Name: using saccadometry with deep brain stimulation to study normal and pathological brain function
Uploaded: 2016-07-14T13:00:00
Description: Watch this Scientific Journal Video about Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function at JoVE.com

Dr. Antoniades was supported by the National Institute of Health Research (NIHR) and by the Dementias and Neurodegenerative Diseases Research Network (DENDRON) and by the Wellcome Trust. Dr FitzGerald was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.

The local ethics committee approved this study and informed consented was obtained from the participants as detailed below in section 1.
1. Participant Consent
<ol>
	<li>Provide participants with an information sheet that explains in detail what the testing session will include.</li>
	<li>After the participants have the opportunity to read and discuss any questions, concerns or other matters related to their taking part in the study, go through the consent form with them, explaining each poi...

<ol>
	<li>Leigh, R. J., Kennard, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Using+saccades+as+a+research+tool+in+the+clinical+neurosciences.">Using saccades as a research tool in the clinical neurosciences.</a> Brain. 127, 460-477 (2004).</li><li>Carpenter, R. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+neural+control+of+looking.">The neural control of looking.</a> Curr Biol. 10, 291-293 (2000).</li><li>Leigh, R. J., Zee, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The Neurology of Eye Movements. , (2006).</li><li>Antoniades, C. A., Xu, Z., Mason, S. L., Carpenter, R. H., Barker, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Huntington's+disease:+changes+in+saccades+and+hand-tapping+over+3+years.">Huntington's disease: changes in saccades and hand-tapping over 3 years.</a> Journal of Neurology. 257, 1890-1898 (2010).</li><li>Blekher, T. M., Yee, R. D., Kirkwood, S. C., Hake, A. M., Stout, J. C., Weaver, M. R., Foroud, T. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oculomotor+control+in+asymptomatic+and+recently+diagnosed+individuals+with+the+genetic+marker+for+Huntington's+disease.">Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease.</a> Vision Research. 44, 2729-2736 (2004).</li><li>Chan, F., Armstrong, I. T., Pari, G., Riopelle, R. J., Munoz, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Deficits+in+saccadic+eye-movement+control+in+Parkinson's+disease.">Deficits in saccadic eye-movement control in Parkinson's disease.</a> Neuropsychologia. 43, 784-796 (2005).</li><li>Antoniades, C. A., Demeyere, N., Kennard, C., Humphreys, G. W., Hu, M. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Antisaccades+and+executive+dysfunction+in+early+drug-naive+Parkinson's+disease:+The+discovery+study.">Antisaccades and executive dysfunction in early drug-naive Parkinson's disease: The discovery study.</a> Mov Disord. , (2015).</li><li>Antoniades, C., 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=An+internationally+standardised+antisaccade+protocol.">An internationally standardised antisaccade protocol.</a> Vision Res. 84, 1-5 (2013).</li><li>Ober, J. 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=Hand-Held+system+for+ambulatory+measurement+of+saccadic+durations+of+neurological+patients.+.">Hand-Held system for ambulatory measurement of saccadic durations of neurological patients. .</a> Modelling and Measurement in Medicine. , (2003).</li><li>Temperli, P., 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=How+do+parkinsonian+signs+return+after+discontinuation+of+subthalamic+DBS.">How do parkinsonian signs return after discontinuation of subthalamic DBS.</a> Neurology. 60, 78-81 (2003).</li><li>Antoniades, C. 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=Deep+brain+stimulation:+eye+movements+reveal+anomalous+effects+of+electrode+placement+and+stimulation.">Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation.</a> PLoS ONE. 7, e32830 (2012).</li><li>Yugeta, 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=Effects+of+STN+stimulation+on+the+initiation+and+inhibition+of+saccade+in+Parkinson+disease.">Effects of STN stimulation on the initiation and inhibition of saccade in Parkinson disease.</a> Neurology. 74, 743-748 (2010).</li><li>Terao, Y., Fukuda, H., Ugawa, Y., Hikosaka, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+perspectives+on+the+pathophysiology+of+Parkinson's+disease+as+assessed+by+saccade+performance:+a+clinical+review.">New perspectives on the pathophysiology of Parkinson's disease as assessed by saccade performance: a clinical review.</a> Clin Neurophysiol. 124, 1491-1506 (2013).</li><li>Temel, Y., Visser-Vandewalle, V., Carpenter, R. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Saccadic+latency+during+electrical+stimulation+of+the+human+subthalamic+nucleus.">Saccadic latency during electrical stimulation of the human subthalamic nucleus.</a> Curr Biol. 18, 412-414 (2008).</li><li>Antoniades, C. 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=Deep+brain+stimulation+abolishes+slowing+of+reactions+to+unlikely+stimuli.">Deep brain stimulation abolishes slowing of reactions to unlikely stimuli.</a> J Neurosci. 34, 10844-10852 (2014).</li><li>Rivaud-Pechoux, 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=Improvement+of+memory+guided+saccades+in+parkinsonian+patients+by+high+frequency+subthalamic+nucleus+stimulation.">Improvement of memory guided saccades in parkinsonian patients by high frequency subthalamic nucleus stimulation.</a> J Neurol Neurosurg Psychiatry. 68, 381-384 (2000).</li><li>Takikawa, Y., Kawagoe, R., Itoh, H., Nakahara, H., Hikosaka, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modulation+of+saccadic+eye+movements+by+predicted+reward+outcome.">Modulation of saccadic eye movements by predicted reward outcome.</a> Experimental brain research. Experimentelle Hirnforschung. 142, 284-291 (2002).</li><li>Dorris, M. C., Munoz, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+neural+correlate+for+the+gap+effect+on+saccadic+reaction+times+in+monkey.">A neural correlate for the gap effect on saccadic reaction times in monkey.</a> Journal of Neurophysiology. 73, 2558-2562 (1995).</li><li>Hanes, D. P., Schall, J. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Countermanding+saccades+in+macaque.">Countermanding saccades in macaque.</a> Visual Neuroscience. 12, 929-937 (1995).</li><li>Opris, I., Barborica, A., Ferrera, V. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=On+the+gap+effect+for+saccades+evoked+by+electrical+microstimulation+of+frontal+eye+fields+in+monkeys.">On the gap effect for saccades evoked by electrical microstimulation of frontal eye fields in monkeys.</a> Experimental brain research. Experimentelle Hirnforschung. 138, 1-7 (2001).</li><li>Takagi, M., Frohman, E. M., Zee, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gap-overlap+effects+on+latencies+of+saccades,+vergence+and+combined+vergence-saccades+in+humans.">Gap-overlap effects on latencies of saccades, vergence and combined vergence-saccades in humans.</a> Vision Res. 35, 3373-3388 (1995).</li><li>Schall, J. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neuronal+activity+related+to+visually+guided+saccades+in+the+frontal+eye+fields+of+rhesus+monkeys:+comparison+with+supplementary+eye+fields.">Neuronal activity related to visually guided saccades in the frontal eye fields of rhesus monkeys: comparison with supplementary eye fields.</a> Journal of Neurophysiology. 66, 559-579 (1991).</li><li>Pare, M., Hanes, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Controlled+movement+processing:+superior+colliculus+activity+associated+with+countermanded+saccades.">Controlled movement processing: superior colliculus activity associated with countermanded saccades.</a> J Neurosci. 23, 6480-6489 (2003).</li></ol>

The most critical factor in obtaining good quality saccadic data is ensuring that the instructions given to the participant are clear and precise. For example, if the instructions for the antisaccadic task are not completely clear, the participant is likely to execute prosaccades instead. Recordings may also be spoiled if the participant cannot clearly see the stimuli or the saccadometer cannot accurately gauge eye position. Thus if the data appear to be of low quality the experimenter should check that the ambient light...

In recent years there has been increasing interest in the use of measurements of reaction times as a quantitative and non-invasive way of gaining information about the high level mechanisms of neural decision making 1. One type of reaction time that has been studied extensively is the time taken to initiate a saccade on presentation of a visual stimulus, known as saccadic latency. Saccades are the fast eye movements that occur when we rapidly shift our gaze from one place to another. They are the commonest type of eye movements we make, occurring at a frequency of typically two or three per second. Each saccade is in effect a decision to look at one cue in the visual world rather than another 2.
The neural pathways controlling eye movements have been studied extensively and are fairly well documented 3. Using sensitive electronic equipment, aspects of oculomotor function can be precisely and objectively quantified. This facilitates the detailed study of eye movements themselves but also allows them to be used as a tool to investigate other areas of neurophysiology and pathophysiology.
Eye movement measurement can provide useful information about disease states. Saccadic eye movements have recently, for example, received much attention as potential biomarkers in neurodegenerative disorders including Huntington&#39;s 4,5 and Parkinson&#39;s diseases 6,7, and it is well established that saccadic reaction times tend to be slower than normal in these conditions. Potential uses of saccadic measurement include aids to diagnosis and disease tracking. Saccadic tasks range from the simple prosaccade (looking as quickly as possible toward a suddenly appearing visual stimulus to left or right) to more complex tasks such as the antisaccade (looking as quickly as possible to the opposite side to a visual stimulus) or memory-guided saccade (looking towards the remembered location of a target that is no longer there).
Deep brain stimulation is an effective treatment for several neurological conditions. It is most commonly used to treat the motor symptoms of Parkinson&#39;s disease including tremor, rigidity, bradykinesia, and dyskinesia. It is also used for other movement disorders including dystonia and essential tremor, and less commonly for neuropathic pain, epilepsy, and psychiatric conditions such as obsessive compulsive disorder. It is the only setting in which scientists have direct electrical access to deep structures of the human brain in vivo and thus offers a precious opportunity for experimental neurology. A variety of targets are stimulated depending on the condition being treated, including several locations in the basal ganglia, many of which are involved in oculomotor pathways. This means that a wide range of studies can be conducted using the DBS system to deliver stimulation to a given brain location and an eye tracking device to record and analyze its effects. Depending on the experimental paradigm, such studies may yield information about the physiology of the region being stimulated, the effects of the disease, or the mechanism by which DBS is working in that particular setting. This article describes a general approach to saccadic eye movement testing in Deep Brain Stimulation patients.
Several different types of eye tracking equipment are available. For the research described in this protocol a portable saccadometer was used to record horizontal saccadic eye movements. Portable saccadometers have the advantage of not requiring head restraint (see Figure 1), which means that sessions are more comfortable for patients with Parkinson&#39;s disease, especially for those suffering with severe dyskinesias. The saccadometer used here is lightweight and approximately 5 cm wide and 10 cm tall. The saccadometer measures eye movements by the use of direct infrared oculography: an infra-red source and sensor positioned in front of the medial canthus use light reflected from the cornea to establish the rotational position of the eyeball at millisecond intervals. In order to acquire good quality data for analysis the saccadometer should sample at a rate of at least 1 kHz with at least a 12 bit resolution. In the saccadometer used here the visual stimuli were three red 13 cd m-2 spots of light produced by built in low power lasers, each spot subtending some 0.1 degrees, with one spot in the midline and the other two at &#177; 10 degrees (i.e., to the right and left).
<img alt="Figure 1" src="/files/ftp_upload/53640/53640fig1.jpg" /> 
Figure 1. The Saccadometer.&#160; Head mounted saccadometer attached to an elastic band and resting on the bridge of the nose. Four miniature lasers project visual targets on to a matte surface, and the participant&#39;s eye movements are measured by differential infrared reflectance transducers on the nasal side of each eye. As the laser targets move with the head, head restraints are not required. <a href="https://www.jove.com/files/ftp_upload/53640/53640fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<table border="0" cellpadding="0" cellspacing="0" width="88">
	<tbody>
		<tr>
			<td>Saccadometer device ( Ober Consulting Poland)</td>
		</tr>
		<tr>
			<td>Computer with Windows environment</td>
		</tr>
		<tr>
			<td>Software, Latency Meter for downloading the raw data from the saccadometer.</td>
		</tr>
	</tbody>
</table>

using saccadometry with deep brain stimulation to study normal and pathological brain function

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including Parkinson's and Huntington's can disrupt it. People with Parkinson's disease, for example, tend to have increased saccadic latencies. Consequently, the quantitative measurement of saccadic eye movements has received considerable attention as a potential biomarker for neurodegenerative conditions. A lot more can be learned about the brain in both health and disease by observing what happens to eye movements when the function of specific brain areas is perturbed. Deep brain stimulation is a surgical intervention used for the management of a range of neurological conditions including Parkinson's disease, in which stimulating electrodes are placed in specific brain areas including several sites in the basal ganglia. Eye movement measurements can then be made with the stimulator systems both off and on and the results compared. With suitable experimental design, this approach can be used to study the pathophysiology of the disease being treated, the mechanism by which DBS exerts it beneficial effects, and even aspects of normal neurophysiology.

Figure 3 shows an example of saccadic eye movement trajectories, from a Parkinson&#39;s disease patient with a subthalamic nucleus DBS system implanted. The two graphs plot the patient&#39;s prosaccades with the stimulator system switched off (upper graph) and switched on (lower graph). Each trace on the graphs shows the trajectory of a single saccade, i.e., how the eye position in degrees away from the midline (y axis) varies as a function of time (x axis). Both...

Watch this Scientific Journal Video about Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function at JoVE.com

Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function

This paper describes the use of quantitative measurement of eye movements in conjunction with stimulation of focal areas of the deep brain in order to study physiology, pathophysiology, and the mechanisms of deep brain stimulation.

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including ...

The overall goal of this procedure is to measure the effects of deep brain stimulation on saccadic eye movements. The combination of deep brain stimulation with saccade measurement provides a tool to study normal and pathological brain function. This method can help answer key questions about the pathophysiology of diseases relating to the basal ganglia.The main advantage of this technique is that it is quantitative and precise, allowing for the accurate detection of subtle abnormalities. These are some of the types of stimulator implants used in deep brain stimulation. They contain a battery and electronics to generate a small electrical stimulus.The stimulus pulses are delivered to precise target locations in the brain using contacts on the end of a wire like this one. Begin by explaining the details of the study and providing the participant with a consent form to sign. Set up the saccadometer so that for each trial the central fixation target is displayed for a random period of 1.0 to 2.0 seconds, after which it is extinguished, and one of the peripheral red targets appears randomly to the right or left.Next, ask the participant to sit 1.5 meters away from a flat matte screen. Place the saccadometer on the participant's head so that it rests on the bridge of the nose and secure with an elastic adjustable strap. Ensure that the ambient lighting is dim so that the stimuli are clearly seen.Then, instruct the participant that the 40 minute testing session consists of five blocks with a one minute break between each block. Prior to the first block, instruct the participant to move their eyes as quickly and accurately as possible in order to follow the red dot jumping from the middle to one side or the other. Explain that they must do this 60 times.Set the saccadometer to generate a sequence of 60 trials, then press the button on the device to start the first block of trials. After the completion of the first block wait one minute before starting the second block. Reset the saccadometer to generate a sequence of 40 trials.Towards the end of the one minute gap, instruct the participant to move their eyes as quickly as possible in the opposite direction of the red dot. Inform them that they will be required to do this 40 times. Then, start the second block of trials.After completion of the second block, wait one minute, then repeat the instructions from the second block two more times for blocks three and four. Finally, after completing the fourth block, wait one minute, then instruct the participants to move their eyes as quickly and accurately as possible to follow the red dot jumping from the middle to one side to the other, exactly as they did in the first block. Reset the saccadometer to generate a sequence of 60 trials and start the final block of trials.Note for participants with deep brain stimulators, or DBS systems, conduct saccadic testing two times. Once with the DBS system running as normal, and a second time with the DBS system turned off. To conduct the off stimulation session, have a trained clinical staff switch off the DBS system 30 minutes prior to testing.Then, complete saccadic testing. Once the session is complete, switch the DBS system back on. To analyze the data, download the raw data from the saccadometer to a computer.Next, use the saccadometer's software program to exclude saccades that are distorted by blinks and head movements. Calculate variables including saccadic latencies, peak velocities, and amplitudes. Here, prosaccadic latency results are shown for a Parkinson's patient after undergoing DBS of the subthalamic nucleus when the DBS is turned on and off.The distribution of saccades is altered when the stimulator is switched on, showing a reduction in the number of long latency saccades, and a corresponding decrease in the mean latency. Once mastered, this technique can be done in about 70 minutes if it is performed properly. While attempting this procedure, it is important to remember to ensure that the saccadometer is sitting centrally on the bridge of the nose and the room lights are dim.Following this procedure, more advanced saccadic tasks can be used in order to answer additional questions, like how the cognitive control of eye movements is affected by deep brain stimulation. After watching this video, you should have a good understanding of how to use psychodometry in subjects with deep brain stimulator systems. Don't forget that working with lasers can be hazardous, and you should take care to ensure that both the participants and the experimentor don't look directly into the laser beams.

Research

JoVE Journal

Medicine

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through ...

Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform ...

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a ...

Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly

Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are ...

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As ...

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Continuous IV Infusion is the Choice Treatment Route for Arginine-vasopressin Receptor Blocker Conivaptan in Mice to Study Stroke-evoked Brain Edema

Stroke is one of the major causes of morbidity and mortality in the world. Stroke is complicated by brain edema and other pathophysiological events. Among ...

Symmetric Bihemispheric Postmortem Brain Cutting to Study Healthy and Pathological Brain Conditions in Humans

Neuropathologists, at times, feel intimidated by the amount of knowledge needed to generate definitive diagnoses for complex neuropsychiatric phenomena ...

Updated Technique for Reliable, Easy, and Tolerated Transcranial Electrical Stimulation Including Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of ...