Randomized controlled trial of neurostimulation treatment for apathy in schizophrenia

Apathy concerns a quantitative reduction of voluntary, goal-directed behaviours
that impairs daily functioning. It is a prominent and severely debilitating
aspect of several psychiatric disorders, most notably schizophrenia.
Surprisingly, little is known regarding the neurobiological basis of these
symptoms. Moreover, currently no treatment for these symptoms is available. In
this study we will investigate the effectiveness of several treatment options
including transcranial Direct-Current Stimulation (tDCS), repetitive
Transcranial Magnetic Stimulation (rTMS), and rTMS in combination with
Behavioural Activation Therapy (BAT) to treat apathy in schizophrenia patients.
By identifying involved neural networks and implementing the treatment study,
contributions may be made to novel treatment strategies that will ultimately
improve patients* lives. The results might also have implications for
understanding apathy in patients with depression, brain damage and
neurodegenerative diseases.

The main objective is to investigate whether tDCS and rTMS treatment targeting
the right dorsolateral prefrontal cortex (rDLPFC) reduces apathy in
schizophrenia patients, and whether tDCS and / or rTMS increases activity of
the dorsolateral PFC * striatal circuit (including the parietal cortex), that
has been shown to be involved in apathy. By reactivating this circuit we aim to
reduce apathy and associated impairments of executive functions. The secondary
objective of the study is to evaluate responses to BAT in combination with
rTMS. A tertiairy aim of the study is to provide insights into which patients
are more likely to benefit from neurostimulative treatment. Applying
near-infrared spectroscopy (NIRS) before, during, and after the first
neurostimulative treatment session will enable us to investigate whether
baseline frontoparietal connectivity is predictive of the clinical response to
neurostimulation. By comparing the response to rTMS treatment measured by NIRS
within group of healthy subjects to patients will help us define compare it to
normal, healthy, brain information processing, as a reaction to rTMS treatment
and point deficiencies in patients.

The proposed study includes tDCS, rTMS, (f)MRI, and NIRS techniques. The entire
study exists of five phases. Within the first phase demographic data are
acquired, neuropsychological tests are performed, interviews are held, and MRI
scanning takes place for structural, and fMRI scans. The neuropsychological
tests and interviews serve to measure the level of apathy and possible
comorbidities. The fMRI scans are necessary to evaluate resting state
connectivity, and brain activation during the execution of tasks that involve
the DLPFC * striatal circuit. During the second phase, participants receive
either real or placebo neurostimulation (tDCS or rTMS) for a duration of two
weeks. Closely before, during and shortly after the treatment (tDCS, rTMS, or
rTMS plus BAT), spontaneous motor behaviour will be recorded by means of an
Acti-meter. This provides a secondary measure of apathy. The third phase is
similar to the first phase. This session also includes applying apathy rating
scales, neuropsychological tests, and an (f)MRI study. The last two phases are
included as a follow-up to measure potential short and long-term effects after
treatment. These follow-up sessions take place four weeks, and 10 weeks after
finishing the (neurostimulative) treatment or sham stimulation. During these
follow-up sessions apathy will be indexed through questionnaires, interviews,
and spontaneous motor behaviour.

Three of the five patient groups (25 patients per group) will receive either
tDCS, rTMS, or rTMS + BAT treatment. The remaining two patient groups are
included as placebo control groups, and will receive either *sham* tDCS or sham
rTMS stimulation. The site of stimulation for tDCS and rTMS will be the right
dorsolateral prefrontal cortex.

Firstly, interviews are held, and the patients are asked to fill in
questionnaires. This will take approximately 150 minutes. Secondly, patients
will undergo (f)MRI scanning, during which participants have to perform two
tasks, in addition to a resting state scan and an anatomy scan. This (f)MRI
session will take approximately 60 minutes. Thirdly, a tDCS, rTMS, or rTMS plus
BAT treatment will be administered. Neurostimulative treatment will be given
once a day for two weeks, five days per week. One group of patients will
receive an additional BAT for ten weeks, after finishing the rTMS treatment.
During the first and last neurostimulative treatment session, NIRS will be
applied simultaneously. Shortly after treatment another appointment is made,
whereby the neuropsychological evaluation and (f)MRI scan will be repeated.
These two sessions will take approximately 130, and 60 minutes respectively.
Four weeks, and again ten weeks after treatment the neuropsychological
interviews, questionnaires, and assessment of motor behaviour (not the
neuropsychological tests) will be repeated to assess possible short and long
term effects of treatment (tDCS, rTMS, or rTMS plus BAT). These last sessions
will approximately take 100 minutes.

Concerning the fMRI scanner, participants will be exposed to a field strength
of 3 Tesla and scanner noise. Thus far, there is no evidence to suggest that
exposing humans to a magnetic field of this strength has a negative influence
on health. With regard to the noise, earplugs and headphones will be provided.
During the tDCS procedure participants are exposed to a very low electrical
current of 2 Ma. The use of tDCS to date has not resulted in significant
adverse effects, apart from mild headache or a mild tingling sensation
underneath the electrodes. During the rTMS procedure participants are exposed
to a magnetic field strength of 1.5 Tesla. The application of TMS is considered
safe and useful as a treatment strategy as long as it is given within
recommended guidelines. The proposed study excludes high risk patients and all
parameters are well within international safety guidelines. However, the risk
of inducing a seizure cannot be fully excluded, so several safety procedures
will be taken. Lastly, the NIRS technique is considered non-intrusive and safe.
It does not involve strong magnetic fields or radio frequency pulses. It also
requires less rigid stabilization of the head and body. The applied light
intensities for the proposed study are considered safe for adults.