Effect of rTMS Over the Medial Cerebellum on Negative Symptoms and Cognitive Dysmetria in Subjects With Treatment Refractory Schizophrenia
Phase: NA
Conditions: Schizophrenia
Sponsor: Seton Healthcare Family

Effect of rTMS over the Medial Cerebellum on Positive and Negative Symptoms and Cognitive Dysmetria 
in subjects with treatment refractory Schizophrenia 
 
Robert J. Buchanan, M.D. 
Zoltan Nadasdy, Ph.D. 
James Underhill, Psy.D. 
Seton Brain and Spine Institute 
UT Austin Department of Psychology and The Neuroscience Institute. 
 
Protocol Document Date: August 23, 2013 
NCT02242578 

 
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Effect of rTMS over the Medial Cerebellum on 
Positive and Negative Symptoms and Cognitive 
Dysmetria in subjects with treatment refractory 
Schizophrenia 
 
Robert J. Buchanan, M.D. 
Zoltan Nadasdy, Ph.D. 
James Underhill, Psy.D. 
Seton Brain and Spine Institute 
UT Austin Department of Psychology and The Neuroscience Institute. 
 
Hypotheses: 
1) Cerebellar stimulation will cause activation of thalamic and frontal 
cortical networks associated with attentional processes. These 
attentional processes are a component of the “distracted” affect of 
schizophrenia (part of both positive and negative symptoms). 
2) Cerebellar stimulation will cause activation of the reticular activating 
system (RAS), and this will allow the “mutism”, which is a negative 
symptom, to be partially improved.  
 
Purpose of Study, Anticipated Benefits 
 
The etiology of negative symptoms in schizophrenia which includes social 
withdrawal, affective flattening, poor motivation, and apathy is poorly understood. 
Symptomatic treatment of these negative symptoms with medications and 
psychotherapy are almost non-existent, whereas treatment of the positive 
symptoms (hallucinations and delusions) has been more effective with 
psychotropic medications. New methods of treating negative symptoms are 
needed.  
 
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 (M. 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 

 
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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, we can increase the decreased level of 
arousal, which in many schizophrenic 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 (fig 1). 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. 
 
 
 
Fig 1. 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. Interestingly, the activity of those intracortical 

 
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inhibitory neurons may be assessed by measuring cortical inhibition of Short 
inetracortical inhibition (SICI) using paired pulse Trans cranial magnetic 
stimulation. (TMS) (Langguth et al 2008). SICI reflects intracortical GABA 
(A)ergic function.  
 
Following this model, activation of Purkinje cell will inhibit the thalamic drive to 
intracortical inhibitory neurons, therefore, decrease the intraccortical inhibitory 
interneuron 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 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 SH, 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 schizophrenic patients 

 
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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, 
schizophrenic 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) psychiatry research: 
Neuroimaging 163 (2008) 193-200 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. 
 
All subjects will have a DSM IV TR Axis I diagnosis of Schizophrenia (295). They 
will be screened to determine that they do not have co-morbid AXIS I disorders, 
and if they do, that they are in remission. Patients with AXIS II disorders will be 
excluded. The patients must also be able to communicate with the examiner and 
also be able to cooperate during the administration of the rating scales. We will 
also ask both the patient and the care-giver if appropriate, to keep a brief Journal 

 
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of both their positive, negative, and mood symptoms daily. The patient must also 
be able to sit in the TMS chair for a 20 minute treatment. This will be determined 
by the Board Certified Psychiatrist, who is also the PI.  
Patients enrolling to the study 
A. must be stable on their medications at the start of their enrollment in the 
study and throughout the duration of the study. 
B. must have no history of substance use of substance-dependence issues 
over at least the past six months, 
C. must be able to and have the capacity to provide consent, 
D. and if older patient, he/she must be able to participate without a safeguard 
to be present. 
 
 
Patients excluded from the study are: 
 
A. 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.). 
B. Patients who have had changes in their medications (i.e., patients must be 
stable on their medications throughout their participation in the study). 
C. Patients with history of substance abuse or substance-dependence 
anytime over the past six months. 
D. Patients who are unable (i.e., do not have the capacity) to consent. 
 
In addition, we require a third-party psychiatrist who is not involved in this study 
making the determination of whether or not the patient has the capacity to 
consent to participate in the research study. For example, the referring or primary 
psychiatrist can state this in their referral letter for the patient.  
 
In order to keep the patients in the study, we will provide taxi rides to the TMS lab 
and back. In addition, we will contact them by phone before the day of their 
appointment, and every day during the experiment to remind them to their 
appointment. Moreover, we will follow up with every patient after they completed 
the TMS sessions to make sure that they keep record of their status in their 
journal. We also provide them with a flyer containing their appointment dates, 
times, location and contact information. The patients can cancel their 
appointment by phone. 
 
Experimental Design and Methods/Procedures 
 
1) rTMS over the vermis of the cerebellum 
2) 3 sessions/week for 1 month 
3) Randomization as explained below. 
4) Patients/subjects will receive pre-treatment protocol neuropsychiatric 
measures. These rating scales are accepted and standardized. 

 
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a. Brief Psychiatric Rating Scale 
b. Scale for the Assessment of Negative Symptoms (SANS) 
c. Scale for the Assessment of Positive Symptoms (SAPS) 
d. Thought Disorder Index 
e. Barnes Akathisia Rating Scale (BARS) 
 
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) 8 rTMS treatments, double-blind, that in 2 treatment 
sessions/week with sham or active rTMS for over period of 4 weeks; and (3) a 
follow-up period of 1 month. The patients will then be reassigned to the other 
Frequency (either high or low) Arm of the study (Table 1). The protocol will then 
be repeated. Patients and the investigators, except the investigator who applied 
rTMS, will be blinded to the treatment arm. During the baseline period, patients 
will be randomized in a) a 3:4 ratio to receive sham (3 in each 7 patients) or b) an 
active (4 in each 7 patients) rTMS. We chose this randomization strategy (3:4) to 
increase the sample size of the active treatment. This strategy of randomization 
is advocated in small sample size phase II trials that do not have adequate 
information on the efficacy of a new treatment (Peto, 1978). The disadvantage of 
this strategy is that it decreases the power of the study (because less information 
from the sham group is provided). However, we accounted for this decrease of 
power (that is minimal with the 3:4 ratio) in our sample size calculation. 
Randomization was performed using the order of entrance in the study and a 
randomization table previously generated by a computer using randomization 
blocks of seven (for each seven patients, three were randomized to sham and 
four to active rTMS) to minimize the risk for unbalanced group sizes. To 
determine the sample size, we assumed a mean reduction in seizures of at least 
50% in the active group. We chose this effect size from our preliminary data and 
because our aim was to assess whether rTMS may have a truly clinically 
meaningful impact. In the sham rTMS group, we assumed mean reduction of 
seizure frequency of 15%. This was based on the placebo effect reported in 
Theodore et.al 
 
 
 
  

 
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Cerebellar stimulation: 
1) At each session, 1000 stimuli rTMS will be delivered at an intensity of 
120% of resting motor threshold (RMT) by a figure of eight coil (double 
circular 90 mm coil), connected to a Magstim Rapid 2 stimulator (Magstim 
Company, Dyfed, UK). This relatively high stimulation intensity is chosen 
in order to ensure that the magnetic field reaches the cerebellum in spite 
of the higher distance from the coil compared to motor cortex stimulation. 
Medial cerebellum (vermis) will be targeted based on individual MRI data. 
The coil will be positioned over the cerebellar vermis (lobule VII At; Fig. 
2a), A neuronavigational system (Brainsight, Montreal, Canada) will be 
used to navigate the coil on the surface of the skull over the targeted brain 
region.  
 
Once the optimal coil position is found, the coil will be held with a mechanical 
arm and its position over the target region will further monitored by the 
neuronavigation system. The handle of the coil will be pointed upwards. The 
current in the coil will be directed downward during the reversal phase of the 
biphasic stimulus, thus inducing an upward current in the region of interest. This 
current direction is considered optimal for cerebellar stimulation (Figure 3). In 
each of the treatments session, a Magstim rapid 2 air cooled 9-cm circular coil 
will be placed on the area of abnormal cerebellar activity. Stimulation will be 
 
PHASE I (Vermis, High Frequency 10 Hz) 
 
I 
TMS lab 
- rTMS treatment (20 minutes, 1 Hz).          
II 
The above protocol is repeated on Tuesday and Thursday, for 4 weeks (8 
treatments). 
III 
Record in Psychiatric Journal over the 4 week treatment period. 
IV Pre and Post rTMS treatment Psychometrics and Journals will be analyzed 
for a change in ratings and behaviors respectively 
1 month washout period. New Neuropsychological Testing (Psychometrics) 
 
PHASE II (Vermis) (Low Frequency 1Hz) 
 
I 
TMS/lab 
         - Pre rTMS, Repeat Psychometric Scales. 
         - rTMS treatment (20 minutes, 1 Hz). 
         
II 
The above protocol is repeated on Tuesday and Thursday, for 4 weeks (8 
treatments). 
III 
Record Psychiatric Journal over the 4 week treatment period. 
IV Pre and Post rTMS treatment Psychometrics and Journals will be analyzed 
for a change in ratings and behaviors respectively. 

 
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given 2 seconds per minute for 20 consecutive minutes per session at an 
intensity of 120% motor threshold, a minimal magnetic pulse that reliably induced 
visible contra lateral thumb movement. The frequencies for the active stimuli will 
be 1 Hz, individualized alpha (8–13 Hz). Sham stimulation will be given by 
applying the “sham coil” to the same cerebellar area. All rating scales were 
administered at screening, baseline (immediately prior to first treatment), 
immediately following the final treatment, and after 4 weeks of washout for each 
condition. 
 
While the technician administering the rTMS procedures could not be blinded, 
the evaluating physician and patients remained unaware of the type of treatment 
throughout the duration of the study. 
 
 
 
  
 
Figure 3. Left side a figure of eight TMS coil is positioned to point to the 
cerebellum. When the coil is positioned exactly orthogonal to the mid-sagittal 
plane the largest magnetic current is applied to the vermis. 
 
 
 
 
 
 
 
Subject Population 
 
Patients diagnosed with schizophrenia (age: 18-80 years old) presenting 
predominantly with negative symptoms and stabilized on current antipsychotic 

 
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medications for at least 30 days will be enrolled in the study. Severity of 
symptoms will be evaluated by the Positive and Negative Syndrome Scale 
(PANSS). During the subject recruitment, a minimum score of 20 on the PANSS 
negative symptom subscale and a maximum score of 19 on the positive 
symptoms subscale are required at baseline. 
 
 
Statistical Analyses  
 
Apriori categorical definition for clinical response will be > 30% baseline-to 
posttreatment reduction, or < 16 at the end of second phase treatment when 
baseline score is lower than 20 on PANSS negative symptom subscale. 
 
Clinical data were analyzed on an intent-to-treat basis with the last observation 
carried forward. Patients with a baseline and at least 1 additional set of 
completed assessments (at least 5 treatment sessions) were included in the 
analysis of mean treatment effect. Efficacy in clinical ratings was evaluated by 
using analyses of variance (ANOVA). The models included 1 between-subjects 
factor of treatment, and 2 within-subjects factors of time and treatment order. 
Covariance for the baseline was used when significant group difference was 
found at the baseline. 
 
 
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