The roles of occipital and parietal regions in visual awareness: A Transcranial Magnetic Stimulation study

In everyday perception, people rarely distinguish between the objective and
subjective aspects of their percepts. The silent assumption is that everything
that meets the eye is consciously seen and creates activations in the brain
that are strong enough to influence thinking and behaviour. However, the past
hundred years of psychophysics research has convincingly demonstrated that this
is not the case. More recently, a wealth of fMRI and TMS studies have
investigated the neural bases of the objective and subjective aspects of
perception.
A particularly striking example of the dissociation between subjective
awareness and objective processing of visual stimulation is the condition
called *blindsight.* Blindsight refers to the phenomenon that, after a lesion
to the primary visual cortex, a subject can exhibit above-chance performance in
detecting or discriminating visual stimuli in a forced-choice setting, despite
the lack of acknowledged consciousness of the stimuli. In some instances,
blindsight subjects can perform at an impressively high level of accuracy
(higher than 80%) in the forced-choice task, even when the subjects believe
that they are guessing.
A related phenomenon, which involves dissociation between objective
processing and subjective visibility, is the condition known as *visual
neglect.* Damage to the posterior parietal cortex (PPC) results in attentional
deficits that concern stimuli presented in the contralesional space. Further,
it has been shown that when neglect patients claim not to see a stimulus in the
contralesional visual field, they still perform higher than chance on
forced-choice tasks. Unfortunately, despite their tremendous importance for
understanding the various aspects of visual processing, cases of blindsight and
visual neglect are very rare. Recently, Boyer et al. (2005) and Nyffeler et al.
(2008) succeeded in inducing blindsight-like and neglect-like conditions,
respectively, in normal subjects using TMS. Such studies allow researchers to
explore the above discussed conditions without the complications of worrying
about side effects of natural lesions.

In the present study we will attempt to produce blindsight-like and
neglect-like conditions in normal subjects using theta burst stimulation (TBS)
and then explore how visual processing proceeds using fMRI. More specifically,
our hypotheses are:
1) TBS to the primary visual cortex V1 will result in a blindsight-like
condition characterized by a significant decrease in subjective awareness of
visual stimuli but relatively unaffected ability to perform visual tasks.
2) TBS to PPC will result in a neglect-like condition characterized by a
significant decrease in subjects* ability to subjectively experience stimuli
presented in their contralateral visual field.

The study is designed as a crossover experiment with healthy adult volunteers.

In the pilot experiment, we will use 40-second continuous theta-burst
stimulation (cTBS). The study will investigate the role of V1 and PPC in visual
perception. Stimulation of both regions will be compared to vertex stimulation.
We expect that stimulation of both V1 and PPC will results in significantly
lower visibility ratings when compared to vertex. Further, we expect that the
effect will be global for V1 but will be localized to the contralateral visual
field in the case of PPC stimulation.
Subjects will first receive 40 seconds of cTBS and then do a visual
task. The visual task will consist of discriminating between different
orientations of low-contrast gratings, and rating the visibility of those
gratings. We will stimulate healthy participants with cTBS in a within
subjects-design. Subjects will come for a total of three sessions - one for
each of the three targets regions: V1, PPC, and vertex.
Prior to the experiment, participants are informed about the study in
detail and about the possible risks. They are screened using a questionnaire to
ensure their eligibility for participation. In the first session of the pilot
experiment, participants receive practice with the behavioural task.
Afterwards, we will establish subjects* active motor threshold (aMT) as
determined using TMS pulses. The aMT is defined as the lowest TMS intensity
needed to evoke a reproducible and measurable (with electromyography) muscle
twitch in the first dorsal interosseus of the right hand (Rossini et al. 1994).
The aMT provides an indication of the excitability of a participant*s brain and
will be used to determine the stimulation intensity in the later TMS sessions.
We will also acquire an anatomical image of the participant's brain to aid
placement of the TMS coil.
In sessions 2-4 participants receive 40 seconds of triplets of 50 Hz pulses in
a 5 Hz rhythm at 80% of the participant*s aMT to V1, PPC and vertex
respectively. The placement of the coil will be guided an anatomical MRI scan
of the individual subject. The stimulation locations will be determined using
the BrainSight TMS-MRI co-registration system. This system allows to navigate
the TMS coil in relation to the individual anatomical MRI in real-time with
millimetre accuracy. Sessions 1, 2, and 3 are spaced at least 7 days apart and
will be counterbalanced across subjects.

The main experiment will be similar to the pilot experiment but will involve
fMRI scanning. Subjects will first receive 40 seconds of cTBS and then do a
visual task while being scanned in an fMRI scanner. As in the pilot experiment,
the visual task will consist of discriminating between different orientations
of low-contrast gratings, and rating the visibility of those gratings. We will
collect data in the fMRI scanner for up to one hour, excluding the time needed
for acquisition of structural images. We will stimulate healthy participants
with cTBS in a within subjects-design. Subjects will come for a total of four
sessions.
Prior to the experiment, participants are informed about the study in
detail and are informed about the risks, and they are screened using a
questionnaire to ensure their eligibility for participation. In the first
session, subjects will receive practice with the behavioural task. The aMT is
established (see above for details) and an anatomical image of the
participant's brain is acquired to aid placement of the TMS coil. Sessions 2-4
will mimic sessions 1, 2, and 3 from the pilot experiment. Subjects will
receive cTBS to either V1, PPC, or vertex with the intensity and placement of
stimulation chosen as above. The only difference is that subjects will do the
visual task after the stimulation in the MRI scanner rather than in front of a
computer.
Sessions 2, 3, and 4 are spaced at least 7 days apart and will be
counterbalanced across subjects.

We will use 40-second continuous theta-burst stimulation (cTBS). cTBS refers to
a simulation paradigm in which participants receive brief trains of pulses of
50 Hz in a 5 Hz (the theta frequency) rhythm. Compared to the more traditional
1Hz repetitive TMS (rTMS), cTBS can be applied at lower thresholds (80% of the
motor threshold), the duration of stimulation is much shorter (20-50 seconds),
and the effect is more consistent and lasts longer than the effect of rTMS.
Traditionally cTBS was predominantly applied to motor regions (cf. Huang et al.
2005, Vallesi et al. 2007; Classen & Stefan 2007), but recent studies showed an
effect of cTBS on V1 (Franca et al., 2006), PPC, and vertex (Hilgetag et al.
2001; Nyffeler et al., 2008). Thus, cTBS has already been tested and found safe
as a method of stimulating all the regions that we will target in the present
study.

When TMS was first developed, several studies have applied stimulation for long
periods of time, at high intensities, with high-frequency (> 5 Hz). Using these
high-intensity high-frequency stimulation resulted in several occasions in an
epileptic phase in the subject (without long-term damage). This resulted in
strict safety regulations for the use of combinations of stimulus strength,
duration, and frequency. Since these regulations have been in place, there have
been no epileptic fits in healthy subjects in studies abiding by there
guidelines. We use these guidelines in the proposed study. Therefore, it is in
principle possible that rTMS causes an epileptic fit, but the risk of this
happening is very small in healthy subjects, unless subjects are stimulated for
prolonged periods of time at frequencies 10-25 hz at high stimulation
intensities. TBS is a recent development in TMS research. Instead of a
continuous stimulation frequency with isochronous intervals TBS uses short
trains of pulses that are repeated at 5 Hz. TBS uses less pulses than rTMS and
lower intensities, while the effects are of the same magitude as for rTMS.
Since its introduction, TBS has been used in a high number of studies. In our
study we will use TBS and all volunteers will be screened using a
questionnaire. We know of no cases in which TBS has caused an epileptic fit in
a healthy volunteer.