Neuro-Cardiac-Guided Transcranial Magnetic Stimulation: a method to probe the depression network. Replication and dose-response.

Autonomic regulation is disturbed in patients with major depressive disorder
(MDD), indicated by a higher heart rate (HR) and lower heart rate variability
(HRV). Moreover, the heart seems to be functionally connected via the vagus
nerve (VN) to other brain structures that are dysregulated in depression, such
as the subgenual anterior cingulate cortex (sgACC), and the dorsolateral
prefrontal cortex (DLPFC), suggesting dysregulated network function in MDD. In
line with this network dysregulation hypothesis of MDD, optimal transcranial
magnetic stimulation (TMS) sites are currently thought to be those that show
functional connectivity to the sgACC such as the DLPFC and multiple studies
have shown that stimulation of the DLPFC, sgACC and nervus vagus decreased
heart rate, suggestive of parasymphatetic action. We hypothesized that this
influence on parasympathetic activity can be used as a functional outcome
measure reflecting adequate targeting of the DLPFC-sgACC network, similar to
the motor evoked potential (MEP) as functional key measure for primary motor
cortex stimulation. Recently, we have conducted a pilot study proposing a new
functional neuronavigation method for localizing the frontal area
representation of DLPFC-sgACC connectivity using HR, called:
Neuro-Cardiac-Guided TMS (NCG-TMS), which we aim to replicate.

To explore whether influence on parasympathetic activity can be used as a
functional outcome measure reflecting adequate targeting of the DLPFC-sgACC
network and, secondary: 1) to explore the dose-response to the intensity of the
TMS output and 2) whether differences can be attributed to age, gender or head
size

Randomized controlled intervention study

All participants receive the same intervention. Session 1: 1 minute of iTBS on
7 different cortical brain locations. Session 2: 1 minute of iTBS spread over 2
different cortical brain locations, with 5 different intensities. In session 2,
for the first 29 participants also deep TMS will be applied, and thus this part
has finished. Results will be analysed. Deep TMS is not randomised to one
hemisphere and is thus the same location for all subjects, resulting in
sufficient power for statistical analysis.

The intervention is not lasting outside the session. There are no specific
rules to follow in between the two sessions.

10 subjects will be tested twice due to a protocol change.

The participants burden is minimal. The main burden is time consummation. There
will be two session, of which each maximal 1 hour. The exact stimulation time
is in the first session just over 1 minute, and in the second session 2
minutes. For the first 29 subjects, deep TMS is applied as well, consisting of
another 750 pulses.

During a session, the participant does not to conduct any tasks, but should
only sit relaxed in the TMS chair. There will be magnetic pulsed applied to the
skull, which is a non-invasive method. The TMS trains can give an uncomfortable
feeling, sometimes lightly painful, but this does not persist after the train.
After a session, there might arise a headache due to stimulation of the muscles
in the face, but this is not dangerous, and will, if applicable, disappear on
itself within a few hours. (Fitzgerald et al., 2009; Machii et al., 2006;
Rusjan et al., 2010). If needed, pain medication can be taken. The risks of
this research are like the risks of the approved treatment TMS. The technique
of TMS in safe and FDA approved, and has no negative consequences on the health
(Rossi et al., 2009). However, TMS will not be applied if epilepsy is common in
the first grade of the participant*s family, or the participant experienced
epilepsy him/herself. Also, no metal is allowed in the participant*s head.

The maximal allowed number of pulses and the maximal allowed intensity are not
violated in this protocol. In the first session, 7 minutes of iTBS will be
applied, spread over 7 different locations, comparable to 1470 pulses, on 100%
of the MT. In session 2, this will be 10 minutes of iTBS, spread over two
cortical areas, comparable to 2100 pulses, on different intensities (70, 80,
890, 100, 110% MT). 10Hz TMS has already numerously been applied for, amongst
others, the treatment of depression, in where the amount of pulses can be as
much as 2500 pulses or even more. Furthermore, stimulation usually is applied
at 110% or 120% of the MT, while our protocol is in a range of 70-110% of the
MT. For the first 29 subjects, also deep TMS will be applied in session two,
consisting of 750 pulses.

The chosen location are locations that surround F3 or F4: FC3, F1, AF3, F5, FC5
en FC4, F2, AF4, F6 en FC6. This means that they are, in fact, all aimed at the
DLPFC. Furthermore, stimulation is applied on or around the motor cortex (C3
and C4). These locations have been stimulated many times now as well, in
various research populations, without negative effects (Fitzgerald et al.,
2009; Machii et al., 2006; Rusjan et al., 2010).

First, heart related effects were studies for safety issues, and later for a
better understanding of the parasympathetic system (Rossi et al., 2016). The
effect of neuromodulation on the heartbeat has been studied extensively and the
lowering of the heart beat has not led to adverse events (Sampaio et al.,
2012). In theory, this effect on the heart rhythm is because an effect on the
parasympathetic system, and not on the basal heart rhythm. Thus, the heart rate
cannot become lower than the basal heart rate.