Original Article

http://dx.doi.org/10.9758/cpn.2015.13.1.83 pISSN 1738-1088 / eISSN 2093-4327

Clinical Psychopharmacology and Neuroscience 2015;13(1):83-93 Copyrightⓒ 2015, Korean College of Neuropsychopharmacology

The Influence of Levetiracetam in Cognitive Performance in Healthy Individuals:

Neuropsychological, Behavioral and Electrophysiological Approach
Julio Cesar Magalhães1, Mariana Gongora1, Renan Vicente1,2, Juliana Bittencourt1,4,7, Guaraci Tanaka1, Bruna
1,2,4 5 5 6 8,9 2
Velasques , Silmar Teixeira , Gledys Morato , Luis F. Basile , Oscar Arias-Carrión , Fernando A.M.S Pompeu ,
3 1,2,4
Mauricio Cagy , Pedro Ribeiro
1
Brain Mapping and Sensory Motor Integration, Institute of Psychiatry, Federal University of Rio de Janeiro (IPUB/UFRJ), Rio de Janeiro,
2
Bioscience Department (EEFD/UFRJ), School of Physical Education, 3Biomedical Engineering Program, COPPE, Federal University of Rio
4 5
de Janeiro, Rio de Janeiro, Institute of Applied Neuroscience (INA), Rio de Janeiro, Brain Mapping and Plasticity Laboratory, Federal
University of Piauí, Teresina, Laboratory of Psychophysiology, Faculdade da Saúde, UMESP, São Paulo, 7Veiga de Almeida University,
6
8
Rio de Janeiro, Brazil, Movement Disorders and Transcranial Magnetic Stimulation Unit, Hospital General Dr. Manuel Gea González, Mexico
9
D.F., Neurology Department, Hospital General Ajusco Medio, Mexico D.F., Mexico

Objective: The present study sought to analyze the influence of Levetiracetam (LEV) in cognitive performance by identifying
the changes produced by LEV in reaction time, in neuropsychological assessment of attention and memory and in absolute
theta power in frontal activity.
Methods: Twelve healthy subjects (5 men and 7 women; mean age, 30.08 years, standard deviation, 4.71) were recruited for
this study. The neuropsychological tests: Trail Making Test (A and B), Digit Span (direct and indirect numerical orders/working
memory); Stroop test (inhibitory control of attention); Tower of London (planning and decision-making) and a quantitative electro-
encephalography were applied in 2 different days after and before the participants ingested the capsule of placebo or 500
mg LEV.
Results: A two-way-ANOVA was implemented to observe the interaction between conditions (placebo or LEV 500 mg) and
moments (pre- and post-ingestion of LEV or placebo). The data were analyzed by the SPSS statistical package (p＜0.05). For
the neuropsychological parameter, the Trail Making Test (A) was the only test that showed significant difference for condition
in the task execution time (p=0.026). Regarding the reaction time in the behavioral parameter, an interaction between both factors
(p=0.034) was identified through a two-way-ANOVA (condition versus moment). Electrophysiological measures showed a sig-
nificant interaction for electrodes: F7, F3, and FZ.
Conclusion: The findings showed that LEV promotes an important cognitive enhancement in the executive functions.

KEY WORDS: Levetiracetam; Neuropsychological tests; Reaction time; Electroencephalography; Absolute theta.

INTRODUCTION were actually born from several attempts to assist cogni-

tive functions in full decline due to specific diseases, such
The improvement of cognitive and perceptual functions as dementia, attention deficit disorder and other various
is considered to be one of the frontiers of knowledge.1) The psychiatric disorders.3-5) In an attempt to achieve a specif-
possibility of expanding our capacities of attention, alert- ic solution for certain diseases, the possibility of a sig-
ness, memory, perception, information integration, deci- nificant change in brain efficiency was envisioned
sion making, planning, and cognitive flexibility is a through the use of drugs that could help to restore or im-
long-term goal for neuroscience.2) Cognitive enhancers prove specific cognitive functions. Since then, several
drugs have been developed in order to improve or expand
Received: October 14, 2014 / Revised: December 2, 2014
cognitive aspects.6)
Accepted: December 23, 2014
Address for correspondence: Mariana Gongora, PhD Among cognitive enhancers, we can find psychostimu-
Brain Mapping and Sensory Motor Integration, Institute of lants (methylphenidate and amphetamines), wakefulness
Psychiatry, Federal University of Rio de Janeiro (IPUB/UFRJ), Rua promoters (modafinil) and glutamate activators (ampa-
Cel. Moreira Cesar, 375 apto. 802. Icaraí- Niterói, RJ. Cep
24230-054, Brazil kines). Considering this, methylphenidate is a strong in-
Tel: +55-21-2711-2530, Fax: +55-21-2259-8129 hibitor of dopamine and noradrenaline reuptake. In turn,
E-mail: marianagongora@gmail.com
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
83
84 J. C. Magalhães, et al.

besides inhibiting the dopamine transporter proteins memory, planning and decision making) and electro-
(reuptake), amphetamines also act on the norepinefrine physiological (absolute theta power) changes in the fron-
existing in the nerve cells, thus blocking its reabsorption tal region.
and increasing the concentration of these neurotransmitters
in the synaptic cleft.7) Therefore, modafinil also seems to METHODS
be involved in the reuptake of dopamine transporters,
causing a substantial increase in the dopamine extra- Sample
cellular level and synaptic concentration.8) And finally, Twelve healthy subjects (five men and seven women;
there are glutamate activators, such as ampakine, which is mean age, 30.08 years, standard deviation [SD], 4.71)
a positive allosteric modulator of α-amino-3-hydroxy-5- were recruited for this study. All subjects were right-hand-
methyl-4-isoxazolepropionic acid (AMPA) receptors.9,10) ed and had normal or corrected-to-normal vision.
In this experiment we used Levetiracetam (LEV) (5- Inclusion criteria were absence of mental or physical im-
enantiomer of 5-α-ethyl-2-oxo-1-pyrrolidine acetamide) pairments and no history of psychoactive or psychotropic
to test the hypothesis of its effects associated with the im- substance use (as confirmed by anamnesis and clinical ex-
provement of cognition.11) LEV has an extremely positive amination). A questionnaire was applied to verify if the
result in epileptic frames, acting as an anticonvulsant. participants met the inclusion criteria. Subjects were not
Unlike cognitive enhancers presented before, LEV en- included if they had slept less than 8 hours prior to the ex-
gages with the synaptic vesicle glycoprotein (SV2A) and periment and/or had ingested caffeine within the 48 hours
also inhibits the presynaptic calcium channels, reducing prior to the experiment. All subjects were made aware of
the neurotransmitter release, acting as a neuromodulator, the entire experimental protocol and signed a consent
thereby preventing the nervous impulse conduction in the form before participating in the study, which was ap-
synaptic cleft. There are few studies demonstrating the ef- proved by the Ethics Committee at the Federal University
ficacy of LEV in epileptic patients (children and adults), of Rio de Janeiro (CAAE:16342213.4.0000.5263) ac-
and we know an even smaller number of experiments in- cording to the Declaration of Helsinki (1964).
12,13)
volving the effects of LEV in healthy individuals. Due
to the sensitivity of the measures, neuropsychological pa- EEG Data Acquisition
rameters may have great difficulty in identifying the ef- The electroencephalography signal acquisition was re-
fects of LEV when compared to the placebo condition, es- corded using the 20-channel Braintech3000 (EMSA
pecially in healthy individuals. Medical Instruments, Rio de Janeiro, Brazil) EEG system.
Therefore, quantitative electroencephalography (qEEG) This program was employed to filter the data: Notch (60
has been employed as a useful tool to examine possible Hz), high-pass of 0.3 Hz and low-pass of 25 Hz (order 2
electrophysiological changes, in particular, the phys- Butterworth). Twenty-one electrodes were arranged on a
icochemical aspect of the subject/drug interactions in sev- lycra cap (EletroCap Inc., Fairfax, VA, USA) along the
14,15)
eral experiments. In addition to the great sensitivity of scalp on the frontal, temporal, parietal and occipital areas,
the measure to detect assumed changes, it is possible to according to the 10/20 system protocol,18) and two more
identify aspects of brain function and regulation through electrodes were positioned on the earlobes, set as a refer-
the presence or absence of a particular activity (frequency) ence point, yielding 20 mono-pole derivations to them
in the prefrontal and frontal areas of the cerebral cortex us- (using Fpz as ground electrode). The caps were individually
ing qEEG. These are critical regions for executive func- adjusted and put on each subject, according to each in-
tions, and several results demonstrate that theta is in- dividual’s circumference and anatomy proportions. The
volved in a wide range of executive functions, such as sus- signal correspondent to each EEG derivation resulted
tained attention, working memory, episodic and semantic from the electric potential difference between each elec-
memory and spatial aspects related to navigation and the trode and the pre-established reference (earlobes). First,
ability to imagine objects or actions.16,17) That’s why we the impedance levels of each electrode were calculated,
observed the behavior of the absolute theta power (4 to 8 and they were kept below 5 kΩ. The ocular electric activ-
Hz). In an attempt to elucidate the effects of LEV in a pop- ity was estimated by attaching two 9-mm-diameter elec-
ulation of healthy individuals as a cognitive amplifier, this trodes in a bipolar montage. The electrodes were posi-
study aims to examine alleged behavioral changes tioned, respectively, above and below the right eye orbit,
(reaction time), neuropsychological (attention, working in order to register vertical ocular movements, and on the
 Levetiracetam Effects in Cognitive Performance in Healthy Individuals 85

external corner of the same eye, in order to register hori-

zontal ocular movements. Visual artifacts were a priori in- Dependent Variables: Neuropsychological Assessments,
spected through a data visualization program using the Behavioral Parameters (Reaction Time) and Electro-
®
Matlab 5.3 (The Mathworks Inc., Natick, MA, USA). encephalographic Measure (Absolute Theta Power)
The following neuropsychological tests were applied to
EEG Data Processing individuals: Trail Making Test (A and B), Digit Span (direct
The electroencephalographic signals collected during and indirect numerical orders/working memory), Stroop
the experiment were processed using methods developed test (inhibitory control of attention) and the Tower of London
by the Brain Mapping and Sensorimotor Integration (planning and decision-making). This neuropsychological
Laboratory of the Psychiatry Institute of the Federal battery has been applied on similar studies that utilized
University of Rio de Janeiro in a Matlab 5.3® environ- different drugs that also acted on cognition.19-21) Other
ment. Visual inspection and independent component anal- studies have used similar neuropsychological tests to
22,23)
ysis (ICA) were applied to quantify reference-free data by measure such executive functions. Software devel-
removing possible sources of task-induced artifacts. Data oped in our own laboratory (DELPHI 5.0) was used to an-
from individual electrodes exhibiting loss of contact with alyze the reaction time. Participants had to choose a
the scalp or high impedances (＞5 kΩ) were deleted as square (25% of total shapes) among various circles, iden-
were data from single-trial epochs that exhibited ex- tifying the reaction time. In terms of electroencephalo-
cessive movement artifact (±100 µV). ICA was then ap- graphic measure, we used absolute theta power to exam-
plied to identify and remove any artifacts that remained af- ine the energy variation among the placebo and LEV
ter the initial visual inspection. ICA is an information conditions.
maximization algorithm that derives spatial filters by
blind source separation of the EEG signals into temporally Cortical Area and EEG Frequency
independent and spatially fixed components. Independent We chose to analyze the frontal region, due to its strong
components resembling an eye blink or muscle artifact relationship with the executive functions. In particular, we
were removed, and the remaining components were then focused on processes related with attention, planning and
projected back onto the scalp electrodes by multiplying short-term memory. We used the theta frequency range,
the input data by the inverse matrix of the spatial filter co- due to its correlation with attentional processes and work-
efficients derived from ICA using established procedures. ing memory. In general, we seek to discuss theta as having
The ICA-filtered data were then re-inspected for residual a behavior similar to alpha; in other words, the greater
artifacts using the rejection criteria described above. presence of theta somehow shows an inhibition of this
24)
cortical region.
Experiment Design
The experiment was randomized and double-blind, ap- Statistical Analysis
plied on two different days with an interval of at least one The results were represented as mean and SD. Conse-
week: one day having ingested 1 gelatin capsule with 500 quently, a two-way-ANOVA was implemented to observe
mg of starch (placebo), and one day having ingested 1 gel- the interaction between conditions (placebo or 500 mg
atin capsule with 500 mg of LEV. All individuals had to be LEV) and moments (pre- and post-use of LEV or place-
familiar with the experimental task. The procedures were bo). Additionally, a paired t-test was performed to com-
standardized in the following sequence: application of pare the moments (pre vs. post) within each condition
neuropsychological tests, reaction time, and EEG record aiming to explore the interaction. The significance crite-
at rest. After this, the participants ingested the capsule of rion was p≤0.05 for all analyses.
placebo or 500 mg LEV. Only after two hours from in- To observe two independents factors: condition (LEV
gestion, the same previous steps (i.e., application of neu- and placebo) and moment (before and after drug in-
ropsychological tests, reaction time and rest EEG) were gestion). For those electrodes where we found interaction
repeated, characterizing the ‘pre’ and ‘post’ intake mo- between factors, a paired t-test was applied, in order to ex-
ments. amine the possible differences. Each electrode was seen
separated, exactly to avoid the Type I error.
86 J. C. Magalhães, et al.

RESULTS sults did not show any interaction or main effect using the
following tests: Trail Making Test (B), Digit Span, Stroop
The present study examined the neuropsychological, test and Tower of London. In particular, the Trail Making
behavioral and electrophysiological effects on subjects Test (A) was the only test that showed significant
who ingested the LEV drug. To date, this substance has difference. A main effect for condition was found at the
been used in medicines for epilepsy patients. In this sec- task execution time (F=5.322; p=0.026), and a main effect
tion, we will describe the findings according to three pa- for moment was found in the number of errors committed
rameters: i) neuropsychological, ii) behavioral, and iii) during the test (F=5.851; p=0.020). The reaction time was
electrophysiological. also analyzed by a two-way-ANOVA (condition vs. mo-
ment), and a main effect for condition (F=9.292; p=0.002)
Neuropsychological and Behavioral Parameters was found (Table 1).
In order to examine alleged neuropsychological
changes due to the use of LEV, a two-way-ANOVA was Electrophysiological Parameter (qEEG)
performed. Specifically, two independent variables were First, the interaction (condition versus moment) results
observed: condition (placebo or LEV) and moment (pre- are presented, followed by the main effects. The following
and post-ingestion of the LEV or placebo). Thus, the re- electrodes were analyzed: FP1, FP2, F3, FZ, F4, F7 and
F8. A significant interaction was observed for the follow-
ing electrodes: F7 (F=33.360, p=0.001; Fig. 1A) and F3
Table 1. Results of neuropsychological and behavioral parameters (F=5.475, p=0.019; Fig. 2A). A main effect for condition
Parameter Mean±SD was also found for the following electrodes: FP1
(F=4.246, p=0.039; Fig. 3A), FP2 (F=3.909, p=0.048;
Trail Making Test (A)*
Execution time statistics Fig. 3B), F8 (F=4.753, p=0.029; Fig. 1B), Fz (F=4.913,
Main effect for condition (F=5.322; p=0.026) p=0.027) and F4 (F=15.269, p=0.000; Fig. 2C). Finally,
Placebo 34.0000±11.97461
significant changes for the main effect for moment were
Levetiracetam 27.7500±6.29182
Number of errors statistics shown for the following electrodes: FP2 (F=10.317,
Main effect for moment (F=5.851; p=0.020) p=0.001; Fig. 3C) and F4 (F=6.482, p=0.011; Fig. 2D).
Pre-drug ingestion 0.0000±0.00000
Post-drug ingestion 0.2083±0.41485
Reaction time
†
DISCUSSION
Main effect for condition (F=9.292; p=0.002)

*Mean and standard deviation (SD) of main effect for condition The present study aimed to investigate the behavioral,
at execution time and main effect for moment at number of
statistical errors for Trail Making Test (A).
neuropsychological and electrophysiological changes
†
Mean and SD of main effect for condition at reaction time. produced by LEV in an attempt to explore its effects as a

Fig. 1. Mean and standard error of absolute theta power. (A) Left inferior prefrontal gyrus (F7) interaction between conditions (placebo
and levetiracetam) and moments (pre and post) (p=0.001). The paired t-test for post moment demonstrated significant difference between
conditions (p=0.004); (B) right prefrontal gyrus (F8) on the placebo and levetiracetam conditions (p=0.029).
 Levetiracetam Effects in Cognitive Performance in Healthy Individuals 87

Fig. 2. Mean and standard error of absolute theta power. (A) Left anterior frontal cortex (F3) interaction between conditions and moments
(placebo vs. levetiracetam vs. pre vs. post) (p=0.019). The paired t-test for post moment demonstrated significant difference between
conditions (p=0.031); (B) midline anterior frontal cortex (FZ) on the placebo and levetiracetam conditions (p=0.027); (C) right anterior frontal
cortex (F4) main effect for condition (p=0.000); (D) main effect for pre- and post-moments was seen at F4 (p=0.011).

neuro-enhancer.25,26) In particular, the goal is to identify (attention), Digit Span (working memory), Stroop test
the behavioral changes produced in the reaction time, the (inhibitory control of attention) and Tower of London
neuropsychological changes in attention and memory, and (planning and decision making).29,30) Our data indicated a
finally examine the alleged electroencephalographic change in the Trail Making Test (A), both for time and er-
changes (qEEG) in absolute theta power in the frontal ror produced by the participants. This difference was ob-
cortex.27,28) In order to examine the effects of LEV in exec- served between placebo and LEV conditions. In partic-
utive functions, a two-way-ANOVA was implemented. ular, there was a reduction in the task execution time when
Specifically, two independent variables were observed: the individual was under the influence of LEV. In contrast,
condition (placebo or LEV) and moment (pre- and a main effect for moment (pre and post) was found; this
post-ingestion of the LEV or placebo). This discussion has means that, when comparing pre- and post-moment, re-
been divided into two distinct sections: i) effects of LEV gardless of treatment, an error increase was observed. The
on executive functions and behavioral aspects; ii) effects Trail Making Test (A) is certainly simpler to apply than the
of LEV on electrophysiological patterns. Trail Making Test (B), since the subjects must follow a
progressive numerical sequence, such as connecting
Executive Functions (Neuropsychological Assessment) points distributed randomly on an A4 sheet from a certain
The neuropsychological evaluation consisted of four initial number. In our case, the subjects were always pre-
neuropsychological tests: Trail Making Test (A and B) sented with the same numerical order starting with num-
88 J. C. Magalhães, et al.

Fig. 3. Mean and standard error of absolute theta power. (A) Left
frontopolar cortex (FP1) on the placebo and levetiracetam
conditions (p=0.039); (B) right frontopolar cortex (FP2) on the
placebo and levetiracetam conditions (p=0.048); (C) main effect
for pre and post moments was seen at FP2 (p=0.001).

ber 1. The purpose of the Trail Making Test is to evaluate processing cycle that takes into account at least three
the mechanisms of attention, although there is a small at- stages in the process as a whole (uptake of the initial stim-
tribute involving working memory (operating).31,32) For ulus, choice of the best option and final motor action). Our
instance, the participants need to remember the previous data demonstrated a decrease of almost 15 milliseconds
number during the test. Our first finding in relation to time (ms) in the reaction time between the LEV and placebo
in the Trail Making Test (A) between conditions (placebo conditions. These data clearly indicate a modulation of
vs. LEV) suggests that the drug had a beneficial effect on LEV in the decision-making cycle in healthy individuals.
the mechanisms of attention and tracking during task Few studies have analyzed the behavior of the reaction
execution. Particularly, this finding supports the hypoth- time and the use of LEV in healthy subjects. Studies on
esis that tasks involving sustained attention are positively LEV combined with reaction time in healthy volunteers
modulated by LEV.33-35) Up to now, few studies have at- were not found. The simple reaction time was examined in
tempted to exclude confounding effects of LEV in healthy an experiment with epileptic subjects and the researchers
subjects. For example, the positive effects of LEV have found no difference between before and after the use of
been associated with pathological conditions, both psy- LEV.14,38) In contrast, our experiment used a reaction time
chiatric and neurological or even different traumas.36,37) of recognition between two different stimuli (e.g., square
Thus, our study attempts to isolate the factors that can dis- or ball), similar to the paradigm used for evoked cognitive
guise the effects of LEV alone. potential (e.g., “odd-ball”).39-41) Perhaps, the reaction time
Another very relevant finding in our experiment was of recognition is a more sensitive measure to detect al-
the reduction of reaction time provided by LEV. The re- leged changes produced by LEV, since it involves the in-
action time in a comprehensive manner, expresses the hibition of the motor act in non-target stimuli (e.g., ball).
 Levetiracetam Effects in Cognitive Performance in Healthy Individuals 89

55,56)
The increased complexity of the task using the reaction sions, and different forms of storage.
time of recognition makes its execution more difficult, As regards the main effect for moment (FP2), there are
thus, it exposes the alleged cognitive impairments pro- singularities between hemispheres. In particular, the right
42,43)
duced by LEV in information processing. frontopolar cortex, as described in previous studies, par-
ticipates in different cognitive processes, including pro-
Effects of LEV on Electrophysiological Parameters spective and working memory.57) Prospective memory
(Absolute Theta Power) considers the idealization of future actions, i.e., remember
The electrophysiological discussion follows the same something that will happen in the future. This increase in
sequence of the results section. The frontal region will be theta may briefly indicate a suppression of the right fron-
discussed, starting from the most anterior electrodes until topolar hemisphere to give way to the more specialized
those positioned just before the central region (FP1, FP2, left hemisphere in more analytical aspects. Our data sug-
F7, F8, F3, Fz and F4). We recognize the complexity of the gest that the emergence of theta in the frontopolar cortex
brain, in particular, the various brain regions that only be- region acts as a specific inhibitory control mechanism.
long to the cortex and its multiple communications at This inhibitory mechanism is not new; it has been seen
varying frequencies. Although this complexity is recog- previously in other studies58,59) and it may partially explain
nized, initially, we will analyze the frontal region asso- our findings in relation to the reaction time. The theta
ciated with executive functions of high hierarchy,44-46) and power increase in the frontopolar region may contribute to
theta frequency by its relation to attentional processes, the response selection, and thus produce a decrease in the
47-49)
working memory and visuospatial aspects. Theta ac- time of choice and perceptual aspect, therefore generating
tivity has been associated with problem solving, several greater efficiency in decision making.60,61)
mental activities related to concentration and attentional
focus. Specifically, theta is also associated with attention Prefrontal Inferior Gyrus (PIG): Left and Right - 47 (F7)
deficit and hyperactivity disorders. In this context, we vs. 45 (F8)
have observed theta behavior and we will try to interpret it Traditionally, functions widely associated with aspects
with the same logic applied to the alpha band. This way, related to language and semantics are attributed to the
theta increase could suggest a deactivation of the re- PIG.62-64) This outlook highlights a localizationist approach
spective region.50,51) of the neuroanatomical structures, besides not showing
completely the complexity of PIG. Our results point out a
Frontopolar Cortex (Anterior Prefrontal Cortex) quite different framework, and a supposed participation of
The anterior region of the cerebral cortex, also known PIG in background executive functions, which goes be-
as frontopolar cortex (Brodmann area-10) has been linked yond the classical view focusing on language issues. In the
to extremely complex executive functions.52-54) The elec- PIG left region (F7), an interaction between condition and
trophysiological data for the pair of electrodes FP1 and moment was observed. A detailed inspection of the inter-
FP2, located in the anterior prefrontal cortex region, action showed that this difference lies in the LEV
showed a similar pattern for the main effect condition. A condition. An increase in theta power was seen after the
decrease in theta power between the placebo and LEV acute effect of LEV.
conditions was observed. In this case, both hemispheres Unlike the frontopolar region (Brodmann area-10), this
had a very similar behavior. However, the FP2 electrode finding suggests that PIG responds in a manner opposite to
showed a main effect for both moment and condition, be- the effects of LEV, suggesting a differentiated function-
fore and after the substance (placebo or LEV) ingestion. ality of the left prefrontal region. The findings about F8
With regards to the main effect for condition (placebo vs show a theta power decline when LEV was compared to
LEV), the decrease in theta power between the placebo placebo. In particular, the theta decrease clearly demon-
and LEV conditions can support the idea of a greater effi- strates an increase of activity in the right region. The right
ciency of the anterior cortex region. Theta power decrease PIG is also related to operating, episodic and recognizing
suggests that the dose of LEV used (500 mg) produced a memory and visuospatial aspects.65,66) Studies with de-
reduction in the amount of slow frequency, compared to pressive patients showed an increased activation in the
the placebo group. These differences could represent an right PIG, which was observed through functional mag-
improvement in some executive functions, such as: action netic resonance image during a recognition task.67,68)
planning, cognitive flexibility, change of plans and deci- These findings suggest that LEV can act more specifically
90 J. C. Magalhães, et al.

on other forms of memory, and the PIG’s right region can gion, the results support the fact that LEV promotes cogni-
distinguish different aspects about information retrieval. tive enhancement in executive functions. In addition, our
data can further investigate the control mechanisms, such
Anterior Frontal Cortex (Brodmann area- 8) - 8 (F3) / as the inhibitory and excitatory mechanisms exercised by
8L (FZ) / 8 (F4) the theta frequency band. Specifically, it is possible to
The Brodmann area-8, also known as frontal visual view and access such control mechanisms and to see how
field, plays a very important and complex role in various they act in different frontal cortical areas through qEEG.
executive functions,69,70) such as: working, recovery and Although this study has shown interesting results, some
planning memory, visual-motor attention and motor learn- limitations are listed as follows: i) we have only observed
ing, proprioceptive aspects and ability to perform the acute effect of LEV, that is, a single dose. We haven't
calculations.71) Brodmann area-8 results were divided in seen the effect of LEV on a prolonged period of time; ii)
different sectors: left (F3), central (FZ) and right (F4). A We initially limited our focus to just looking at absolute
different behavior was detected for each of these areas. theta power, therefore leaving other variables and fre-
The F3 electrode showed a significant interaction between quencies for future analyses: coherence, asymmetry and
condition and moment. A careful investigation of the in- relative power in other cortical areas and different fre-
teraction showed a difference for the LEV condition be- quencies, such as alpha, beta and gamma are a few exam-
tween moments. Similarly to the behavior of the F7 elec- ples of this; iii) our neuropsychological findings are quite
trode (left hemisphere), this region also showed a sig- discrete and affirmations about the use of LEV as a cogni-
nificant increase in absolute theta power after the action tive enhancer should be more moderate.
peak effect of LEV. This theta increase may suggest an in-
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