Parkinsonism and Related Disorders xxx (2014) 1e5
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement George T. Gitchel a, b,1, 2, Paul A. Wetzel b,1, Abu Qutubuddin a, c, d, Mark S. Baron a, d, *,1 a Southeast Parkinson’s Disease Research, Education, and Clinical Center (PADRECC), Hunter-Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA b Virginia Commonwealth University, Department of Biomedical Engineering, Richmond, VA, USA c Virginia Commonwealth University, Department of Physical Medicine and Rehabilitation, Richmond, VA, USA d Virginia Commonwealth University, Department of Neurology, Richmond, VA, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 February 2014 Received in revised form 17 March 2014 Accepted 30 March 2014
Introduction: Our recent report of ocular tremor in Parkinson’s disease (PD) has raised considerable controversy as to the origin of the tremor. Using an infrared based eye tracker and a magnetic head tracker, we reported that ocular tremor was recordable in PD subjects with no apparent head tremor. However, other investigators suggest that the ocular tremor may represent either transmitted appendicular tremor or subclinical head tremor inducing the vestibulo-ocular reflex (VOR). The present study aimed to further investigate the origin of ocular tremor in PD. Methods: Eye movements were recorded in 8 PD subjects both head free, and with full head restraint by means of a head holding device and a dental impression bite plate. Head movements were recorded independently using both a high sensitivity tri-axial accelerometer and a magnetic tracking system, each synchronized to the eye tracker. Results: Ocular tremor was observed in all 8 PD subjects and was not influenced by head free and head fixed conditions. Both magnetic tracking and accelerometer recordings supported that the ocular tremor was fully independent of head position. Conclusion: The present study findings support our initial findings that ocular tremor is a fundamental feature of PD unrelated to head movements. Although the utility of ocular tremor for diagnostic purposes requires validation, current findings in large cohorts of PD subjects suggest its potential as a reliable clinical biomarker. Published by Elsevier Ltd.
Keywords: Ocular tremor Parkinson’s disease Bite plate Oscillopsia Biomarker Eye movements
1. Introduction Duval and Beuter [1] originally noted ocular oscillations (binocular or monocular) among four subjects with PD with their heads moderately restrained. The authors found no correlation between the ocular and appendicular tremor and concluded that the ocular tremor represented primary eye oscillations [1].
* Corresponding author. Southeast Parkinson’s Disease Research, Education, and Clinical Center (PADRECC), Hunter-Holmes McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Room 2C-110, Richmond, VA 23249, USA. E-mail addresses: [email protected], [email protected] (G.T. Gitchel), [email protected] (P.A. Wetzel), [email protected] (A. Qutubuddin), [email protected] (M.S. Baron). 1 Authors contributed equally to this study. 2 George Gitchel responsibility for the integrity of the data and the accuracy of the data analysis.
Although also apparent in published figures in a number of other studies [2e4], all of which utilized some form of head restraint, ocular tremor had otherwise been a largely unrecognized feature of PD. Utilizing comparatively more modern and sensitive eye tracking equipment, we consistently observed binocular tremor in 112 subjects with PD and in 2 of 60 asymptomatic control subjects, both who converted to clinical PD within 3 years of their initial evaluations [5]. In response to our publication, Kaski et al. [6,7] and Leigh and MartinezeConde [8] suggested that the perceived ocular oscillations might represent an oscillatory vestibulo-ocular reflex (VOR) induced by head tremor (either subclinical head tremor or transmitted arm tremor). Using a high resolution magnetic position tracking system in a subset of 62 subjects in our previous study, we however consistently failed to detect head tremor that would result in VOR activation [5]. Kaski et al. suggested that magnetic tracking systems lack sufficient resolution to detect subclinical head
http://dx.doi.org/10.1016/j.parkreldis.2014.03.028 1353-8020/Published by Elsevier Ltd.
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
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G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5
movements, though others have reported their high sensitivity and accuracy, specifically for tremor [9,10]. While scleral search coil systems represent the undisputed gold standard in eye tracking research, magnetic tracking systems utilize identical technology [11,12]. Specifically against the postulate that the ocular oscillations could originate from subclinical head tremor, we never observe similar ocular tremor in subjects with Essential Tremor, [13] a condition in which one could more readily anticipate subclinical head tremors. Negating the possibility that ocular oscillations reflect transmitted appendicular tremor, we, as well as Duval and Beuter [1], found no correlations between the ocular and appendicular tremors. Further, as would be expected, in our large cohort, many patients had no appreciable appendicular tremor [5]. Despite these many arguments in favor of a primary origin for ocular tremor [14], Kaski et al., in particular, maintain that ocular tremor could not originate from primary eye oscillations or it would be seen on fundoscopy and would cause oscillopsia [7]. In order to add objective scientific evidence to the ongoing discussion [7,8,14,15], we elected here to more rigorously investigate the origin of the ocular tremor in PD. 2. Methods Eight patients (mean age 60.4 years, SD 10.1, range: 43e72 years) with medication confirmed PD completed oculomotor recordings and comprised the study population. Subjects were recruited from the Southeast Veterans Affairs Parkinson’s Disease Research, Education, and Clinical Center (PADRECC) at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, VA. Patients with additional neurological disorders, deep brain stimulators, or ophthalmic conditions which either limited the subjects ability to complete the testing, or would introduce additional confounding abnormal features were excluded. Minor cataracts or mild visual acuity loss, for example, were not deemed exclusionary criteria. Also, because dental impressions were used to restrain subjects’ heads, anyone with dentures was excluded. The study was approved by the Institutional Review Board at the Hunter Holmes McGuire VAMC and written informed consent was obtained from all subjects prior to testing. Among the 8 study patients, the average duration of PD symptoms was 4.5 years (SD 4.4, range: 0.75e13 years), with an average Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor score of 13.7 (4.8, range: 8e24), while taking their usual prescribed medication (dopa-equivalent Average: 1020.3 S.D. 400.8). Two subjects were young onset PD (one with a strong family history of PD) and two were akinetic/rigid subtype without appreciable appendicular tremor. One subject was de novo untreated at the time of testing, but subsequently showed a marked beneficial response to levodopa. As per our previous study, horizontal and vertical binocular eye gaze positions were recorded at 500 Hz using a video based eye tracker (EyeLink II, SR Research Ltd). The system incorporates a built in head motion correction by means of tracking external optical landmarks mounted on the stimuli display. Full depth rigid dental impressions of the upper and lower sets of teeth were made for each subject from hard dental wax molded around a 3 mm thick aluminum plate. These individualized bite plates were attached to a locking ball head mount, creating a head holding apparatus which also included a rigid chin cup (See Fig 1). The entire head holding apparatus was securely mounted to an aluminum optical bench (2.0 0.76 m, VERE, New Kensington, PA). The setup was designed to eliminate potential head movement and was well tolerated. Two measures were simultaneously used to assess head stability [16e18]: 1) magnetic tracking, used in our prior study and 2) acceleration, new to the present study. Head position was recorded at 125 Hz with a six degree of freedom magnetic tracking system (trakSTAR, Ascension Technology Corp, Burlington VT), while a tri-axial accelerometer (Freescale Semiconductor, Tempe, AZ, model MMA7260QT, 800 mV/g sensitivity) measured head acceleration, also at 125 Hz. The magnetic sensor was attached to the Eyelink II headband, which in turn, placed it just above the patient’s left temple. The transmitter for the magnetic tracking system was mounted rigidly on a nonferromagnetic platform and attached to the aluminum optical bench, for a total distance of w20 cm from sensor to transmitter. The accelerometer was similarly mounted to the Eyelink II headband, on the opposite side, placing it just above the subject’s right temple. Analog signals from the tri-axial accelerometer and synchronization pulse were sampled by a 14 bit analog to digital converter (USB 6009 Multifunction DAQ, National Instruments, Austin, TX). The sampling process and digital storage were controlled by the host computer through a custom written LabVIEW program (National Instruments, Austin, TX). Two separate magnetic sensors were employed on the head, one rigidly attached to the EyeLink II headband and one taped to the subject’s temple to assess for any movement or slippage between the head and eye tracker headband. Finally, appendicular tremor was measured in two subjects, one with prominent tremor and one akinetic/rigid subject with no outwardly visible tremor, via a magnetic tracking sensor attached to the tip of the
Fig. 1. Head holding apparatus with an example of the rigid dental bite plate used in this study. After sterilization, the wax was softened with a heat gun, and the patient bit down firmly to create impressions. Note the full depth impressions of the entire mandible from incisors to molars. The patient was then asked to bite onto the plate as installed in the apparatus, and once comfortable, the ball joint was tightened, and the chin cup raised to firmly lock the lower jaw in place and ensure a firm bite and fully immobilize the head. index finger on the more affected side. These appendicular tremor assessments were conducted during the eye tracking recordings, with the limb fully at rest on the subject’s lap. The magnetic position sensors, accelerometer, and eye tracker were all synchronized by recording a timing pulse from the parallel output port of the EyeLink II computer at the beginning and end of each measurement trial. The eye tracking setup and target stimuli presentation have been largely described previously [5,13]. Subjects were recorded twice, with and without head restraint. Also, using both direct and indirect fundoscopy, three different observers (one a trained ophthalmologist) examined the fundi and scleral blood vessels of each eye for outwardly visible tremor. Direct fundoscopy was done with a standard or PanOptic ophthalmoscope variably held by the examiner or held rigidly by a metal arm bolted to the optic table with the subject’s head supported in a chin cup and forehead rest. Additionally, a prosthetic eye was used to approximate the threshold required to visualize simulated ocular tremor in a more idealized setting. To achieve this, the prosthetic eye was attached to the stalk of a mirror galvanometer motor and driven at various amplitudes and frequencies, while the imitation corneal vessels were examined using a restrained fundoscope with a corneal viewing magnification lens (see Fig 2). To further address the sensitivity and accuracy of magnetic tracking devices, a separate methodological experiment was performed with the trakSTAR system. One
Fig. 2. Setup used to assess the threshold for observing simulated ocular tremor in an idealized setting. An artificial eye was attached to the stalk of a mirror galvanometer motor and driven at various amplitudes and frequencies similar to the observed behavior in PD patients. The ophthalmoscope with a corneal viewing magnification lens was positioned as closely as possible, set to maximum magnification, and was locked in place. The setup was designed to removal all movements except for that of the eye. Inset demonstrates the quality of the artificial eye and vessels.
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5 sensor was mounted to an optical post attached to a micrometer-driven XYZ translating stage (Thorlabs, pair of PT1A, and a single MVS005). The sensor and translating stage combination, along with the transmitter for the magnetic tracking system, were bolted to the aluminum optical bench to obviate potential noise or vibration. Each axis was adjusted independently by means of the micrometer and the resultant change in position reported by the trakSTAR was observed in real time. Separately, the sensor was also attached to a micrometer driven rotational stage (Thorlabs, PR01), and the rotational attitude was observed in real time as the micrometer was adjusted. Eye movement data were analyzed off line using an interactive custom written plotting program (P.A.W). Fixations were analyzed for duration, spectral frequency content, and stability parameters. All statistical analysis was conducted using SPSS Statistics 17.0. Power spectral analyses were completed in MATLAB. For statistical analyses, a was set to 0.05.
3. Results With unrestrained heads, all 8 subjects exhibited constant ocular tremor during fixations, consistent with our prior report [5]. No correlation was found between eye and head movements (strongest correlation R2: 0.140, p: 0.203). Power spectral analysis showed an average ocular tremor frequency of 7.1 3.1 Hz and an average head movement (accelerometer) frequency of 1.1 1.8 Hz. This slower head movement frequency is expected in unrestrained subjects due to slow natural drifts of the head. With the head restrained, in every subject, ocular tremor continued to be constantly observed during fixations. Both
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magnetic tracking and accelerometer outputs consistently showed a complete (three dimensional) lack of head movement, confirmed by power spectral analyses of accelerometer and magnetic tracker data showing fundamental frequencies approaching zero. Ocular tremor was observed at an average fundamental frequency of 6.5 Hz (S.D. 1.5 Hz), whereas head movement frequency analysis showed an average fundamental frequency of 0.12 Hz (S.D. 0.23 Hz). The frequency of the ocular tremor during head restraint did not differ statistically from that recorded during head free tracking (p ¼ 0.852). The magnetic tracking device affirmed an absence of slippage between the head and headband of the eye tracker. Eye and head movements continued to show no correlations (strongest correlation R2: 0.117, p: 0.193). Additionally, during head restraint, all subjects had maximal head accelerations of less than 0.025 g, well below the minimum threshold of 0.04 g required for VOR activation [19]. Fig. 3 shows a representative trace of eye and head movement recordings during head restraint. Data derived from individual study subjects during restraint is presented in Table 1. All subjects tolerated the bite plate well and had no complaints of discomfort. In the methodological experiment, the trakSTAR proved to be reliable in repeatedly detecting translation of the sensor in movements as small as 0.177 mm (0.007 inches) in each axis independently. Additionally, it was capable of repeatedly detecting rotation of the sensor in increments as small as 1.5 arc minutes (0.025 ).
Fig. 3. Illustrative monocular and head traces recorded from the same PD subject. A) Head free condition, and B) with head restrained in bite plate. The red horizontal dotted lines at 0.04 g indicate the minimum acceleration required to induce the vestibulo-ocular reflex (VOR) [19]. The accelerometer traces are both within the realm of noise, equivalent to recordings from the accelerometer when rigidly attached to an optical bench. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
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G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5
Table 1 Experimental data during head restraint. Subject
1 2 3 4 5 6 7 8
Power spectra fundamental (Hz) Eye
Head
8.7 7.6 7.1 4.3 5.0 5.3 7.5 6.7
0.10 0.03 0.05 0.03 0.03 0.70 0.03 0.01
Maximum head acceleration (g)a
0.012 0.024 0.020 0.022 0.023 0.025 0.020 0.025
Eye-head correlation R2
Significance (p)
0.08 0.11 0.08 0.05 0.04 0.05 0.10 0.18
0.30 0.17 0.32 0.56 0.65 0.48 0.26 0.19
a The minimum acceleration required to evoke the vestibulo-ocular reflex (VOR) is reported to be 0.04 g [19].
Further, ocular tremor could not be observed by three examiners in the fundi and more superficially at the level of the scleral vessels with either direct or indirect fundoscopy, with or without the fundoscope firmly restrained. Lastly, in a more idealized experimental setup using an artificial eye attached to the stalk of a mirror galvanometer, the imitation corneal vessels could not be appreciated to oscillate until the amplitude of the simulated tremor reached w0.5 (observer’s uncorrected acuity: 20/12). From our extensive experience, this amplitude well exceeds the size of the ocular tremor recorded in most all subjects with PD (averaging 0.3 ). 4. Discussion Ocular tremor was consistently demonstrated here in a cohort of PD subjects with their heads fully immobilized using dental impressions. Using a highly sensitive magnetic tracker and multi-axis accelerometers, all subjects showed absolutely stable head positions during the recordings of oscillatory eye movements. Furthermore, in conflict with suggestions that fundoscopy necessarily should permit visualization of the ocular tremor [6,8], the simulated very small oscillations of ocular tremor could not be visualized even in a more idealized experimental setting using a restrained ophthalmoscope to examine a “tremulous” prosthetic eye. These experimental findings support our initial findings [5], as well as the results of other groups [1], that the recorded eye movements represent true ocular oscillations and refute suggestions that they are compensatory for head movement or arising from translation of appendicular tremor. Although some investigators have suggested that eye oscillations should be visible by direct fundoscopy, ocular tremor in PD is typically around 0.27, which (assuming a 13.5 mm center rotational position of the eye) would mean visualizing a translational movement of only 50 microns (approximately half the thickness of a sheet of paper) at frequencies greater than 5 Hz. When observing the fundus, there is no point of reference to which you can compare to judge illusory motion of only 50 microns. Furthermore, the size of the ocular oscillations is miniscule and as such, is masked by unavoidable comparatively larger movements of the patient’s head and both the examiner’s head and hand during normal ophthalmoscopic examinations. To overcome these natural confounding movements, we simulated ocular tremor using an artificial eye and examined the artificial scleral vessels with a rigidly mounted ophthalmoscope, in which the only potential motion was of the prosthetic eye and the observer’s head. Even under these idealized laboratory conditions, we were unable to observe oscillations of less than w0.5 ; that is, at the frequencies observed in PD subjects. As the simulated oscillations approached 0.5 , the motion could be perceived only as a slight blurring of the artificial vessels, which was confirmed upon stopping the galvanometer motor. This subtle
finding however would not be expected to be perceived in patients upon ophthalmoscopy and in fact, three investigators, including a trained ophthalmologist, were unable to perceive any abnormalities at the level of the fundi or scleral vessels in PD subjects. Some investigators have additionally suggested that if ocular tremor indeed represents primary eye oscillations then it should lead to oscillopsia [6]. However, oscillatory eye movements have been reported in a number of conditions which do not regularly cause oscillopsia [20]. Furthermore, the literature does not report any specific threshold of movement above which oscillopsia would be expected [21,22]. This is in part due to the fact that oscillopsia represents a perceptual complaint and as such is not fundamentally quantifiable. Acquired chronic progressive external ophthalmoplegia (CPEO), for example, does not cause oscillopsia even though subjects are unable to make compensatory eye movements upon head rotations [23,24]. As CPEO evolves, oscillopsia is thought to be prevented by compensatory increases in visual motion detection thresholds [23,24]. In the presence of ocular oscillations, metabolic activity in the visual cortex is shown to be suppressed, thereby potentially protecting individuals from experiencing oscillopsia, yet inducing blur [25,26]. Similarly, in PD patients, the visual cortex or more proximal visual circuitry could adapt to evolving ocular tremor; thereby, preventing oscillopsia. Consistent with this idea, PD subjects do regularly experience visual problems such as blurring that are unrelated to acuity [27]. Indeed, small amplitude, high frequency eye oscillations have been reported to lead to blurring of vision, but not oscillopsia [28]. In summary, with subjects’ heads rigidly restrained, and utilizing two sensitive and independent measures of head motion, in addition to the head movement corrective mechanisms built into the eye tracker itself [29], we provide here compelling, objective experimental support that ocular tremor in PD does not originate from head movement. Even under highly idealized laboratory conditions, simulated oscillatory movements are not observable with a restrained ophthalmoscope until they reach a magnitude considerably larger than that normally seen in PD subjects. We additionally propose that ocular tremor should not necessarily result in oscillopsia, but rather the visual system may have the ability to adapt to slowly emerging ocular tremor and thereby prevent oscillopsia. Current clinical tests such a fundoscopy are not well suited to assess for ocular tremor, but more appropriate testing methods must be developed for clinical utility. Funding This study was supported by the Department of Veterans Affairs. Author roles 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; George T. Gitchel: 1B, 1C, 2A, 2B, 3A, 3B. Paul A Wetzel: 1A, 1C, 2C, 3B. Abu Qutubuddin: 1C, 2C, 3B. Mark S Baron: 1A, 1C, 2C, 3A, 3B. References [1] Duval C, Beuter A. Fluctuations in tremor at rest and eye movements during ocular fixation in subjects with Parkinson’s disease. Parkinsonism Relat Disord 1998;4:91e7.
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Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement George T. Gitchel a, b,1, 2, Paul A. Wetzel b,1, Abu Qutubuddin a, c, d, Mark S. Baron a, d, *,1 a Southeast Parkinson’s Disease Research, Education, and Clinical Center (PADRECC), Hunter-Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA b Virginia Commonwealth University, Department of Biomedical Engineering, Richmond, VA, USA c Virginia Commonwealth University, Department of Physical Medicine and Rehabilitation, Richmond, VA, USA d Virginia Commonwealth University, Department of Neurology, Richmond, VA, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 February 2014 Received in revised form 17 March 2014 Accepted 30 March 2014
Introduction: Our recent report of ocular tremor in Parkinson’s disease (PD) has raised considerable controversy as to the origin of the tremor. Using an infrared based eye tracker and a magnetic head tracker, we reported that ocular tremor was recordable in PD subjects with no apparent head tremor. However, other investigators suggest that the ocular tremor may represent either transmitted appendicular tremor or subclinical head tremor inducing the vestibulo-ocular reflex (VOR). The present study aimed to further investigate the origin of ocular tremor in PD. Methods: Eye movements were recorded in 8 PD subjects both head free, and with full head restraint by means of a head holding device and a dental impression bite plate. Head movements were recorded independently using both a high sensitivity tri-axial accelerometer and a magnetic tracking system, each synchronized to the eye tracker. Results: Ocular tremor was observed in all 8 PD subjects and was not influenced by head free and head fixed conditions. Both magnetic tracking and accelerometer recordings supported that the ocular tremor was fully independent of head position. Conclusion: The present study findings support our initial findings that ocular tremor is a fundamental feature of PD unrelated to head movements. Although the utility of ocular tremor for diagnostic purposes requires validation, current findings in large cohorts of PD subjects suggest its potential as a reliable clinical biomarker. Published by Elsevier Ltd.
Keywords: Ocular tremor Parkinson’s disease Bite plate Oscillopsia Biomarker Eye movements
1. Introduction Duval and Beuter [1] originally noted ocular oscillations (binocular or monocular) among four subjects with PD with their heads moderately restrained. The authors found no correlation between the ocular and appendicular tremor and concluded that the ocular tremor represented primary eye oscillations [1].
* Corresponding author. Southeast Parkinson’s Disease Research, Education, and Clinical Center (PADRECC), Hunter-Holmes McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Room 2C-110, Richmond, VA 23249, USA. E-mail addresses: [email protected], [email protected] (G.T. Gitchel), [email protected] (P.A. Wetzel), [email protected] (A. Qutubuddin), [email protected] (M.S. Baron). 1 Authors contributed equally to this study. 2 George Gitchel responsibility for the integrity of the data and the accuracy of the data analysis.
Although also apparent in published figures in a number of other studies [2e4], all of which utilized some form of head restraint, ocular tremor had otherwise been a largely unrecognized feature of PD. Utilizing comparatively more modern and sensitive eye tracking equipment, we consistently observed binocular tremor in 112 subjects with PD and in 2 of 60 asymptomatic control subjects, both who converted to clinical PD within 3 years of their initial evaluations [5]. In response to our publication, Kaski et al. [6,7] and Leigh and MartinezeConde [8] suggested that the perceived ocular oscillations might represent an oscillatory vestibulo-ocular reflex (VOR) induced by head tremor (either subclinical head tremor or transmitted arm tremor). Using a high resolution magnetic position tracking system in a subset of 62 subjects in our previous study, we however consistently failed to detect head tremor that would result in VOR activation [5]. Kaski et al. suggested that magnetic tracking systems lack sufficient resolution to detect subclinical head
http://dx.doi.org/10.1016/j.parkreldis.2014.03.028 1353-8020/Published by Elsevier Ltd.
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
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G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5
movements, though others have reported their high sensitivity and accuracy, specifically for tremor [9,10]. While scleral search coil systems represent the undisputed gold standard in eye tracking research, magnetic tracking systems utilize identical technology [11,12]. Specifically against the postulate that the ocular oscillations could originate from subclinical head tremor, we never observe similar ocular tremor in subjects with Essential Tremor, [13] a condition in which one could more readily anticipate subclinical head tremors. Negating the possibility that ocular oscillations reflect transmitted appendicular tremor, we, as well as Duval and Beuter [1], found no correlations between the ocular and appendicular tremors. Further, as would be expected, in our large cohort, many patients had no appreciable appendicular tremor [5]. Despite these many arguments in favor of a primary origin for ocular tremor [14], Kaski et al., in particular, maintain that ocular tremor could not originate from primary eye oscillations or it would be seen on fundoscopy and would cause oscillopsia [7]. In order to add objective scientific evidence to the ongoing discussion [7,8,14,15], we elected here to more rigorously investigate the origin of the ocular tremor in PD. 2. Methods Eight patients (mean age 60.4 years, SD 10.1, range: 43e72 years) with medication confirmed PD completed oculomotor recordings and comprised the study population. Subjects were recruited from the Southeast Veterans Affairs Parkinson’s Disease Research, Education, and Clinical Center (PADRECC) at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, VA. Patients with additional neurological disorders, deep brain stimulators, or ophthalmic conditions which either limited the subjects ability to complete the testing, or would introduce additional confounding abnormal features were excluded. Minor cataracts or mild visual acuity loss, for example, were not deemed exclusionary criteria. Also, because dental impressions were used to restrain subjects’ heads, anyone with dentures was excluded. The study was approved by the Institutional Review Board at the Hunter Holmes McGuire VAMC and written informed consent was obtained from all subjects prior to testing. Among the 8 study patients, the average duration of PD symptoms was 4.5 years (SD 4.4, range: 0.75e13 years), with an average Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor score of 13.7 (4.8, range: 8e24), while taking their usual prescribed medication (dopa-equivalent Average: 1020.3 S.D. 400.8). Two subjects were young onset PD (one with a strong family history of PD) and two were akinetic/rigid subtype without appreciable appendicular tremor. One subject was de novo untreated at the time of testing, but subsequently showed a marked beneficial response to levodopa. As per our previous study, horizontal and vertical binocular eye gaze positions were recorded at 500 Hz using a video based eye tracker (EyeLink II, SR Research Ltd). The system incorporates a built in head motion correction by means of tracking external optical landmarks mounted on the stimuli display. Full depth rigid dental impressions of the upper and lower sets of teeth were made for each subject from hard dental wax molded around a 3 mm thick aluminum plate. These individualized bite plates were attached to a locking ball head mount, creating a head holding apparatus which also included a rigid chin cup (See Fig 1). The entire head holding apparatus was securely mounted to an aluminum optical bench (2.0 0.76 m, VERE, New Kensington, PA). The setup was designed to eliminate potential head movement and was well tolerated. Two measures were simultaneously used to assess head stability [16e18]: 1) magnetic tracking, used in our prior study and 2) acceleration, new to the present study. Head position was recorded at 125 Hz with a six degree of freedom magnetic tracking system (trakSTAR, Ascension Technology Corp, Burlington VT), while a tri-axial accelerometer (Freescale Semiconductor, Tempe, AZ, model MMA7260QT, 800 mV/g sensitivity) measured head acceleration, also at 125 Hz. The magnetic sensor was attached to the Eyelink II headband, which in turn, placed it just above the patient’s left temple. The transmitter for the magnetic tracking system was mounted rigidly on a nonferromagnetic platform and attached to the aluminum optical bench, for a total distance of w20 cm from sensor to transmitter. The accelerometer was similarly mounted to the Eyelink II headband, on the opposite side, placing it just above the subject’s right temple. Analog signals from the tri-axial accelerometer and synchronization pulse were sampled by a 14 bit analog to digital converter (USB 6009 Multifunction DAQ, National Instruments, Austin, TX). The sampling process and digital storage were controlled by the host computer through a custom written LabVIEW program (National Instruments, Austin, TX). Two separate magnetic sensors were employed on the head, one rigidly attached to the EyeLink II headband and one taped to the subject’s temple to assess for any movement or slippage between the head and eye tracker headband. Finally, appendicular tremor was measured in two subjects, one with prominent tremor and one akinetic/rigid subject with no outwardly visible tremor, via a magnetic tracking sensor attached to the tip of the
Fig. 1. Head holding apparatus with an example of the rigid dental bite plate used in this study. After sterilization, the wax was softened with a heat gun, and the patient bit down firmly to create impressions. Note the full depth impressions of the entire mandible from incisors to molars. The patient was then asked to bite onto the plate as installed in the apparatus, and once comfortable, the ball joint was tightened, and the chin cup raised to firmly lock the lower jaw in place and ensure a firm bite and fully immobilize the head. index finger on the more affected side. These appendicular tremor assessments were conducted during the eye tracking recordings, with the limb fully at rest on the subject’s lap. The magnetic position sensors, accelerometer, and eye tracker were all synchronized by recording a timing pulse from the parallel output port of the EyeLink II computer at the beginning and end of each measurement trial. The eye tracking setup and target stimuli presentation have been largely described previously [5,13]. Subjects were recorded twice, with and without head restraint. Also, using both direct and indirect fundoscopy, three different observers (one a trained ophthalmologist) examined the fundi and scleral blood vessels of each eye for outwardly visible tremor. Direct fundoscopy was done with a standard or PanOptic ophthalmoscope variably held by the examiner or held rigidly by a metal arm bolted to the optic table with the subject’s head supported in a chin cup and forehead rest. Additionally, a prosthetic eye was used to approximate the threshold required to visualize simulated ocular tremor in a more idealized setting. To achieve this, the prosthetic eye was attached to the stalk of a mirror galvanometer motor and driven at various amplitudes and frequencies, while the imitation corneal vessels were examined using a restrained fundoscope with a corneal viewing magnification lens (see Fig 2). To further address the sensitivity and accuracy of magnetic tracking devices, a separate methodological experiment was performed with the trakSTAR system. One
Fig. 2. Setup used to assess the threshold for observing simulated ocular tremor in an idealized setting. An artificial eye was attached to the stalk of a mirror galvanometer motor and driven at various amplitudes and frequencies similar to the observed behavior in PD patients. The ophthalmoscope with a corneal viewing magnification lens was positioned as closely as possible, set to maximum magnification, and was locked in place. The setup was designed to removal all movements except for that of the eye. Inset demonstrates the quality of the artificial eye and vessels.
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5 sensor was mounted to an optical post attached to a micrometer-driven XYZ translating stage (Thorlabs, pair of PT1A, and a single MVS005). The sensor and translating stage combination, along with the transmitter for the magnetic tracking system, were bolted to the aluminum optical bench to obviate potential noise or vibration. Each axis was adjusted independently by means of the micrometer and the resultant change in position reported by the trakSTAR was observed in real time. Separately, the sensor was also attached to a micrometer driven rotational stage (Thorlabs, PR01), and the rotational attitude was observed in real time as the micrometer was adjusted. Eye movement data were analyzed off line using an interactive custom written plotting program (P.A.W). Fixations were analyzed for duration, spectral frequency content, and stability parameters. All statistical analysis was conducted using SPSS Statistics 17.0. Power spectral analyses were completed in MATLAB. For statistical analyses, a was set to 0.05.
3. Results With unrestrained heads, all 8 subjects exhibited constant ocular tremor during fixations, consistent with our prior report [5]. No correlation was found between eye and head movements (strongest correlation R2: 0.140, p: 0.203). Power spectral analysis showed an average ocular tremor frequency of 7.1 3.1 Hz and an average head movement (accelerometer) frequency of 1.1 1.8 Hz. This slower head movement frequency is expected in unrestrained subjects due to slow natural drifts of the head. With the head restrained, in every subject, ocular tremor continued to be constantly observed during fixations. Both
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magnetic tracking and accelerometer outputs consistently showed a complete (three dimensional) lack of head movement, confirmed by power spectral analyses of accelerometer and magnetic tracker data showing fundamental frequencies approaching zero. Ocular tremor was observed at an average fundamental frequency of 6.5 Hz (S.D. 1.5 Hz), whereas head movement frequency analysis showed an average fundamental frequency of 0.12 Hz (S.D. 0.23 Hz). The frequency of the ocular tremor during head restraint did not differ statistically from that recorded during head free tracking (p ¼ 0.852). The magnetic tracking device affirmed an absence of slippage between the head and headband of the eye tracker. Eye and head movements continued to show no correlations (strongest correlation R2: 0.117, p: 0.193). Additionally, during head restraint, all subjects had maximal head accelerations of less than 0.025 g, well below the minimum threshold of 0.04 g required for VOR activation [19]. Fig. 3 shows a representative trace of eye and head movement recordings during head restraint. Data derived from individual study subjects during restraint is presented in Table 1. All subjects tolerated the bite plate well and had no complaints of discomfort. In the methodological experiment, the trakSTAR proved to be reliable in repeatedly detecting translation of the sensor in movements as small as 0.177 mm (0.007 inches) in each axis independently. Additionally, it was capable of repeatedly detecting rotation of the sensor in increments as small as 1.5 arc minutes (0.025 ).
Fig. 3. Illustrative monocular and head traces recorded from the same PD subject. A) Head free condition, and B) with head restrained in bite plate. The red horizontal dotted lines at 0.04 g indicate the minimum acceleration required to induce the vestibulo-ocular reflex (VOR) [19]. The accelerometer traces are both within the realm of noise, equivalent to recordings from the accelerometer when rigidly attached to an optical bench. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
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G.T. Gitchel et al. / Parkinsonism and Related Disorders xxx (2014) 1e5
Table 1 Experimental data during head restraint. Subject
1 2 3 4 5 6 7 8
Power spectra fundamental (Hz) Eye
Head
8.7 7.6 7.1 4.3 5.0 5.3 7.5 6.7
0.10 0.03 0.05 0.03 0.03 0.70 0.03 0.01
Maximum head acceleration (g)a
0.012 0.024 0.020 0.022 0.023 0.025 0.020 0.025
Eye-head correlation R2
Significance (p)
0.08 0.11 0.08 0.05 0.04 0.05 0.10 0.18
0.30 0.17 0.32 0.56 0.65 0.48 0.26 0.19
a The minimum acceleration required to evoke the vestibulo-ocular reflex (VOR) is reported to be 0.04 g [19].
Further, ocular tremor could not be observed by three examiners in the fundi and more superficially at the level of the scleral vessels with either direct or indirect fundoscopy, with or without the fundoscope firmly restrained. Lastly, in a more idealized experimental setup using an artificial eye attached to the stalk of a mirror galvanometer, the imitation corneal vessels could not be appreciated to oscillate until the amplitude of the simulated tremor reached w0.5 (observer’s uncorrected acuity: 20/12). From our extensive experience, this amplitude well exceeds the size of the ocular tremor recorded in most all subjects with PD (averaging 0.3 ). 4. Discussion Ocular tremor was consistently demonstrated here in a cohort of PD subjects with their heads fully immobilized using dental impressions. Using a highly sensitive magnetic tracker and multi-axis accelerometers, all subjects showed absolutely stable head positions during the recordings of oscillatory eye movements. Furthermore, in conflict with suggestions that fundoscopy necessarily should permit visualization of the ocular tremor [6,8], the simulated very small oscillations of ocular tremor could not be visualized even in a more idealized experimental setting using a restrained ophthalmoscope to examine a “tremulous” prosthetic eye. These experimental findings support our initial findings [5], as well as the results of other groups [1], that the recorded eye movements represent true ocular oscillations and refute suggestions that they are compensatory for head movement or arising from translation of appendicular tremor. Although some investigators have suggested that eye oscillations should be visible by direct fundoscopy, ocular tremor in PD is typically around 0.27, which (assuming a 13.5 mm center rotational position of the eye) would mean visualizing a translational movement of only 50 microns (approximately half the thickness of a sheet of paper) at frequencies greater than 5 Hz. When observing the fundus, there is no point of reference to which you can compare to judge illusory motion of only 50 microns. Furthermore, the size of the ocular oscillations is miniscule and as such, is masked by unavoidable comparatively larger movements of the patient’s head and both the examiner’s head and hand during normal ophthalmoscopic examinations. To overcome these natural confounding movements, we simulated ocular tremor using an artificial eye and examined the artificial scleral vessels with a rigidly mounted ophthalmoscope, in which the only potential motion was of the prosthetic eye and the observer’s head. Even under these idealized laboratory conditions, we were unable to observe oscillations of less than w0.5 ; that is, at the frequencies observed in PD subjects. As the simulated oscillations approached 0.5 , the motion could be perceived only as a slight blurring of the artificial vessels, which was confirmed upon stopping the galvanometer motor. This subtle
finding however would not be expected to be perceived in patients upon ophthalmoscopy and in fact, three investigators, including a trained ophthalmologist, were unable to perceive any abnormalities at the level of the fundi or scleral vessels in PD subjects. Some investigators have additionally suggested that if ocular tremor indeed represents primary eye oscillations then it should lead to oscillopsia [6]. However, oscillatory eye movements have been reported in a number of conditions which do not regularly cause oscillopsia [20]. Furthermore, the literature does not report any specific threshold of movement above which oscillopsia would be expected [21,22]. This is in part due to the fact that oscillopsia represents a perceptual complaint and as such is not fundamentally quantifiable. Acquired chronic progressive external ophthalmoplegia (CPEO), for example, does not cause oscillopsia even though subjects are unable to make compensatory eye movements upon head rotations [23,24]. As CPEO evolves, oscillopsia is thought to be prevented by compensatory increases in visual motion detection thresholds [23,24]. In the presence of ocular oscillations, metabolic activity in the visual cortex is shown to be suppressed, thereby potentially protecting individuals from experiencing oscillopsia, yet inducing blur [25,26]. Similarly, in PD patients, the visual cortex or more proximal visual circuitry could adapt to evolving ocular tremor; thereby, preventing oscillopsia. Consistent with this idea, PD subjects do regularly experience visual problems such as blurring that are unrelated to acuity [27]. Indeed, small amplitude, high frequency eye oscillations have been reported to lead to blurring of vision, but not oscillopsia [28]. In summary, with subjects’ heads rigidly restrained, and utilizing two sensitive and independent measures of head motion, in addition to the head movement corrective mechanisms built into the eye tracker itself [29], we provide here compelling, objective experimental support that ocular tremor in PD does not originate from head movement. Even under highly idealized laboratory conditions, simulated oscillatory movements are not observable with a restrained ophthalmoscope until they reach a magnitude considerably larger than that normally seen in PD subjects. We additionally propose that ocular tremor should not necessarily result in oscillopsia, but rather the visual system may have the ability to adapt to slowly emerging ocular tremor and thereby prevent oscillopsia. Current clinical tests such a fundoscopy are not well suited to assess for ocular tremor, but more appropriate testing methods must be developed for clinical utility. Funding This study was supported by the Department of Veterans Affairs. Author roles 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; George T. Gitchel: 1B, 1C, 2A, 2B, 3A, 3B. Paul A Wetzel: 1A, 1C, 2C, 3B. Abu Qutubuddin: 1C, 2C, 3B. Mark S Baron: 1A, 1C, 2C, 3A, 3B. References [1] Duval C, Beuter A. Fluctuations in tremor at rest and eye movements during ocular fixation in subjects with Parkinson’s disease. Parkinsonism Relat Disord 1998;4:91e7.
Please cite this article in press as: Gitchel GT, et al., Experimental support that ocular tremor in Parkinson’s disease does not originate from head movement, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.028
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