Tracing the origin of psychosis in schizophrenia - A repetitive TMS/neuroimaging study of frontostriatal interaction

Schizophrenia is characterized by positive symptoms (i.e. psychotic episodes
characterized by delusions and hallucinations) and negative symptoms (i.e.
decline in cognitive and social functioning and emotional blunting). Positive
symptoms are associated with abnormal function of the striatum, whereas
negative symptoms have been related to dysfunction of the prefrontal cortex. It
has been hypothesized that the deficits underlying positive and negative
symptoms are linked, in that prefrontal regulation of the striatum fails due to
dopamine disfunctioning, giving rise to psychosis and related symptoms.
Although supported by several findings, direct evidence from human studies for
this hypothesis is still lacking.

The objective of this study is to directly test, in humans, the hypothesis that
reduced prefrontral control leads to dysregulation of the striatum.

Using neuroimaging techniques and repetitive transcranial magnetic stimulation
we will localize prefrontal regions that are involved in controlling activity
in the striatum (Study 1 and Study 2). Besides, we will clarify frontostriatal
activation patterns on fMRI by investigating underlying genetic mechanisms in
dopaminereceptors that may be responsible for these effects. The effects of
frontal suppression on striatal activation will then be investigated in healthy
siblings of schizophrenia patients and healthy control subjects (Study 3).

In the Pilot study and Study 3, healthy siblings of schizophrenia patients and
healthy control subjects are randomly assigned to an experimental or control
subgroup. The experimental subgroups will receive repetitive transcranial
magnetic stimulation over prefrontal regions, whereas the control groups
receive stimulation over a brain region that does not interact with the
frontostriatal system. In Study 2, healthy control subjects will take part in
both the experimental and control conditions. In the two experimental
conditions subjects will receive rTMS over prefrontal regions. In the control
condition subjects will receive sham rTMS. The order of rTMS treatment (i.e.
experimental vs control) is counterbalanced across subjects. For gene
investigation there will be blood collection of healthy controls only, whereas
blood collection of schizophrenia patients and their siblings already has been
performed under a different protocol (04-003).

The burden of this study differs per experiment and study group. Studies will
take at maximum two and a half hours per day. Furthermore, only non-invasive
techniques will be used. Given careful screening, there are no known risks
associated with magnetic resonance imaging. When severe abnormalities will be
noticed on the magnetic resonance scans, a radiologist will be asked for
advise, Repetitive transcranial magnetic stimulation is also a safe technique,
but some, generally mild, adverse events have been identified, including
headache. More severe adverse events associated with repetitive transcranial
magnetic stimulation (e.g. tinnitus and (pseudo)seizures) are rare. To minimize
the risk of severe adverse events we will take extensive safety measures.
First, subjects will be screened carefully for contraindications to
transcranial magnetic stimulation. Second, repetitive transcranial magnetic
stimulation will be applied in compliance with international safety guidelines
that have been approved by the National Institute of Neurological Disorders and
Stroke and the National Institute of Health. Third, repetitive transcranial
magnetic stimulation will be administered by technicians or investigators who
have been trained as *first responders* in order to render appropriate care in
the event of a seizure. They are under supervision of an appropriately trained
and licensed physician who will be immediately available if necessary. Fourth,
repetitive transcranial magnetic stimulation will be performed in a medical
setting with appropriate emergency facilities to manage seizures and their
consequences, located at the Department of Clinical Neurophysiology at
University Medical Center Utrecht. Finally, we will conduct repetitive
transcranial magnetic stimulation experiments in healthy volunteers only.
Subjects can leave the study at any time for any reason if they wish to do so
without any consequences. Besides financial remuneration, no immediate benefits
are to be expected from participation in this study. In the long run, increased
understanding of brain function and the aetiology of schizophrenia may
contribute to diagnosis, early detection, and prediction of treatment outcome.
Blood collection is a safe technique with very mild adverse events, as
haematomas in inner elbow.