Bromazepam Impairs Motor Response: An ERSP Study

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Bromazepam Impairs Motor Response: An ERSP Study Julio G. Silva1,13,§, Oscar Arias-Carrión*,2,§, Flávia Paes3,4,5, Bruna Velasques6,7, Silmar Teixeira6, Luis F. H. Basile8,9, Maurício Cagy10, Roberto Piedade6, Antonio E. Nardi3,5, Sergio Machado*,3,5,12,§ and Pedro Ribeiro6,7,11 1

Physical Therapy Department, Federal University of Rio de Janeiro (IPUB/UFRJ), Brazil

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Department of Neurology, Philipps University, Marburg, Germany

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Panic & Respiration Laboratory, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. 4

Faculty of Psychology, Brazilian Institute of Medicine and Rehabilitation (IBMR), Rio de Janeiro, Brazil

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National Institute of Translational Medicine (INCT-TM), Brazil

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Brain Mapping and Sensory Motor Integration, Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ), Brazil 7

Institute of Applied Neuroscience (INA), Rio de Janeiro, Brazil

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Division of Neurosurgery, University of São Paulo Medical School, Brazil

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Laboratory of Psychophysiology, Faculdade de Psicologia e Fonoaudiologia, UMESP, Brazil

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Division of Epidemiology and Biostatistics, Institute of Health Community, Federal Fluminense University (UFF), Rio de Janeiro, Brazil

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School of Physical Education, Bioscience Department (EEFD/UFRJ), Brazil

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Quiropraxia Program, Central University, Chile

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Masters Program (Science Rehabilitation) Centro Universitario Augusto Motta (UNISUAM), Brazil Abstract: This study aimed to investigate the acute modulatory effect of bromazepam, a benzodiazepine derivative drug, on alpha and beta bands (8-35Hz) in primary motor areas (M1) through event-related spectral perturbation (ERSP). Ten healthy subjects were submitted to a cross-over double-blind design. Subjects performed a visuomotor task where they had to identify rapidly the ball launched horizontally and catch it quickly, while electroencephalographic activity was acquired. We found a statistically significant difference on the time windows of 2920 ms for 13Hz in the electrodes C3 and Cz, and on the time window of 2000 ms for 18Hz in the electrodes C3, when compared the bromazepam and placebo conditions. We concluded that the acute effects of bromazepam provoked changes in information process in the left M1 represented by electrode C3 in both 13 Hz and 18 Hz. Our paradigm is relevant for a better understanding of the brain dynamics due to the information related to bromazepam effects on sensorimotor processes. We consider this report an invitation to conduct more studies in order to associate electro-cortical activity and psychometric tests.

Keywords: EEG, ERSP, bromazepam, catching, sensorimotor integration, visuomotor task. INTRODUCTION Quantitative electroencephalography (qEEG) is a useful tool to explore and to understand possible changes in the cortical activity related to psychoactive substances. Within this context, qEEG has been used to monitor the effects of distinct medications on brain dynamics since cortical activity is responsive to the unique characteristics of psychoactive substances, e.g., bromazepam [1-3]. The EEG sensitivity in identifying changes produced by a specific substance may be improved by methods of quantitative EEG analyses [4], such as event-related spectral perturbation (ERSP). ERSP represent analysis of event-related changes in spectral power *Address correspondence to these authors at the Department of Neurology, Philipps University-Marburg, Baldingerstrasse D-35033 Marburg, Germany; Tel: +49-6421-28-66088; Fax: +49-6421-28-66122; E-mail: [email protected] and Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; E-mail: [email protected] §

Equal contribution. 1871-5273/11 $58.00+.00

and phase consistency across single trials time-locked to experimental events that can characterize event-related perturbations in the oscillatory dynamics of ongoing EEG signals. Generally, ERSP can be interpreted as either decrease (desynchronization) or increase (synchronization) in power, in a given frequency band, that reflect a decrease or increase in synchrony of the underlying neuronal populations, depending on the frequency band [5, 6]. ERSP explores the event-locked changes in spectral power measure the appearance and degree of this consistency near experimental events [7], and thus, may contribute to elucidate cognitive and sensorimotor processes under psychotropic action, e.g., bromazepam. This substance is the most prescribed and abused substance (worldwide) for the management of anxiety and insomnia [8, 9]. Bromazepam have been used to understand how the cerebral cortex works during the performance of sensorimotor integration tasks [1-3], however, this is still not understood. On the one hand, some studies showed that bromazepam may impair psychomotor capacity when individuals are submitted to neuropsychological testing [10-13], suggesting that the impairment caused by © 2011 Bentham Science Publishers

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bromazepam takes place on the early stages of sensorimotor integration, such as, stimulus detection and attention [2, 13]. On the other hand, other studies suggest that low dosages of bromazepam improve cognitive and motor performance [2, 14].

BL2 for verifying significant electrophysiological differences between the groups.

Our study aimed to investigate the modulatory acute effects of bromazepam on alpha and beta bands (8-40Hz) in the primary motor areas through event-related spectral perturbation (ERSP), when subjects were submitted to a visuomotor task, where they have to identify rapidly the object (i.e., a ball) launched horizontally to immediately catch it. To our knowledge, there are no previous reports on the role of bromazepam during performance of sensorimotor test.

EEG - The International 10/20 System for electrodes [16] was used with the 20-channel EEG system Braintech-3000 (EMSAMedical Instruments, Brazil). The 20 electrodes were arranged in a nylon cap (ElectroCap Inc., Fairfax, VA, USA) yielding monopolar derivations referred to linked earlobes. In addition, two 9-mm diameter electrodes were attached above and on the external corner of the right eye, in a bipolar electrode montage, for eye-movement (EOG) artifacts monitoring. Impedance of EEG and EOG electrodes was kept between 5-10K. The data acquired had total amplitude of less than 100V. The EEG signal was amplified with a gain of 22.000, analogically filtered between 0.01Hz (high-pass) and 100Hz (low pass), and sampled at 240 Hz. The software Ball Acquisition (Delphi 5.0), developed at the Brain Mapping and Sensory Motor Integration Lab, was employed with the following digital filters: notch (60 Hz), high-pass of 0.3 Hz and low-pass of 25 Hz.

MATERIAL AND METHODS Sample The sample was composed of 10 healthy young subjects (3 female; mean age: 25.6 ± 4.8 yrs), right-handed as defined in the Edinburgh inventory [15]. Inclusion criteria were: absence of mental or physical impairments and no history of psychoactive or psychotropic substance use (screened by a previous anamnesis and a clinical examination). Moreover, those subjects had not had less than 6 hours of uninterrupted sleep on the night prior to the experiment; do not ingest alcohol, soda or coffee at least 48 hours prior to the experiment and no previous experience in the task. All subjects signed a consent form and were aware of the experimental protocol before participation commenced. The experiment was approved by the Ethics Committee of the Federal University of Rio de Janeiro. Experimental Procedures Participants were equally distributed in control (CG; n = 10) and Br (BrG; n = 10; 10 mg/subject) groups using a cross-over design. Then, participants were subjected to measurement in each of three phases: Baseline (BL), Practice Blocks (PB), and Post Task Moment (PTM). The first phase included baseline resting EEG acquisition with eyes open before (BL1) and one hour after (BL2) placebo or Br ingestion. ERSP was examined in BL phases in order to determine whether electrophysiological differences existed between groups prior to task engagement. For example, we first tested for non-task related differences in cortical dynamics while the subjects were at rest. The second measurement phase consisted of 4 blocks of 40 trials. EEG was recorded continuously while participants performed catching trials in a sound and light-attenuated room in order to minimize sensory interference. All participants sat in a comfortable chair placed in front of the electromagnetic system. The electromagnetic system composed of two solenoids was controlled by the software Ball acquisition and it was interfaced with the electromyography (EMG). Ball Acquisition determined the ball passage by solenoids and consequently the ball launch through sensors coupled with the system. The ball passage by solenoids is related to the moment which the ball cross the solenoids and slide into the pipe. The reaction time (RT) was verified due to the first sensor (i.e., responsible for the start of the RT count) placed in front of a couple of pulleys responsible for the ball launch. The second sensor was placed in last centimeter of the pipe, registering the end of the ball launch. The information sent out by sensors was registered through the peaks registered by the sensors. The electromagnetic system was placed right in front of the subject and launched 8-cm balls by a pipe, one at a randomized interval of 7 to 9 s, at 15 cm straight onto the subject’s hand. The right hand was placed in a support that allows it stays in the launch line, with right forearm in flex and pronation position. After participants catch the ball, it was immediately discharged. Each launched ball composed a trial into the task composed of 4 blocks with 40 trials. Finally, the third moment, the PM, was performed two minutes after the last block, in the same conditions as BL1 and

Data Acquisition

EMG - The activity of the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), extensor carpi radialis (ECR) and extensor carpi ulnaris (ECU) was recorded by an EMG device (LynxEMG1000), to monitor and assess any voluntary movement during the task. Bipolar electrodes (2mm recording diameter) were attached to the skin. The reference electrode was fixed on the skin overlying the lateral epicondyle near the wrist joint. The skin was cleaned with alcohol prior to electrode attachment. The EMG was amplified (1000), filtered (10–3000 Hz), digitized (10,000 samples/s), and recorded synchronously to the EEG onto the computer’s hard drive. In each trial, the EMG signal was rectified and averaged over the 500 ms starting from the trigger onset. EMG was used in order to detect and remove possible artifacts related to the balls launch that could affect the electroencephalographic signal. Moreover, it was processed and analyzed on EEGLAB through rectified mean value (ARV – average rectified value). In this process, it was identified the maximum value and it was considered the moment of the maximum electrical activity in the muscles involved in the task execution. This maximum value was used like parameter to register the exact moment of the ball apprehension and to verify the reaction time (RT). Data Processing and Statistical Analysis Continuous EEG recordings were initially epoched into 8-s windows with reference to target onset events on a single-trial basis from 2000 ms before to 6000 ms with a randomized intertrial interval of 7 to 9 s. The interest period was at a time window of 2000 ms to +6000 ms. The EMG peak of every epoch was used to align them and to promediate them. The precedent period to EMG peak was comprised of a time window of -2000 ms (moment 0 ms) to 2000 ms (i.e., apprehension moment). After it (i.e., EMG peak; 2000 ms), the period of register to analysis extended as far as 6000 ms. In this way, the reference period used as baseline in the ERSP analysis was the time window of 0 ms to 2000 ms. Our data were filtered between 0.1 to 50 Hz, and then, to quantify reference-free data, a visual inspection and the independent component analysis (ICA) were applied to identify and remove any remaining artifacts. Data from individual electrodes exhibiting loss of contact with the scalp or high impedances (> 10k) were deleted and data from single-trial epochs exhibiting excessive movement artifact (±100 V) were also deleted. ICA is an information maximization algorithm that derives spatial filters by blind source separation of the EEG signals into temporally independent and spatially fixed components [5, 6, 17]. Independent components resembling eye-blink or muscle artifact were removed and the remaining components were then back-projected onto the scalp electrodes by multiplying the input data by the inverse matrix

Effects of Bromazepam on Alpha and Beta Bands

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of the spatial filter coefficients derived from ICA using established procedures (5, 6). The ICA-filtered data were then reinspected for residual artifacts using the same rejection criteria described above, and only 7 subjects remained in the analysis.

this in mind, the analyses were limited to three topographically representative electrode sites of M1 (i.e., C3, Cz, C4).

Of the 2240 trials from the 7 subjects after task execution, 38 of the single-trial epochs were retained for subsequent signal processing and statistical analysis. Event-related spectral perturbation (ERSP) [5,6] was derived from these clean single-trial data and log spectral estimates (dB) were obtained using multi-taper decomposition comprising discrete prolate spheroidal sequences. Based on our main interest in the stimulus-related cortical dynamics associated with complex sensorimotor demands and because of the temporal variability of the response related to qEEG, we confined our analyses to an early stimulus-related window (- 1500 ms to 6496 ms). Specifically, peak amplitude (dB) and latency (ms) values for both alpha and beta frequency bands were derived from a 2000-ms window following target onset (0 ms to 2000 ms with baseline correction from -500 ms to 0 ms) for each electrode.

Reaction Time

The resulting power-time curve consisted of 200 temporal points from -996 ms to + 5962 ms and 192 frequency points from 0.2 Hz to 45 Hz for each task condition. Spectral estimates were averaged across alpha (8–13 Hz) and beta (14-40 Hz) frequency bands and peak amplitude and latency values were determined in both frequency bands to statistical analyses. With this in mind, 113 components (i.e., analysis of conglomerate) coming from epochs were obtained of the 7 subjects in both conditions by individual variance less than 15% for the signal processing and statistical analysis. After the component analysis 8 components remained to explain the experiment. Statistical analyses were conducted separately for peak amplitude and latency values for alpha (8-13Hz) and beta (1440Hz) frequency bands using mixed linear models with two-tailed significance levels at alpha < 0.05 (SPSS 16.0). In addition, RT was subsequently averaged to yield a final value for each subject. Statistical analyses were related to time window of -2000 ms to 6000 ms regarding the ball apprehension, allowing verifying quantitative significant differences between conditions. Keeping

RESULTS During the visual-motor task, subjects (each block, both conditions) correctly catch the balls during the EEG recording. No significant differences were found between conditions. Event-Related Spectral Perturbation With regard to the statistical analyses, we found significant differences between bromazepam and placebo conditions in alpha (13Hz) and beta (18Hz) bands. However, regarding the reaction time, no significant differences were found between conditions. We described only the results relating to the statistical differences based on permutation test. ERSP Alpha – 13 Hz A significant statistical difference was found on the time windows of 2920 ms for 13Hz in the electrodes C3 and Cz when compared the bromazepam and placebo conditions (Permutation test; p = 0.01). A soft desynchronization was observed respectively in the electrodes C3 and Cz in the bromazepam condition, while in the placebo condition a desynchronization and synchronization were observed respectively in the electrodes C3 and Cz (Fig. 1). ERSP Beta – 18-25 Hz A significant statistical difference was found on the time window of 2000 ms for 18Hz in the electrodes C3 when compared the bromazepam and placebo conditions (Permutation test; p = 0.01). A soft and spreading desynchronization was observed in the bromazepam condition on the electrode C3, while a desynchronization was observed in the placebo condition on the same electrode (Fig. 2). DISCUSSION This study aimed to investigate the modulatory acute effects of bromazepam on alpha and beta bands (8-30Hz) in the primary

Fig. (1). Scalp maps of ERSP alpha in 13 Hz at the time of 2920ms. Statistical difference of p = 0.01.

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Fig. (2). Scalp maps of ERSP beta in 18 Hz at the time of 2000ms. Statistical difference of p = 0.01.

motor areas through event-related spectral perturbation (ERSP) when subjects were submitted to a visuomotor task, where they had to identify rapidly the object (i.e., a ball) launched horizontally to immediately catch it. We expected to find a delay on information processing, which may be seen through possible changes in sensorimotor rhythms of ERSP and not in motor performance regarding the acute effects of bromazepam.

experiments demonstrated that alpha desynchronization represents the activation of neural networks involved in a particular stimulus [20-24, 26]. Moreover, historically there is an idea that alpha oscillation represents an ‘idling’ rhythm that characterizes an alert but-still brain state. Today, the idling hypothesis has been largely replaced by a framework where the amplitude of an oscillation reflects a level of cortical inhibition [26].

Based on our statistical analysis, we found differences between bromazepam and placebo conditions in the alpha (13Hz) and beta (18Hz) bands. Our findings demonstrated deleterious effects induced by bromazepam in information process when compared to the placebo condition.

Considering that alpha is inversely related to cortical activity [26], the findings of the bromazepam condition then may indicate a possible failure in sensorimotor information processing in left M1 (i.e., responsible for the movement of the right hand) due to the drug’s action. Cortically, we assume that the soft desynchronization reflects an inhibition of the left M1 activity, which led to impairment in the cooperation of both M1 to perform the task [2024, 26]. With regard to the placebo condition, the findings represent the normal pattern of cortical activity according to the current literature of electrophysiology. In line with this, it seems that left and right M1 maintained an harmonic cooperation during task execution, with right M1 using the sensory feedback information such as, visual and somatosensory information from speed, trajectory and spatial position of the limb from premotor areas, and somatosensory information regarding temporal organization and coordination of sequential movements from SMA [18, 19], in order to providing the correct coordinates to left M1 executes the task. Therefore, these findings may reflect a delay in information processing related to motor processes. Bromazepam seems to inhibit the neuronal activity in the M1, causing deleterious effects on cortical activity during task performance.

ERSP Alpha – 13 Hz When observed the time window of 2920 ms (i.e., 920 ms after the ball apprehension), our findings showed different patterns of cortical activity. Regarding the bromazepam condition, a lower alpha desynchronization was observed in the electrode C3 while in comparison with the electrode C4. Considering the placebo condition, an alpha synchronization was noted in the electrode Cz while an alpha desynchronization was found in both electrodes C3 and C4. The electrodes C3 and C4 are placed on the primary motor cortex (M1) in each hemisphere that is functionally linked to motor programming, awareness of movement intention, perception and execution of movement. The CZ electrode represents the M1 of both hemispheres and the supplementary motor area (SMA), which is functionally related to temporal organization and coordination of sequential movements. The hemispheric specialization could be a reasonable explanation for our findings. According to Serrien et al. [18, 19], each hemisphere has specific functions and contributes to motor control in distinctive ways. The left hemisphere plays a dominant role for motor skills, while the right hemisphere plays a dominant role for sensory integration. Several studies reported that voluntary movement caused a desynchronization in alpha band (10-13 Hz). This activity starts 2s before contralateral activity on the C3 electrode, and immediately after movement, desynchronization occurs bilaterally on both M1 [20-24]. Alpha band (8–13 Hz) is known as sensitive to variations in perception, cognition and motor action [25, 26], and previous

ERSP Beta – 18 Hz In the frequency range of 18 Hz, our findings showed different patterns of cortical activity. In the time window at 2000 ms (i.e., moment of ball apprehension), a soft and spreading bilaterally beta desynchronization was observed in the bromazepam condition over the electrodes C3, P3, Pz and P4, while in the placebo condition a higher beta desynchronization was noted in the electrode C3. This soft and spreading desynchronization may indicate an increase in the necessity of new neural networks for a better information processing related to task execution as a form of CNS compensates for drug effects, in contrast to the focal activation observed in the

Effects of Bromazepam on Alpha and Beta Bands

placebo condition over the electrode C3 at the moment of ball apprehension. Beta band is involved in somesthetic processing and spatial coordinates of the upper limb. Individuals who are exposed to sensorimotor tasks generally presented beta reactivity in different regions of the somatomotor cortex [27, 28]. In line with that, some studies have showed a desynchronization when subjects are exposed to sensorimotor tasks, involving hand or finger movements, e.g., the cutaneous stimulation of index finger. Such desynchronization may suggest an increasing in magnitude of activation in specific cortical areas requested for the sensorimotor action [28, 29]. For instance, Neuper and Pfurtscheller [23] discussed that brain uses a neurophysiological mechanism that increases the focal activation of specific cortical areas and decreases the activity in other peripheral regions that are not relevant to the motor task. Our data in the placebo condition showed a desynchronization outstanding in the contralateral area responsible for movements and, intriguingly, bromazepam condition revealed a soft and spreading bilateral desynchronization activity, as described by Neuper and Pfurtscheller [23]. Such factors should have been caused by inhibitory action of bromazepam on gabaergic receptors [4], changing the thalamo-cortical connections directly involved in desynchronization/synchronization process at the precise moment of task execution [30-32]. Thalamic structures (interaction between thalamic nuclei and thalamic reticular nucleus) activate specific cortical areas at a certain time of the relevant information processing and deactivate others not used during the task execution [30]. Such process could be interpreted as an electroencephalographic correlate of activated cortical areas involved in the sensory information processing and motor behavior production [31]. This might indicate a participation of a broader neural network in the information processing [32]. Our results reinforce the finding in favor of a deactivation of cortical neural networks under bromazepam effects, leading to an inhibition of motor response. CONCLUSION We concluded that the acute effects of bromazepam provoked changes in information process in the left M1 represented by electrode C3 in both 13Hz and 18 Hz. Thus, the acute use of bromazepam may impair motor response. Our paradigm is relevant for a better understanding of the brain dynamics due to the information related to acute bromazepam effects on sensorimotor processes. In future studies, it is important to investigate the association of electro-cortical activity and psychometric tests, this in order to investigate not only the acute but also the chronic effects of bromazepam on possible states of anxiety prior task and, their influence on motor control.

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[3]

[4]

[5] [6] [7] [8] [9] [10]

[11]

[12] [13] [14] [15] [16] [17]

[18] [19] [20]

ABREVIATION EEG

=

Electroencephalography

[21]

EMG

=

Electromyography

[22]

ERSP

=

Event related spectral perturbation

[23]

ICA

=

Independent component analysis

M1

=

Primary motor areas

RT

=

Reaction time

[24] [25]

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Received: September 13, 2011

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Revised: December 22, 2011

Accepted: December 22, 2011