Publications

@article{L2026,

title = {Digital measurement of ocular microtremor in Parkinson’s Disease: Analytical and clinical validation},

author = {Lisa Graham and Rodrigo Vitorio and Patrick Tait and Richard Walker and Alan Godfrey and Rosie Morris and Samuel Stuart },

editor = {Hualou Liang},

doi = {https://doi.org/10.1371/journal.pdig.0001439},

issn = {2767-3170},

year  = {2026},

date = {2026-06-18},

urldate = {2026-06-18},

journal = {Digit Health},

volume = {5},

number = {e0001439},

issue = {6},

abstract = {Ocular microtremor (OMT) is an involuntary fixational eye movement linked to brainstem activity. OMT is thought to have a mean frequency range of 70–90 Hz in healthy adults. Previous research suggests OMT may be reduced in neurological diseases like Parkinson’s Disease. Historically, OMT has been measured invasively in specialist laboratories using lengthy and expensive protocols. Developments now allow for OMT measurement quickly and non-invasively using hand-held technology (i.e., iTremor ONE). This pilot study aimed to examine the analytical and clinical validation of OMT measurement via the iTremor ONE in people with Parkinson’s Disease (PwPD). 33 PwPD and 31 age matched healthy controls participated in this study. For analytical validation, 22 PwPD completed a test re-test reliability assessment of OMT measurement, assessed using interclass correlation coefficients (ICC). For clinical validation, OMT frequency in PwPD (n = 33) was compared to controls. Correlations were explored with demographics and clinical scales. Additionally, 24 PwPD were tested ‘OFF’ (12hr withdrawal) and ‘ON’ their anti-Parkinson’s (dopaminergic) medication to compare OMT response to a known intervention. The iTremor ONE demonstrated excellent test-retest reliability (ICC > 0.9) for measuring OMT frequency in PwPD. Mean OMT frequency was significantly lower in PwPD (63.78 ± 4.82 Hz) compared to controls (69.44 ± 6.47 Hz, p < .001), with good discriminative ability (AUC 0.75-0.77). OMT frequency correlated with age in both groups and with specific motor features (speech, facial expression, gait) in PwPD. No significant differences in OMT frequency were observed between ‘OFF’ and ‘ON’ dopaminergic medication states. This is the first study to demonstrate that a non-invasive hand-held device can reliably measure OMT in PwPD and presents OMT analytical and clinical validation evidence. OMT frequency may provide a supporting measure for diagnosis or screening. Further research is required to understand the neural mechanisms underpinning OMT in PwPD and the role it could play in clinical practice.},

keywords = {Biomarkers, Dopaminergics, Eye movements, Gait analysis, iTremor, Measurement equipment, Medical devices and equipment, OMT, Parkinson disease, Parkinson's, Vision},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39775540b,

title = {Digital measurement of ocular microtremor in Parkinson's disease: Protocol for a pilot study to assess reliability and clinical validation},

author = {Lisa Graham and Rodrigo Vitorio and Richard Walker and Alan Godfrey and Rosie Morris and Samuel Stuart},

doi = {10.1371/journal.pone.0313452},

issn = {1932-6203},

year  = {2025},

date = {2025-01-01},

urldate = {2025-01-01},

journal = {PLoS One},

volume = {20},

number = {1},

pages = {e0313452},

abstract = {Ocular microtremor (OMT) is a fixational eye movement that cannot be seen with the naked eye but is always present, even when the eye appears motionless/still. The link between OMT and brain function provides a strong rationale for investigation as there lies potential for its use as a biomarker in populations with neurological impairments. OMT frequency is typically 70-80Hz in healthy adults and research suggests that this will be reduced in those with neurological disease such as Parkinson's Disease (PD). This study aims to examine OMT in people with PD compared to healthy older adults. This is an exploratory, observational study that will use a novel handheld device-The iTremor ONE, which has been developed to rapidly, non-invasively assess and evaluate OMT frequency. This device uses incident laser technology directed at the sclera. People with PD who meet the inclusion criteria will participate in a home-based assessment involving cognitive, motor (using the UPDRS-III) and OMT measures. With OMT as the primary outcome, assessment with the iTremor is quick, taking just three seconds to obtain a reading. People with PD will be invited into the laboratory to perform extensive cognitive assessments along with an assessment of balance, gait, and turning using wearable sensors. People with PD will be assessed both off, and on, their anti-parkinsonian medication following a 12 hour washout period. We will recruit 30 People with PD, 30 people with suspected PD and 30 age-matched healthy control participants for assessment of OMT. 20 People with PD will complete a test-retest reliability assessment at the same approximate time, exactly one week after their initial visit under the same conditions to explore consistency. This will be the first study of its kind to non-invasively investigate OMT frequency as a marker/monitor for PD with advanced technology that could be used within the clinic, laboratory, or home. Identifying OMT as a PD biomarker could better support clinical assessment, enabling improved provision of care to patients with advanced disease monitoring. Clinical trial registration: This trial is registered at clinicaltrials.gov (NCT06051877; September 2023).},

keywords = {Biomarkers, Dopaminergics, Eye movements, Gait analysis, iTremor, Measurement equipment, Medical devices and equipment, OMT, Parkinson disease, Parkinson's, Vision},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Clinical validity of IntelliSpace Cognition digital assessment platform in mild cognitive impairment},

author = {Huijbers W, Pinter NK, Spaltman M, Cornelis M, Schmand B, Alnaji B, Yargeau M, Harlock S, Dorn RP, Ajtai B, Westphal ES and van Elswijk G (2024) Clinical validity of IntelliSpace Cognition digital assessment platform in mild cognitive impairment. Front. Psychol. 15:1451843. doi: 10.3389/fpsyg.2024.1451843},

editor = {Silvia Paola Caminiti},

doi = {https://doi.org/10.3389/fpsyg.2024.1451843},

year  = {2024},

date = {2024-12-30},

urldate = {2024-12-30},

journal = {Frontiers in Psychology},

volume = {15},

abstract = {We evaluated a digital cognitive assessment platform, Philips IntelliSpace Cognition, in a case-control study of patients diagnosed with mild cognitive impairment (MCI) and cognitively normal (CN) older adults. Performance on individual neuropsychological tests, cognitive z-scores, and Alzheimer's disease (AD)-specific composite scores was compared between the CN and MCI groups. These groups were matched for age, sex, and education. Performance on all but two neuropsychological tests was worse in the MCI group. After ranking the cognitive scores by effect size, we found that the memory score was the most impaired, followed by executive functioning. The Early AD/MCI Alzheimer's Cognitive Composite (EMACC) and Preclinical Alzheimer's Cognitive Composite (PACC) scores were constructed from the digital tests on Philips IntelliSpace Cognition. Both AD-specific composite scores showed greater sensitivity and specificity than the Mini-Mental State Examination or individual cognitive z-scores. Together, these results demonstrate the diagnostic value of Philips IntelliSpace Cognition in patients with MCI.},

keywords = {Alzheimer's disease, Cognitive composites, Digital health, Factor scores, HDx Cognition, Intellispace, ISC, Neuropsychology, Philips, Philips IntelliSpace, Philips ISC},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Test–retest reliability and reliable change index of the Philips IntelliSpace Cognition digital test battery},

author = {Klaming, L., Spaltman, M., Vermeent, S., van Elswijk, G., Miller, J. B., & Schmand, B. (2024). Test–retest reliability and reliable change index of the Philips IntelliSpace Cognition digital test battery. The Clinical Neuropsychologist, 38(7), 1707–1725. https://doi.org/10.1080/13854046.2024.2315747},

doi = {https://doi.org/10.1080/13854046.2024.2315747},

year  = {2024},

date = {2024-02-15},

urldate = {2024-02-15},

journal = {The Clinical Neuropsychologist },

volume = {38},

issue = {7},

pages = {1707-1725},

abstract = {Objective

This article provides the test–retest reliability and Reliable Change Indices (RCIs) of the Philips IntelliSpace Cognition (ISC) platform, which contains digitized versions of well-established neuropsychological tests.



Method

147 participants (ages 19 to 88) completed a digital cognitive test battery on the ISC platform or paper-pencil versions of the same test battery during two separate visits. Intraclass correlation coefficients (ICC) were calculated separately for the ISC and analog test versions to compare reliabilities between administration modalities. RCIs were calculated for the digital tests using the practice-adjusted RCI and standardized regression-based (SRB) method.



Results

Test–retest reliabilities for the ISC tests ranged from moderate to excellent and were comparable to the test-retest reliabilities for the paper-pencil tests. Baseline test performance, retest interval, age, and education predicted test performance at visit 2 with baseline test performance being the strongest predictor for all outcome measures. For most outcome measures, both methods for the calculation of RCIs show agreement on whether or not a reliable change was observed.



Conclusions

RCIs for the digital tests enable clinicians to determine whether a measured change between assessments is due to real improvement or decline. Together, this contributes to the growing evidence for the clinical utility of the ISC platform.},

keywords = {Cognitive Tests, Digital technology, HDx Cognition, Intellispace, Intraclass correlation, ISC, Neuropsychology, Philips, Philips IntelliSpace, Philips ISC, Practice effects, Reliable change index, Test–retest reliability},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37632535b,

title = {Ocular microtremor: a structured review},

author = {Lisa Graham and Julia Das and Rodrigo Vitorio and Claire McDonald and Richard Walker and Alan Godfrey and Rosie Morris and Samuel Stuart},

doi = {10.1007/s00221-023-06691-w},

issn = {1432-1106},

year  = {2023},

date = {2023-09-01},

urldate = {2023-09-01},

journal = {Exp Brain Res},

volume = {241},

number = {9},

pages = {2191--2203},

abstract = {Ocular microtremor (OMT) is the smallest of three involuntary fixational micro eye movements, which has led to it being under researched in comparison. The link between OMT and brain function generates a strong rationale for further study as there is potential for its use as a biomarker in populations with neurological injury and disease. This structured review focused on populations previously studied, instrumentation used for measurement, commonly reported OMT outcomes, and recommendations concerning protocol design and future studies. Current methods of quantifying OMT will be reviewed to analyze their efficacy and efficiency and guide potential development and understanding of novel techniques. Electronic databases were systematically searched and compared with predetermined inclusion criteria. 216 articles were identified in the search and screened by two reviewers. 16 articles were included for review. Findings showed that piezoelectric probe is the most common method of measuring OMT, with fewer studies involving non-invasive approaches, such as contact lenses and laser imaging. OMT frequency was seen to be reduced during general anesthesia at loss of consciousness and in neurologically impaired participants when compared to healthy adults. We identified the need for a non-invasive technique for measuring OMT and highlight its potential in clinical applications as an objective biomarker for neurological assessments. We highlight the need for further research on the clinical validation of OMT to establish its potential to identify or predict a meaningful clinical or functional state, specifically, regarding accuracy, precision, and reliability of OMT.},

keywords = {Biomarkers, Eye movements, iTremor, Neurological disease, Neurological injury, Ocular microtremor},

pubstate = {published},

tppubtype = {article}

}

@article{tandf_ntcn2036_1997.bib,

title = {Philips IntelliSpace Cognition digital test battery: Equivalence and measurement invariance compared to traditional analog test versions},

author = {Stefan Vermeent, Mandy Spaltman,G ijs van Elswijk, Justin B. Miller, Ben Schmand},

doi = {https://doi.org/10.1080/13854046.2021.1974565},

year  = {2021},

date = {2021-02-25},

urldate = {2021-02-25},

journal = {The Clinical Neuropsychologist},

volume = {36},

number = {8},

pages = {2278–-2299},

abstract = {Objective: To collect evidence of validity for a selection of digital tests on the Philips IntelliSpace Cognition (ISC) platform.



Method: A total of 200 healthy participants (age 50-80) completed both the ISC battery and an analog version of the battery during separate visits. The battery included the following screeners and cognitive tests: Mini-Mental State Examination (2nd edition), Clock Drawing Test, Trail-Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (ROCFT), Letter Fluency, Star Cancellation Test, and Digit Span Test. The ISC tests were administered on an iPad Pro and were automatically scored using designated algorithms. The analog tests were administered in line with existing guidelines and scored by trained neuropsychologists. Criterion validity was established through relative agreement coefficients and raw score equivalence tests. In addition,measurement invariance analysis was used to compare the factor structures of both versions. Finally, we explored effects of demographics and experience with digital devices on performance.



Results: We found fair to excellent relative agreement between test versions. Absolute equivalence was found for RAVLT, Letter Fluency, Star Cancellation Test, and Digit Span Test. Importantly, we demonstrated equal loadings of the digital and analog test versions on the same set of underlying cognitive domains. Demographic effects were mostly comparable between modalities, and people’s experience with digital devices was found to only influence performance on TMT B.



Conclusions: This study provides several sources of evidence for the validity of the ISC test battery, offering an important step in validating ISC for clinical use.},

keywords = {Automation, Cognition, Digital technology, HDx Cognition, Intellispace, ISC, Measurement invariance, Neuropsychology, Philips, Philips IntelliSpace, Philips ISC, Psychological tests},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25674709b,

title = {Simultaneous drift, microsaccades, and ocular microtremor measurement from a single noncontact far-field optical sensor},

author = {James P Ryle and Brian Vohnsen and John T Sheridan},

doi = {10.1117/1.JBO.20.2.027004},

issn = {1560-2281},

year  = {2015},

date = {2015-02-01},

urldate = {2015-02-01},

journal = {J Biomed Opt},

volume = {20},

number = {2},

pages = {27004},

abstract = {We report on the combined far-field measurement of the three involuntary eye movements, drift, microsaccades, and ocular microtremor (OMT), using a noncontact far-field optical method. We review the significance of the smallest and least measured, and thus least understood, of the three, OMT. Using modern digital imaging techniques, we perform detailed analysis, present experimental results, and examine the extracted parameters using a noncontact far-field sensor. For the first time, in vivo noncontact measurements of all fixational in-plane movements of the human eye are reported, which simultaneously provide both the horizontal (left-right) and vertical (up-down) displacement results.},

keywords = {Adult, Algorithms, Computer-assisted / methods*, Diagnostic techniques, Eye movements / physiology*, Fixation, Humans, Image processing, iTremor, Male, Ocular / physiology*, Ophthalmological, Saccades / physiology, Tremor / physiopathology, Young adult},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24853319b,

title = {Non-contact in vivo measurement of ocular microtremor using laser speckle correlation metrology},

author = {E Kenny and D Coakley and G Boyle},

doi = {10.1088/0967-3334/35/7/1229},

issn = {1361-6579},

year  = {2014},

date = {2014-07-01},

urldate = {2014-07-01},

journal = {Physiol Meas},

volume = {35},

number = {7},

pages = {1229--1243},

abstract = {Ocular microtremor (OMT) is a small involuntary eye movement present in all subjects. In this paper we present the results of in vivo OMT measurement using a novel non-contact laser speckle technique. OMT signals have not previously been measured from the sclera using this laser speckle correlation technique. To verify the system's ability to record eye movements, it is first tested using a large angle eye rotation. Next, the system is tested with a group of 20 subjects and OMT parameters are extracted. The results of OMT measurements gave a mean frequency of 78 ± 3.86 Hz and peak-to-peak amplitude of 21.42 ± 7.01 µrad, these values are consistent with known values from eye-contacting methods.},

keywords = {Adult, Biological, Blinking, Computer-assisted, Eye movement measurements* / instrumentation, Eye movements, Female, Humans, iTremor, Lasers, Male, Models, Motion, Saccades, Signal processing, Time, Young adult},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23306826b,

title = {Ocular microtremor measurement using laser-speckle metrology},

author = {Emer Kenny and Davis Coakley and Gerard Boyle},

doi = {10.1117/1.JBO.18.1.016010},

issn = {1560-2281},

year  = {2013},

date = {2013-01-01},

urldate = {2013-01-01},

journal = {J Biomed Opt},

volume = {18},

number = {1},

pages = {16010},

abstract = {We describe a novel, noninvasive measurement approach for recording a small involuntary tremor of the eye known as ocular microtremor. The method is based on measuring out-of-plane angular displacements of a target by using laser-speckle correlation of images recorded in the Fourier plane of a lens. The system has a dynamic range of 4 to 5000 μrad, resolution of 4 μrad, and a bandwidth of 250 Hz. The design and optimization of the system is presented with an in vitro validation of the system against its specification.},

keywords = {Biological, Computer simulation, Computer-assisted / methods*, Computer-assisted*, Eye movements, Humans, Image processing, iTremor, Lasers, Models, Photography / methods*, Signal processing},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23638348b,

title = {Simultaneous recordings of ocular microtremor and microsaccades with a piezoelectric sensor and a video-oculography system},

author = {Michael B McCamy and Niamh Collins and Jorge Otero-Millan and Mohammed Al-Kalbani and Stephen L Macknik and Davis Coakley and Xoana G Troncoso and Gerard Boyle and Vinodh Narayanan and Thomas R Wolf and Susana Martinez-Conde},

doi = {10.7717/peerj.14},

issn = {2167-8359},

year  = {2013},

date = {2013-01-01},

urldate = {2013-01-01},

journal = {PeerJ},

volume = {1},

pages = {e14},

abstract = {Our eyes are in continuous motion. Even when we attempt to fix our gaze, we produce so called "fixational eye movements", which include microsaccades, drift, and ocular microtremor (OMT). Microsaccades, the largest and fastest type of fixational eye movement, shift the retinal image from several dozen to several hundred photoreceptors and have equivalent physical characteristics to saccades, only on a smaller scale (Martinez-Conde, Otero-Millan & Macknik, 2013). OMT occurs simultaneously with drift and is the smallest of the fixational eye movements (∼1 photoreceptor width, >0.5 arcmin), with dominant frequencies ranging from 70 Hz to 103 Hz (Martinez-Conde, Macknik & Hubel, 2004). Due to OMT's small amplitude and high frequency, the most accurate and stringent way to record it is the piezoelectric transduction method. Thus, OMT studies are far rarer than those focusing on microsaccades or drift. Here we conducted simultaneous recordings of OMT and microsaccades with a piezoelectric device and a commercial infrared video tracking system. We set out to determine whether OMT could help to restore perceptually faded targets during attempted fixation, and we also wondered whether the piezoelectric sensor could affect the characteristics of microsaccades. Our results showed that microsaccades, but not OMT, counteracted perceptual fading. We moreover found that the piezoelectric sensor affected microsaccades in a complex way, and that the oculomotor system adjusted to the stress brought on by the sensor by adjusting the magnitudes of microsaccades.},

keywords = {iTremor, Microsaccades, Ocular microtremor},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19256709b,

title = {Compact portable ocular microtremor sensor: design, development and calibration},

author = {James P Ryle and Mohammed Al-Kalbani and Niamh Collins and Unnikrishnan Gopinathan and Gerard Boyle and Davis Coakley and John T Sheridan},

doi = {10.1117/1.3083435},

issn = {1083-3668},

year  = {2009},

date = {2009-01-01},

urldate = {2009-01-01},

journal = {J Biomed Opt},

volume = {14},

number = {1},

pages = {014021},

abstract = {Ocular microtremor (OMT) is a physiological high-frequency (up to 150 Hz) low-amplitude (25-2500 nm peak-to-peak) involuntary motion of the human eye. Recent studies suggest a number of clinical applications for OMT that include monitoring the depth of anesthesia of a patient in surgery, prediction of outcome in coma, and diagnosis of brain stem death. Clinical OMT investigations to date have used mechanical piezoelectric probes or piezoelectric strain gauges that have many drawbacks which arise from the fact that the probe is in contact with the eye. We describe the design of a compact noncontact sensing device to measure OMT that addresses some of the above drawbacks. We evaluate the system performance using a calibrated piezoelectric vibrator that simulates OMT signals under conditions that can occur in practice, i.e., wet eye conditions. We also test the device at low light levels well within the eye safety range.},

keywords = {Diagnostic techniques, Equipment design, Equipment failure analysis, Eye movement measurements / instrumentation*, Eye movements / physiology*, Humans, Interferometry / instrumentation*, iTremor, Lasers, Miniaturization, Ophthalmological / instrumentation*, Reproducibility of results, Sensitivity and specificity, Transducers*, Vibration},

pubstate = {published},

tppubtype = {article}

}

@article{pmid17921180,

title = {A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders},

author = {Aasef G Shaikh, Kenichiro Miura, Lance M Optican, Stefano Ramat, R John Leigh, David S Zee},

doi = {10.1093/brain/awm240},

issn = {1460-2156},

year  = {2007},

date = {2007-11-01},

urldate = {2007-11-01},

journal = {Brain.},

volume = {130},

number = {11},

pages = {3020--31},

abstract = {Tremor disorders pose fundamental questions about disease mechanisms, and challenges to successful neurotherapeutics: What causes motor circuits to oscillate in disorders in which the central nervous system otherwise seems normal? How does inheritance 'determine' the clinical phenotype in familial tremor disorders? Here, we address these questions. Analogies between the neural circuits controlling rapid eye movements (saccades) and those controlling limb movements allow us to translate the interpretations from the saccadic systems to the limb movement system. Moreover, the relatively well understood neurophysiology of the ocular motor system offers a unique opportunity to test specific hypotheses about normal and abnormal motor control of both eye and limb movements. We describe a new familial disorder--'micro-saccadic oscillations and limb tremor (microSOLT)'--in a mother and daughter who had tiny saccadic oscillations of the eyes and tremor of the hands. This unique oscillatory movement disorder resembles other common tremor disorders (such as essential tremor) that occur in patients who have an otherwise normally functioning central nervous system. We hypothesize that microSOLT is caused by an inherited abnormality that results in abnormal membrane properties causing reduced external inhibition in the premotor neurons that generate the high-frequency discharge (burst) for saccades and for ballistic limb movements. To test this hypothesis, we recorded hand tremor and eye movements in two patients with microSOLT and particularly during natural circumstances when inhibition of the premotor saccadic burst neurons is removed (e.g. eye closure). We then simulated a conductance-based model for the premotor commands which included excitatory and reciprocally inhibitory burst neurons. The structure of this physiologically realistic model was based upon known cell types and anatomical connections in the brainstem (for saccades) and the thalamus (for limb movements). The physiological phenomenon of post-inhibitory rebound in premotor burst neurons makes the circuit inherently unstable and prone to oscillate unless prevented by external inhibition. Indeed, with simulated reduction of external inhibition (in this case glycinergic), saccadic oscillations and limb tremor were reproduced. Our results suggest that a single-inherited deficit can alter membrane properties, which impairs inhibition in an inherently unstable neural circuit causing the eye and limb oscillations in microSOLT. This concept has broad implications for understanding the mechanism and designing rationale pharmacotherapy for abnormal oscillations and may be applicable to other common disorders in which there are no structural abnormalities in the brain such as essential tremor.},

keywords = {Brain stem / pathology, Case-control studies, Computer simulation*, Female, Hand, Humans, iTremor, Models, Neural conduction / physiology, Neural pathways / physiology, Neurological*, Neurons / physiology, Ocular motility disorders / complications, Ocular motility disorders / genetics*, Ocular motility disorders / physiopathology, Syndrome, Thalamus / pathology, Tremor / complications, Tremor / genetics*, Tremor / physiopathology},

pubstate = {published},

tppubtype = {article}

}

@article{pmid17921180b,

title = {A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders},

author = {Aasef G Shaikh and Kenichiro Miura and Lance M Optican and Stefano Ramat and R John Leigh and David S Zee},

doi = {10.1093/brain/awm240},

issn = {1460-2156},

year  = {2007},

date = {2007-11-01},

urldate = {2007-11-01},

journal = {Brain},

volume = {130},

number = {Pt 11},

pages = {3020--3031},

abstract = {Tremor disorders pose fundamental questions about disease mechanisms, and challenges to successful neurotherapeutics: What causes motor circuits to oscillate in disorders in which the central nervous system otherwise seems normal? How does inheritance 'determine' the clinical phenotype in familial tremor disorders? Here, we address these questions. Analogies between the neural circuits controlling rapid eye movements (saccades) and those controlling limb movements allow us to translate the interpretations from the saccadic systems to the limb movement system. Moreover, the relatively well understood neurophysiology of the ocular motor system offers a unique opportunity to test specific hypotheses about normal and abnormal motor control of both eye and limb movements. We describe a new familial disorder--'micro-saccadic oscillations and limb tremor (microSOLT)'--in a mother and daughter who had tiny saccadic oscillations of the eyes and tremor of the hands. This unique oscillatory movement disorder resembles other common tremor disorders (such as essential tremor) that occur in patients who have an otherwise normally functioning central nervous system. We hypothesize that microSOLT is caused by an inherited abnormality that results in abnormal membrane properties causing reduced external inhibition in the premotor neurons that generate the high-frequency discharge (burst) for saccades and for ballistic limb movements. To test this hypothesis, we recorded hand tremor and eye movements in two patients with microSOLT and particularly during natural circumstances when inhibition of the premotor saccadic burst neurons is removed (e.g. eye closure). We then simulated a conductance-based model for the premotor commands which included excitatory and reciprocally inhibitory burst neurons. The structure of this physiologically realistic model was based upon known cell types and anatomical connections in the brainstem (for saccades) and the thalamus (for limb movements). The physiological phenomenon of post-inhibitory rebound in premotor burst neurons makes the circuit inherently unstable and prone to oscillate unless prevented by external inhibition. Indeed, with simulated reduction of external inhibition (in this case glycinergic), saccadic oscillations and limb tremor were reproduced. Our results suggest that a single-inherited deficit can alter membrane properties, which impairs inhibition in an inherently unstable neural circuit causing the eye and limb oscillations in microSOLT. This concept has broad implications for understanding the mechanism and designing rationale pharmacotherapy for abnormal oscillations and may be applicable to other common disorders in which there are no structural abnormalities in the brain such as essential tremor.},

keywords = {iTremor},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18173910,

title = {Non-invasive brainstem monitoring: the ocular microtremor},

author = {James Robertson and Shelly Timmons},

doi = {10.1179/016164107X240198},

issn = {0161-6412},

year  = {2007},

date = {2007-10-01},

urldate = {2007-10-01},

journal = {Neurol Res},

volume = {29},

number = {7},

pages = {709--711},

abstract = {The ocular microtremor (OMT) is mediated by the oculomotor area of the brainstem and is altered in several pathologic states, including traumatic brain injury, general anesthesia, brain death, coma, Parkinsonism and multiple sclerosis. The EYETECT tremor monitor is a non-invasive means of measuring the frequency and amplitude of this microscopic tremor. It has been clinically tested in these clinical scenarios and has been found to be a reliable means of detecting the depth of anesthesia, and has been useful in predicting outcome in coma and traumatic brain injury patients and in confirming brain death. This paper reviews the scientific literature on the EYETECT OMT monitor, describes the underlying physiology and discusses the potential for future works and clinical use of this innovative technology.},

keywords = {Anesthesia, Brain death / diagnosis, Brain stem / anatomy & histology, Brain stem / physiopathology*, Coma / diagnosis, Coma / physiopathology, Eye movements, Humans, iTremor, Monitoring, Oculomotor muscles / innervation, Oculomotor muscles / physiopathology, physiologic / methods*, Predictive value of tests, Tremor / diagnosis*, Tremor / etiology, Tremor / physiopathology},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18002589,

title = {An automated ocular microtremor feature extraction using the Gabor thresholding technique},

author = {M Al-Kalbani and N Collins and G Boyle and F Hegarty and T Foran and N Sheahan and D Coakley},

doi = {10.1109/IEMBS.2007.4352923},

issn = {2375-7477},

year  = {2007},

date = {2007-01-01},

urldate = {2007-01-01},

journal = {Annu Int Conf IEEE Eng Med Biol Soc},

volume = {2007},

pages = {2851--2854},

abstract = {Ocular Microtremor (OMT) is a very fine continuous eye movement which has potential in monitoring and identifying a number of clinical conditions. There is a need for improved analysis and processing techniques to extract useful, quantifiable parameters from the OMT signal. A number of papers have shown the clinical significance of looking at the 'bursts' and 'baseling' patterns of the OMT signal. Analysis to date relies on visual inspection alone. This paper introduces an automated approach to burst/baseline identification based on a time-varying filter using the Gabor transform.},

keywords = {Algorithms, Artifacts, Computer-assisted, Eye movements, Humans, iTremor, Signal processing, Tremor*},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15333410,

title = {Ocular microtremor during general anesthesia: results of a multicenter trial using automated signal analysis},

author = {Mairead Heaney, Leo G Kevin, Alex R Manara, Tracey J Clayton, Shelly D Timmons, John J Angel, Kenneth R Smith, Brent Ibata, Ciaran Bolger, Anthony J Cunningham},

doi = {10.1213/01.ANE.0000133145.98702.C0},

issn = {1526-7598},

year  = {2004},

date = {2004-09-01},

urldate = {2004-09-01},

journal = {Anesth Analg.},

volume = {99},

number = {3},

pages = {775--780},

abstract = {Ocular microtremor (OMT) is a fine physiologic tremor of the eye related to neuronal activity in the reticular formation of the brainstem. The frequency of OMT is suppressed by propofol and sevoflurane and predicts the response to command at emergence from anesthesia. Previous studies have relied on post hoc computer analysis of OMT wave forms or on real-time measurements confirmed visually on an oscilloscope. Our overall aim was to evaluate an automated system of OMT signal analysis in a diverse patient population undergoing general anesthesia. In a multicenter trial involving four centers in three countries, we examined the accuracy of OMT to identify the unconscious state and to predict movement in response to airway instrumentation and surgical stimulation. We also tested the effects of neuromuscular blockade and patient position on OMT. We measured OMT continuously by using the closed-eye piezoelectric technique in 214 patients undergoing extracranial surgery with general anesthesia using a variety of anesthetics. OMT decreased at induction in all patients, increased transiently in response to surgical incision or airway instrumentation, and increased at emergence. The frequency of OMT predicted movement in response to laryngeal mask airway insertion and response to command at emergence. Neuromuscular blockade did not affect the frequency of OMT but decreased its amplitude. OMT frequency was unaffected by changes in patient position. We conclude that OMT, measured by an automated signal analysis module, accurately determines the anesthetic state in surgical patients, even during profound neuromuscular blockade and after changes in patient position.},

keywords = {Adult, Anesthesia, Brain stem / physiology, Computer-assisted, Eye movements, general*, Humans, iTremor, Neuromuscular blocking agents / pharmacology, Posture, Signal processing, Tremor*},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12393354,

title = {Comparison of ocular microtremor and bispectral index during sevoflurane anaesthesia},

author = {L G Kevin and A J Cunningham and C Bolger},

doi = {10.1093/bja/aef225},

issn = {0007-0912},

year  = {2002},

date = {2002-10-01},

urldate = {2002-10-01},

journal = {Br J Anaesth},

volume = {89},

number = {4},

pages = {551--555},

abstract = {BACKGROUND: A practical and reliable monitor of depth of anaesthesia would be a major advance on current clinical practice. None of the present monitors is both simple to use and accurate. Ocular microtremor (OMT) is a physiological tremor that is suppressed by propofol in a dose-dependent manner. We studied OMT during propofol induction and nitrous oxide-oxygen-sevoflurane maintenance of anaesthesia in 30 patients, and compared OMT with the bispectral index (BIS) as a predictor of response to verbal command.nnMETHODS: OMT was measured using the closed-eye piezoelectric strain-gauge technique. OMT and BIS were measured at specific times during the anaesthetic, including at loss of consciousness, at end-tidal sevoflurane 1 and 2%, and at emergence.nnRESULTS: OMT decreased significantly after induction, did not decrease as end-tidal sevoflurane was increased from 1 to 2%, and increased at emergence in all patients. By logistic regression, OMT was more sensitive and specific than BIS in distinguishing the awake from the anaesthetized state (OMT, 84.9 and 93.1% respectively; BIS, 75.7 and 69.0%).nnCONCLUSIONS: OMT is suppressed by sevoflurane and accurately predicts response to verbal command. OMT may be a useful monitor of depth of hypnosis.},

keywords = {Adolescent, Adult, Anesthetics, Electroencephalography / drug effects*, Eye movements / drug effects*, Female, Humans, inhalation / pharmacology*, intraoperative / methods*, iTremor, Logistic models, Male, Methyl ethers / pharmacology*, Middle aged, Monitoring, ROC curve, Sensitivity and specificity, Sevoflurane},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11382800,

title = {Effect of age on ocular microtremor activity},

author = {C Bolger and S Bojanic and N F Sheahan and D Coakley and J F Malone},

doi = {10.1093/gerona/56.6.m386},

issn = {1079-5006},

year  = {2001},

date = {2001-06-01},

urldate = {2001-06-01},

journal = {J Gerontol A Biol Sci Med Sci},

volume = {56},

number = {6},

pages = {M386--M390},

abstract = {BACKGROUND: Ocular microtremor (OMT) is a high-frequency tremor of the eyes. It is present in all individuals and is related to brainstem activity. The OMT signal appears as an irregular oscillatory movement with intermittent burst-like components. The clinical interest in OMT has centered on its use in the assessment of the comatose patient, with broad agreement among authors of its prognostic value. The purpose of this study was to examine the changes in OMT activity related to aging.nnMETHODS: OMT was recorded from 72 normal healthy subjects using the piezoelectric strain gauge technique. The subjects ranged in age from 21 to 88 years (54.22 +/- 20.43 years, mean +/- SD).nnRESULTS: Our results show that the overall frequency and frequency content of the bursts falls with age (p < .002 and p < .001, respectively). There is a highly significant drop in all three frequency parameters of OMT (p < .0001) in subjects older than 60 years of age.nnCONCLUSIONS: These results suggest that different values of normality should operate for subjects over 60 years of age when considering the clinical application of OMT.},

keywords = {80 and over, Adult, Aged, Humans, iTremor, Middle aged, Oculomotor muscles / physiopathology*, Reference values, Regression analysis, Transducers, Tremor / physiopathology},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11573625b,

title = {Ocular microtremor: a tool for measuring depth of anaesthesia?},

author = {S Bojanic and T Simpson and C Bolger},

doi = {10.1093/bja/86.4.519},

issn = {0007-0912},

year  = {2001},

date = {2001-04-01},

urldate = {2001-04-01},

journal = {Br J Anaesth},

volume = {86},

number = {4},

pages = {519--522},

abstract = {Ocular microtremor (OMT) is a fine high frequency tremor of the eyes caused by extra-ocular muscle activity stimulated by impulses emanating in the brain stem. Several studies have shown that the frequency of this tremor is reduced in patients whose consciousness is reduced by anaesthesia or head injury. Therefore, OMT may possibly be used to determine depth of anaesthesia. Twenty-two unpre-medicated subjects undergoing surgery with general anaesthesia were studied. OMT activity was measured at admission using the open eye piezoelectric strain gauge technique. Anaesthesia was induced with propofol using a target controlled infusion delivery system (Diprifusor). OMT activity was then recorded at predicted plasma propofol concentrations of 1, 2, 3 and 5 microg ml(-1). The patient's level of consciousness (response to command or stimulation) was assessed after each OMT measurement. OMT activity was reduced progressively at predicted plasma concentrations of propofol of I and 2 microg ml(-1) and then plateaued between 3 and 5 microg ml(-1). There was a significant difference between the last awake OMT recording and the first recording at loss of consciousness (P < 0.001). OMT recording holds promise as a practical indicator of the depth of anaesthesia.},

keywords = {Adult, Aged, Anesthesia, Anesthetics, Consciousness / drug effects, Consciousness / physiology, Dose-response relationship, drug, Eye movements / drug effects*, Eye movements / physiology*, Female, general, Humans, intraoperative / methods*, intravenous / blood, intravenous / pharmacology*, iTremor, Male, Middle aged, Monitoring, Oculomotor muscles / drug effects, Propofol / blood, Propofol / pharmacology*, Tremor / physiopathology},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18356988b,

title = {Interferometry for ocular microtremor measurement},

author = {G Boyle and D Coakley and J F Malone},

doi = {10.1364/ao.40.000167},

issn = {1559-128X},

year  = {2001},

date = {2001-01-01},

urldate = {2001-01-01},

journal = {Appl Opt},

volume = {40},

number = {1},

pages = {167--175},

abstract = {The eyes of all normal subjects undergo a continuous, low-amplitude, high-frequency tremor called ocular microtremor (OMT). A number of potential clinical applications of OMT have been identified, including the prediction of outcome in coma. To date, OMT has been investigated primarily with an eye-contacting piezoelectric probe. We describe a laser-based, noncontacting, interferometric technique for the measurement of OMT. The technique employs an in-plane-sensitive, phase-modulating speckle interferometer to detect the movement of the sclera, or white of the eye.},

keywords = {iTremor, Ocular microtremor},

pubstate = {published},

tppubtype = {article}

}