Exp Brain Res
DOI 10.1007/s00221-016-4746-x
RESEARCH ARTICLE
Prefrontal activity decline in women under a single dose
of diazepam during rule‑guided responses: an fMRI study
Z. Muñoz‑Torres1,2 · J. L. Armony3 · D. Trejo‑Martínez4 · R. Conde4 ·
M. Corsi‑Cabrera1 
Received: 27 December 2015 / Accepted: 28 July 2016
© Springer-Verlag Berlin Heidelberg 2016
Abstract  Daily life events confront us with new situations
demanding responses to usual and unusual rules. Diazepam
(DZ), a clinically important drug, facilitates the inhibitory
activity of the GABAergic system. Prefrontal cortex, rich
in DZ receptors, coordinates necessary resources to direct
actions according to rules. The balance between excita-
tory and inhibitory activity is critical to achieve optimal
function of brain systems leading to complex functions.
Major sex differences in the physiological mechanisms of
the GABAergic system have been reported. However, the
differential influence of DZ on men and women in neural
activity during behavior directed by frontal lobes remains
unexplored. The ability of healthy volunteers to select
responses following usual/congruent and novel/incongruent
rules, and brain correlates were measured with fMRI under
the administration of DZ and a placebo. 10 mg of DZ was
enough to decrease the performance in a different manner
between men and women. While reaction times increased
Electronic supplementary material  The online version of this
article (doi:10.1007/s00221-016-4746-x) contains supplementary
material, which is available to authorized users.
* M. Corsi‑Cabrera
corsi@unam.mx
1
Laboratory of Sleep, Faculty of Psychology, Universidad
Nacional Autonoma de Mexico, Av. Universidad 3004,
Mexico City, Mexico 04510
2 of the prefrontal cortex (PFC) has been implicated in the
Unidad de Trastornos del Movimiento y Sueño (TMS),
Hospital General Ajusco Medio, Secretaria de Salud, Mexico
City, Mexico
3
Department of Psychiatry and Douglas Mental Health
University Institute, McGill University, Montreal, Canada
4
Department of Magnetic Resonance, Hospital Angeles del
Pedregal, Mexico City, Mexico
in both men and women, women committed more errors
selecting responses than men under DZ. Men demonstrated
increased activity, while women demonstrated decreased
activity in frontal regions involved in response selection of
rules. These findings could have important consequences
in understanding the differential influences of DZ between
the sexes in complex daily life situations. More impor-
tantly, this study emphasizes the importance of understand-
ing the differential effects on men and women of drugs
widely employed by society, thereby achieves better thera-
peutic results and avoids side effects that the present study
revealed to be different between sexes.
Keywords  Benzodiazepine · Diazepam · Sex differences ·
fMRI · Rule-guided behavior · Frontal lobes
Introduction
Diazepam (DZ) is a widely prescribed anxiolytic benzo-
diazepine (BDZ) that reduces alertness and can interfere
with cognitive processes in daily life. Normally, the effects
generated by drugs are tested just on men or on men and
women as a group, masking important differences that
may occur between men and women. DZ receptors are dis-
tributed all over the cerebral cortex including the frontal
lobes, the brain region that plays a central role in coordi-
nating responses guided by rules. The ventrolateral region
maintenance of rules during a delay (Compte et al. 2003),
while the dorsolateral PFC is associated with response
selection (Curtis and D’Esposito 2003) regardless of the
type of response emitted (Passingham and Rowe 2002).
The posteroanterior gradient of PFC activity related to the
complexity of the rules was seen as: the more complex
13

the rule, the more polar the activity (Christoff et al. 2009;
Azuar et al. 2014). Likewise, the anterior cingulate cortex
(ACC) is considered important for error detection (Rush-
worth et al. 2007), conflict monitoring (Botvinick 2007)
and response selection (Buckley et al. 2009). All these
frontal areas are in reciprocal communication with other
brain regions allowing a management of the entire pro-
cess underlying rule-guided responses (Bunge et al. 2005).
These complex processes require a balance of inhibitory
and excitatory influences.
Significant sex differences have been reported in neu-
rophysiology, neuroanatomy, cognition and behavior (for
review Corsi-Cabrera et al. 2007). Tasks involving spa-
tial (Schöning et al. 2007; Hausmann et al. 2009), verbal
(Hausmann et al. 2009) and memory (Munro et al. 2012)
skills have been identify as sex-sensitive. Sex differences
related to frontal lobe functions are less explored, and
results are not conclusive. In general, a better inhibitory
control is reported for women than men (Mansouri et al.
2016) which is in accordance with the higher prevalence for
addictive and impulsive behavior observed in men versus
women (Cotto et al. 2010; Hammerslag and Gulley 2016).
Error monitoring and subsequent behavioral adjustment are
cognitive processes linked to frontal lobe functions (Rid-
derinkhof et al. 2004). It has been reported that women
display increased post-error slowing following failed inhi-
bitions in a stop-signal task (Thakkar et al. 2014), while
other studies found no differences employing the same task
(Li et al. 2009) or a flanker task, although women showed
longer overall response times (Larson et al. 2011).
In addition, neuroimaging studies have identify differ-
ences of the neural network employed by men and women
during cognitive tasks demanding frontal lobe functions
while not observing behavioral sex differences (Weiss et al.
2003; Schöning et al. 2007; Li et al. 2009). These results
reveal different task approaches between sexes due differ-
ent strategies or information processing (Pletzer 2014),
supported by eye-tracking studies with men and women
focusing on distinct stimuli aspects (Sæther et al. 2009),
participants self-reports (Gluck and Fitting 2003), or by
using instructions or categories that favor the use of one
strategy over another (Saucier et al. 2002).
On the other hand, the γ-aminobutyric acid (GABA)
system, primary inhibitory neurotransmitter involved in the
effects of BDZ, has a sexually dimorphic expression. It has
been shown that cortical GABA levels are higher in women
than men (Sanacora et al. 1999) and women have signifi-
cantly greater number of available GABAA BDZ recep-
tors than men (Esterlis et al. 2013). Also, the prevalence
of mood disorders such as anxiety and the prescription use
of BDZ are significantly higher among women than men
(Wittchen and Jacobi 2005; Altemus et al. 2014). Under the
effects of DZ, the electroencephalographic activity during
13
Exp Brain Res
rest exhibited an increment of theta activity on women,
but not on men, while the coherent activity between brain
hemispheres resulted in male subjects being more affected
(Romano-Torres et al. 2002). Animal models have shown
that the sexual dimorphic response to DZ depends on the
sex steroids influence during the perinatal critical period
in which profound changes take place differentiating male
and female brains (Ugalde et al. 1998; Corsi-Cabrera et al.
2000; Fernandez-Guasti et al. 2003).
The study of differential influences of BDZ on meta-
bolic brain activity between men and women is missing.
No experiment has been conducted to investigate a differ-
ential influence of diazepam between men and women in
the hemodynamic neural activity during the selection of
rule-guided actions. In order to explore these sex differ-
ences, we reanalyze the data of a previous study (Muñoz-
Torres et al. 2011a).
We hypothesized that the susceptibility to DZ will
be higher in women than in men, which will be reflected
in both the hemodynamic response of frontal lobes and
rule-guided actions. Specifically, under DZ, task perfor-
mance will be impaired on both, men and women, being
women more affected than men in performance with
the same doses of DZ. Additionally, a reduction of activ-
ity in the frontal lobes is expected, which will be intensi-
fied in women because of the inhibitory action of DZ and
the higher availability of GABA and GABAA receptors in
women than in men.
Materials and methods
Subjects
Twenty healthy volunteers were recruited for this prelimi-
nary study. Data of two subjects were removed due tech-
nical problems; eighteen subjects (9 men and 9 women)
remained for analysis. Subjects ranged in age from 21 to
35 years old and had a body mass mean index of 23.4 kg/
m2. Subjects reported having completed 14–21 years of
education. None of them had a history of head trauma or
surgery, mental illness or drug addiction, and all were free
of medications known to affect the central nervous sys-
tem, the hormonal cycle, or the DZ metabolism as deter-
mined by medical history and personal interview. Subjects
refrained from using alcohol or any medication 72 h before
the scanning sessions. All subjects were right-handed as
assessed by Annett´s test (Annett 1967). The study has
been performed in accordance with the Declaration of Hel-
sinki and was approved by the Faculty of Medicine Eth-
ics Committee of the National Autonomous University of
Mexico. An informed consent was obtained from all par-
ticipants prior to the study.
Exp Brain Res

Table 1  Summary of demographic, body composition data, and diaz- at the end of the sessions. Table 1 shows demographic,
epam blood levels body composition information, and diazepam levels for
Men (n = 9) Women p each group. No statistical differences in age, education,
(n = 9) body mass index or blood diazepam levels were observed
Mean SD Mean SD between men and women. Height and weight values of men
were larger than women.
Age (years) 25.5 3.5 24.1 3.0 0.19
Education (years) 16.5 2.2 16.6 2.0 0.44 Cognitive task
Height (cm) 173 0.3 159 0.4 <0.001
Weight (kg) 71.7 9.8 57.7 5.4 <0.001 During scanning, subjects performed a reaction-time rule-
Body mass index (kg/m2) 24.0 3.5 22.9 2.9 0.21 guided response selection task, based on stimulus-depend-
Diazepam level (mcg/ml) 170.6 56.6 167 61.0 0.43 ent complex arbitrary rules, which had been previously
validated in a similar group of 39 healthy individuals in a
pilot study. The task required subjects to select between
Subjects ingested one of two similarly looking cap- two alternative responses (1 or 2 clicks) depending on a set
sules containing either 10 mg of DZ or placebo (PL) in a of arbitrary rules. Following a preparatory screen with a
repeated measures counterbalanced design. Scanning was central fixation point and two lateral squares, a white arrow,
performed between 2 and 5 h after the capsule intake, in which could point to either side, left or right, appeared at
a period when DZ distribution has been reported as sta- the center of the screen for 500 ms, immediately followed
ble (Friedman et al. 1985). All participants underwent two by the target (a red or green cross), which appeared in one
experimental sessions separated by 3–5 weeks. Women had of the squares for 100 ms. An interval of 4000 ms separated
regular menstrual cycles, and none were taking contracep- the trials, same general characteristics were maintained
tives determined by personal interview before the first ses- constant for the different stimuli types (see Fig. 1a).
sion. All women were scanned in the early follicular phase Four rules were given to guide the response selection,
(between the 3rd and 5th day) of hormonal cycle (Solís- a congruent rule and three incongruent ones that modified
Ortiz et al. 1994). Arterial blood samples from all subjects the required response based on the relationship between
were obtained just before or after fMRI scanning (counter- the direction of the arrow and the target color. Accord-
balanced) to determine DZ concentration, and in the female ingly, there were four different stimuli, which, critically,
group, progesterone and estrogen levels were also meas- were unequal in their congruency with expected prepotent
ured; only women that presented plasma levels correspond- responses. Specifically, responses to the target when the
ing to the early follicular phase were included in the study arrow was pointing toward its location should be facilitated
(estradiol 29.46 mcg/ml, SD 8.95; progesterone 0.13 mcg/ compared to when they were pointing away from it (“Pos-
ml, SD 0.03). Participants were conducted to their homes ner effect”) and responses to a green target should be faster

Fig.  1  a Schematic representa-

tion of a trial. b Illustration of
the stimuli and the required
response (for the black and
white version: the two first
stimuli correspond to the green
cross and the last two to the
red cross). c Sagittal view of
slice placement. Regions of the
frontal lobes covered included
orbitofrontal, dorsolateral
prefrontal, medial prefrontal,
cingulate, and premotor cortices

13

than to a red one, based on the usual meaning of green
(“go”) and red (“stop”) signals. The congruent rule fol-
lowed the usual convention of “Green = Go” and the con-
gruency between the direction of the arrow and the location
of the target. Therefore, in this case, the instruction was: “If
the arrow points to the same location as the green target, a
double click is required” (fully congruent: CC). The three
incongruent rules reversed one or both of these familiar
associations: (1) “If the arrow points to the opposite side
from the green target, a single click is required” (direction
incongruent: DI); (2) “If the arrow points to the same side
as the red target, a single click is required” (color incon-
gruent: CI), and (3) “If the arrow points to the opposite
side from the red target, a double click is required” (fully
incongruent: II). All the other sensorial and time proprie-
ties remain the same across stimuli to prevent confounding
factors. An illustration of the four rules is shown in Fig. 1b.
Pilot studies confirmed that the three incongruent rules,
considered as more difficult because they go against usual
behavior, were associated with longer reaction times. Non-
rule, or “catch trials”, in which no target followed the arrow
and a response was not required, were also presented.
Catch trials were presented to add a change in the interval
inter-stimuli, ensuring a different timing for the sample of
brain slices and as a control for the contrasts. Subjects were
required to press a key two times (as a double click) or just
one time (i.e., inhibit one click), with the right index finger
as fast as possible, depending on the rule.
Each rule was presented with the same frequency in a
pseudo-random order with the constraint that no more than
three stimuli of the same type appeared consecutively. Four
blocks of 44 stimuli were presented (10 of each of the four
rules and 4 non-rule trials randomly presented for each rule
type). The time window to respond was during the fixation
point for 2100 ms, just after the cross (target) presentation.
The response system consisted of a hand-held box with two
buttons and optical fiber technology MR-compatible that
allows for high resolution tracking. The task was run inside
the scanner with E-Prime (Psychology Software Tools,
Pittsburgh, Pennsylvania). Subjects performed a practice
trial outside the scanner to ensure the instructions were cor-
rectly understood.
MRI acquisition
Functional MRI data were acquired with a General Elec-
tric 1.5 Tesla MR system at the Hospital Angeles del
Pedregal. For each subject and each session, 240 echo-
planar image volumes were acquired (8 6-mm-thick axial
slices; TR = 3 s; TE = 27 ms; interslice gap: 4 mm; field
of view: 24 × 24 cm, matrix: 128 × 128), in four runs of
60 scans with three dummy scans discarded before analysis
due to T1 saturation effects. Before the functional runs, a
13
Exp Brain Res
T1-weighted anatomical scan was obtained (TR = 18.4 ms,
TE  = 4.2 ms, 0.47 × 0.47 × 3 mm3 voxel size). Slices
location is shown in Fig. 1c.
Data analysis
Behavioral data
Performance data (reaction times and correct responses)
were subjected to a mixed factorial three-way analysis of
variance (ANOVA) with two levels of sex (men, women)
as the between factor, two levels of drug (PL, DZ) and four
rules (CC, DI, CI, II), both, as repeated measures corre-
sponding to the within subjects factor.
Further post hoc Tukey analyses were conducted when
appropriate to better identify the source of the observed sta-
tistically significant difference between conditions. A sig-
nificance level of p < 0.05 was adopted for statistical com-
parisons. Partial eta squared (η2) was estimated to measure
effect sizes. Power and confidence intervals (CIs) at 95 %
are reported for statistically significant results. Reac-
tion times were transformed to natural logarithms before
obtaining the CIs. Confirmatory randomization hypothesis
tests were conducted comparing mean pairs by shuffling
the results 2000 times under the null hypothesis for sex and
drug.
fMRI data
Functional data were preprocessed following standard pro-
cedures using SPM2 (www.fil.ion.ucl.ac.uk/spm/software/
spm2). Functional images for each subject were realigned
to the first image of each session to correct for head move-
ment between scans. Images were then spatially normal-
ized to a standard space (Talairach and Tournoux 1988)
using the MNI template (Evans et al. 1994). Finally, images
were spatially smoothed using an isotropic Gaussian kernel
of 8 mm FWHM.
There were five trial types (the four rules and the non-
rule trial). Events were modeled as events coinciding with
the presentation of the target, or the fixation point for non-
rule trials; convolved with the synthetic hemodynamic
response function.
After whole brain analyses, and in order to enhance the
statistical power, we conducted a statistical analysis of the
results extracted from the frontal lobes including: the lower
part of the superior frontal gyrus, the medial and inferior
frontal gyri, the orbitofrontal cortex including the anterior,
posterior, medial and lateral orbital gyri, and the cingulate
gyrus. The selected area for analyses is shown in Fig. 1c.
Frontal lobe responses associated with each experimen-
tal condition were estimated according to the general lin-
eal model for an event-related design at each voxel (Friston
Exp Brain Res

et al. 1995). In order to explore sex differences in brain Results

activity associated with the performance of the rule-guided
response selection task, with and without the influence of Behavioral results
an external agent, we analyzed the neural activity under
each condition (PL/DZ) separately. We first explore the Behavioral data distribution for each condition and group is
differences under normal conditions (PL) computing three shown in the supplementary material (Fig. S1).
contrasts for each subject: (1) a contrast of overall rule
selection for the four rules versus non-rule (catch) trials (2) Reaction times
a contrast comparing the incongruent rules (DI, CI, II) with
the catch trials; and (3) a contrast between the congruent A mixed ANOVA was conducted to analyze potential dif-
or easy rule (CC) and the catch trials. The same contrasts ferences in reaction times (RTs) and accuracy as a func-
were performed for each subject under DZ. These contrasts tion of the experimental variables (sex, drug, and rule).
were taken to a second-level (random-effects) one-sample t Figure 2a shows the increase in RTs with DZ in compari-
test. Activations are reported for clusters of 15 contiguous son with PL (F(1,16) = 10.79, p = 0.004, partial η2 = 0.4,
voxel that surpassed an uncorrected threshold of p < 0.001, 95 % CIs [555.7, 743.8] and [443.5, 597.1], respectively,
as well as a corrected cluster level of p < 0.05. Finally, to power = 0.87). The main effect rule (Fig. 2b) showed the
assess the differences between men and women on brain fastest RTs for the congruent rule (CC) in comparison
activity as a function of the rule selection task and drug, with the other three (DI, CI, II) and the slowest RTs were
all the estimated values that resulted statistically signifi- observed for the rules that required inhibiting one response
cant from the previous contrasts were extracted to compare (DI, CI). A significant (F(3,48)  = 30.62, p  = 0.009, par-
them through two-way (between-within subjects) ANOVAS tial η2 = 0.7, 95 % CIs [440, 597.8], [546, 703.1], [536.3,
(sex × drug). Only the statistical differences (p < 0.05) are 717.2], and [515.5, 646.1], respectively, power = 1) factor
reported. interaction showed the RTs under DZ effects are higher in

Fig. 2  Effects in task perfor- a Reacon Times by Drug b Rules Reacon Times

mance a mean and standard 900
800
Reacon Times (msec)
Reacon Times (msec)

errors of reaction times in ms ** **

750
as a function of drug, b as 600
**
CC
a function of rule. c Correct 600
responses as a function of drug. DI
400 450
d Correct responses for women CI
300
(left) and men (right) for each 200 II
rule by drug. Brackets indicate 150
statistical differences (p < 0.05) 0 0
PL DZ PL DZ
between two conditions. Aster‑
isks, above each bar in b, show
statistical differences (p < 0.05) c
between all rules with placebo 100 Accuracy by Drug
Correct Responses (%)

and diazepam for the specified

rule 95

90

85

80
PL DZ

d Correct Responses of Women Correct Responses of Men

PL PL
100 100
DZ
Correct Responses (%)

DZ
Correct Responses (%)

95 95

90 90

85 85

80 80
CC DI CI II CC DI CI II

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 Exp Brain Res

Table 2  Frontal brain Voxel Coordinates Brain regions Brodmann Cluster

activation differences between Z score PLACEBO area size
men and women under placebo x y z
for: response selection minus
non-response, congruent rule Rule selection > non-rule
minus non-rule and incongruent  3.58 14 44 8 R Anterior cingulate gyrus 32 163
rules minus non-rule
 3.45 22 56 2 R Superior frontal gyrus 10
 3.29 22 54 10 R Superior frontal gyrus 10
 3.55 46 40 16 R Middle frontal gyrus 46 16
Congruent rule > non-rule
 3.37 22 54 12 R Superior frontal gyrus 10 51
 3.26 16 44 8 R Anterior cingulate gyrus 32 12
Incongruent rules > non-rule
 3.47 14 44 8 R Anterior cingulate gyrus 32 95
 3.31 20 54 −2 R Superior frontal gyrus 10
 3.3 26 60 6 R Superior frontal gyrus 10

R right hemisphere

responses of the rules CC, DI and II in comparison with
all the responses with PL, and in comparison with the
responses following the congruent rule (CC) under DZ.
Also, under DZ, RTs were higher for rules demanding
inhibiting one click (DI and CI) in comparison with the
fully incongruent (II) rule. RTs with PL were fastest for
the congruent rule in comparison with the other three (DI,
CI, II). No significant main effects or interactions were
observed between men and women in reaction time, neither
with PL nor with DZ.
Randomization tests confirmed the differences
observed in reaction times with PL in comparison with DZ
(p = 0.01) and the lack of differences between sexes with
PL (p = 0.28) and DZ (p = 0.26) separately.
Accuracy
A three-way ANOVA for correct responses showed a sig-
nificant main effect of drug (F(1,16)  = 5.05, p  = 0.03,
partial η2  = 0.24, 95 % CIs [95.1, 97.4] and [88.2, 96.3],
power  = 0.56) with a decrease in accuracy under DZ
(Fig.  2c). As expected, the main effect for rules showed
less correct responses for fully incongruent (II) rule in
comparison with the congruent rule (CC) (F(3,48) = 4.15,
p  = 0.01, partial η2  = 0.21, 95 % CIs [88.56, 95.97] and
[90, 99.2], power = 0.82). A factor interaction between sex,
drug and rule was significant (F(3,48)  = 3.00, p  = 0.03,
partial η2  = 0.2, power = 0.67). Importantly, Tukey’s
post hoc tests for multiple comparisons showed that
under DZ women presented more errors than men for the
rules that required a double response (CC and II) and the
color incongruent rule (CI), 95 % CIs for women [81.76,
99.53], [73.07, 97.5], [87.88, 97.92]; and men [95.84, 100],
[84.59, 100], [91.07, 99.32], respectively, while the same
percentage of correct responses was observed between men
and women under PL for all the rules. As shown in Fig. 2d,
the percentage of correct responses in the female group
decreased with DZ in comparison with PL in the rules CC,
CI and II. The II rule responses were more sensitive to the
effects of DZ showing a reduction in percentage in compar-
ison with CI rule, while no differences in accuracy between
rules were observed in the group of men.
Randomization tests for accuracy confirmed the differ-
ence observed between PL and DZ (p = 0.02), as well as
the detrimental effect of DZ on women’s accuracy com-
pared with PL (p = 0.02), while in men, no accuracy differ-
ences were observed between PL and DZ (p = 0.31).
fMRI results
Rule selection
In normal conditions (PL), there were differences between
men and women during rule selection, this is when the
cross was presented. More activity was observed in men
than in women in the right side of the frontal lobe, specifi-
cally, in the middle frontal gyrus (BA 46), and the anterior
cingulate cortex (BA32) (Fig. 3; Table 2).
Under DZ, more brain areas showed differences
between men and women during the task. Figure 3 shows
the main effects between men and women; more activity
was exhibited by men in the left inferior frontal gyrus (BA
45) (Table 3). Gender drug interactions showed a signifi-
cant effect of DZ with a reduction of BOLD signal for the
women under DZ in comparison with PL and in compari-
son with men in the left middle frontal gyrus (BA 46/10/9)
and the right superior frontal gyrus (BA9/10). As well, the
right subgenual cingulate cortex (BA 25) BOLD signal

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Exp Brain Res

RULE SELECTION
PLACEBO
Right Anterior Cingulate (BA 32) Right Middle Frontal Gyrus (BA 46)
1.5 1.5

BOLD signal

BOLD signal
1 1
0.5 0.5
0 0
-0.5 -0.5
-1 MEN WOMEN -1 MEN WOMEN
-1.5 -1.5

DIAZEPAM
Left Inferior Frontal Gyrus (BA 45)
1.5
1
BOLD signal

0.5
0
-0.5
-1 MEN WOMEN
-1.5

Left Middle Frontal Gyrus (BA 46/10/9) Right Superior Frontal Gyrus (BA 10/9)
1.5 1.5
BOLD signal

1 1 PL
BOLD signal

PL 0.5 DZ
0.5
DZ 0
0
-0.5 -0.5
-1 -1
-1.5 -1.5
MEN WOMEN MEN WOMEN

Right Subgenual Cingulate (BA 25)

1.5
BOLD signal

1 PL
0.5 DZ
0
-0.5
-1
-1.5
MEN WOMEN

Fig. 3  Significant effects and statistical maps showing differences on men and women in the contrast between rule selection (all stimuli) minus
non-rule/catch trials for placebo (on top) and diazepam (bottom)

showed lower activity in women than in men under PL and frontal gyrus (BA 10) (Fig. 4). Under DZ, in comparison
DZ. with PL, women presented a reduction in activity in bilat-
eral medial frontal gyrus (BA 9) and right superior (BA 10)
Incongruent versus non‑rule frontal gyrus, while in men an activity increase in the left
frontal gyrus (BA 45) under DZ was observed. Less activ-
When the rule selection implied incongruent rules under ity was observed in women than in men under DZ in the
PL, men showed more activity than women in the right left medial (BA 9) and inferior (BA 45) frontal gyrus and
anterior cingulate cortex (BA32) and the right superior the right superior gyrus (BA 10).

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 Exp Brain Res

Table 3  Frontal brain activation Voxel Coordinates Brain regions Brodmann Cluster

differences between men and Z score DIAZEPAM area size
women under diazepam for: x y z
response selection minus non-
response, congruent rule minus Rule selection > non-rule
non-rule and incongruent rules  3.79 −48 42 14 L Middle frontal gyrus 46 260
minus non-rule
 3.64 −38 40 16 L Middle frontal gyrus 10
 3.55 −14 42 20 L Medial frontal gyrus 9
 3.51 18 58 20 R Superior frontal gyrus 10 114
 3.1 16 50 26 R Superior frontal gyrus 9
 3.37 −44 20 14 L Inferior frontal gyrus 45 26
 3.34 2 14 -2 R Anterior cingulate gyrus 25 27
Congruent rule > non-rule
 4.02 −46 42 18 L Middle frontal gyrus 46 161
 3.2 −20 44 14 L Medial frontal gyrus 9 25
Incongruent rules > non-rule
 3.72 −16 42 20 L Medial frontal gyrus 9 125
 3.67 18 58 20 R Superior frontal gyrus 10 180
 3.28 16 50 26 R Superior frontal gyrus 9
 3.47 4 14 −4 R Anterior cingulate gyrus 25 30
 3.47 −48 42 12 L Inferior frontal gyrus 46 15
 3.45 −42 20 14 L Inferior frontal gyrus 45 31
 3.4 −36 40 16 L Middle frontal gyrus 10 27

R right hemisphere, L left hemisphere

Congruent versus non‑rule incongruent). Additionally, women committed more errors

When the rule selection implied congruent rules, men
showed more activity than women under PL in the right
superior frontal gyrus (BA 10) and in the right anterior cin-
gulate cortex (BA32) (Fig. 5).
Under DZ, the activity in the middle (BA 46) and the
medial (BA 9) left frontal gyri was higher for men than
women; these differences were accentuated under DZ.
Discussion
We explored the behavioral and neural differences between
men and women of a single DZ dose during the implemen-
tation of congruent and incongruent rules. As hypothesized,
DZ elicited higher effects on women than on men in brain
activity as well as in behavior. Under DZ influence, women
presented more errors than men when implementing com-
plex rules.
Task performance
The accuracy analysis of the task revealed that the per-
centage of correct responses with diazepam was lower
for women in comparison with men for those rules that
required a double response (fully congruent and fully
in the rules requiring the inhibition of one response and in
the congruent rule under diazepam than under the placebo.
These data are in accordance with studies finding higher
impairment in women than men in attention demanding
tasks under the effects of benzodiazepines (Fluck et al.
2001; Jackson et al. 2005). These results also suggest
that the advantage showed in women to inhibit prepotent
responses is affected by 10 mg of DZ. No statistical dif-
ferences were observed in reaction times between men and
women implementing complex rules, neither with placebo
nor with diazepam, suggesting a dissociation of the mecha-
nisms involved in accuracy and speed of responses in men,
being the network related to reaction times more vulnerable
than the one involved in accuracy.
Neural correlates
Comparing the brain function between men and women
during rule implementation under placebo, men showed
more activity than women in the right prefrontal cortex and
anterior cingulate gyrus, brain areas implicated in com-
plex cognitive processes and attention. This result might
be related to a difference in strategy adopted between men
and women during the task, as performance was equally
effective because men and women performed the task with
the same level of accuracy and velocity under PL. Result

13
Exp Brain Res

INCONGRUENT > NON-RULE

PLACEBO
Right Anterior Cingulate (BA 32/10)
1.5
1

BOLD signal
0.5
0
-0.5
-1 MEN WOMEN
-1.5

DIAZEPAM
Right Subgenual Cingulate (BA 25) Left Medial Frontal Gyrus (BA 9)
1.5 1.5
1 1 PL
BOLD signal

BOLD signal
0.5 0.5 DZ
0 0
-0.5 -0.5
-1 MEN WOMEN -1 MEN WOMEN
-1.5 -1.5

Left Medial Frontal Gyrus (BA 9) Right Superior Frontal Gyrus (BA 10)
1.5 1.5

1 1
BOLD signal

PL PL
BOLD signal

0.5 0.5
DZ DZ
0 0

-0.5 -0.5

-1 -1

-1.5 -1.5
MEN WOMEN MEN WOMEN

Left Inferior Frontal Gyrus (BA 45)

1.5
1
PL
BOLD signal

0.5
DZ
0
-0.5
-1
-1.5
MEN WOMEN

Fig. 4  Significant effects and statistical maps showing differences between men and women in the contrast incongruent (DI, CI, II) versus non-
rule for placebo (on top) and diazepam (bottom)

that is in accordance with neuroimaging studies show- women (Pletzer 2014). Another possible difference is the
ing differences in brain activity between men and women use of internal language to guide the responses in the case
during cognitive tasks with a lack of difference in perfor- of women versus a spatial solution in men; however, future
mance (Weiss et al. 2003; Schöning et al. 2007; Li et al. studies should be conducted to evaluate the specific strate-
2009). Observations that have conducted to propose differ- gies used in this task.
ences in cognitive strategies, supported by empirical data Differences in brain activity between men and women
(Saucier et al. 2002; Sæther et al. 2009), are reflecting a were amplified under DZ, including a larger region of the
global/holistic strategy in men and local/decomposed in prefrontal cortex of both hemispheres. The reduction in

13
 Exp Brain Res

CONGRUENT > NON-RULE

PLACEBO
Right Superior Frontal Gyrus (BA 10) Right Anterior Cingulate (BA 32)
1.5 1.5

1 1
BOLD signal

BOLD signal
0.5 0.5

0 0

-0.5 -0.5

-1 -1
MEN WOMEN MEN WOMEN
-1.5 -1.5

DIAZEPAM
Left Middle Frontal Gyrus (BA 46) Left Medial Fontal Gyrus (BA 9)
1.5 1.5

1
PL
1 PL
BOLD signal

BOLD signal

0.5
DZ 0.5 DZ
0 0

-0.5 -0.5

-1 -1
MEN WOMEN MEN WOMEN
-1.5 -1.5

Fig. 5  Significant effects and statistical maps showing differences between men and women in the contrast between congruent (CC) versus non-
rule for placebo (on top) and diazepam (bottom)

activity observed in women under DZ is in accordance to
our hypothesis and might explain the detrimental effect
observed in the performance of the task which was more
affected in women than in men. Studies exploring rule
implementation are centered in measuring the effect just in
men or men and women together (Passingham and Rowe
2002; Christoff et al. 2009; Azuar et al. 2014) masking dif-
ferences between sexes that may exist.
In a previous study including men and women together
to assess the effects of DZ in brain activity, we observed
that more brain regions (especially posterior) were
recruited during the same rule-guided task under DZ in
comparison with PL, while in frontal lobes, slightly activity
changes were observed (Muñoz-Torres et al. 2011a). The
present results show the importance of analyzing men and
woman separately in order to differentiate the contribution
of each group that sometimes goes in opposite direction
between sexes, covering crucial changes.
Analyzing the brain activity by considering the rule type
(congruent/incongruent) required to be implemented under
PL demonstrated that women showed less activity than
men in superior frontal cortex and cingulate gyrus for con-
gruent rules and in frontal pole and dorsal cingulate gyrus
for incongruent rules, confirming the participation of fron-
tal pole for more complex rules, especially in men. The
activity pattern of women was different from that normally

13
Exp Brain Res
reported, requiring less frontal activation to implement the
rules. This result might indicate different strategies imple-
mented by men and women in order to select the proper
response to a specific rule.
DZ elicited an opposite effect in brain activity between
men and women during rule implementation. Following
congruent rules, an increase in activity was observed in
men while in women, activity decreased in frontal regions
of the left hemisphere. While for incongruent rules the
same effect was observed in both hemispheres, for women,
a reduction in activity under DZ in comparison with PL and
in comparison with men, was observed in regions that have
been reported to be involved during the task (Bunge et al.
2005), such as the dorsolateral region of the prefrontal cor-
tex (BA 9/46), and the anterior cingulate cortex, both con-
sidered important for response selection (Passingham and
Rowe 2002; Curtis and D’Esposito 2003; Buckley et al.
2009); and the anterior prefrontal cortex (BA 10) related to
processing of complex rules (Christoff et al. 2009; Azuar
et al. 2014).
An important issue to consider is that the distribution
of DZ is over the entire body, reaching other brain regions
involved in rule selection. Indeed, DZ has sedative and
hypnotic effects that reduce the vigilance level which can
lead to undesired side effects, including drowsiness, per-
formance deficits in vigilance tasks (Muñoz-Torres et al.
2011b) and attention (Coull et al. 1995). However, the
differential effect observed in brain activity for the dif-
ferent rules is contributing to the growing notion (Coull
et al. 1999; Deakin et al. 2004) that the influence of ben-
zodiazepines goes beyond global sedative effects and that
has selective detrimental effects on complex rule-guided
actions requiring rapid responses.
The cortical regions reported to be involved during the
task and affected under DZ are related to higher order pro-
cessing, specifically to decision making and action guided
by rules (Bunge et al. 2005; Christoff et al. 2009; Buck-
ley et al. 2009; Azuar et al. 2014), these results cannot be
explained by the motor output since it has been shown
that these regions are not recruited when subjects perform
motor tasks, such as tapping (Bednark et al. 2015; Bonzano
et al. 2015; Wurster et al. 2015) and a distinct activity pat-
tern between prefrontal and motor cortices is observed in
reaching movement following rules (Hoshi 2008).
In general, the aversive effects of DZ at behavioral and
at brain function level were more accentuated in women
than in men. The sex differences shown in the present study
might be the result of a brain dimorphic organization origi-
nated in the period of brain sex differentiation by hormo-
nal influence and/or by influence of sexual genes. However,
the oscillatory effect of sex hormones could be interacting
through the GABAergic system since has been shown to be
modulated by menstrual cycle phases and the contribution
of sex steroid hormones to brain activity has been reported
by measuring behavior (Solís-Ortiz and Corsi-Cabrera
2008; Colzato et al. 2010), electric brain responses (Ugalde
et al. 1998; Corsi-Cabrera et al. 2000; Fernandez-Guasti
et al. 2003) and metabolic responses (Schöning et al. 2007;
Hausmann et al. 2009; Weis et al. 2011). Even though ses-
sions were conducted at the beginning of the follicular
phase, when the hormonal levels are low, it is known that
cortical GABA levels declined across the menstrual cycle
(Epperson et al. 2002) and the composition of GABAA
receptor subunits correlates with fluctuations in progester-
one (Maguire and Mody 2009), perhaps some of the sex
differences observed in the present study might be driven
by these hormonal fluctuations that in men are not present.
Therefore, further studies exploring the influence of cyclic
changes driven by sex hormones in complex behaviors
under DZ are required.
Limitations
One limitation of the present study is that with fMRI,
as with other techniques, is not possible to distinguish
between excitatory and inhibitory activity, although some
efforts have been directed to assess the participation of the
GABAergic and glutamatergic systems in BOLD activity
(Buzsáki et al. 2007), the physiological basis in relation to
specific neurotransmitter systems remains unclear.
Other information to keep in mind is that given the small
number of participants, which leaves open the possibil-
ity to commit type II errors, additional effects might have
been missed. However, even though this limitation does not
allow us to reject null hypotheses with total certainty, ran-
domization hypothesis tests give additional support to the
behavioral results. The results of this research should there-
fore be taken as exploratory and further studies including
a higher number of subjects are necessary to elucidate
additional differences between men and women under the
effects of DZ during rule-guided actions.
Considering that structural brain differences confer a dif-
ferent substrate for functional organization and may under-
lie sex differences, it will be important in further studies to
include measures of brain morphology such as intracranial
volume which is greater in men than women (Allen et al.
2003) or ultrastructural differences like the proportion of
gray to white matter which is larger in women than in men
(Filipek et al. 1994; Allen et al. 2003), especially in dorso-
lateral prefrontal cortex (Schlaepfer et al. 1995). These data
will be useful to clarify the interaction between the struc-
tural brain composition and the effects induced by drugs
such as the DZ and to estimate how convenient is to con-
sider it for therapeutic decisions.
The accuracy in this task was very high for both sexes
under placebo condition; therefore, it will be important
13

to explore tasks with a higher level of difficulty in order
to evaluate the effects of DZ in relation to errors, which
can help to elucidate whether the activations observed are
related to a compensatory effect under DZ or whether accu-
racy is changing between men and women with higher cog-
nitive loads.
Conclusion
The present findings indicate that a single dose of diaz-
epam, on women and not on men, impairs the behavior
and the neural activity of frontal lobes, resulting in a nega-
tive impact on the ability to select the response based on
complex rules, especially when the information is new and
goes against the habitual behavior. Women are more sensi-
tive than men to the same dose of diazepam and showed a
greater number of errors together with a decrease in meta-
bolic activity of cortical regions involved in processing
complex information. Men recruited a greater number of
areas under the effect of diazepam compared with women
and with placebo condition which may indicate a compen-
satory mechanism.
This preliminary study emphasizes the importance of
analyzing the data of men and women separately as some
effects found in one of the groups might be attenuated when
analyzing the group as a whole, pointing out the necessity
of searching for an adequate doses for each gender, and not
using the same treatment for both men and women. Finally,
the results derived from studies investigating sex difference
effects can provide a better understanding about the brain
mechanisms implicated in the interaction of drugs and cog-
nition with different genetic and hormonal background and
thus improve therapeutic results.
Acknowledgments We are very grateful to Madalyn Marabella for
correcting the English version of the manuscript. This work was sup-
ported by CONACYT, Project: 50709. Z. Muñoz-Torres received a
grant from CONACYT. This work constitutes part of an academic
thesis of the Biomedical Science Ph.D. program at UNAM. We thank
Dr. Julian A. Sanchez Cortazar of Aceleracion Nuclear y Resonancia
Magnetica S.A. de C.V.; Dr. Bernardo Ronzon Fernandez, and QFB
Alma Delia Guerrero Huesca at Laboratorio y Banco de Sangre for
the facilities of fMRI and blood analyses at Hospital Angeles del
Pedregal.
References
Allen JS, Damasio H, Grabowski TJ et al (2003) Sexual dimor-
phism and asymmetries in the gray-white composition of
the human cerebrum. Neuroimage 18:880–894. doi:10.1016/
S1053-8119(03)00034-X
Altemus M, Sarvaiya N, Neill Epperson C (2014) Sex differences in
anxiety and depression clinical perspectives. Front Neuroendo-
crinol 35:320–330. doi:10.1016/j.yfrne.2014.05.004
13
Exp Brain Res
Annett M (1967) The binomial distribution of right, mixed and left
handedness. Q J Exp Psychol 4:327–333
Azuar C, Reyes P, Slachevsky A et al (2014) Testing the model of
caudo-rostral organization of cognitive control in the human
with frontal lesions. Neuroimage 84:1053–1060. doi:10.1016/j.
neuroimage.2013.09.031
Bednark JG, Campbell MEJ, Cunnington R (2015) Basal ganglia and
cortical networks for sequential ordering and rhythm of com-
plex movements. Front Hum Neurosci 9:1–13. doi:10.3389/
fnhum.2015.00421
Bonzano L, Tacchino A, Roccatagliata L et al (2015) An engineered
glove for investigating the neural correlates of finger movements
using functional magnetic resonance imaging. Front Hum Neu-
rosci 9:1–12. doi:10.3389/fnhum.2015.00503
Botvinick MM (2007) Conflict monitoring and decision making: rec-
onciling two perspectives on anterior cingulate function. Cogn
Affect Behav Neurosci 7:356–366
Buckley MJ, Mansouri FA, Hoda H et al (2009) Dissociable com-
ponents of rule-guided behavior depend on distinct medial
and prefrontal regions. Science 325:52–58. doi:10.1126/
science.1172377
Bunge SA, Wallis JD, Parker A et al (2005) Neural circuitry under-
lying rule use in humans and nonhuman primates. J Neurosci
25:10347–10350. doi:10.1523/JNEUROSCI.2937-05.2005
Buzsáki G, Kaila K, Raichle M (2007) Inhibition and brain work.
Neuron 56:771–783
Christoff K, Keramatian K, Gordon A et al (2009) Prefrontal organi-
zation of cognitive control according to levels of abstraction.
Brain Res 1286:94–105
Colzato L, Hertsig G, van der Wildenberg W, Hommel B (2010)
Estrogen modulates inhibitory control in healthy human
females: evidence from the stop-signal paradigm. Neuroscience
167:709–715
Compte A, Constantinidis C, Tegner J et al (2003) Temporally irregu-
lar mnemonic persistent activity in prefrontal neurons of mon-
keys during a delayed response task. J Neurophysiol 90:3441–
3454. doi:10.1152/jn.00949.2002
Corsi-Cabrera M, Ugalde E, del Río-Portilla Y, Fernandez-Guasti A
(2000) Organizational and activational effects of gonadal steroid
hormones on the EEG of male and female rats. Dev Psychobiol
37:194–207
Corsi-Cabrera M, del Río-Portilla Y, Muñoz-Torres Z (2007) Sex-
steroid dimorphic effects on functional brain organization: dif-
ferences in cognition, emotion and anxiolysis. In: Czerbska M
(ed) Psychoneuroendocrinology research trends. Nova Biomedi-
cal Books, New York, pp 7–72
Cotto JH, Davis E, Dowling GJ et al (2010) Gender effects on drug
use, abuse, and dependence: a special analysis of results from the
National Survey on Drug Use and Health. Gend Med 7:402–413.
doi:10.1016/j.genm.2010.09.004
Coull J, Sahakian B, Middleton H et al (1995) Differential effects of
clonidine, haloperidol, diazepam and tryptophan depletion on
focused attention and attentional search. Psychopharmacology
121:222–230
Coull J, Frith C, Dolan R (1999) Dissociating neuromodulatory
effects of diazepam on episodic memory encoding and executive
function. Psychopharmacol 145:213–222
Curtis CE, D’Esposito M (2003) Persistent activity in the prefrontal
cortex during working memory. Trends Cogn Sci 7:415–423.
doi:10.1016/S1364-6613(03)00197-9
Deakin J, Aitken M, Dowson J et al (2004) Diazepam produces disin-
hibitory cognitive effects in male volunteers. Psychopharmacol-
ogy 173:88–97. doi:10.1007/s00213-003-1695-4
Epperson C, Haga K, Mason G (2002) Cortical {gamma}-aminobu-
tyric acid levels across the menstrual cycle in healthy women
Exp Brain Res
and those with premenstrual dysphoric disorder: a proton mag-
netic. Arch Gen Psychiatry 59:851–858
Esterlis I, McKee SA, Kirk K et al (2013) Sex-specific differences in
GABAA-benzodiazepine receptor availability: relationship with
sensitivity to pain and tobacco smoking craving. Addict Biol
18:370–378. doi:10.1111/j.1369-1600.2011.00403.x
Evans A, Kamber M, Collins D, Macdonald D (1994) An MRI-based
probabilistic atlas of neuroanatomy. In: Shorvon S, Fish D,
Andermann F et al (eds) Magnetic resonance scanning and epi-
lepsy. Plenum, New York, pp 263–274
Fernandez-Guasti A, del Río-Portilla Y, Ugalde E, Corsi-Cabrera M
(2003) Diazepam and progesterone produce sexually dimorphic
actions on the rat EEG: role of the neonatal sexual differentiation
process. Pshychoneuroendocrinology 28:85–100
Filipek P, Richelme C, Kennedy D, Caviness VJ (1994) The young
adult human brain: an MRI-based morphometric analysis. Cereb
Cortex 4:344–360
Fluck E, Fernandes C, File S (2001) Are lorazepam-induced deficits
in attention similar to those resulting from aging? J Clin Psy-
chopharmacol 21:126–130
Friedman H, Ochs H, Greenblatt D, Shader R (1985) Tissue distri-
bution of diazepam and its metabolite desmethyldiazepam: a
human autopsy study. J Clin Pharmacol 25:613–615
Friston K, Holmes A, Worsley K et al (1995) Statistical parametric
maps in functional imaging: a general linear approach. Hum
Brain Mapp 2:189–210
Gluck J, Fitting S (2003) Spatial strategy selection: interesting incre-
mental information. Int J Test 3:293–308
Hammerslag LR, Gulley JM (2016) Sex differences in behavior and
neural development and their role in adolescent vulnerability
to substance use. Behav Brain Res 298:15–26. doi:10.1016/j.
bbr.2015.04.008
Hausmann M, Schoofs D, Rosenthal H, Jordan K (2009) Interactive
effects of sex hormones and gender stereotypes on cognitive sex
differences–a psychobiosocial approach. Psychoneuroendocri-
nology 34:389–401
Hoshi E (2008) Differential involvement of the prefrontal, premo-
tor and primary motor cortices in rule-based motor behavior.
In: Bunge SA, Wallis JD (eds) Neuroscience of rule behavior.
Oxford University Press, New York, p 472
Jackson A, Stephens D, Duka T (2005) Gender differences in
response to lorazepam in a human drug discrimination study. J
Psychopharmacol 19:614–619. doi:10.1177/0269881105056659
Larson M, South M, Clayson P (2011) Sex differences in error-related
performance monitoring. NeuroReport 22:44–48
Li CR, Zhang S, Duann J-R et al (2009) Gender differences in
cognitive control: an extended investigation of the stop sig-
nal task. Brain Imaging Behav 3:262–276. doi:10.1007/
s11682-009-9068-1
Maguire J, Mody I (2009) Steroid hormone fluctuations and GABA A
R plasticity. Psychoneuroendocrinology 34:1–12. doi:10.1016/j.
psyneuen.2009.06.019.Steroid
Mansouri FA, Fehring DJ, Gaillard A et al (2016) Sex dependency of
inhibitory control functions. Biol Sex Differ 7:11. doi:10.1186/
s13293-016-0065-y
Muñoz-Torres Z, Armony JL, Trejo-Martínez D et al (2011a) Behav-
ioural and neural effects of diazepam on a rule-guided response
selection task. Neurosci Res 70:260–268. doi:10.1016/j.
neures.2011.03.009
Muñoz-Torres Z, del Río-Portilla Y, Corsi-Cabrera M (2011b) Diaze-
pam-induced changes in EEG oscillations during performance of
a sustained attention task. J Clin Neurophysiol 28:394–399
Munro CA, Winicki JM, Schretlen DJ et al (2012) Sex differences
in cognition in healthy elderly individuals. Neuropsychol Dev
Cogn B Aging Neuropsychol Cogn 19:759–768. doi:10.1080/13
825585.2012.690366.Sex
Passingham RE, Rowe J (2002) Dorsal prefrontal cortex: Mainte-
nance in memory or attentional selection? In: Stuss DT, Knight
RT (eds) Principles of frontal lobe function. Oxford University
Press, Oxford, pp 221–232
Pletzer B (2014) Sex-specific strategy use and global-local process-
ing: a perspective toward integrating sex differences in cogni-
tion. Front Neurosci 8:1–6. doi:10.3389/fnins.2014.00425
Ridderinkhof K, Ullsperger M, Crone E, Nieuwenhuis S (2004) The
role of the medial frontal cortex in cognitive control. Science
306(5695):443–447
Romano-Torres M, Borja-Lascurain E, Chao-Rebolledo C et al (2002)
Effect of diazepam on EEG power and coherent activity: sex dif-
ferences. Psychoneuroendocrinology 27:821–833. doi:10.1016/
S0306-4530(01)00082-8
Rushworth MFS, Buckley MJ, Behrens TEJ et al (2007) Functional
organization of the medial frontal cortex. Curr Opin Neurobiol
17:220–227. doi:10.1016/j.conb.2007.03.001
Sæther L, Van Belle W, Laeng B et al (2009) Anchoring gaze when
categorizing faces’ sex: evidence from eye-tracking data. Vis Res
49:2870–2880. doi:10.1016/j.visres.2009.09.001
Sanacora G, Mason GF, Rothman DL et al (1999) Reduced cortical
gamma-aminobutyric acid levels in depressed patients deter-
mined by proton magnetic resonance spectroscopy. Arch Gen
Psychiatry 56:1043–1047
Saucier D, Green S, Leason J et al (2002) Are sex differences in
navigation caused by sexually dimorphic strategies or by dif-
ferences in the ability to use the strategies? Behav Neurosci
116:403–410
Schlaepfer T, Harris G, Tien A et al (1995) Structural differences in
the cerebral cortex of healthy female and male subjects: a mag-
netic resonance imaging study. Pshychiatry Res 61:129–135
Schöning S, Engelien A, Kugel H et al (2007) Functional anat-
omy of visuo-spatial working memory during mental rota-
tion is influenced by sex, menstrual cycle, and sex steroid
hormones. Neuropsychologia 45:3203–3214. doi:10.1016/j.
neuropsychologia.2007.06.011
Solís-Ortiz S, Corsi-Cabrera M (2008) Sustained attention is favored
by progesterone during early luteal phase and visuo-spatial
memory by estrogens during ovulatory phase in young women.
Psychoneuroendocrinology 33:989–998
Solís-Ortiz S, Ramos J, Arce C et al (1994) EEG oscillations during
menstrual cycle. Int J Neurosci 76:279–292
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the
human brain: 3-dimensional proportional system: an approach to
cerebral imaging. Thieme, New York
Thakkar KN, Congdon E, Poldrack RA et al (2014) Women are more
sensitive than men to prior trial events on the stop signal task. Br
J Psychol 105:254–272
Ugalde E, del Rı́o-Portilla I, Juarez J et al (1998) Effect of diazepam
and sex hormones on EEG of gonadectomized male and female
rats. Pshychoneuroendocrinology 23:701–712
Weis S, Hausmann M, Stoffers B, Sturm W (2011) Dynamic changes
in functional cerebral connectivity of spatial cognition during the
menstrual cycle. Hum Brain Mapp 32:1544–1556. doi:10.1002/
hbm.21126
Weiss E, Siedentopf CM, Hofer A et al (2003) Sex differences in
brain activation pattern during a visuospatial cognitive task: a
functional magnetic resonance imaging study in healthy volun-
teers. Neurosci Lett 344:169–172
Wittchen HU, Jacobi F (2005) Size and burden of mental disor-
ders in Europe—a critical review and appraisal of 27 stud-
ies. Eur Neuropsychopharmacol 15:357–376. doi:10.1016/j.
euroneuro.2005.04.012
Wurster DC, Graf H, Ackermann H et al (2015) Neural correlates
of rate-dependent finger-tapping in Parkinson’ s disease. Brain
Struct Funct 220:1637–1648. doi:10.1007/s00429-014-0749-1
13