This work was supported by EFRI-MC3: # 1137237 awarded to S.V.S. and J.T.G.

All tasks were performed according to an approved protocol submitted to the Institutional Review Board (IRB) of the Cleveland Clinic Foundation. An informed consent process was conducted with each patient prior to all research activities. In this example, a subject that meets study criterion that has had stereo-electroencephalography (SEEG) electrodes implanted for seizure is chosen. The project was discussed with the subject and they have consented to participate.
1. Patient Enrollment
<ol>...

<ol>
	<li>Rosenow, F., Luders, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Presurgical+evaluation+of+epilepsy.">Presurgical evaluation of epilepsy.</a> Brain. 124, 1683-1700 (1093).</li><li>Adelson, P. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Use+of+subdural+grids+and+strip+electrodes+to+identify+a+seizure+focus+in+children.">Use of subdural grids and strip electrodes to identify a seizure focus in children.</a> Pediatr. Neurosurg. 22 (4), 174-180 (1995).</li><li>Jayakar, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Invasive+EEG+monitoring+in+children:+When,+where,+and+what.">Invasive EEG monitoring in children: When, where, and what.</a> J Clin Neurophysiol. 16, 408-418 (1999).</li><li>Almeida, A. N., Martinez, V., Feindel, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+first+case+of+invasive+EEG+monitoring+for+the+surgical+treatment+of+epilepsy:+Historical+significance+and+context.">The first case of invasive EEG monitoring for the surgical treatment of epilepsy: Historical significance and context.</a> Epilepsia. 46, 1082-1085 (2005).</li><li>Dinner, D. S., Luders, H. O., Klem, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+electrocorticography:+Cleveland+clinic+experience.">Chronic electrocorticography: Cleveland clinic experience.</a> Electroencephalogr Clin Neurophysiol. , 58-69 (1998).</li><li>Bancaud, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Functional+Stereotaxic+Exploration+(Seeg)+of+Epilepsy.">Functional Stereotaxic Exploration (Seeg) of Epilepsy.</a> Electroencephalogr Clin Neurophysiol. 28, 85 (1970).</li><li>Chassoux, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intralesional+recordings+and+epileptogenic+zone+in+focal+polymicrogyria.">Intralesional recordings and epileptogenic zone in focal polymicrogyria.</a> Epilepsia. 49, 51-64 (2008).</li><li>Lo Russo, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Focal+cortical+resection+in+malformations+of+cortical+development.">Focal cortical resection in malformations of cortical development.</a> Epileptic Disord. 5, S115-S123 (2003).</li><li>Avanzini, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Discussion+of+stereoelectroencephalography.">Discussion of stereoelectroencephalography.</a> Acta neurologica Scandinavica Supplementum. , 152-170 (1994).</li><li>Cossu, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereo-EEG+in+children.">Stereo-EEG in children.</a> Child Nerv Syst. 22, 766-778 (2006).</li><li>Cossu, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epilepsy+surgery+in+children:+Results+and+predictors+of+outcome+on+seizures.">Epilepsy surgery in children: Results and predictors of outcome on seizures.</a> Epilepsia. 49, 65-72 (2008).</li><li>Cossu, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereoelectroencephalography+in+the+presurgical+evaluation+of+focal+epilepsy+in+infancy+and+early+childhood+Clinical+article.">Stereoelectroencephalography in the presurgical evaluation of focal epilepsy in infancy and early childhood Clinical article.</a> J Neurosurg-Pediatr. 9, 290-300 (2012).</li><li>Gonzalez-Martinez, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereoelectroencephalography+in+the+&amp;#34;difficult+to+localize&amp;#34;+refractory+focal+epilepsy:+early+experience+from+a+North+American+epilepsy+center.">Stereoelectroencephalography in the &amp;#34;difficult to localize&amp;#34; refractory focal epilepsy: early experience from a North American epilepsy center.</a> Epilepsia. 54, 323-330 (2013).</li><li>Vadera, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereoelectroencephalography+following+subdural+grid+placement+for+difficult+to+localize+epilepsy.">Stereoelectroencephalography following subdural grid placement for difficult to localize epilepsy.</a> Neurosurgery. 72, 723-729 (2013).</li><li>Hill, N. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recording+human+electrocorticographic+(ECoG)+signals+for+neuroscientific+research+and+real-time+functional+cortical+mapping.">Recording human electrocorticographic (ECoG) signals for neuroscientific research and real-time functional cortical mapping.</a> Journal of visualized experiments : JoVE. , (2012).</li><li>Ibanez, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Motor-language+coupling:+direct+evidence+from+early+Parkinson's+disease+and+intracranial+cortical+recordings.">Motor-language coupling: direct evidence from early Parkinson's disease and intracranial cortical recordings.</a> Cortex; a journal devoted to the study of the nervous system and behavior. 49, 968-984 (2013).</li><li>Caplan, J. B., Madsen, J. R., Raghavachari, S., Kahana, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Distinct+patterns+of+brain+oscillations+underlie+two+basic+parameters+of+human+maze+learning.">Distinct patterns of brain oscillations underlie two basic parameters of human maze learning.</a> J Neurophysiol. 86, 368-380 (2001).</li><li>Watrous, A. J., Fried, I., Ekstrom, A. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Behavioral+correlates+of+human+hippocampal+delta+and+theta+oscillations+during+navigation.">Behavioral correlates of human hippocampal delta and theta oscillations during navigation.</a> J Neurophysiol. 105, 1747-1755 (2011).</li><li>Roman, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hippocampal+negative+event-related+potential+recorded+in+humans+during+a+simple+sensorimotor+task+occurs+independently+of+motor+execution.">Hippocampal negative event-related potential recorded in humans during a simple sensorimotor task occurs independently of motor execution.</a> Hippocampus. , (2013).</li><li>Jerbi, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exploring+the+electrophysiological+correlates+of+the+default-mode+network+with+intracerebral+EEG.">Exploring the electrophysiological correlates of the default-mode network with intracerebral EEG.</a> Front Syst Neurosci. 4, 27 (2010).</li><li>Krolak-Salmon, P., Henaff, M. A., Vighetto, A., Bertrand, O., Mauguiere, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Early+amygdala+reaction+to+fear+spreading+in+occipital,+temporal,+and+frontal+cortex:+a+depth+electrode+ERP+study+in+human.">Early amygdala reaction to fear spreading in occipital, temporal, and frontal cortex: a depth electrode ERP study in human.</a> Neuron. 42, 665-676 (2004).</li><li>Hudry, J., Perrin, F., Ryvlin, P., Mauguiere, F., Royet, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Olfactory+short-term+memory+and+related+amygdala+recordings+in+patients+with+temporal+lobe+epilepsy.">Olfactory short-term memory and related amygdala recordings in patients with temporal lobe epilepsy.</a> Brain. 126, 1851-1863 (2003).</li><li>Rektor, I., Bares, M., Kubova, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Movement-related+potentials+in+the+basal+ganglia:+a+SEEG+readiness+potential+study.">Movement-related potentials in the basal ganglia: a SEEG readiness potential study.</a> Clin Neurophysiol. 112, 2146-2153 (2001).</li><li>Rektor, I., Louvel, J., Lamarche, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intracerebral+recording+of+potentials+accompanying+simple+limb+movements:+a+SEEG+study+in+epileptic+patients.">Intracerebral recording of potentials accompanying simple limb movements: a SEEG study in epileptic patients.</a> Electroencephalogr Clin Neurophysiol. 107, 277-286 (1998).</li><li>Mitra, P., Bokil, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Observed Brain Dynamics. , (2008).</li><li>Lachaux, J. P., Axmacher, N., Mormann, F., Halgren, E., Crone, N. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High-frequency+neural+activity+and+human+cognition:+past,+present+and+possible+future+of+intracranial+EEG+research.">High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research.</a> Progress in neurobiology. 98, 279-301 (2012).</li><li>Rogers, R. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Choosing+between+small,+likely+rewards+and+large,+unlikely+rewards+activates+inferior+and+orbital+prefrontal+cortex.">Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex.</a> The Journal of neuroscience : the official journal of the Society for Neuroscience. 19, 9029-9038 (1999).</li><li>Lachaux, J. -. P., Axmacher, N., Mormann, F., Halgren, E., Crone, N. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High-frequency+neural+activity+and+human+cognition:+Past,+present+and+possible+future+of+intracranial+EEG+research.">High-frequency neural activity and human cognition: Past, present and possible future of intracranial EEG research.</a> Prog. Neurobiol. 98, 279-301 (2012).</li><li>Gale, J. T., Martinez-Rubio, C., Sheth, S. A., Eskandar, E. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intra-operative+behavioral+tasks+in+awake+humans+undergoing+deep+brain+stimulation+surgery.">Intra-operative behavioral tasks in awake humans undergoing deep brain stimulation surgery.</a> Journal of visualized experiments : JoVE. , (2011).</li></ol>

Here we have presented a method for performing intracranial electrophysiological studies in humans as they engage in a behavioral task. This methodology and its simple permutations are important for studying human movement and cognition. While there inherently exists advantages and disadvantages to any technique, recording from intracranial electrodes has advantages over other electrophysiological and imaging techniques. Two of the major advantages are the ability to collect high quality data with better control and desi...

Epilepsy is one of the most common brain disorders, characterized by chronically recurrent seizures resulting from excessive electrical discharges from groups of neurons. Epilepsy affects about 50 million people worldwide and approximately 40% of all individuals with epilepsy have intractable seizures that cannot completely be controlled by medical therapy1. Surgery may result in seizure free status if the brain areas responsible for the generation of seizures (the epileptogenic zone - EZ) are localized and surgically removed or disconnected. In order to define the anatomical location of the EZ and its proximity with possible cortical and subcortical eloquent areas, an array of non-invasive tools are available: analysis of seizure semiology, video-scalp electroencephalographic recordings (ictal and interictal recordings), neuropsychological testing, magnetoencephalography (MEG) and MRI2. When the noninvasive data is insufficient to precisely define the location of the hypothetical EZ, when there is the suspicion of early involvement of eloquent cortical and subcortical areas or when there is the possibility for multi-focal seizures, chronic invasive monitoring may be required3,4.
Methods of chronic invasive monitoring for defining the location and boundaries of an EZ may include subdural grids and strips, with electrodes placed on the brain&#8217;s surface, and stereo-electroencephalography (SEEG), when multiple depth electrodes are placed in the brain in a three-dimensional fashion. Subdural intracranial recordings were initially reported in 1939 when Penfield and colleagues used epidural single contact electrodes in a patient with an old left temporal-parietal fracture and whose pneumoencephalography disclosed diffuse cerebral atrophy5 . Subsequently, the use of subdural grid arrays became more popular after multiple publications during the 1980&#39;s demonstrated their safety and efficacy6. The SEEG method was developed and popularized in France by Jean Tailarach and Jean Bancaud during the 50&#8217;s and has been mostly used in France and Italy as the method of choice for invasive mapping in refractory focal epilepsy7-9.
The principle of SEEG is based on anatomo-electro-clinical correlations, which takes as its main principle the 3-dimensional spatial-temporal organization of the epileptic discharge within the brain in correlation with seizure semiology. The implantation strategy is individualized, with electrode placement based on a preimplantation hypothesis that takes into consideration the primary organization of the epileptiform activity and the hypothetical epileptic network involved in the propagation of seizures. According to several European and recent North American reports, SEEG methodology enables precise recordings from deep cortical and subcortical structures, multiple noncontiguous lobes, and bilateral explorations while avoiding the need for large craniotomies10-15. Afterwards, postoperative images are taken to obtain the exact anatomical position of the implanted electrodes. Subsequently, a monitoring period starts in which patients remain in the hospital for a period of 1 to 4 weeks in order to record interictal and ictal activities from the implanted electrodes. This monitoring period is an opportune time for studying brain function using event-related SEEG analysis, as there is no added risk and the patient typically views the research study as a welcome reprieve from the mundane monitoring period. The recordings garnered from intracranial electrodes are not only vital to improved evaluation and care of epilepsy patients, but additionally provide the exceptional opportunity to study human brain activity during behavioral paradigms.
Several researchers have already realized the opportunity to study invasive recordings from epilepsy patients. Hill et al. reported on the methodology for recording electrocorticographic (ECoG) signals from patients for functional cortical mapping16. ECoG recordings have also provided insight to motor-language coupling17. Patients with implanted depth electrodes have performed navigational tasks to study brain oscillations in memory, learning18 and movement19. Depth electrode recordings were also used to study paradigms with otherwise unattainable temporal resolution such as hippocampal evoked activity20, neural activity in the default-mode network21, and the temporal course of emotional processing22. Hudry et al studied patients with temporal lobe epilepsy who had SEEG electrodes implanted into their amygdala for short-term olfactory stimuli matching23. Another group has studied simple limb movements such as hand flexion or unilateral movement of the hand or foot in healthy brain sites from epileptic patients with implanted SEEG24,25.
The studies described above are a small sampling of a very diverse collection of relevant literature. There exists an insurmountable potential to learn and understand how the human brain works using a combination of behavioral tasks and intracranial recordings. While there are other methods for achieving this goal, intracranial recordings possess several benefits including high temporal and spatial resolution as well as access to deeper structures. The authors aim to describe the general methodology for recording from patients with intracranial electrodes during behavioral tasks. However, there are several deterrents and barriers to successfully completing clinical research in patients receiving care. Limitations, confounding effects, and significance of this research will also be identified and explored.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
		</tr>
		<tr>
			<td>InMotion ARM</td>
			<td>Interactive Motion Technologies</td>
			<td>InMotion Arm</td>
			<td><a href="http://interactive-motion.com/inmotion-arm-the-new-standard-of-care/">http://interactive-motion.com/inmotion-arm-the-new-standard-of-care/</a> 
			Equipment our lab used, can use other equipment to collect data</td>
		</tr>
		<tr>
			<td>MATLAB</td>
			<td>Mathworks Inc</td>
			<td>MATLAB</td>
			<td><a href="http://www.mathworks.com/">http://www.mathworks.com/</a> 
			Need version r2007b or higher to run Monkeylogic</td>
		</tr>
		<tr>
			<td>Data Acquisition Toolbox</td>
			<td>Mathworks Inc</td>
			<td>Data Acquisition Toolbox</td>
			<td><a href="http://www.mathworks.com/products/daq/">http://www.mathworks.com/products/daq/</a> 
			Must have to run Monkeylogic</td>
		</tr>
		<tr>
			<td>Image Processing Toolbox</td>
			<td>Mathworks Inc</td>
			<td>Image Processing Toolbox</td>
			<td><a href="http://www.mathworks.com/products/image/">http://www.mathworks.com/products/image/</a> 
			Must have to run Monkeylogic</td>
		</tr>
		<tr>
			<td>Monkeylogic</td>
			<td>Wael Asaad and David Freedman</td>
			<td>Monkeylogic</td>
			<td><a href="http://www.brown.edu/Research/monkeylogic/">http://www.brown.edu/Research/monkeylogic/</a> 
			Free download, must have MATLAB to run</td>
		</tr>
		<tr>
			<td>Chronux&#160;</td>
			<td>Medametrics, LLC&#160;</td>
			<td>Data Processing Toolbox</td>
			<td><a href="http://www.chronux.org/">http://www.chronux.org/</a></td>
		</tr>
		<tr>
			<td>Brainstorm</td>
			<td></td>
			<td>MEG/EEG Analysis Application</td>
			<td><a href="http://neuroimage.usc.edu/brainstorm/">http://neuroimage.usc.edu/brainstorm/</a></td>
		</tr>
		<tr>
			<td>Laptop</td>
			<td>Dell</td>
			<td>Latitude E5530</td>
			<td><a href="http://www.dell.com/us/business/p/latitude-e5530/pd?ST=dell%20latitude%20e5530&amp;dgc=ST&amp;cid=263756&amp;lid=4781504&amp;acd=12309152537461010">http://www.dell.com/us/business/p/latitude-e5530/pd?ST=dell%20latitude%20e5530&#38;dgc=ST&#38;cid=263756&#38;lid=4781504&#38;acd=12309152537461010</a></td>
		</tr>
		<tr>
			<td>NI Card</td>
			<td>National Instruments</td>
			<td>NI USB-6008</td>
			<td><a href="http://sine.ni.com/nips/cds/view/p/lang/en/nid/201986">http://sine.ni.com/nips/cds/view/p/lang/en/nid/201986</a> 
			12-Bit, 10 kS/s Low-Cost Multifunction DAQ</td>
		</tr>
	</tbody>
</table>

performing behavioral tasks in subjects with intracranial electrodes

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in different areas of their brain for the localization of their seizure focus and eloquent areas. After implantation, the patient must remain in the hospital until the pathological area of brain is found and possibly resected. During this time, these patients offer a unique opportunity to the research community because any number of behavioral paradigms can be performed to uncover the neural correlates that guide behavior. Here we present a method for recording brain activity from intracranial implants as subjects perform a behavioral task designed to assess decision-making and reward encoding. All electrophysiological data from the intracranial electrodes are recorded during the behavioral task, allowing for the examination of the many brain areas involved in a single function at time scales relevant to behavior. Moreover, and unlike animal studies, human patients can learn a wide variety of behavioral tasks quickly, allowing for the ability to perform more than one task in the same subject or for performing controls. Despite the many advantages of this technique for understanding human brain function, there are also methodological limitations that we discuss, including environmental factors, analgesic effects, time constraints and recordings from diseased tissue. This method may be easily implemented by any institution that performs intracranial assessments; providing the opportunity to directly examine human brain function during behavior.

In these results we present the analysis of the SEEG data from the limbic system captured in one subject playing the War Task. We can demonstrate that various aspects of the War Task evoke significant gamma-band (40 - 150 Hz) modulation in the limbic system (Figure 1). As seen, in the visual cortex, the presentation of an object on the screen results in a fast latency (~200 msec) wide band response regardless of the task contingency. In addition, there appears to be differences in the duration of the res...

Watch this Scientific Journal Video about Performing Behavioral Tasks in Subjects with Intracranial Electrodes at JoVE.com

Performing Behavioral Tasks in Subjects with Intracranial Electrodes

Patients implanted with intracranial electrodes provide a unique opportunity to record neurological data from multiple areas of the brain while the patient performs behavioral tasks. Here, we present a method of recording from implanted patients that can be reproducible at other institutions with access to this patient population.

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in ...

performing-behavioral-tasks-in-subjects-with-intracranial-electrodes

Research

JoVE Journal

Behavior

11.2K visualizações.  Cleveland Clinic Foundation.  Os pacientes implantados com eletrodos intracranianos oferecem uma oportunidade única para gravar dados neurológicos de várias áreas do cérebro, enquanto o paciente realiza tarefas comportamentais. Aqui, apresentamos um método de gravação de pacientes implantados que podem ser reprodutível em outras instituições com acesso a esta população de pacientes. 