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 point on the consent form and giving them the opportunity to ask any questions they might have. Ask the participant to complete the form.</li>
</ol>
2. Setting up the Saccadometer
<ol>
	<li>Place the device on the patient&#39;s head, secured by an adjustable elastic strap and resting on the bridge of the nose. Because the stimuli move exactly with the head, no head-restraint is necessary and the device is comfortable to wear.</li>
	<li>Ask the patient to sit at 1.5 m from a flat matte screen.</li>
	<li>Ensure that the ambient lighting is dim so that the stimuli (red light spots) are clearly seen.</li>
</ol>
3. Recording a Saccadic Session
Note: As an example a standard protocol that tests both prosaccades and antisaccades 8 is described here. This protocol consists of five blocks: 60 prosaccades, 40 antisaccades x 3, and 60 prosaccades with a break of 1 min between blocks. The session lasts about 40 min.
<ol>
	<li>Set up the saccadometer so that for each trial the central fixation target is displayed for a random fore-period of 1.0 - 2.0 sec, after which it is extinguished and one of the peripheral targets appears, randomly to right or left 9. 
	Note: The three targets are spots of red light projected onto the screen in front of the participant (see 2.2) by low powered lasers built into the saccadometer. The saccadometer automatically switches the lasers on and off to display/extinguish the targets in the necessary sequence.</li>
	<li>Instruct the participant that the testing consists of five blocks with a one minute break between blocks.</li>
	<li>Prior to the first block instruct the participant to move their eyes as quickly and accurately as possible to follow the red dot jumping from the middle to one side or the other and instruct them to do this 60 times.</li>
	<li>Set the saccadometer to generate a sequence of 60 trials. Press the button on the saccadometer to start the first block of trials (prosaccades).</li>
	<li>After completion of the first block, leave a one minute gap before the second block. Reset the saccadometer to generate a sequence of 40 trials, and towards the end of the one minute gap, instruct the participant for the next block to move their eyes as quickly as possible in the opposite direction to the red dot, and explain that they will be required to do this 40 times. Start the second block of trials (antisaccades).</li>
	<li>After completion of the second block, leave a further 1 min gap, repeat the instruction in step 3.5 and start the third block of trials (antisaccades).</li>
	<li>After completion of the third block, leave a further 1 min gap, repeat the instruction in step 3.5 and start the fourth block of trials (antisaccades).</li>
	<li>After completion of the fourth block, leave a further 1 min gap, and explain that for the final block of tests ask the participants to move their eyes as quickly and accurately as possible to follow the red dot jumping from the middle to one side or the other, exactly as they did in the first block.</li>
	<li>Reset the saccadometer to generate a sequence of 60 trials, and start the final block of trials (prosaccades).</li>
</ol>
<img alt="Figure 2" src="/files/ftp_upload/53640/53640fig2.jpg" /> 
Figure 2. Eye Movement Tasks. Schematic illustration showing two examples of saccadic tasks. The solid blue spot represents the target and the dotted blue circle represents the area of fixation. LEFT shows a prosaccadic task where the subject is prompted to look towards the target. RIGHT shows an antisaccade where the subject is asked to look away from the visual stimulus. This requires inhibition of the more natural prosaccade response and generation of a saccade in the opposite direction. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53640/53640fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
4. Deep Brain Stimulator Settings
Note: For participants with deep brain stimulators conduct the testing so far with stimulator system running as normal, i.e., an &#39;on stimulation&#39; dataset has been obtained. Testing now needs to be repeated with the stimulator system turned off (for healthy control participants without DBS systems this section will not apply).
<ol>
	<li>Switch the DBS system off. Do this by a trained clinical staff. Allow 30 min before testing.</li>
	<li>Repeat the saccadic testing (steps 3.2 - 3.9) to obtain a complete &#39;off stimulation&#39; dataset.</li>
	<li>Switch the DBS system back on (again this should be done by appropriately trained clinical staff).</li>
</ol>
5. Data Analysis
Note: For participants with deep brain stimulators conduct the testing so far with stimulator system running as normal, i.e., an &#39;on stimulation&#39; dataset has been obtained. Testing now needs to be repeated with the stimulator system turned off (for healthy control participants without DBS systems this section will not apply).
<ol>
	<li>Download the raw data from the saccadometer to a computer for analysis.</li>
	<li>Use the saccadometer&#39;s software program to exclude saccades distorted by blinks and head movements, and to calculate variables including saccadic latencies, peak velocities, and amplitudes. 
	Note: Records contaminated by excessive head movements or blinks are automatically removed by the software.
	<ol>
		<li>Remove saccades with latency less than 80 msec or greater than 1,000 msec. 
		Note: Saccadic latency is computed automatically using a saccade-detection algorithm based on velocity and acceleration. The onset of a saccade is identified as the point when the eye velocity exceeds a threshold of 5 degrees/sec.</li>
	</ol>
	</li>
</ol>

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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. 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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 authors have nothing to disclose.

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 is not too bright and that the saccadometer is sitting properly on the bridge of the nose.
Deep brain stimulation allows the direct modification of neural activity at a various locations in the basal ganglia. Coupled with equipment that can accurately and objectively quantify eye movements, DBS can be used to investigate the normal and abnormal functioning of these brain areas.
Experiments using saccadometry in conjunction with DBS must often contend with more than one unknown simultaneously. The brains under study are diseased to a variable extent, and we do not know for certain the mechanism by which DBS is achieving its effects, with hypotheses including activation of neurons in the targeted area, depolarizing blockade of neurons, stimulation of afferent and/or efferent axons, and more complex effects on network activity.
Subjects with neurodegenerative conditions are frequently on medication and this will be nearly universal for patients with PD patients who have DBS systems. Saccades are affected by antiparkinsonian medication, and in order to make a valid assessment of the effects of DBS on saccadic parameters, medication state must be similar when testing with DBS on and DBS off. This means either having the subject off all medication for the duration of testing (including a withdrawal period beforehand), or else conducting on-DBS and off-DBS tests within a reasonably short period of time. It has been shown that the complete wearing off of the effects of DBS on saccades takes several hours but that most of the change takes place within 30 min 10. The time course suggests multiple mechanisms with different time courses, from very fast (electrical effects) to much more prolonged (e.g., protein synthesis). The 30 min suggested in the protocol will therefore capture most of the DBS induced change, and is much shorter than the typical dosing interval of several hours. It does not give adequate time for the slower mechanisms to settle to steady state, and retesting at longer intervals may be useful in providing insight into these mechanisms. With longer gaps one could not assume that medication levels while testing on and off DBS were approximately similar, thus longer intervals are likely to be easier to interpret when testing off medication.
Most of the literature on the effects of DBS on eye movements has focused on high frequency stimulation of the subthalamic nucleus in PD. Prosaccadic latency is prolonged in PD and it is well established that STN DBS can substantially reduce it toward normal values (exactly how remains open to debate). However when saccadometry is performed in the early postoperative period, within hours to days of lead insertion and before electrical stimulation is switched on, it is found that latencies are actually increased 11. Electrode insertion causes edema and this will lead to temporary functional ablation of the brain immediately surrounding the electrode; this settles within a few weeks and saccadic parameters return to baseline (stimulators are commonly not turned on until a few weeks postoperatively to allow this time to settle). The oppositeness of the effects of electrode insertion and stimulation is of considerable interest, because it illustrates that one of the theories previously advanced to explain how DBS is working, by blockade of the stimulated structure (i.e., functional ablation), cannot comprehensively explain its mechanism of action. Other studies have found similar effects 12-14.
It is possible to construct experiments combining DBS and saccadometry to investigate normal physiology. Great care must be taken with experimental design and interpretation of results, because the experimental subject necessarily has some neurological condition. One approach is to compare the results of saccadic testing with DBS off and on to results from healthy control participants without DBS. If the results in DBS subjects with their stimulators turned off resemble those in controls, then it is reasonable to proceed on the basis that changes in the eye movements seen in response to DBS are likely to be similar to those which would be seen if the experiment could be done in participants without disease. For example, the performance in a prosaccade task which has been set up so that the visual stimulus is more likely to appear on one side than the other, is similar for healthy participants and PD patients with STN DBS systems in place but turned off. Latencies shorten for saccades in the direction where the target is more likely to appear, and lengthen in the less likely direction. When the systems are turned on, the lengthening of latency in the less likely direction disappears, and the interpretation was that the STN is performing a probability normalization function 15. The patients in this study had PD, but that was not directly relevant to the result. Of course this is a significant assumption and it is possible that the disease modulates the response to DBS even though it did not affect the baseline performance. Furthermore, the similarity of off-DBS and control data may be the result of compensatory mechanisms rather than a lack of effect of pathology on the parameters being measured. Results must be interpreted with this in mind.
Once the basic techniques described in the protocol have been mastered the approach can be extended to more complex paradigms. Many different saccadic tasks have been developed of which the probability based task described in the previous paragraph is just one. Further examples include memory guided saccades 16 (looking towards the remembered location of a stimulus that is no longer there) or reward-based saccadic tasks designed to invoke limbic function 17.
Here we have described one of the simplest saccadic tasks, a 10-degree visually guided horizontal step task. Many modifications of the task are possible such as inserting a temporal gap between fixation point disappearance and peripheral target appearance 18-20 or an overlap 21 where fixation point and lateral target are present simultaneously. Paradigms of this sort have been used in order to understand saccadic initiation and neural correlates have been observed in the frontal eye fields 20,22 and the superior colliculus 23. A detailed discussion of the various uses of different saccadic paradigms is beyond the scope of this article; for a review see 1.
Saccadometry has wide application outside its use in DBS. Saccadic pathways involve multiple parts of the basal ganglia and saccadic changes are a potential biomarker for any condition that damages or perturbs the function of these structures. Saccadometry has for example been investigated for use in neurodegenerative conditions including PD, Huntington&#39;s disease, frontotemporal dementia, amyotrophic lateral sclerosis as well as in head injury and in metabolic disorders including hepatic encephalopathy.
In conclusion, saccadometry is a useful quantitative tool by itself, but combining it with deep brain stimulation opens up a range of experimental approaches that may shed new light on brain function in both health and disease.

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.remotexs.ntu.edu.sg/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 leftward and rightward saccades are shown on the graph as deflections to positive degree values. Time zero is the moment that the central target disappears and the peripheral target appears. The interval between this and the onset of the saccade (the moment when the trace deflects from zero degrees) is termed saccadic latency, and the main observation is that the distribution of saccades is altered when the stimulator is switched on, with a reduction in the number of long latency saccades and a corresponding decrease in mean latency.
<img alt="Figure 3" src="/files/ftp_upload/53640/53640fig3.jpg" /> 
Figure 3. Prosaccadic Trajectory Results. This shows the saccadic eye movement latency results from a Parkinson&#39;s patient after undergoing Deep Brain Stimulation of the subthalamic nucleus. UPPER shows the latency profile of the patient when the stimulator is switched off LOWER shows the latency profile of the same patient when the stimulator is switched on. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53640/53640fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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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 ...

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Nanyang Technological University

Research

JoVE Journal

Medicine

7.4K Views.  The University of Oxford. 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.

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

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 implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor 1. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials 2. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. 
DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation 3. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity 4,5. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain. This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.

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

Eye Tracking Young Children with Autism

The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a direct, detailed and objective measure of gaze behavior, eye-tracking has become a valuable tool for examining abnormal perceptual strategies in clinical populations and has been used to identify disorder-specific characteristics1, promote early identification2, and inform treatment3. In particular, investigators of autism spectrum disorders (ASD) have benefited from integrating eye-tracking into their research paradigms4-7. Eye-tracking has largely been used in these studies to reveal mechanisms underlying impaired task performance8 and abnormal brain functioning9, particularly during the processing of social information1,10-11. While older children and adults with ASD comprise the preponderance of research in this area, eye-tracking may be especially useful for studying young children with the disorder as it offers a non-invasive tool for assessing and quantifying early-emerging developmental abnormalities2,12-13. Implementing eye-tracking with young children with ASD, however, is associated with a number of unique challenges, including issues with compliant behavior resulting from specific task demands and disorder-related psychosocial considerations. In this protocol, we detail methodological considerations for optimizing research design, data acquisition and psychometric analysis while eye-tracking young children with ASD. The provided recommendations are also designed to be more broadly applicable for eye-tracking children with other developmental disabilities. By offering guidelines for best practices in these areas based upon lessons derived from our own work, we hope to help other investigators make sound research design and analysis choices while avoiding common pitfalls that can compromise data acquisition while eye-tracking young children with ASD or other developmental difficulties.

Eye tracking has long been used to study gaze patterns in typically-developing individuals, but recent technological advancements have made its use with clinical populations, including autism, more feasible. While eye-tracking young children with autism can offer insight into early symptom manifestations, it involves methodological challenges. Suggestions for best practices are provided.

The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a ...

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 PrPSc 1. PrPC is detergent-soluble and sensitive to proteinase K (PK)-digestion, whereas PrPSc forms detergent-insoluble aggregates and is partially resistant to PK2-6. The conversion of PrPC to PrPSc is known to involve a conformational transition of &alpha;-helical to &beta;-sheet structures of the protein. However, the in vivo pathway is still poorly understood. A tentative endogenous PrPSc, intermediate PrP* or "silent prion", has yet to be identified in the uninfected brain7.
Using a combination of biophysical and biochemical approaches, we identified insoluble PrPC aggregates (designated iPrPC) from uninfected mammalian brains and cultured neuronal cells8, 9. Here, we describe detailed procedures of these methods, including ultracentrifugation in detergent buffer, sucrose step gradient sedimentation, size exclusion chromatography, iPrP enrichment by gene 5 protein (g5p) that specifically bind to structurally altered PrP forms10, and PK-treatment. The combination of these approaches isolates not only insoluble PrPSc and PrPC aggregates but also soluble PrPC oligomers from the normal human brain. Since the protocols described here have been used to isolate both PrPSc from infected brains and iPrPC from uninfected brains, they provide us with an opportunity to compare differences in physicochemical features, neurotoxicity, and infectivity between the two isoforms. Such a study will greatly improve our understanding of the infectious proteinaceous pathogens. The physiology and pathophysiology of iPrPC are unclear at present. Notably, in a newly-identified human prion disease termed variably protease-sensitive prionopathy, we found a new PrPSc that shares the immunoreactive behavior and fragmentation with iPrPC 11, 12. Moreover, we recently demonstrated that iPrPC is the main species that interacts with amyloid-&beta; protein in Alzheimer disease13. In the same study, these methods were used to isolate Abeta aggregates and oligomers in Alzheimer's disease13, suggesting their application to non-prion protein aggregates involved in other neurodegenerative disorders.

A new species of cellular prion protein (PrPC) has recently been identified in uninfected human brains using the methods described here. These methods can be used to isolate various PrP species, while some of them are also useful in isolating other misfolded protein aggregates from human brains.

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

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue.
Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules.
Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed.
Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 &mu;m from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads 5-7. In addition, the ICW provides many challenges when optimizing the imaging.

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

We describe a novel in vivo imaging technique that couples fluorescent chimeric mice with intracranial windows and high-resolution 2-photon microscopy. This imaging platform aids studies of dynamic changes in brain tissue and microvasculature, at a single-cell level, following pathological insults and is adaptable to assess intracranial drug delivery and distribution.

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 exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests1,2. However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs.
LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors.
While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures.

Lesion Explorer (LE) is a semi-automatic, image-processing pipeline developed to obtain regional brain tissue and subcortical hyperintensity lesion volumetrics from structural MRI of Alzheimer's disease and normal elderly. To ensure a high level of accuracy and reliability, the following is a video-guided, standardized protocol for LE's manual procedures.

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

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As such, primary or &#39;neuronal-like&#39; cell culture systems are commonly utilized. While&#160;these systems are relatively easy to work with, and are useful model systems in which various functional outcomes (such as cell death) can be readily quantified, the examined outcomes and pathways in cultured immature neurons (such as excitotoxicity-mediated cell death pathways) are not necessarily the same as those observed in mature brain, or in intact tissue. Therefore, there is the need to develop models in which cellular mechanisms in mature neural tissue can be examined. We have developed an in vitro technique that can be used to investigate a variety of molecular pathways in intact nervous tissue. The technique described herein utilizes rat cortical tissue, but this technique can be adapted to use tissue from a variety of species (such as mouse, rabbit, guinea pig, and chicken) or brain regions (for example, hippocampus, striatum, etc.). Additionally, a variety of stimulations/treatments can be used (for example, excitotoxic, administration of inhibitors, etc.). In conclusion, the brain slice model described herein can be used to examine a variety of molecular mechanisms involved in excitotoxicity-mediated brain injury.

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

We have developed a brain slice model which can be used to examine molecular mechanisms involved in excitotoxicity-mediated brain injury.&#160;This technique generates viable mature brain tissue and reduces animal numbers required for experimentation, whilst keeping the neuronal circuitry, cellular interactions, and postsynaptic compartments partly intact.

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 according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson&#39;s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.
Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson&#39;s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.

Adaptive deep brain stimulation (aDBS) is effective for Parkinson&#8217;s disease, improving symptoms and reducing power consumption compared to conventional deep brain stimulation (cDBS). In aDBS we track a local field potential biomarker (beta oscillatory amplitude) in real time and use this to control the timing of 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 over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

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 the most important players in the development and evolution of stroke-evoked brain edema is the hormone arginine-vasopressin and its receptors, V1a and V2. Recently, the V1a and V2 receptor blocker conivaptan has been attracting attention as a potential drug to reduce brain edema after stroke. However, animal models which involve conivaptan applications in stroke research need to be modified based on feasible routes of administration. Here the outcomes of 48 hr continuous intravenous (IV) are compared with intraperitoneal (IP) conivaptan treatments after experimental stroke in mice. We developed a protocol in which middle cerebral artery occlusion was combined with catheter installation into the jugular vein for IV treatment of conivaptan (0.2 mg) or vehicle. Different cohorts of animals were treated with 0.2 mg bolus of conivaptan or vehicle IP daily. Experimental stroke-evoked brain edema was evaluated in mice after continuous IV and IP treatments. Comparison of the results revealed that the continuous IV administration of conivaptan alleviates post-ischemic brain edema in mice, unlike the IP administration of conivaptan. We conclude that our model can be used for future studies of conivaptan applications in the context of stroke and brain edema.

Our studies have revealed that the beneficial effects of conivaptan are dependent on the method of delivery after experimental stroke in mice. We have developed a research protocol for delivery of the receptor blocker via IV catheter on stroke-evoked brain edema formation in mice.

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 described in those patients for whom a brain autopsy has been requested. Although the advancements of biomedical sciences and neuroimaging have revolutionized the neuropsychiatric field, they have also generated the misleading idea that brain autopsies have only a confirmatory value. This false idea created a drastic reduction of autopsy rates and, consequently, a reduced possibility to perform more detailed and extensive neuropathological investigations, which are necessary to comprehend numerous normal and pathological aspects yet unknown of the human brain. The traditional inferential method of correlation between observed neuropsychiatric phenomena and corresponding localization/characterization of their possible neurohistological correlates continues to have an undeniable value. In the context of neuropsychiatric diseases, the traditional clinicopathological method is still the best possible methodology (and often the only available) to link unique neuropsychiatric features to their corresponding neuropathological substrates, since it relies specifically upon the direct physical assessment of brain tissues. The assessment of postmortem brains is based on brain cutting procedures that vary across different neuropathology centers. Brain cuttings are performed in a relatively extensive and systematic way based on the various clinical and academic contingencies present in each institution. A more anatomically inclusive and symmetric bi-hemispheric brain cutting methodology should at least be used for research purposes in human neuropathology to coherently investigate, in depth, normal and pathological conditions with the peculiarities of the human brain (i.e., hemispheric specialization and lateralization for specific functions). Such a method would provide a more comprehensive collection of neuropathologically well-characterized brains available for current and future biotechnological and neuroimaging techniques. We describe a symmetric bi-hemispheric brain cutting procedure for the investigation of hemispheric differences in human brain pathologies and for use with current as well as future biomolecular/neuroimaging techniques.

Organized brain cutting procedures are necessary to correlate specific neuropsychiatric phenomena with definitive neuropathologic diagnoses. Brain cuttings are performed differently based on various clinico-academic contingencies. This protocol describes a symmetric bihemispheric brain cutting procedure to investigate hemispheric differences in human brain pathologies and to maximize current and future biomolecular/neuroimaging techniques.

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

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

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Chapters in this video

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

Eye Tracking Young Children with Autism

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

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

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

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

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

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

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

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