http://journal.frontiersin.org/article/10.3389/fneur.2016.00003/full?
- 1Neurology, Carrick Institute, Cape Canaveral, FL, USA
- 2Global Clinical Scholars Research Training Program (GCSRT), Harvard Medical School, Boston, MA, USA
- 3Institute of Neurology and Neurosurgery, Havana, Cuba
- 4Bedfordshire Centre for Mental Health Research, University of Cambridge, Cambridge, UK
- 5Electrical and Computer Engineering, University of Wyoming, Laramie, WY, USA
Context: Eye-movement training (EMT) can
induce altered brain activation and change the functionality of saccades
with changes of the brain in general.
Objective: To determine if EMT would result in
changes in quantitative electroencephalogram (qEEG) and NIH Stroke
Scale (NIHSS) in patients suffering from acute middle cerebral artery
(MCA) infarction. Our hypothesis is that there would be positive changes
in qEEG and NIHSS after EMT in patients suffering from acute MCA
ischemic stroke.
Design: Double-blind randomized controlled trial.
Setting and participants: Thirty-four subjects with acute MCA ischemic stroke treated at university affiliated hospital intensive care unit.
Interventions: Subjects were randomized into a
“control” group treated only with aspirin (125 mg/day) and a
“treatment” group treated with aspirin (125 mg/day) and a
subject-specific EMT.
Main outcome measures: Delta–alpha ratio, power ratio index, and the brain symmetry index calculated by qEEG and NIHSS.
Results: There was strong statistical and
substantive significant improvement in all outcome measures for the
group of stroke patients undergoing EMT. Such improvement was not
observed for the “control” group, and there were no adverse effects.
Conclusion: The addition of EMT to a MCA
ischemic stroke treatment paradigm has demonstrated statistically
significant changes in outcome measures and is a low cost, safe, and
effective complement to standard treatment.
Introduction
Stroke is one of the leading causes of death in the
United States and is a major cause of adult disability; although from
2001 to 2011 the relative rate of stroke death fell by 35.1% and the
actual number of stroke deaths declined by 21.2%, the number of persons
suffering from a stroke is still significant (≈795,000 each year in the
United States alone) and its consequences are serious (in 2011, stroke
caused ≈1 of every 20 deaths in the United States) (1).
Its etiology is a change in blood flow to a specific area of the brain
due to ischemia or hemorrhage, and it is usually manifested as brain
dysfunction with consequent effects such as hemiparesis, dysphasia,
ataxia, diplopia, or visual field loss. Strokes are diagnosed by
physical and neurological examination, with the help of neurological
scales specifically developed to quantify the impairment caused by a
stroke, in particular the NIH Stroke Scale (NIHSS). This scale
originally consisted of a 15-item examination (2), then amended to an 11-item examination (3),
scored on a scale from 0 to 2, 3, or 4 depending on the item, for a
total score ranging from 0 (normal function) to 42 (severe stroke).
Several studies have reported that the baseline NIHSS (taken at
hospitalization/diagnosis time) is a good predictor of outcome after a
stroke (4–7).
Diagnostic tools for strokes include CT scans (with or without
contrast), MRI scans (especially diffusion-weighted imaging – DWI, and
with magnetic resonance angiography – MRA), Doppler ultrasound, and
digital subtraction angiography. In particular, for ischemic stroke, MRI
scans have shown a higher sensitivity and specificity than CT scans
without contrast (8).
Once patients are hospitalized, electroencephalograms (EEG) are used to
continuously monitor their brain function as well as to drive clinical
management, since EEG abnormalities are typical manifestation of an
ischemic stroke. In particular, quantitative electroencephalogram (qEEG)
(9) has been used for monitoring and formulating prognosis in acute and sub-acute ischemic stroke (10).
Of all the numerical parameters that can be obtained from the qEEG, of
particular interest are the ratio of mean scalp delta to alpha power
[known as the alpha delta ratio (ADR), or its inverse the delta alpha
ratio (DAR)] (11, 12), the power ratio index (PRI) of mean “slow” (delta and theta) to mean “fast” (alpha and beta) activity (12–14), and the brain symmetry index (BSI or mBSI) (15, 16).
Standard treatment plans for patients affected by
ischemic stroke involve fibrinolytic therapy (administration of
recombinant tissue-type plasminogen activator – rt-PA), antiplatelet
agents (such as aspirin), and mechanical thrombectomy (removal of the
clot causing the blood flow obstruction). After the acute phase is
concluded, the most effective rehabilitation programs involve carefully
directed, well-focused, repetitive practice to relearn skills that are
lost when part of the brain is damaged.
Saccades are fast eye movements that allow humans to
voluntarily very quickly change the direction of gaze. Extensive studies
have been conducted to characterize the different brain and eye
mechanisms generating such movements and how different pathologies
affect them (17).
A number of standard parameters have been used to characterize
saccades: latency or reaction time (the time it takes for the eyes to
start moving once a stimulus is presented), velocity (at how many deg/s
the eyes move), amplitude (how many degrees the eyes move), and duration
(how much time it takes) (18).
All of these eye movements can be quantified with diagnostic equipment,
such as video-nystagmography (VNG), but they can be observed at the
bedside as well. Standardized objective examination of eye movements is
of great value in the detection and clarification of sub-clinical
lesions in the central nervous system. Even patients with multiple
sclerosis (MS) with lesions beyond the primary visual pathway have both
saccadic latency and smooth pursuit abnormalities of oculomotor
dysfunction (19).
Patients suffering from mild closed-head injury also demonstrate
prolonged saccadic latencies, and quantitative tests of oculomotor
function may provide sensitive markers of cerebral dysfunction (20)
that can assist and direct patient assessment. For instance, a cerebral
vascular lesion in the right and/or left hemisphere produces a general
slowing in the saccadic latency and a general reduction in the accuracy
of saccades with respect to a healthy subject’s performance (21). Abnormalities in the control of saccades have been described in patients with cerebral pathology (22),
suggesting that they might be robust biomarkers that could be utilized
in guiding and interpreting treatment outcomes. Discrepancy in
horizontal and vertical tilt angle coefficients can cause eye positions
to lie on a twisted rather than a planar surface, resulting in eye
velocities that change during a visual saccade (23).
The coordination of eye movements is dependent upon the non-linear
addition of visual saccades and the pursuit components of catch-up
saccades that can be measured to assess function and disability (24).
There are many variables that can result in different clinical
scenarios for patients with similar disease states or injuries. For
example, elderly patients demonstrate an increased latency and decreased
peak velocity from age-related degenerative changes in the central
nervous system with diseases of the central nervous system often causing
saccadic disorders (25).
Different disease states and sites of neurological injury may affect
one component of a visual task while not affecting another. Alzheimer’s
patients show increased latency to initiation of saccades but no
difference in their amplitude and velocity when compared to healthy
controls (26).
We have observed slowing of visual saccades and saccadic intrusions of
visual pursuits in patients with acute middle cerebral artery (MCA)
infarction. Abnormal saccadic intrusions consisting of frequent sporadic
horizontal square wave jerks occur in a large percentage of patients
with acute or chronic focal cerebral lesions (27).
Low-amplitude cerebral square wave jerks can be detected clinically by
fundoscopy at the bedside. Reflexive visually guided saccade triggering
may be facilitated or inhibited by the cerebral cortex.
Pierrot-Deseilligny and colleagues observed pathology of saccades made
toward and away from suddenly appearing visual targets in patients with
limited unilateral cerebral infarction (28).
Different phenomenology of eye movements have been observed with
lesions of both the right and left cerebral hemisphers. For example,
ischemic lesions of the left frontal eye field (FEF) have been
associated with abnormal reflexive visually guided saccades (gap and
overlap tasks), antisaccades, predictive saccades, memory-guided
saccades, smooth pursuit, and optokinetic nystagmus (29).
Eye-movement analysis not only identifies functional lesions but can
also act as a biomarker for treatment outcomes. Hemispatial neglect
affects the ability to explore space on the side opposite a brain lesion
that is also mirrored in abnormal saccadic eye-movement patterns that
provide a sensitive means to assess the extent of neglect recovery (30).
Russell and colleagues provided the first evidence for a deficit in
remapping visual information across saccades underlying right-hemisphere
constructional apraxia (RHCA) (31).
RHCA is a common disorder after right parietal stroke, often persisting
after initial problems such as visuospatial neglect have resolved.
Concurrent saccade programing is bilaterally impaired with extensive
right cerebral damage with an inability to produce a corrective saccade
within 100 ms after the end of a primary saccade (32).
Visual field defects after striate lesions are associated with changes
in the frontoparietal network underlying the cortical control of
saccades, but may improve search strategies with appropriate training of
saccades (33).
Nelles and colleagues used functional magnetic resonance imaging (fMRI)
to study the effects of eye-movement training (EMT) on cortical control
of saccades (34).
EMT induced altered brain activation in the striate and extrastriate
cortex as well as in oculomotor areas and a relative decrease of
activation in the left FEF. The cerebellum plays a major role in
saccadic adaptation representing a well-established model of
sensory–motor plasticity (35).
The cerebellum remains intact after MCA infarction, while the
intraparietal sulcus may be the neural substrate for remapping of the
visual environment by saccadic training (36).
But saccade training may not be enough in EMT as repetitive
contralesional smooth visual pursuit training has been shown to induce
superior, multimodal therapeutic effects in mild and severe chronic
stroke patients with neglect syndrome (37).
Exploratory findings suggest that measurements of
saccades, smooth pursuit, and vergence are useful in detecting changes
associated with mild traumatic brain injuries (38),
and it is reasonable to utilize them in other brain syndromes,
including stroke. EMT has been used with vestibular rehabilitation in
the successful treatment of Post-Traumatic Stress Disorder (PTSD) in
combat veterans after traumatic brain injury (39–41).
Dong and colleagues evaluated the sensitivity of measuring cognitive
processing in the ocular motor system as a marker for recovery of
deficit in post-stroke patients (42).
They tested ocular motor function and compared outcomes in the NIHSS
score, modified Rankin Scale (mRS), and standard cognitive function
assessments. Ocular motor function was more sensitive in identifying
cognitive dysfunction and improvement compared with NIHSS or mRS. They
concluded that ocular motor assessment demonstrates cognitive effects of
even mild stroke and may provide improved quantifiable measurements of
cognitive recovery post-stroke. We desired to see if EMT might be
beneficial in the treatment of acute MCA infarction and hypothesized
that it would result in positive changes of qEEG and NIHSS.
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