The Use of Transcranial Direct Current Stimulation (TDCS) to Enhance the Rehabilitative Effect of Vision Restoration Therapy

The specific aim of this study is to improve recovery of visual function after brain injury.
A prominent theme of current neuroscience research regarding the sequelae of brain injury
posits that activity-dependent plasticity underlies neuro-recovery. If that is the case,
there is good reason to believe that neurological changes underling recovery can be
facilitated by established means of enhancing cortical activity. Studies suggest that
altering cortical excitability may prime or prepare the cortex for subsequent training and
furthermore, may improve overall functional outcomes (Webster et al, 2006; Brown & Pilitsis,
2006; Khedr et al, 2005). The working hypothesis of this pilot study is that computer-based
visual rehabilitative training (using NovaVision's Vision Restoration TherapyTM; "VRT"
software) enhances visual function (defined as an increase in functional visual field) by
reinforcing synaptic connections within sensory networks of visual cortex associated with
the visual field loss (Kasten et al., 1998; Sabel, 1999). Potentially, this reinforcement
can be enhanced by concurrent transcranial direct current stimulation (TDCS) leading in
turn, to enhanced visual performance (quantified by the extent of visual field measured by
visual perimetry allowing for a direct statistical comparison of visual field change over
time and on an individual basis) in patients with partial of complete hemianopic visual
field loss caused by brain injury. Both computer based visual rehabilitative training and
TDCS are established techniques and this novel approach aims to provide preliminary data
regarding the safety and efficacy of a combined intervention.

We expect that results from this study will provide an objective basis for a larger, formal
randomized controlled study combining the two therapies. Our long term goals are to maximize
the benefits of a modern vision rehabilitative therapy, lay the groundwork for
neurophysiological correlates associated with the recovery of visual function following
brain injury and propose possible refinements for future neurorehabilitation strategies.
Data from our collaborators at Columbia University Medical Center as well as others indicate
that a 6 month course treatment therapy of VRT can lead to dramatic improvements in visual
function (as quantified by increases in functional visual field) (Kasten et al., 1998;
Kasten et al., 2006). TDCS is well known to bring about transient positive changes in both
functional as well as electrophysiological measures of cortical brain function. If overall
visual function can be further enhanced via a combined synergetic effect of VRT and TDCS, we
will conduct a larger randomized controlled study. If there is no enhancement effect with
combined TDCS and VRT, we will need to reconsider factors as to why this is the case. For
example, a lack of enhancement effect could be related to patient selection including the
degree and profoundness of vision loss prior to treatment, the age of the individual and
duration of the insult, as well as their level of motivation in participating with the
computer-based training program. Other considerations include longer combined treatment
duration.

The loss of visual function following brain injury can be highly debilitating for an
individual. Typically, damage to the occipital cortex or optic radiations following a brain
lesion or trauma leads to a loss of visual function in visuotopically corresponding parts of
the visual field while sparing the remaining areas (e.g. half the visual field as in the
case with hemianopia). This partial blindness and loss in visual function has generally been
considered untreatable due to the fact that the highly specific neuronal organization
underlying normal visual function is determined early in development and not regenerative
particularly after the "critical period" of development has been reached. More recent
evidence (including that from our laboratory) has demonstrated that a considerable degree of
plasticity and reorganization of the visual system occurs not only after cerebral damage but
also in adulthood, that is, well after the critical period of development has occurred. For
example, evidence of spontaneous post-lesion neuroplasticity has been demonstrated in the
adult visual system as documented by extensive receptive field reorganization following
lesions in the retina or visual cortex (e.g. Kass 1990).

Computer-based training strategies have been developed to train and rehabilitate various
cerebral functions such as language learning deficits. Computer-based training has also been
extensively studied as a treatment for partial blindness in adult brain-injured patients
(Kasten et al., 1998; Sabel and Trauzettel-Klosinksi, 2005; Sabel et al., 2005). However,
the neurophysiological mechanisms underlying the reported beneficial effect following VRT
remains poorly understood. One important issue is that if the restoration of visual field
and function is the result of localized neuroplastic changes in cortical circuitry within
visual cortex, one can posit that modulation of cortical excitability should in turn
influence the degree of this restorative effect. More specifically, increasing the level of
overall cortical excitability of the visual cortex should potentiate synaptic neuroplastic
interactions and thus translate into improved visual functional gains.

Transcranial Direct Current Stimulation (TDCS) represents a noninvasive method of brain
stimulation that could potentially modulate such an effect. TDCS utilizes low amplitude
direct currents applied via scalp electrodes to inject currents in the brain and thus
modulate the level of excitability. Direct Current (DC) stimulation has been used in various
forms since the inception of modern electrophysiology at the beginning of nineteenth
century. There has been a recent upsurge in interest in TDCS as a tool for neuroscience
research as well as an assessment and treatment modality for various neurological and
neuropsychiatric disorders including depression, Parkinsonism, stroke recovery, and chronic
neuropathic pain. TDCS has the distinct advantage of being inexpensive, easy to administer,
noninvasive and painless. We have extensive experience with TDCS and are currently running
parallel studies. We now wish to extend these principles into the visual rehabilitation
domain.

VRT: Computer-based training strategies have been developed to train and rehabilitate adult
brain-injured patients with partial visual loss due to brain damage (Kasten et al., 1998;
Sabel and Trauzettel-Klosinksi, 2005; Sabel et al., 2005). Vision restoration therapy (VRT)
involves identifying and stimulating regions in the visual field that are only partly
damaged by brain injury or trauma. Patients receive a customized program designed for their
visual field deficits to use at home daily. Through a specific pattern of visual stimuli
that gauge the user's ability to identify and react, users can gradually expand their visual
fields and restore lost vision. The training can be done at home in front of a
computer-based device, usually in 30-minute sessions, twice a day. During the training,
hundreds of visual stimulations are presented on the monitor to the areas of residual
vision. It has been proposed that repetitive stimulation of damaged visual areas leads to
neuroplastic changes altering nerve activity related to vision, and strengthening synaptic
interactions that can help restore some of a person's visual functions. Work by Sabel and
colleagues reported findings from fifteen patients that underwent six and 12 months of VRT
(Kasten et al., 2006). Visual field assessments were performed before and after VRT and then
repeated an average of 46 months after completing VRT. After six months of VRT, sample
stimulus detection increased significantly from about 54% to 63%. The number of undetected
stimuli decreased significantly in both eyes. Continuing VRT for 12 months improved the
results achieved at six months. The follow-up examination after a therapy-free interval of
more than three years showed that the benefits of VRT remained stable, and vision loss did
not occur in most instances. According to this study, patients with vision loss after brain
injury benefit regardless of the severity of the lesion or how much of their vision is
affected. Furthermore, the larger the areas of residual vision, the better the outcome with
VRT. It is clear that VRT has varying results. In this study, one-third of patients studied
had little or no effect from VRT, one-third had moderate but noticeable improvement, and
one-third had strong or dramatic improvement. Patient compliance with VRT is reported to be
very good.

NovaVision VRTâ„¢ is the first and only FDA-cleared medical device or rehabilitative therapy
clinically proven to improve visual field defects in brain injury survivors who have become
left partially blind due to their condition. In an on-going multi-center trial sponsored by
NovaVision, over 70% of study participants from 16 U.S. centers who underwent a six-module
(six month) course of therapy showed a three percent or greater improvement in stimulus
detection on visual field testing. The average improvement in stimulus detection was 12
percent. Previous studies suggest that people who regain three percent or more of their
visual field have functional improvements that may include enhanced quality of life through
better reading performance, watching television and playing sports, although functional
outcomes were not measured in this study. These results were presented at the 2007 Academy
of Neurology meeting in Boston, MA.

TDCS: Transcranial direct current stimulation (TDCS) has been used for several decades.
Numerous human clinical and animal studies have demonstrated that this technique is able to
modulate neuronal activity and function through the delivery of polarizing currents applied
to the surface of the brain. Surface anodal polarization of the cortex increases spontaneous
neuronal activity, whereas cathodal polarization generally depresses neuronal activity
(Creutzfeld et al., 1962). Recent human studies have demonstrated that stimulation with
TDCS changes motor cortex excitability according to the stimulation polarity: whereas anodal
stimulation increases cortical excitability, cathodal stimulation decreases it (Nitsche et
al., 2003a and b). Moreover, and from a clinical therapeutic point of view, the effects of
TDCS appear to be long-standing. For example, 13 minutes of TDCS has been shown to modulate
cortical excitability and last up to 2 hours following the stimulation period itself
(Nitsche and Paulus, 2001). Two recent studies (including one by a co-investigator listed
here) explored the effects of TDCS on motor function in stroke patients and showed that
these modulatory effects of TDCS can be used to improve motor function (Fregni et al.,
2005a; Hummel et al., 2005a and b). Interestingly, similar modulatory effects have also been
described in the visual cortex (Antal et al., 2001; Antal et al., 2004) leading support to
the notion that activity within visual cortical areas can be modulated and in turn lead to
behavioral changes.

TDCS modulates the excitability of a targeted brain region non-invasively by altering
neuronal membrane potentials (Bindman et al. 1962; Purpura & McMurtry, 1965). Thus, this
technique can be used to increase or decrease the excitability of neurons in a targeted
brain area and this can establish a causal relation between a given region of the brain and
a specific sensory, motor or cognitive function. Unlike Transcranial Magnetic Stimulation
(TMS), TDCS does not depolarize neurons causing them to fire. TDCS only alters the
likelihood that neurons will fire by depolarizing or hyperpolarizing brain tissue (depending
on the stimulation parameters used). The neurophysiological basis of TDCS has been
attributed to a mechanism akin to long-term potentiation (LTP) and long-term depression
(LTD) (Hattori et al. 1990; Moriwaki, 1991; Islam et al. 1995). Certain medications such as
dextromethorphan (an NMDA antagonist) suppress post-TDCS stimulation effects of both anodal
and cathodal stimulation which strongly suggests the involvement of NMDA receptors in both
types of DC-induced neuroplasticity. In contrast, Carbamazepine selectively eliminates
anodal effects. Since Carbamazepine stabilizes the membrane potential voltage-dependently,
the results reveal that after-effects of anodal TDCS require a depolarization of membrane
potentials (Liebetanz et al., 2002). This study by Liebetanz et al., (2002) provided
pharmacological evidence that induction of the after-effects of TDCS requires a combination
of glutamatergic (excitatory) and membrane mechanisms, similar to the induction of
established types of short- or long-term neuroplasticity.

In animals, anodal cortical stimulation of 5-30 minutes has been shown to cause excitability
increases lasting for hours after the stimulation, primarily through modulation of the
resting membrane potential (Terzuolo & Bullock, 1956; Creutzfeldt et al. 1962; Eccles et al.
1962; Bindman et al. 1964; Purpura & McMurtry, 1965; Artola et al. 1990; Malenka & Nicoll,
1999). In humans, 13 min of TDCS resulted in an increase in excitability up to 150% and
lasting 90 min (Nitsche & Paulus, 2001). Research with TDCS has revealed that anodal
stimulation can induce transient (on the order of 30 minutes) improvements in performance on
cognitive, motor and linguistic tasks. For example, Hummel et al. (2005a,b) found that
anodal TDCS delivered to the primary motor area in the lesion hemisphere elicited
significant improvements in motor control of the paretic limb. The effect lasted for more
than 25 minutes after stimulation. In a recent study, Fregni et al (2005a) also verified
that anodal TDCS to the affected hemisphere and cathodal TDCS to the contralesional
hemisphere improved motor function. Other examples highlighting the efficacy of anodal TDCS
include Fregni et al. (2005b) - anodal TDCS to dorsolateral prefrontal cortex elicited an
improvement in working memory; Nitsche et al. (2003a) - stimulation to primary motor cortex
improved motor learning; Antal et al. (2004) - TDCS delivered to primary motor area or to
visual area V5 induced improvements in visuo-motor coordination; Kincses et al. (2004) -
anodal stimulation of fronto-polar regions improved probabilistic classification learning;
and Lyer et al. (2005) - left prefrontal cortical stimulation lead to increased verbal
fluency. These studies attest to the efficacy and safety of TDCS in brain injury patients,
as well as its potential for therapeutic applications in brain lesion recovery.

In summary, we propose to conduct a pilot experiment testing whether visual function
in-patients with hemianopic field loss caused by brain injury can be improved by combining
transcranial direct stimulation and computer based vision training. We hypothesize that
computer based vision training will reinforce visual cortical networks primed by concurrent
transcranial direct current stimulation (TDCS) and lead to improved visual performance. The
BIDMC investigators will be responsible for TDCS application and VRT, as well as associated
data processing / interpretation.