performance. Asterisk (*)
indicates a significant difference. *** p < 0.001. n.s.: not significant. (J) Detected versus missed targets. FDetect: detected targets. FMiss: missed targets.
D: distractors. (K) Temporal response characteristics of TS neurons. FAll: all fixations on targets. FFirst: the first fixation on target. DBefore: fixations on distractors
before the first fixation on target. DAfter: fixations on distractors after the first fixation on target. Asterisk (*) indicates a significant difference between fixation types.
*** p < 0.001.
See also Figure S1, S2, S3, and S4.

targets did so even when comparing target and distractor fixa-
tions that landed on visually identical objects (n = 27 neurons,
two-tailed paired t test on difference in firing rate against 0:
p = 0.0019; Figures 2F and 2G show two example neurons,
both p < 0.001, sign-test). Similarly, the distractor-preferring
TS neurons increased their firing rate to distractors compared
to targets when only considering fixations on identical visual ob-
jects (n = 23, two-tailed paired t test on difference in firing rate
against 0: p < 0.001). Because in this comparison the visual cate-
gory of the stimuli is identical, this result indicates that the differ-
ential response of TS neurons must be driven by target detection
alone.
TS Neurons Predict Behavioral Target Detection
We next investigated the relationship between the response of
TS cells and behavior by quantifying the response of TS cells
during individual fixations using a target-selectivity index (TSI).
The TSI is equal to the neuronal response during an on-target fix-
ation, normalized by the average response during fixations on
distractors (see Equations 1 and 2 and STAR Methods). As ex-
pected, the TSI for TS cells was significantly larger during fixa-
tions on targets compared to fixations on distractors (n = 50,
two-tailed two-sample Kolmogorov–Smirnov [KS] test, p <
10122; Figures 2H and S4C; this finding is also true for target-
and distractor-preferring neurons considered separately, see

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A B C D E

F G H I

J K L M N

Figure 3. Category Cells Are Fixation Sensitive and Visually Tuned during Search and Are Modulated by Top-Down Goal Relevance
(A–C) Example neurons that increased firing rate to face cues (selection by two-tailed t test during search cue presentation: p < 103).
(D and E) Example neurons that increased firing rate to non-face cues (p < 104). Each raster (upper) and peristimulus time histogram (PSTH) (lower) is shown with
color coding as indicated. Trials are aligned to cue presentation (gray lines). Trials within each category are sorted according to reaction time (black line).
Waveforms for each unit are shown in the raster plot. In the PSTH plot, asterisk (*) indicates a significant difference between the response to face-target trials and
non-face-target trials in that bin (p < 0.05, two-tailed t test, Bonferroni-corrected; bin size = 250 ms). Shaded area denotes ± SEM across trials.
(F and G) Cue-aligned average PSTH of all neurons that significantly increased firing rate for face cues (F) and non-face cues (G), respectively.
(H and I) Object category selectivity tuning showing ordered average responses from the best to the worst stimulus. Neurons with category selectivity were
identified by one-way ANOVA across 14 object categories (p < 0.05). Neurons that did not reach statistical significance (unselected neurons) were shown for
comparison purposes. Responses were normalized by the response to the best stimulus. Asterisks (*) in (H) indicate significant difference between selected and
unselected neurons: + p < 0.1, * p < 0.05, ** p < 0.01, and *** p < 0.001. (I) Amygdala (solid line) and hippocampal (dashed line) category neurons showed a similar
category tuning. No significant differences in category selectivity were found between amygdala and hippocampal neurons at all stimulus levels (two-tailed two-
sample t test, all p values > 0.16), although unselected amygdala neurons showed a stronger visual selectivity.
(J–N) Summary of DOS. (J) DOS during cue presentation (left) and fixations on targets during search (right). Face: face-selective neurons. Category: category-
selective neurons. Note that DOS values are dependent on the number of categories, making DOS values of face-selective and category-selective cells not
comparable. Error bars for category neurons denote one SEM across cells. Chance performance was calculated by permutation tests by shuffling the label of
categories. Error bars for chance values denote one SD across permutations. Asterisk (*) indicates a significant difference by permutation test. *** p < 0.001. (K)
Correlation of DOS (evaluated with 14 object categories) between cue presentation and search. Each circle represents a neuron. Magenta circles denote
the category-selective neurons (n = 32) and gray circles denote the unselected neurons (n = 196). The magenta line is the linear fit for category-selective neurons

(legend continued on next page)

4 Current Biology 28, 1–12, July 9, 2018
 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092
Figures S4D–S4I). This result confirms that the single-fixation
response of TS cells is strong enough for single-fixation analysis
(also see Figure S4A and S4B for ROC analysis). Permutation
tests by shuffling the label of target and distractor further
confirmed our results: TS cells (30.6% ± 17.3%, mean ± SD
across cells; Figure 2I) had a significantly higher TSI compared
to chance (8.68% ± 1.09%, p < 0.001), whereas the TSI of all
non-TS cells (12.1% ± 10.8%; Figure 2I) did not differ from
chance (12.3% ± 0.83%, p = 0.60).
We first tested whether TS neurons responded differently to
targets as a function of whether the target was detected by the
subject (detected versus misses, where misses were target fixa-
tions for which patients failed to press the target-present button
immediately; see STAR Methods). TS neurons had a significantly
higher response to targets that were detected relative to those
that were missed (TSI: 31.1% ± 18.6% versus 16.9% ± 79.5%,
mean ± SD across cells, KS-test, p < 0.001; Figure 2J; see [28]
for a similar analysis in macaques). Nevertheless, the response
of TS neurons to missed targets was significantly larger than
that to distractors (TS index: 16.9% ± 79.5% versus 0.0% ±
0.0% (by default); KS-test, p < 107; Figure 2J). Thus, TS cells
distinguished targets from distractors even when targets were
not behaviorally detected by button press. Nevertheless, the
maximal response of TS cells was only evoked if an on-target fix-
ation coincided with behavioral detection of the target, suggest-
ing that the target detection signal may be graded, from a
strength insufficient for behavioral choice, to a strength sufficient
for the behavioral choice and typically accompanied by
conscious recognition of the target.
Temporal Response Characteristics of TS Neurons
Above, we considered all fixations on distractors regardless of
whether they occurred before or after the target had been fixated
intermittently. However, in a subset of 25.3% ± 19.1% of trials,
subjects continued to fixate on at least one of the distractors after
they first fixated on the target (note that above, fewer fixations
were considered as misses because we required at least 3 fixa-
tions before button press). We next used these trials to explore
how TS neurons responded to targets and distractors as a conse-
quence of fixating on targets. As expected, TS neurons had a
significantly higher TSI when comparing all target fixations
(30.6% ± 17.3%, mean ± SD across cells) to the subset of
distractor fixations that preceded the first target fixation
(0.34% ± 4.56%; KS-test: p < 1020; Figure 2K). This was also
true when only considering the first target fixation in each trial
compared to the distractor fixations that preceded this first target
fixation (26.2% ± 16.0% versus 0.34% ± 4.56%; KS-test: p <
1020; Figure 2K). On the other hand, when only considering dis-
tractor fixations that occurred after the first fixation on a target
(21.0% ± 36.4%), TS neurons still showed a significantly higher
TSI for all targets (30.6% ± 17.3%; KS-test: p < 0.001; Figure 2K).
(r = 0.65, p < 104) and the gray line is the linear fit for all neurons (r = 0.65, p < 1028). (L) DOS for targets versus distractors. T: fixations on targets. D: fixations on
distractors. Error bars denote one SEM across cells. Asterisk (*) indicates a significant difference by two-tailed paired t test. *** p < 0.001. (M) Correlation of DOS
(evaluated with 14 object categories) between fixations on targets and distractors. Each circle represents a neuron. Magenta circles denote the category-se-
lective neurons (n = 32) and gray circles denote the unselected neurons (n = 196). The magenta line is the linear fit for category-selective neurons (r = 0.59,
p = 0.00039) and the gray line is the linear fit for all neurons (r = 0.63, p < 1025). (N) DOS for TS neurons did not differ between target and distractor fixations.
Legend follows (J). n.s.: not significant.
See also Figure S5.
Thus, the response of TS cells remained sensitive to the type of
stimulus fixated (target or distractor) even after the target had
already been fixated. However, the TSI for distractor fixations
increased significantly for those that were fixated after the target
was already fixated at least once compared to those before the
first on-target fixation (KS-test: p < 109; Figure 2K). This indi-
cates that despite subjects not stopping the search, the presence
of the target did influence the response of TS cells immediately
following the first fixation on the target, which here resulted in
TS cells responding to some degree also to distractor fixations
that followed the first on-target fixation.
Category Cells Are Modulated by Target Detection
We next asked whether the previously described category-se-
lective cells in the MTL [39] might also be modulated by detection
of the target. We identified two types of category cells: face-se-
lective and general visual category-selective responses. We
tested separately for face-selective cells because of their prom-
inence in the MTL [42]. We then proceeded to compare the
response of both types of category cells between fixations on
targets and distractors to determine whether their response
discriminated targets from distractors, in addition to visual
categories.
To identify face-selective neurons, we compared the response
between face and non-face stimuli during cue presentation. The
response of 39 neurons (17.1%; p < 1011) had a significant
response difference (31/39 increased their firing rate for faces
compared to non-faces, whereas 8/39 increased their firing
rate for non-faces compared to faces but did not further distin-
guish non-face categories; see Figures 3A–3E and S5 for exam-
ples and Figures 3F and 3G for group average). To select cate-
gory-selective neurons, we grouped the objects into 14 visual
categories (see STAR Methods). The response of 32 neurons
(14.0%; p < 107) co-varied significantly as a function of visual
category during cue presentation (one-way ANOVA of 14 cate-
gories, p < 0.05). Figure 3H shows the ordered responses from
the best to the worst stimulus for these neurons. Compared to
the unselected neurons, category-selective neurons showed
steeper changes from the best to the worst stimulus, a difference
that was significant at all stimulus levels (two-tailed two-sample t
test, all p values < 0.022; FDR corrected) except the best and
worst stimuli (Figure 3H; similar results were obtained for amyg-
dala and hippocampal neurons separately, see Figure 3I).
To summarize the response of category neurons during
search, we used the depth of selectivity (DOS) index (see
STAR Methods and Equation 3) [43]. DOS values range between
0–1, with 1 indicating tuning to only a single category (note
the dependence of DOS values on the number of categories,
making DOS values of face-selective and category-selective
cells not comparable). During the cue period, the mean DOS of
face-selective and category-selective cells was 0.42 ± 0.14
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 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
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A B

C D

Figure 4. Population Summary for MTL

(A) Most selective neurons were either only TS (n = 38) or only face-selective (n = 27) neurons, with a minority qualifying as both (n = 12).
(B) Most selective neurons were either only TS (n = 43) or category-selective (n = 25) neurons, with a minority qualifying as both (n = 7).
(C and D) Response of all recorded neurons as a function of visual selectivity (C) DOS index for face selectivity; (D) DOS index for category selectivity; chance DOS
was subtracted to correct for baseline) and target selectivity (TSI; chance TSI was subtracted to correct for baseline). Each circle represents a neuron. Color of the
circle indicates classification of the neuron (Red: target neurons. Brown: visually selective neurons. Blue: both. Gray: neither).

(chance: 0.14; permutation test: p < 0.001; Figure 3J) and 0.68 ±
0.16 (chance: 0.58; permutation test: p < 0.001; Figure 3J),
respectively. We found that category cells identified during the
cue period remained visually selective during search: using
neuronal responses aligned at fixation onset, selectivity re-
mained significantly above chance for both face-selective
(mean DOS 0.36 ± 0.22 versus 0.22 expected by chance; permu-
tation test: p < 0.001; Figure 3J) and category-selective neurons
(mean DOS 0.76 ± 0.16 versus 0.69 expected by chance; p <
0.001; Figure 3J). Also, the DOS index of category cells
computed during search and during cue presentation was corre-
lated (face-selective: r = 0.44, p = 0.0047, category-selective: r =
0.65, p < 104, all: r = 0.65, p < 1028; Figure 3K), indicating that
their tuning remained stable. Note that the analysis of category-
cell activity during search is statistically independent of cell se-
lection because category cells were selected based only on their
response during the cue period. This result shows that category
cells selected for tuning to the cue remained visually selective
when considering fixation-onset triggered responses.
We next compared the selectivity of category cells during
search between fixations on targets versus distractors. We
found that category cells were significantly more tuned during
fixations on targets compared to distractors (numbers are DOS
index values; face-selective neurons: 0.36 ± 0.22 [mean ± SD]
versus 0.20 ± 0.15 for target and distractor, respectively; two-
tailed paired t test: p = 0.00047; category-selective neurons:
0.76 ± 0.16 versus 0.62 ± 0.17, p < 104; Figure 3L). Also, visual
selectivity was significantly correlated between fixations on tar-
gets and distractors when considering all neurons, regardless
of whether they were category cells (DOS for face-selectivity:
r = 0.39, p < 1011; DOS for category-selectivity: r = 0.63, p <
1025; Figure 3M). Together, this result shows that category cells
are modulated both by sensory information about the visual ob-
ject category and by target detection during the search task.
TS and Category Cells Are Largely Distinct
We next investigated whether target cells were also visual cate-
gory-selective [39]. The DOS values of TS neurons were not
larger than those expected by chance (mean DOS 0.49 ± 0.21
versus 0.49 expected by chance; evaluated during cue presen-
tation period with 14 object categories; permutation test by
scrambling object identity: p = 0.58; Figure 3N). This result
shows that the response of TS cells was, on average, not visually
tuned.
Were there cells that were both TS and category cells? We
found a small number of such cells: only 12 (5.26%) of neurons
were both TS and face-selective cells (Figure 4A), and only 7
(3.07%) of neurons were both TS and category-selective cells

6 Current Biology 28, 1–12, July 9, 2018

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

A B C D E

Figure 5. TS Neurons in the Pre-SMA Respond before TS Neurons in the MTL

(A and B) Example TS neurons from pre-SMA.
(C and D) Two TS neurons simultaneously recorded in the pre-SMA (C) and MTL (D). Legend conventions as in Figures 2A–2E.
(E) Cumulative firing rate for TS neurons from the pre-SMA (dotted lines; n = 31 neurons) and MTL (solid lines; n = 27 neurons). Note that only TS neurons that had a
greater firing rate for targets than distractors are shown. Shaded area denotes ± SEM across neurons. Red: fixations on targets. Blue: fixations on distractors. Top
bars show clusters of time points with a significant difference (one-tailed pairwise t test; p < 0.01; FDR-corrected; cluster size > 10 time points). Arrows indicate
the first time point of the significant cluster. Magenta: MTL neurons. Black: pre-SMA neurons.
(F) Difference in cumulative firing rate (same data as shown in [E]) Shaded area denotes ± SEM across neurons. Arrows indicate the first time point of the sig-
nificant cluster. Magenta: MTL neurons. Black: pre-SMA neurons.
See also Figure S6.

(Figure 4B). The proportion of cells that qualified as both was
not greater than expected from independence of these two
attributes, i.e., TS neurons had a similar percentage of category
neurons as the entire population (c2-test: p = 0.25 and p = 0.99,
respectively; Figures 4A and 4B), and category neurons had a
similar percentage of TS neurons as the entire population
(p = 0.23 and p = 0.99, respectively). A scatterplot of TSI versus
DOS for all recorded neurons further showed that TS neurons
and category neurons were largely separate populations (Fig-
ures 4C and 4D show DOS values during cue period for face-se-
lective and category-selective neurons, respectively). Further-
more, TSI and DOS were not correlated for all cells (r = 0.061,
p = 0.36), TS cells (r = 0.062, p = 0.67), category cells
(r = 0.057, p = 0.76), or cells that were qualified as both TS
and category (r = 0.21, p = 0.66; similar results were found
using face-selective DOS). Lastly, a two-way ANOVA (TS X cate-
gory) of the entire population of neurons confirmed that neither
face-selective cells (Figure 4C; TSI: p = 0.95; DOS: p = 0.81;
main effects p < 106 as by selection) nor category-selective
cells (Figure 4D; TSI: p = 0.60; DOS: p = 0.88; main effects p <
1020 as by selection) interacted with TS cells. Together with
the preceding selectivity analysis, this result suggests that TS
and category cells are largely distinct.
had a spontaneous firing rate of > 0.2 Hz, and 211 neurons from
the aMCC, 162 of which had a firing rate of > 0.2 Hz. We found 51
TS neurons in the pre-SMA (Figures 5A and 5B; 39.5%; binomial
p < 1050; 31 cells had a greater response to targets relative to
distractors) and 42 TS neurons in the aMCC (25.9%, binomial
p < 1050; 18 cells had a greater response to targets relative to
distractors). We next proceeded to compare the onset latency,
relative to fixation onset, of the TS neurons between MFC
and MTL. This revealed that pre-SMA TS neurons responded
significantly earlier than MTL TS neurons (Figures 5E and 5F;
pre-SMA: 163 ms relative to fixation onset; MTL: 44ms; permu-
tation test: p = 0.005; see Figures 5C and 5D for individual exam-
ples). This result was similar for aMCC TS neurons, which also
responded significantly earlier than MTL TS neurons (Figure S6A
and S6B; aMCC: 140 ms relative to fixation onset; MTL: 44 ms;
permutation test: p = 0.042). This result held when restricting
analysis to neurons recorded simultaneously (Figure S6C and
S6D; permutation test: p = 0.023). Together, these data show
that target-relevance signals are available earlier in MFC
compared to MTL, suggesting that the MTL target signal might
represent top-down input from the frontal cortex. In addition,
TS neurons in MFC also differentiate between detected versus
missed targets like MTL TS neurons (see STAR Methods).

MTL TS Neurons Respond Later than MFC TS Neurons
Where do the MTL target detection signals originate? To explore
the origins of the target detection signal, we also recorded from
two medial frontal brain areas: the pre-supplementary motor
area (pre-SMA) and the anterior mid-cingulate cortex (aMCC).
Nine patients (10 sessions) performed the identical task. We re-
corded in total 182 single neurons in the pre-SMA, 129 of which
MTL Neurons Encode Category Signals Earlier than
Target Detection Signals
Was the response latency of category and TS cells in the MTL
different? To answer this question, we selected a population of
category neurons whose response differentiated between fixa-
tions on faces and non-faces during search (two-tailed two-sam-
ple t test; n = 27; 17 neurons had a greater response for faces and

Current Biology 28, 1–12, July 9, 2018 7

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

A Pop-out Task B C
80

Pop−out [normalized firing rate %]

60
Target
Present ? Absent 40
20
Correct
RT 0
Up to 14 sec +
−20
1 sec −40
ITI −60
1-2 sec
−80
−50 0 50
Standard [normalized firing rate %]

Figure 6. MTL TS Neurons Do Not Require an Explicit Search Target

(A) Task structure for the control pop-out task. The target was defined as an ‘‘oddball’’: there was either one face among vehicles or one vehicle among faces.
Subjects were instructed to indicate by button press as soon as they determined whether there was an oddball (the same button press as the standard task). Trial-
by-trial feedback is given immediately after button press.
(B) Sample stimuli of pop-out task. Each circle represents a fixation. Green circle: first fixation. Magenta circle: last fixation. Yellow line: saccades. Blue dot: raw
gaze position. Red box: target. In this example, the target (oddball) is a face.
(C) Scatterplot of the mean normalized firing rate between the standard and pop-out task. Each circle represents the mean normalized firing rate difference
between fixations on targets and fixations on distractors for a neuron. Magenta circles denote the TS neurons (derived from the standard task; n = 28) and gray
circles denote the unselected neurons. The magenta line is the linear fit for TS neurons and the gray line is the linear fit for all neurons that had an overall firing rate >
0.2 Hz for both tasks in comparison (n = 157).

we focused on this subset here). We found that category neurons
with faces as the preferred stimulus responded significantly faster
than TS neurons (Figure S6E and S6F; category: 155 ms relative
to fixation onset; TS: 44 ms; permutation test: p = 0.026) relative to
fixation onset. Similarly, we found that face-selective neurons
selected during cue presentation (Figures 3A–3G) also responded
earlier than TS neurons during search (Figures S6G–S6I).
Together, our results show that MTL neurons encode visual infor-
mation earlier than target-detection responses.
Interestingly, even though category cells became selective
before TS cells, when we separately analyzed DOS in each
consecutive 50 ms time window, we found that DOS increased
immediately after TS cells became selective (
44 ms; Fig-
ure S6M). This result further supports the idea that category neu-
rons are modulated by goal relevance signals in the MTL.
MTL TS Neurons Do Not Depend on Explicitly Defined
Targets
To further characterize TS cells, we conducted a comparison
‘‘pop-out’’ task while recording from the same neurons as the
above ‘‘standard’’ task (9 sessions, 157 MTL neurons with an over-
all firing rate > 0.2 Hz). In this pop-out task (Figures 6A and 6B), no
explicit search cue was given. Instead, the target was defined as
an ‘‘oddball’’: there was either one face among vehicles or one
vehicle among faces. Patients were instructed to indicate by but-
ton press as soon as they determined whether there was an
oddball (target). This allowed us to examine target or distractor re-
sponses in the absence of an explicitly provided search cue.
We examined whether the subset of TS neurons selected from
the standard task for which we also recorded the pop-out task
(28 TS neurons; 9 target-preferring and 19 distractor-preferring)
also signaled target detection in the pop-out task. We found that
this was the case: TS cell responses were significantly correlated
between the standard and pop-out tasks (Figure 6C; r(28) = 0.49,
p = 0.0082 for TS neurons and r(157) = 0.25, p = 0.0015 for all
neurons). The correlation results were further confirmed by com-
parison to chance performance (note that this test was indepen-
dent from selection): neurons had above-baseline discrimination
of targets versus distractors in the pop-out task (two-tailed one-
sample t test: p = 0.037). Together, the consistency between the
standard and pop-out tasks suggests that MTL neurons encode
search goals irrespective of goal format.
Lastly, we compared the onset latency of MFC TS neurons
(n = 29; 20 from the pre-SMA and 9 from the aMCC) and MTL
TS neurons (n = 9) in the pop-out task. We found that MFC TS
neurons responded significantly earlier than MTL TS neurons,
just as had been the case in the standard task (Figure S6K and
S6L; MFC: 160 ms relative to fixation onset; MTL: 16 ms; per-
mutation test: p = 0.008). This result suggests that MFC neurons
can signal task relevance in at least two different ways: through
instructions held in working memory and by detection of oddball
stimuli. It is also worth noting that MTL TS neurons responded
earlier in the pop-out task (16 ms) compared to the standard
task (44 ms; permutation test: p = 0.028), but MFC TS neurons
responded with a similar latency (standard task: 171 ms,
pop-out task: 160 ms; permutation test: p = 0.58), suggesting
that MTL neurons receive top-down signals faster when less
working memory is involved (i.e., Dt between MFC and MTL;
standard task: 215 ms, pop-out task: 176 ms).
DISCUSSION
Our results reveal two distinct visually responsive populations of
neurons in the human MTL. One population shows response
selectivity to visual object categories including faces as
described before [39, 42, 44]. A second population, described
here for the first time, shows response selectivity to targets
and distractors in memory-based visual search. Our results sug-
gest a population-level response in the MTL that represents the
meaning of visual stimuli by encoding both their category mem-
bership and their task relevance. Differential latency analysis
suggests that the target detection signal in the MTL likely origi-
nates from frontal cortex. In addition, in the MTL, visual category
information was available earlier than the target-detection

8 Current Biology 28, 1–12, July 9, 2018

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092
response. Lastly, a control experiment suggested that the MTL
target response is independent of the format of the search goals.
TS cells constitute a single-neuron correlate of an aspect of
MTL function that so far has received relatively little attention:
the online guidance of behavior [45]. Despite an absence of de-
mands on long-term memory, lesion studies have consistently
shown that patients with MTL lesions exhibit deficits in suffi-
ciently demanding visual search tasks [17, 18]. A critical compo-
nent of visual search is working memory, which is required to
keep in mind the current search goal and to keep track of visited
locations. It has been suggested that the effects of MTL lesions
are due to the increasingly recognized role of the MTL in support-
ing memory for even brief periods of time (seconds) when
distractors and other competing demands are present
[16, 26, 46]. In contrast, here, we provide evidence for a second
role of the MTL during search: the detection of goal relevance.
This result is compatible with the finding that patients with MTL
lesions miss targets more frequently and fixate distractors longer
than controls [47]. Our subjects sometimes also missed targets
despite directly looking at them, in which case the activity of
TS cells was reduced. Together, our data provide direct evi-
dence for a role of the human MTL in the implementation of
behaviorally relevant goals.
We found that the response of TS cells during on-target fixa-
tions was modulated by whether the subject detected the target.
In addition to goal relevance, their response was thus indicative
of the choice made by the subject. Note that a similar relation-
ship has been observed for visually selective neurons in the infe-
rotemporal cortex of macaques [28]. Here, in contrast, we show
that non-visually selective TS neurons exhibit this relationship.
This finding adds to the increasing evidence that the activity of
MTL neurons reflects choices made about visual stimuli rather
than the sensory input [48] and that it may track visual awareness
of the presented stimulus [49–52].
Modulation of neural activity by goal relevance has been
observed in a number of other brain areas. For example, in mon-
keys, in both single-saccade tasks [2, 53, 54] and tasks with natu-
ralistic free viewing [9, 27, 28], temporal lobe cortical neurons
show an enhanced response to visual stimuli presaccadically
when the stimulus in the receptive field becomes the target. Simi-
larly, during delayed match-to-sample tasks at fixation, visual re-
sponses to ‘‘match’’ stimuli in IT and perirhinal cortex are modu-
lated by goal relevance [11, 12]. Here, we provide four new pieces
of data relative to this literature. First, visually tuned cells in the hu-
man MTL are similarly modulated by goal relevance, a response
which they might inherit from their input [2, 11, 12]. Although visu-
ally tuned cells responded with a shorter latency than TS cells,
their selectivity increased after TS cells became selective, further
confirming the modulation of TS cells (cf. Figure S6M). Second,
non-visually tuned target-selective cells were indicative of goal
relevance alone, a kind of response that has not previously
been documented in the MTL of either humans or macaques.
Third, we identified TS cells in the MFC that responded signifi-
cantly earlier than those of simultaneously recorded TS cells in
the MTL. Fourth, MTL neurons encoded search goals irrespective
of goal format. Responses indicating behavioral relevance have
been investigated intensively in the frontal cortex, in particular
the frontal eye fields [55–57]. This information is thought to top-
down modulate other areas [34]. Our findings suggest that MTL
TS cells reflect a top-down signal within the MTL that originates
in the frontal cortex. Here, this conclusion rests on latency differ-
ences alone. Future experiments are needed to test the causality
of this pathway more directly.
We found that MFC neurons responded to targets and MTL
neurons responded to faces
150 ms prior to fixation onset,
suggesting that the neurons respond to what is currently at-
tended, but not yet fixated. Given the observed fixation duration
(Figure 1D;
300 ms), patients must have begun processing the
next to-be-fixated item in the middle of the present fixation,
consistent with prior reports that subjects can identify a search
target at least one fixation in advance [58]. Here, we found
neuronal responses supporting such look-ahead processing.
Recordings from monkey superior colliculus have even shown
that the process of target selection can encompass at least
two future saccade targets [59].
Visually selective cells are a prominent feature of the human
MTL [38–40, 60]. Category cells increase their firing rate shortly
after the onset of only a set of preferred stimuli shown in isolation.
The latency, amplitude, and duration of this activity increase is
modulated by a variety of factors that include anatomical loca-
tion, tuning sparsity, speed of stimulus presentation, and visual
awareness [46, 50, 61]. These properties of category cells can
all be explained using a feedforward view of sensory processing.
In contrast, we now show here that category-cell activity is
modulated by the top-down factor of search goal relevance. A
second form of top-down modulation that modulates category-
cell activity is spatial attention [42]. We also observed such mod-
ulation in our task because category-cell activity was sensitive to
the currently fixated object. Our subjects actively searched the
array, a situation where the current gaze position is an accurate
indication of the location of spatial attention (except for brief mo-
ments of time preceding saccades [28, 62, 63]). Together, our re-
sults reveal that during active search, category-cell activity is
jointly modulated by the two top-down factors of spatial atten-
tion and goal relevance.
Searching for a face in a crowd is perhaps one of the most
common visual search tasks that humans perform, making it
important to independently investigate face cells. Here, we
found that face cells were strongly modulated by the top-down
factors of spatial attention and goal relevance. This result was
also true when restricting our analysis to face cells recorded in
the amygdala, which reveals that the social inference processes
that are thought to rely on face cells in the amygdala [64, 65] can
be modulated by goal relevance. In conclusion, our results pro-
vide important insights into how the brain detects goal-relevant
targets in the environment. While behavioral work has long indi-
cated that the MTL is important in the online control of behavior,
it has so far remained unclear what specifically its contribution is.
Here, we provide direct evidence for one such contribution: the
detection of goal-relevant targets.
STAR+METHODS
Detailed methods are provided in the online version of this paper
and include the following:
d KEY RESOURCES TABLE
d CONTACT FOR REAGENT AND RESOURCE SHARING
Current Biology 28, 1–12, July 9, 2018 9
 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092
d EXPERIMENTAL MODEL AND SUBJECT DETAILS
d METHOD DETAILS
B Stimuli
B Task
B Electrophysiology
B Eye tracking
d QUANTIFICATION AND STATISTICAL ANALYSIS
B Fixation analysis
B Spikes
B Single-neuron ROC analysis
B TSI
B Depth of selectivity (DOS) index and visual selectivity
B Differential latency
d DATA AND SOFTWARE AVAILABILITY
SUPPLEMENTAL INFORMATION
Supplemental Information includes six figures and one table and can be found
with this article online at https://doi.org/10.1016/j.cub.2018.04.092.
ACKNOWLEDGMENTS
We thank all patients for their participation, Juan Xu for creating the array item
labels, and Ming Jiang for helping with the analyses. This research was sup-
ported by the Rockefeller Neuroscience Institute, the Autism Science Founda-
tion and the Dana Foundation (to S.W.), the Simons Foundation (Simons
Collaboration on the Global Brain Award 543015SPI to R.A.), an NSF CAREER
award (1554105 to U.R.), and the NIMH (R01MH110831 to U.R. and Conte
Center P50MH094258 to R.A.). The funders had no role in study design,
data collection/analysis, decision to publish, or preparation of the manuscript.
AUTHOR CONTRIBUTIONS
S.W., R.A., and U.R. designed experiments and wrote the paper. S.W., A.N.M.,
and U.R. performed research. S.W. and U.R. analyzed data. All authors dis-
cussed the results and contributed toward the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 5, 2018
Revised: April 3, 2018
Accepted: April 27, 2018
Published: June 14, 2018
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Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092
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 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

STAR+METHODS

KEY RESOURCES TABLE

REAGENT or RESOURCE SOURCE IDENTIFIER

Software and Algorithms
MATLAB R2013b MathWorks https://www.mathworks.com/products/
matlab.html
OSort N/A http://www.rutishauserlab.org/osort
Psychophysics toolbox PTB3 N/A http://psychtoolbox.org
Other
Neuralynx Neurophysiology System Neuralynx (https://neuralynx.com) Cat# ATLAS 128
EyeLink Eye Tracker SR Research (https://www.sr-research.com) Cat# 1000 Plus Remote
Ad-Tech 8-contact Microelectrode Ad-Tech (https://adtechmedical.com/ Cat# WB09R-SP00X-014
subdural-electrodes)
Cedrus Response Box Cedrus (https://cedrus.com/) Cat# RB-844

CONTACT FOR REAGENT AND RESOURCE SHARING

Further information and requests for resources should be directed to and will be fulfilled by the Lead Contact, Ralph Adolphs
(radolphs@hss.caltech.edu).

EXPERIMENTAL MODEL AND SUBJECT DETAILS

There were 11 sessions from 8 patients in total. Three patients did two sessions. All sessions had simultaneous eye tracking. All par-
ticipants provided written informed consent according to protocols approved by the institutional review boards of the Cedars-Sinai
Medical Center and the California Institute of Technology. We also compared our patients’ behavioral task performance with that of 8
healthy individuals to confirm that our patients performed normally in the task. These healthy individuals have been characterized in a
previous study [37].

METHOD DETAILS

Stimuli
We used 20 distinct visual search arrays. In each array there were 24 items whose spatial locations were randomized between the
20 arrays. 12 items contained faces (faces and people with different postures, emotions, ages, and genders, etc.) and 12 items did
not contain faces (furniture, toys, food, etc.) (see Figure 1B for an example). These face and non-face items composing the array stim-
uli have been characterized and described previously [37, 66]. From each array stimulus, we randomly assigned 4 face items and
4 non-face items as targets (on 8 distinct trials). For each array, we also had 2 target-absent trials, i.e., the target was not among
the objects in the search array (one target-absent trial with a face target, and one with a non-face target). Therefore, in total we
had 100 trials with face targets and 100 trials with non-face targets, and 20% of trials were target-absent trials. The entire task
was separated into two blocks. Each block had 100 trials. Patients finished at least one block. Importantly, low-level properties of
face and non-face items were equalized within each search array. The face and non-face items did not differ in standard low-level
saliency as quantified by the Itti-Koch model [67, 68], distance to center or size (all p values > 0.79). In the analysis of visual tuning to
object category, we further categorized the items into 14 finer categories: face, clock, vehicle, furniture, electronics, stationery, sign,
plant, toy, sport, bag, comb, clothes, and food.
In the pop-out task, we only used face items and vehicle items from those in the standard task. There were still 24 items in total in
each search array, but each array was generated online with a randomly selected subset of face and vehicle items. The spatial loca-
tion of each item was also randomly decided online. Target-present arrays had one face among vehicles or one vehicle among faces,
and target-absent arrays had homogeneously all faces or all vehicles.

Task
The task (Figures 1A and 1B) has been described in a previous study [37]. A target was presented for 1 s followed by the search array.
Patients were instructed to find the item in the array that matched the target and explicitly told that the array might or might not contain
the target. The search array stayed up for at most 14 s, or until the subject responded by a Cedrus button box, either by pushing the

Current Biology 28, 1–12.e1–e4, July 9, 2018 e1

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

left button to indicate that the target was found in the array, or by pushing the right button to indicate that the target was absent in the
array. A feedback message (‘Correct’ or ‘Incorrect’) was then displayed for 1 s. Subjects were instructed to respond as quickly and
accurately as possible. If subjects did not respond within 14 s after array onset, a message ‘Time Out’ was displayed. An inter-trial-
interval (ITI) was jittered between 1 to 2 s. The array and target orders were completely randomized for each subject. Subjects prac-
ticed 5 trials before the experiment to familiarize themselves with the task. In the end, the overall percentage of correct answers was
displayed to patients as a motivation.
The control pop-out task used different search arrays (Figure 6B) but the same task as the standard task, except that targets were
pre-defined and thus there was no search cue. Patients were still instructed to report target presence as quickly and accurately as
possible. Each block had 100 trials.
Patients sat approximately 60 cm from an LCD display with a 17-inch screen (screen resolution: 1024 3 768). The refresh rate of
the display was 60Hz and the stimuli occupied the center of the display (31.5 3 25.4 visual angle). Stimuli were presented using
MATLAB with the Psychtoolbox 3 [69] (http://psychtoolbox.org).

Electrophysiology
We recorded bilaterally from implanted depth electrodes in the amygdala, hippocampus, aMCC, and pre-SMA from patients with
pharmacologically intractable epilepsy. Target locations were verified using post-implantation structural MRIs as shown in Figure S1.
At each site, we recorded from eight 40 mm microwires inserted into a clinical electrode as described previously [70, 71]. Efforts were
always made to avoid passing the electrode through a sulcus, and its attendant sulcal blood vessels, and thus the location varied but
was always well within the body of the targeted area. Microwires projected medially out at the end of the depth electrode and exam-
ination of the microwires after removal suggests a spread of about 20-30 degrees. The amygdala electrodes were likely sampling
neurons in the mid-medial part of the amygdala and the most likely microwire location is the basomedial nucleus or possibly the
deepest part of the basolateral nucleus. Bipolar wide-band recordings (0.1-9kHz), using one of the eight microwires as reference,
were sampled at 32kHz and stored continuously for offline analysis with a Neuralynx system. The raw signal was filtered with
zero-phase lag 300-3kHz bandpass filter and spikes were sorted using a semi-automatic template matching algorithm as described
previously [72]. Units were carefully isolated and recording and spike sorting quality were assessed quantitatively (Figure S2).

Eye tracking
Patients were recorded with a remote non-invasive infrared Eyelink 1000 system (SR Research, Canada). One of the eyes was
tracked at 500Hz. The eye tracker was calibrated with the built-in 9-point grid method at the beginning of each block. Fixation extrac-
tion was carried out using software supplied with the Eyelink eye tracking system. Saccade detection required a deflection of greater
than 0.1 , with a minimum velocity of 30 /s and a minimum acceleration of 8000 /s2, maintained for at least 4 ms. Fixations were
defined as the complement of a saccade, i.e., periods without saccades. Analysis of the eye movement record was carried out offline
after completion of the experiments.
Rectangular regions of interest (ROI) were used to define array items in the search array [37]. The ROI boundaries tightly encom-
passed the entire array item and varied between items, depending on the item size. Fixations within the ROIs were counted as falling
on items. Each fixation was treated individually, and multiple consecutive fixations that fell on the same array item were counted as
discrete samples.
Patients occasionally failed to consciously detect targets, conditional on targets having been fixated. We defined ‘‘misses’’ as fix-
ations that landed on the target even though the target was not detected. We excluded the last 3 fixations landing on the target for
misses because they corresponded to target detection [37].

QUANTIFICATION AND STATISTICAL ANALYSIS

Fixation analysis
We included fixations from target-present trials only to analyze target response, and fixations from both target-present and target-
absent trials to analyze visual selectivity. We included all trials, but qualitatively the same results were derived when analyzing correct
trials only. We drew rectangular regions of interest (ROIs) that tightly encompassed the array items (Figure 1B). 64.4% ± 3.63%
(mean ± SD across sessions) fixations were on items (the rest were in margins), and multiple consecutive fixations within the
same array item were counted as discrete samples. 18.0% ± 5.09% fixations from target-present trials fell onto targets. To analyze
target response, we contrasted fixations on targets to all other fixations in target-present trials, including those in the margins, which
were broadly defined as ‘‘distractors.’’ Qualitatively the same results were derived when only including fixations fully within the item
ROIs. To analyze visual selectivity, we only considered fixations fully within the item ROIs.
Trials in which targets had ever been fixated (regardless of whether they had been detected by button press), had on average
5.09 ± 1.35 and 0.65 ± 0.63 fixations on distractors before and after the first fixation on target, respectively. Furthermore, patients
occasionally failed to consciously detect targets even when they had been fixated. We defined ‘‘misses’’ as fixations that landed
on the target even though the trial was not immediately terminated by button press from the subject, i.e., at least 3 fixations away
from button press. We excluded the last 3 fixations landing on the target for misses because they corresponded to target detection
[37]. 7.38% ± 6.18% of target-present trials contained such misses.

e2 Current Biology 28, 1–12.e1–e4, July 9, 2018

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

Spikes
Only units with an average firing rate of at least 0.2Hz (entire task) were considered. Only single units were considered. Trials were
aligned to stimulus onset or button press. Fixations were aligned to fixation onset. Average firing rates (PSTH) were computed by
counting spikes across all trials in consecutive 250 ms bins and across all fixations in consecutive 50 ms bins. Pairwise comparisons
were made using a two-tailed t test at p < 0.05 and Bonferroni-corrected for multiple comparisons in the group PSTH.

Single-neuron ROC analysis

Neuronal ROCs were constructed based on the spike counts in a time window 500 to 500 ms around button press for trial-wise
analysis, and in a time window of 200 ms before fixation onset to 200 ms after fixation offset for fixation-wise analysis. We varied
the detection threshold between the minimal and maximal spike count observed, linearly spaced in 20 steps. The AUC of the
ROC was calculated by integrating the area under the ROC curve (trapezoid rule). The AUC value is an unbiased estimate for the
sensitivity of an ideal observer that counts spikes and makes a binary decision based on whether the number of spikes is above
or below a threshold. We defined the category with higher overall firing rate as ‘true positive’ and the category with lower overall firing
rate as ‘false positive’. Therefore, the AUC value was always above 0.5 by definition.

TSI
In target-preferring neurons (n = 27), the normalized firing rate (i.e., the firing rate was normalized by dividing by average baseline
(the firing rate 1000 ms before cue onset) across all trials, separately for each unit) was 1.41 ± 0.28 and 1.03 ± 0.17 for fixations
on targets and distractors, respectively (two-tailed paired t test, p = 9.94 3 1011), whereas in distractor-preferring neurons
(n = 23), the normalized firing rate was 0.71 ± 0.24 and 0.92 ± 0.26 for fixations on targets and distractors, respectively (two-tailed
paired t test, p = 4.83 3 107). This result shows that the subset of TS neurons that have a larger response to distractors than targets
are decreasing their activity for targets rather than increasing their activity for distractors.
We quantified for each neuron whether its response differed between fixations on targets and fixations on distractors using a
single-fixation TSI (Equation 1). The TSI facilitates group analysis and comparisons between different types of cells (i.e., target-
and distractor-preferring cells in this study), as motivated by previous studies [44, 73, 74]. The TSI quantifies the response during
fixation i relative to the mean response to fixations on distractors and baseline (a 1 s interval of blank screen right before target
cue onset). The mean response and baseline was calculated individually for each neuron.
FRi  meanðFRDistractor Þ
TSIi = ,100% (Equation 1)
meanðFRBaseline Þ
For each fixation i, which can be either target or distractor, TSIi is the baseline normalized mean firing rate (FR) during an interval
from 200 ms before fixation-onset to 200 ms after fixation offset (the same time interval as cell selection). Different time intervals were
tested as well, to ensure that results were qualitatively the same and not biased by particular spike bins.
If a neuron distinguishes fixations on target from fixations on distractors, the average value of TSIi will be significantly different from
0. Since target-preferring neurons have more spikes in fixations on targets and distractor-preferring neurons have more spikes in
fixation on distractors (the selection process is described above), on average TSIi is positive for target-preferring neurons and nega-
tive for distractor-preferring neurons. To get an aggregate measure of activity that pools across neurons, TSIi was multiplied by 1 if
the neuron is classified as a distractor-preferring neuron (Equation 2). This makes TSIi on average positive for both types of target
neurons. Notice that the factor 1 depends only on the neuron type, which is determined by t tests on fixations as described above,
but not fixation type. Thus, negative TSIi values are still possible.
FRi  meanðFRDistractor Þ
TSIi =  ,100% (Equation 2)
meanðFRBaseline Þ
After calculating TSIi for every fixation, we subsequently averaged all TSIi of fixations that belong to the same category. By defi-
nition, the average value of TSIi for fixation on distractors will be equal to zero because the definition of TSIi is relative to the response
to fixation on distractors (see Equation 2). The mean baseline firing rate was calculated across all trials. The same FRDistractor was
subtracted for both types of fixations.
The cumulative distribution function (CDF) was constructed by calculating for each possible value x of the TSI how many examples
are smaller than x. That is, F(x) = P(X % x), where X is a vector of all TSI values. The CDF of fixations on targets and distractors were
compared using two-tailed two-sample Kolmogorov–Smirnov tests. All error bars are ± SE unless indicated otherwise.
8.95% ± 3.19% of all fixations in target-present trials that landed on an item (not in the blank) were consecutive (i.e., on the same item
as the previous fixation), and 48.5% ± 17.5% of these consecutive fixations were fixations on targets. Because there were fewer fixations
on targets than on distractors overall, the percentage of consecutive fixations on targets (24.6% ± 8.08%) was significantly higher than
that on distractors (5.77% ± 2.99%; two-tailed paired t test: p < 105). However, even though there were multiple fixations on targets, the
fixations were not always consecutive: we found that in 28.6% ± 16.1% of trials with multiple fixations on targets, there were distractors in
between fixations on targets, resulting in an average of 0.71 ± 0.58 fixations (absolute count) on distractors between fixations on targets.
Similar results could be derived when excluding consecutive fixations on targets and distractors: we could still identify 37 TS neurons
(16.2%; binomial p < 1010) with an average TSI of 32.4% ± 19.8%. Lastly, when using only the first fixations on targets and distractors,
we could still identify 30 TS neurons (13.2%; binomial p < 106) with an average TSI of 31.0% ± 18.8%.

Current Biology 28, 1–12.e1–e4, July 9, 2018 e3

 Please cite this article in press as: Wang et al., Encoding of Target Detection during Visual Search by Single Neurons in the Human Brain, Current
Biology (2018), https://doi.org/10.1016/j.cub.2018.04.092

Moreover, we confirmed our results by excluding fixations in the margins (i.e., not on an item) of the search array (only including
fixations fully within the item ROIs): we could identify 37 TS neurons (16.2%; binomial p < 1010) with an average TSI of 45.6% ±
29.0%. Notably, our TS neurons did not have a significant difference in firing rate between fixations on distractors and margins
(two-tailed paired t test: p = 0.74).
Lastly, similar to MTL neurons, aMCC TS neurons also had a significantly higher response to targets that were detected relative to
those that were missed (TSI: 34.2% ± 29.0% versus 13.2% ± 66.9%, mean ± SD across cells, KS-test, p = 0.0081), and the response
of aMCC TS neurons to missed targets was significantly larger than that to distractors (TSI: 13.2% ± 66.9% versus 0.0% ± 0.0% (by
default); KS-test, p < 106). Similarly, we found that pre-SMA TS neurons also had a significantly higher response to targets that were
detected relative to those that were missed (TSI: 84.2% ± 112.5% versus 8.51% ± 92.3%, mean ± SD across cells, KS-test, p <
107). In addition, however, the response of pre-SMA TS neurons to missed targets was significantly lower than that to distractors (TS
index: 8.51% ± 92.3% versus 0.0% ± 0.0%; KS-test, p < 0.05), indicating that the response to missed targets was suppressed.
Notably, when we compared between brain areas, we found that TSI of neurons from the aMCC did not differ significantly from
that from the MTL (p = 0.53 for detected targets, p = 0.84 for missed targets, and p = 0.91 for the difference between detected
and missed targets), whereas TSI of neurons from the pre-SMA was significantly higher for detected targets (p = 0.0014) and in partic-
ular the difference between detected and missed targets (p = 0.012; but not missed targets only: p = 0.16). Together, this shows that
TS neurons in MFC differentiate between detected versus missed targets like MTL TS neurons. In addition, these data suggest that
the pre-SMA was more strongly correlated with behavioral detection of targets relative to the MTL.

Depth of selectivity (DOS) index and visual selectivity

We quantified the DOS for each neuron:

P .
n
n j = 1 rj rmax
DOS = (Equation 3)
n1
where n is the number of categories (n = 2 and 14 for face-selective and category-selective neurons, respectively), rj is the mean
response to category j, and rmax is the maximal mean response. DOS varies from 0 to 1, with 0 indicating an equal response to all
categories and 1 exclusive response to one but none of the other categories. Thus, a DOS value of 1 is equal to maximal sparseness.
When we selected visually selective neurons, we used a tighter fixation time window of 0 to 300 ms after fixation onset to ensure
that visual inputs were restricted to fixations. However, using the identical time window for target neurons that included saccades
before and after fixations, we derived qualitatively the same results.
To assess statistical significance, we estimated the null distribution by first randomly shuffling the category labels of fixations/
target cues and then computing DOS. We used 1000 runs for the permutation analysis. We compared the observed DOS with
this null distribution of DOS to obtain p values.

Differential latency
We binned spike trains into 1-ms bins and computed the cumulative sum. We then averaged the cumulative sums for fixations on
targets and distractors, respectively. We here only analyzed target-preferring neurons because distractor-preferring neurons had
different temporal dynamics. We then compared, at every point of time, whether the cumulative sums of a group of neurons were
different (p < 0.01, one-tailed pairwise t test; FDR corrected). The first point of time of the significant cluster (cluster size > 10
time points) was used as the estimate of the differential latency. Note that this method is not sensitive to differences in baseline firing
rate between neurons because the latency estimate is pairwise for each neuron individually.
To compare latency between TS and category neurons, we selected a population of 27 neurons that differentiated fixations on
faces versus non-faces during search (two-tailed two-sample t test, p < 0.05), so that they were comparable to TS neurons (i.e.,
both were selected based on fixations during search). The majority of this subset of neurons (17 neurons) had a greater response
for faces than non-faces and we focused on the neurons with faces as preferred stimulus. In addition, we confirmed our results
with the category neurons selected during cue presentation. We examined face-selective neurons, which had a clear preferred
and non-preferred category. We conducted two analyses, with fixations on targets. The first one focused on face-selective neurons
with faces as the preferred stimulus (i.e., neurons that increased their firing rate for faces). The second one combined face-selective
neurons with faces as preferred stimulus and face-selective neurons with non-faces as the preferred stimulus by inverting the latter,
so that the preferred response of all face-selective neurons was a firing rate increase.
To assess statistical significance, we estimated the null distribution by first randomly shuffling the labels for groups and then
repeated the above latency analysis. We used 1000 runs for the permutation analysis. We compared the observed latency difference
between groups with this null distribution of latency difference to obtain p values.

DATA AND SOFTWARE AVAILABILITY

The spike detection and sorting toolbox OSort was used for data processing, which is available as open source. Data and custom
MATLAB analysis scripts are available upon reasonable request.

e4 Current Biology 28, 1–12.e1–e4, July 9, 2018