Treating Refractory Schizophrenia With rTMS

Background and Significance

There is increasing evidence from neuropsychological and imaging studies that cerebellar
function is relevant not only to motor coordination, but equally to cognition and behavior
(Rapoport et al., 2000). Selective modulation of cerebello-thalamocortical pathways, in turn,
is believed to provide an additional means of modulating cortical function. Repetitive
transcranial magnetic stimulation (rTMS) can modulate cortical excitability focally in
conscious subjects. Trains with slow frequency (i.e.,1 Hz) are known to suppress cortical
excitability (Chen et al., 1997), whereas facilitation occurs if frequencies higher than 5 Hz
are used (Berardelli et al., 1998). With respect to rTMS of the cerebellum, a major impact on
cognitive function (Oliveri et al., 2007) has been described.

The cerebellum is a very good candidate to be the generator for intracortical inhibition; its
stimulation can modulate the cortical inhibition. Invasive studies by Robert Heath at Tulane
University revealed that the cerebellum is strongly connected to 2 structures at the core of
the proposed abnormal circuitry in schizophrenia, the septal nuclei and the hippocampus (HC).
According to his theory and findings, the septal nuclei are involved in positive mood
regulation, pleasure. The firing of the HC was correlated with negative affect and sadness
(Heath et al, 1980). By stimulating the fastigial nucleus and vermis of the cerebellum, the
septal nuclei were facilitated to fire and the HC was inhibited. The other component of what
Heath referred to as the "aversive system", the amygdala was also inhibited. This central
role of the cerebellum in this circuit is analogous to its role in "smoothing" the flow of
movements. When considering emotion and cognition, the cerebellum has a smoothing function.
Aside from direct monosynaptic connections between these sites, there is evidence that the
deep cerebellar nuclei are connected to the parietal cortex, temporal cortex, as well as the
cingulate gyrus. These are all areas that have limbic function. The cerebellum is also
directly connected to the midbrain reticular activating system (RAS). This region is
responsible for levels of consciousness and arousal. By potentiating the activation of the
RAS, wthe investigators e can increase the decreased level of arousal, which in many
schizophrenia patients is akin to psychomotor retardation and mutism (catatonic). Midline
deep cerebellar nuclei efferents have been traced to the hypothalamus, central nuclei of the
thalamus, which are also associative (cognitive) and limbic in function. The Locus Ceruleus
and the substantia nigra, in the brain stem are also monosynaptically connected to the
cerebellum.

The cerebellum is connected to thalamus and motor cortex (frontal cortex) through
cerebello-thalamo-cortical pathway. And as stated above it is also connected to a vast array
of limbic structures, making it a good choice to use to modulate abnormal activity in these
structures.

Purkinje cells, the output neurons of cerebellar cortex reduce the excitatory drive from the
deep cerebellar nuclei via the ventrolateral thalamus to inhibitory neurons in the motor
cortex. Activation of Purkinje cells will inhibit the thalamic drive to intracortical
inhibitory neurons, therefore, decrease the intracortical inhibitory interneuron activity and
decrease in SICI and CSP. On the other hand, inhibition of Purkinje cerebellar cells is
expected to have opposite effect and release the thalamus from inhibitory control, increase
the thalamic drive to stimulate the inhibitory interneurons which can be demonstrated by
increase in SICI and CSP Indeed, applying inhibitory rTMS at frequency of 1 Hz resulted in
increase in SICI (Langguth et al., 2008).

The midline deep cerebellar nuclei, those that are anatomically and phylogenetically related
to the vermis, also send collaterals to the reticular activating system (RAS) of the brain
stem. By increasing the excitatory (Glu) drive on the RAS, the subject will experience
increased awareness and connection to their environment.

For decades, the cerebellum has been thought to be predominantly involved in motor
performance and cognitive operations. Recently, however, a growing body of evidence indicates
that the cerebellum is also involved in emotion. The first evidence for cerebellar
involvement in emotion came from the work of Robert G. Heath during the early fifties.
Although his initial work predominantly involved the electrical stimulation of the septum, he
then began research on stimulation of the cerebellum, thinking that it might provide a better
entry to the emotional circuitry of the brain. Several cerebellar pacemaker studies by Heath
did indeed demonstrate positive effects on mood and personality in patients with psychiatric
illness after electrical stimulation of the cerebellum. Moreover, Schmahmann and Sherman
provided clinical support for the role of the cerebellum and particularly the vermis in the
regulation of emotion and mood. Given its modulatory role on emotion, the midline cerebellar
vermis together with the fastigial nucleus and the flocculonodular lobe have been designated
the limbic cerebellum (Schutter and van Honk 2005). Furthermore, additional evidence for the
involvement of the cerebellum in schizophrenia was supported by genetic, structural and
functional imaging data (Sandyk et al., 1991; Nopoulos et al., 1999; Ichimiya et al., 2001;
Varnas et al., 2007) as well as by clinical evidence (Deshmukh et al., 2002; Ho et al., 2004;
Varambally et al., 2006). For example, in an animal model for schizophrenia using prenatal
infection of mice with human influenza virus, the animal developed behavioral changes similar
to those of schizophrenia and was associated with altered expression of cerebellar genes
(Fatemi et al., 2008). Some studies reported smaller bilateral cerebellar volumes as compared
to controls in first episode schizophrenia patients (Bottmer et al., 2005). One of the first
studies to demonstrate the importance of a dysfunctional cerebellar circuitry in
schizophrenia was a positron emission tomography (PET) study (Andreasen et al., 1996). The
authors examined memory performance in schizophrenia patients and correlate it to blood flow
in cerebello-thalamo-cortical pathway. They used two tasks for memory, namely an easy and a
relatively difficult one. While patients with schizophrenia showed normal performance on the
easy practiced memory task they already demonstrated decreased blood flow in the
cerebello-thalamo-cortical pathway. By contrast, in the relatively more difficult memory
task, schizophrenia patients performed worse than healthy controls and displayed
significantly lowered frontal and cerebellar blood flow (Andreasen et al., 1996).

Consistent with the assumed disruption of the cerebellothalamo- cortical pathway in
schizophrenia is evidence from two proton magnetic resonance spectroscopic imaging (HMRS)
studies. Lower levels of N-acetylaspartate (NAA), a marker for neuron density and viability,
were found in the thalamus and cerebellar vermis (Deicken et al., 2001) in patients with
schizophrenia. In keeping with these findings, lower NAA levels in the vermis and cerebellar
cortex have also been found (Ende et al., 2005) as well as in mediodorsal region of the
thalamus (Ende et al., 2001). In addition, poor executive functioning in patients with
schizophrenia was associated with volumetric reductions in the cerebello-thalamo-cortical
network (Rusch et al., 2007). Moreover, a diffusion tensor imaging (DTI) study has shown that
patients with schizophrenia demonstrate abnormality in the connectivity between cerebellum
and thalamus with possible difference between the right and left cerebellum (Magnota et al.,
2008). Investigating connectivity between the cerebellum and thalamus in schizophrenia using
diffusion tensor tractography: A pilot study). Another DTI study found neuronal
disorganization in the superior peduncle with neuronal disorganization being associated with
poor cognitive performance (Okugawa et al., 2006). Finally, the activity of right and left
cerebellum may not be the same. For example, impaired working memory in schizophrenia is
associated with over and under-activation along the cerebellothalamo- cortical pathway with
under-activation of the left DLPFC and right cerebellum and over-activation of the left
cerebellum (Mendrek et al., 2005).

To date, cerebellar involvement in schizophrenia remains a subject of ongoing study. It was
shown that motor impairments in schizophrenia are related to cerebellar malfunction. Several
studies report that the cerebellum is indeed involved in cognitive (Eyler et al., 2004; Aasen
et al., 2005; Kiehl et al., 2005) and affective (Paradiso et al., 2003; Takahashi et al.,
2004; Stip et al., 2005) impairments. This study aims to clarify the role of the cerebellum
in development of negative symptoms through its regulation of cortical inhibition, activation
of the septal region with reciprocal inactivation of the hippocampus, and RAS activation.

Experimental Design and Methods/Procedures

1. rTMS over the vermis of the cerebellum

2. 5 sessions/week for 1 week

3. Randomization as explained below.

Patients will be randomly assigned to either the high frequency or low frequency Medial
Cerebellum Target Treatment protocol. Each group will then be entered into a randomized,
double-blind, sham-controlled, parallel-design clinical trial that consists of three main
phases: (1) Baseline Psychiatric and Psychometric Testing Exam; (2) 5 rTMS treatments,
double-blind, in 5 treatment sessions/week with active or sham rTMS for over a period of 1
week; and (3) a follow-up period of 3 weeks. The patients will then be reassigned to the
other Frequency (either high or low) Arm of the study. The protocol will then be repeated.
Patients and the investigators, except the investigator who applied rTMS, will be blinded to
the treatment arm.

Inclusion Criteria:

- Patients enrolling to the study:

- must be stable on their medications at the start of their enrollment in the study
and throughout the duration of the study;

- must have no history of substance use of substance-dependence issues over at
least the past six months;

- must be able to and have the capacity to provide consent;

- and if older patient, he/she must be able to participate without a safeguard to
be present.

Exclusion Criteria:

- Patients excluded from the study are:

- Patients with typical clinical considerations that exclude them from treatment
with TMS (i.e., patients who have had head injuries, patients with metal
implants, patients with a history of seizures, patients with elevated risk of
seizures, patients who are taking medications that may interfere with TMS or
potentiate the related side effects, etc.).

- Patients who have had changes in their medications (i.e., patients must be stable
on their medications throughout their participation in the study).

- Patients with history of substance abuse or substance-dependence anytime over the
past six months.

- Patients who are unable (i.e., do not have the capacity) to consent.