Partial training-induced recovery of visual function in hemianopic patients after stroke

Annual incidence of cerebral infarctions or stroke is estimated at 41000 in the
Netherlands (source: hartstichting.nl); some 30% remain visually impaired after
the event. Only in this country we estimate some 50000 patients with visual
defects after a CVA can be found. These numbers are likely to increase as our
life expectancy increases and post-stroke care improves. Patients with cortical
blindness have damage to the postgeniculate optic pathways, which results in a
reduction of vision in the same part of the visual field of both eyes.
Different localization, size, and cause of damage result in various visual
field disorders. Visual field defects may vary between an absolute hemianopic
loss, to a relative loss where vision is partly impaired. Such field defects
can seriously interfere with daily life activities like reading, recognition
(of familiar persons, locations or objects) mobility (disorientation, stumbling
into objects, loss of a driving licence), and job security. Full spontaneous
recovery occurs rarely.
Long after the event causing the defect, an assiduous visual rehabilitative
training can reduce the field defect significantly in a part of the patients.
The training effort is considerable for the patient, hence any gain of the
efficacy of the training is desirable.

In our (and others') previous studies, about 70% of the patients shows a
reduction of the visual field defect ranging from a few to tens of degrees. In
about half of the cases the reduction of the defect is accompanied by
significant behavioural improvements in reading and visual navigation. Although
these results are important indicators of success the mere fact that in about
half of the patients the training causes significant field enlargement leaves
ample room for improvement. Can we then increase both the number of
successfully trained patients as well as the magnitude of the visual field
recovery?

We identify three potential causes for non-response to the training: (1) the
stimulus is not effective enough (2) the patient is not
effectively training at home because he/she does not fixate properly (3) the
damage to the cortex is so deep and complete that there are only few sites
along the field defect that contain potentially trainable remainders of
circuitry.

ad 1) Our earlier studies indicate that reduction of the visual field defect by
itself can lead to behavioural improvements only if the extent of the recovered
field is sufficiently large. The extent that is required depends on the
eccentricity of the defect: at higher eccentricity more degrees of visual field
must be recovered to improve reading or visual navigation. Thus the standard
training protocol (using single point targets) may be not particularly
effective when the visual defect is eccentric. In case, a point target
stimulates only a fraction of the retinal region that needs to be recovered by
training!
ad 3) So far, we have very little means to predict whether a training effort
will be successful. It is likely that cortical structure in the border region
of the defected field is important for recovery, because we have found that the
recovery shows a very gradual spatial shift of the visual field border(Bergsma
et al. 2009). Thus, can we find neurobiological measures of change following
training and derive from these correlates to visual field recovery and
behavioural improvements? This may give important leads as to which particular
structural changes relative to initial state in the border region of the defect
are indicative of recovery potential.

Previously we have shown that visual field defects in hemianopes can be reduced
by visual training and that it improves performance in daily life activities
like reading, car driving (in a simulator), and stimulus identification. Not
all patients profit from the training effort. This project aims to develop the
training protocol further to offer patients a better chance of visual field
recovery and a larger extent of the recovery.

Four goals can be distinguished within this overall perspective.
(1) To find a more efficient stimulus for training than the previously used
standard procedure of using point targets
(2) To improve the training efficiency at home by patients, by control and
feedback of the patient's eye fixation
(3) To collect a broad range of objective MRI measures to follow the effects
of the training on the defect and compare these with a series of behavioural
and perceptual effects of the training
(4)To evaluate the impact of the field recovery on daily life activities.

These data are needed to identify cortical regions/connections that modify by
training and regions that have e.g. functional activity that correspond to the
defect; i.e. cortical visual responsiveness without reaching awareness.
This knowledge will serve the further target of building towards an improved
protocol for training patients with cerebral blindness to recover part of their
lost visual functions.

Each patient is its own control in a double-training paradigm. Each patient
receives two rounds of training.
One training is directed at the hemisphere with the intact visual field
(control). The test-training is directed at the field defect.

Each training variant is preceded and followed by a round of dependent
measurements that determine
(1) the status of the DEFECTIVE visual field by subjective (perimetry) methods
(2) the status of the DEFECTIVE visual field by objective techniques (fMRI of
cortical visual maps , structural MRI of cortico-cortical pathways )
(3) the status of the visuo-behavioural performance in a driving simulator
(4) reading performance

Apart from the training order, there is one further manipulation: the training
stimulus. One group of patients receives training with point stimuli. The other
group receives training with extended optic flow stimuli that fill the majority
of the visual field (diameter: ~ 100 deg). Thus, the 40 patients are randomly
allotted to 4 groups according to training order and training stimulus. (the
training stimulus is identical for control and test training).

A training effect (for the test- or control training) means the change in the
status of each of above mentioned dependent measures (1-4) as determined from a
comparison of the pre-training and the post training measurements. An overall
training effect (of test / control training irrespective of order) means the
change in status of each dependent measure prior to all training and following
both training rounds.

Our tests for the effectiveness of the visual-training compare the effects of
the test training of the field defect with the effects of the control training
of the intact field for each output measure separately.

Finally, to evaluate the Quality of life improvement further each patient
participates in three QoL questionnaires and a (G)oal (A)ttainment (S)caling
assessment at the start and the end of the study.

The training is performed at home with a computer/display system that manages
the training (stimuli) and controls the eye fixation by the patient (using a
webcam). When the patient breaks fixation the training stimulus is terminated
and the trial discounted and repeated later. Patients train 5 days a week for
one hour during 16 weeks (8 weeks test-training and 8 weeks control-training).

Most measurements (see section study design) are carried out three times (prior
to the first training, in between the two training periods and following the
second training). The measurements will be done on three successive days (day
1: MRI; day 2: Behavior/perception; day 3: Behavior/perception). Each test-day
comprises on average 2 hours of measurements.

Patients will undergo standard perimetrical tests to map out the visual field.
Eye fixation is monitored during perimetry.

Functional and structural MRI measurements are done at the Donders' Centre for
Cognitive Neuroimaging in Nijmegen.
During structural MRI the patient is placed in the dark without a task. During
fMRI a visual stimulus is presented that activates different parts of the
visual field successively. Off-line analysis of the MRI signals allows
reconstruction of the retinotopic fields of the occipital and other visually
sensitive cortex. One important limitation in many investigations is the
limited visual stimulus size that one can offer in the bore of the MRI scanner.
We have solved this problem largely by an in-house custom-built projection
system that allows stimulation with a diameter of about 120 degrees. This
results in a much extended cortical activation region.
We place a projection screen very close (± 3cm) to the eye. Because the naked
eye cannot accommodate at this nearby projection surface, the patient needs to
wear a soft contactlens of about 30 Diopters in one eye. We provide this
contactlens. The other eye is covered. The patient places the contactlens in
his/her eye and may ask for assistence from the investigator if need arises. To
this end the investigator has received an instruction session from the supplier
(Visser Contact B.V. Nijmegen).

In earlier studies we observed that virtually all patients (voluntary
applicants) were able to conform to the requested training efforts. This means
that the requested regime of a daily 1-hour training for 5 days per week is not
an excessive burden. In case that a patient should find one straight hour of
training too long, he/she is allowed to train 2 x 30 minutes or 3 x 20 minutes
per day.
Perimetry measurements are common practice in opthalmological settings. Both
perimetry and head-mounted camera-based eye tracking procedures provide no risk
or burden.
The MRI scanner produces a lot of noise, therefore each patient receives
earplugs during scanning. As far as is known, there are no risks involved in
functional MRI acquisition. Patients are screened for MRI counter indications.
If these are absent, MRI scanning is safe.