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The relationship between pre-treatment heart rate variability and response to low-frequency accelerated repetitive transcranial magnetic stimulation in major depression


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BACKGROUND Major depressive disorder (MDD) is now the first cause of disability worldwide. So far, no validated and scalable biomarker has been identified to help with response prediction to antidepressant treatment. Cardiac biomarkers such as heart rate variability (HRV) have been studied in MDD, but few studies have examined its potential use for outcome prediction to repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE We recorded pre-treatment HRV in MDD participants prior to an rTMS course. We hypothesized that higher pre-treatment HRV would be correlated with better clinical outcomes. METHODS HRV was recorded as part of a single-arm, open-label rTMS feasibility study. Pre-treatment HRV was assessed in N = 30 MDD participants before they underwent a one-week (5 days, 8 daily sessions, 40 sessions total) accelerated rTMS (arTMS) course using a low-frequency 1 Hz course (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex at 120% of the resting motor threshold. Clinical outcomes were captured using the Beck Depression Inventory-II (BDI-II). We tested for an association between pre-treatment HRV and clinical outcomes on the BDI-II using a linear mixed effects model. RESULTS Although average BDI-II score significantly changed over time, these changes were not significantly associated with pre-treatment HRV (p = 0.60). This finding remained when adjusting for age, sex, and HR, individually and collectively. CONCLUSION The current study did not find a relationship between pre-treatment HRV and response to low frequency rTMS. Other approaches using cardiac biomarkers may have potential for response prediction.
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Journal of Aective Disorders Reports 6 (2021) 100270
Available online 11 November 2021
2666-9153/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
The relationship between pre-treatment heart rate variability and response
to low-frequency accelerated repetitive transcranial magnetic stimulation
in major depression
Jean-Philippe Miron
, Jack Sheen
, Tony Panzarella
, Molly Hyde
Farrokh Mansouri
, Linsay Fox
, Helena Voetterl
, V´
eronique Desbeaumes Jodoin
Paul Lesp´
, Christophe Longpr´
, Robert-Paul Juster
Zaris J. Daskalakis
, Daniel M. Blumberger
, Jonathan Downar
Centre Hospitalier de lUniversit´
e de Montr´
eal (CHUM) et Centre de Recherche du CHUM (CRCHUM), Universit´
e de Montr´
eal, QC, Canada
epartement de Psychiatrie et dAddictologie, Facult´
e de M´
edecine, Universit´
e de Montr´
eal, QC, Canada
Institute of Medical Science, Faculty of Medicine, University of Toronto, ON, Canada
Krembil Research Institute, University Health Network, Toronto, ON, Canada
Dalla Lana School of Public Health, University of Toronto, ON, Canada
Research Institute Brainclinics, Nijmegen and Department of Psychiatry, University of Amsterdam, the Netherlands
Department of Psychiatry, Faculty of Medicine, University of Toronto, ON, Canada
Department of Psychiatry, University of California San Diego, California, USA
Temerty Centre for Therapeutic Brain Intervention at the Centre for Addiction and Mental Health, Toronto, ON, Canada
Heart rate variability
Background: Major depressive disorder (MDD) is now the rst cause of disability worldwide. So far, no validated
and scalable biomarker has been identied to help with response prediction to antidepressant treatment. Cardiac
biomarkers such as heart rate variability (HRV) have been studied in MDD, but few studies have examined its
potential use for outcome prediction to repetitive transcranial magnetic stimulation (rTMS).
Objective: We recorded pre-treatment HRV in MDD participants prior to an rTMS course. We hypothesized that
higher pre-treatment HRV would be correlated with better clinical outcomes.
Methods: HRV was recorded as part of a single-arm, open-label rTMS feasibility study. Pre-treatment HRV was
assessed in N =30 MDD participants before they underwent a one-week (5 days, 8 daily sessions, 40 sessions
total) accelerated rTMS (arTMS) course using a low-frequency 1 Hz course (600 pulses per session, 50-minute
intersession interval) over the right dorsolateral prefrontal cortex at 120% of the resting motor threshold.
Clinical outcomes were captured using the Beck Depression Inventory-II (BDI-II). We tested for an association
between pre-treatment HRV and clinical outcomes on the BDI-II using a linear mixed effects model.
Results: Although average BDI-II score signicantly changed over time, these changes were not signicantly
associated with pre-treatment HRV (p =0.60). This nding remained when adjusting for age, sex, and HR,
individually and collectively.
Conclusion: The current study did not nd a relationship between pre-treatment HRV and response to low fre-
quency rTMS. Other approaches using cardiac biomarkers may have potential for response prediction.
Major depressive disorder (MDD) is a debilitating illness with serious
socioeconomic repercussions (Lam et al., 2016). Even though effective
treatments are available, up to a third of patients do not respond to
rst-line approaches, such as antidepressant medication and psycho-
therapy (Kennedy et al., 2016). Alternative treatment options are
therefore needed.
Repetitive transcranial magnetic stimulation (rTMS) has been stud-
ied for over 25 years for MDD and is well-established as an effective
* Corresponding author.
Co-senior authors
Contents lists available at ScienceDirect
Journal of Affective Disorders Reports
journal homepage:
Received 24 May 2021; Received in revised form 25 October 2021; Accepted 5 November 2021
Journal of Aective Disorders Reports 6 (2021) 100270
intervention (Milev et al., 2016). With an advantageous side effect
prole over medication, response and remission rates have been esti-
mated to be as high as 4060% and 2535%, respectively, in recent
meta-analyses (Milev et al., 2016). Unfortunately, rTMS is burdened by
several limitations that decreases accessibility (Miron et al., 2021a,
2021b, 2020; 2019b, 2019a): equipment costs are high, technical
operation complex, and treatment courses lengthy, requiring daily ses-
sions over several weeks. This reinforces the need for careful patient
selection to maximize treatment outcomes and avoid futile treatment
Treatment response prediction through biomarkers, allowing more
objective and personalized care, has been dubbed The Holy Grail of
Psychiatry (Alhajji and Nemeroff, 2015; Nemeroff, 2015;bib442014).
MDD is increasingly recognized as a highly heterogeneous disorder
(GOLDBERG, 2011), with various clinical presentations requiring
different treatment approaches. Unfortunately, MDD subtyping using
clinical features has not yielded any benets regarding treatment
response prediction at the individual level. On the other hand, some
have favored a more agnostic approach, using machine-learning to
‘biotypeand cluster MDD patients according to brain activity features
(Drysdale et al., 2016). Even though this approach is promising, it is
currently too complex and costly for routine clinical use. Biomarkers
that are both well-validated and practical for widespread use are
therefore needed.
Cardiac function abnormalities in MDD have been extensively
described, with a particular focus on decreased vagal control, which
could represent a failure of the prefrontal cortex (PFC) to inhibit sym-
pathetic activity (Sgoifo et al., 2015). At the neurobiological level,
subcortical hyperactivity is thought to be responsible for increased
sympathetic tone in response to stress (Wayne C Wayne C. Drevets et al.,
2008; Sgoifo et al., 2015). The PFC regulates sympathetic and para-
sympathetic activity by top-down mechanisms through connections
with the vagus nerve, via the subgenual anterior cingulate cortex
(sgACC) (Sgoifo et al., 2015). In MDD, these mechanisms could be
compromised, given the known dysfunctions of the PFC in the depressed
state. Since rTMS is theorized to normalize PFC activity (Wayne C.
Wayne C. Drevets et al., 2008; Koenigs and Grafman, 2009), its effects
could therefore be captured by cardiac activity recording (Wayne C
Wayne C Drevets et al., 2008; Koenigs and Grafman, 2009). Cardiac
activity has the advantage of being simple to monitor, cost-effective, and
made possible through a plethora of simple, robust and well-validated
One cardiac index in particular has been the subject of several
studies: heart rate variability (HRV). HRV is thought to be linked to
autonomic nervous system (ANS) balance. Indeed, lower HRV is asso-
ciated with increased sympathetic or decreased parasympathetic tone in
chronic stress or diseased state (Thayer and Lane, 2009). By contrast,
higher HRV is linked to better emotional regulation, social engagement,
and decrease in negative bias (Geisler et al., 2013). Decreased HRV has
been observed in MDD in several studies (Hartmann et al., 2019; Kemp
et al., 2012, 2010; Koch et al., 2019; Yeh et al., 2016). The presence of
melancholic features seems to increase this imbalance, suggesting that
the level of autonomic disturbance might be associated with the severity
of the depressive state (Kemp et al., 2014). HRV has also been used to
distinguish between unipolar and bipolar depression (Chang et al.,
The effects of rTMS on HRV has also been assessed. Preclinical
studies have conrmed a modulatory effect of rTMS on the ANS (Hong
et al., 2002). High-frequency (HF) rTMS over the left dorsolateral pre-
frontal cortex (DLPFC) in healthy controls has been shown to signi-
cantly increase HRV over sham (Choi and Jeon, 2020; Remue et al.,
2016; Vernieri et al., 2014; Yoshida et al., 2001). In another study,
treatment-naïve MDD participants were treated with either rTMS (N =
27) or antidepressants (N =25) (Udupa et al., 2007). The group treated
with antidepressants did not experience any HRV changes, whereas a
signicant increase was observed in the rTMS group by the end of the
treatment course. This was later replicated by the same group (Udupa
et al., 2011), but not observed in another, more recent rTMS study
(Tabitha A Tabitha A Iseger et al., 2019).
The use of HRV for response prediction to rTMS in MDD has not been
well studied. We therefore assessed the role of pre-treatment (baseline)
resting HRV in MDD participants who received an accelerated rTMS
(arTMS) course of 1 Hz stimulation delivered to the right DLPFC over a
5-day period (Miron et al., 2021a). We hypothesized that higher
pre-treatment HRV would be associated with greater improvement.
Participants and procedures
We conducted a prospective, single-arm, open-label feasibility study
in N =30 participants; complete methods are described elsewhere
(Miron et al., 2021a). In brief, adult outpatients age 1885 were
included for study participation if they 1) had a Mini International
Neuropsychiatric Interview (MINI) conrmed MDD diagnosis (single or
recurrent episode) and 2) maintained a stable medication regimen from
4 weeks before treatment start to the end of the study. Exclusion criteria
were: 1) history of substance dependence or abuse within the last 3
months; 2) concomitant major unstable medical illness; 3) cardiac
pacemaker or implanted medication pump; 4) active suicidal intent; 5)
diagnosis of any personality disorder as assessed by a study investigator
to be primary and causing greater impairment than MDD; 6) diagnosis of
any psychotic disorder; 7) any signicant neurological disorder or insult
(including, but not limited to: any condition likely to be associated with
increased intracranial pressure, space occupying brain lesion, any his-
tory of seizure conrmed diagnostically by neurological assessment
[except those therapeutically induced by electroconvulsive therapy -
ECT], cerebral aneurysm, Parkinsons disease, Huntingtons chorea,
dementia, stroke, neurologically conrmed diagnosis of traumatic brain
injury, or multiple sclerosis); 8) if participating in psychotherapy must
have been in stable treatment for at least 3 months prior to entry into the
study (with no anticipation of change in the frequency of therapeutic
sessions, or the therapeutic focus over the duration of the study); 9) any
clinically signicant laboratory abnormality in the opinion of the
investigator; 10) a dose of more than 2 mg daily lorazepam (or equiv-
alent) currently (or in the last 4 weeks) or any dose of an anticonvulsant
due to the potential to limit rTMS efcacy; 11) any non-correctable
clinically signicant sensory impairment and 12) any signicant car-
diovascular or metabolic disorder or insult including, but not limited to:
coronary artery disease, abnormal heart rhythms, heart failure, cardiac
valve disease, congenital heart disease, cardiomyopathy, vascular dis-
ease, dyslipidemia, diabetes, or hypertension. All participants provided
informed consent and this study was approved by the Research Ethics
Board of the University Health Network. rTMS was delivered with a
MagPro R20 stimulator equipped with a MC-B70 coil (MagVenture,
Farum, Denmark). Resting motor threshold (rMT) was determined ac-
cording to standard techniques (McClintock et al., 2017). Treatment
consisted of an arTMS course of 8 hourly sessions per day over 5
consecutive weekdays (Monday through Friday), totaling 40 sessions.
Each rTMS session consisted of low-frequency (LF) 1 Hz stimulation
delivered over a 10 min period (1 single train, 600 pulses per session,
50-minute intersession interval) at 120% of rMT over the right dorso-
lateral prefrontal cortex (R-DLPFC), localized according to a previously
published heuristic approximating the F4 EEG site (Mir-Moghtadaei
et al., 2017).
Clinical outcomes were measured using the self-rated Beck Depres-
sion Inventory-II (BDI-II) (BECK et al., 1961). Participants completed the
BDI-II at baseline on the week prior to rTMS initiation, daily on the
morning on each treatment day, at the end of the last day of treatment,
and 1 and 4 weeks after treatment (9 assessments for each participant).
J.-P. Miron et al.
Journal of Aective Disorders Reports 6 (2021) 100270
Data acquisition
Cardiac data acquisition was captured through electrocardiogram
(ECG) recordings. ECG acquisition was performed one week prior to
treatment through a single-lead attached to the left wrist. This lead was
part of a 16-lead EEG system (EasyCap, Brain Products, Munich, Ger-
many), as the acquisition was done during an EEG session for which the
results are reported elsewhere (Voetterl et al., 2021). The reference
electrode was at the FCz location and ground electrode at the AFz
location. Impedances of <5kΩ were achieved. Each ECG recording
consisted of a 5-minute resting-state condition, prior to a TMS-EEG
session. During the recording, participants sat comfortably in a chair,
eyes-closed, and were asked to relax. Patients were asked not to change
anything regarding their usual routine the morning of the recording.
Data processing
Data was sampled at 512 Hz. Any potential linear trend was
removed. A highpass butterworth lter was applied at 0.5 Hz, ltering
data twice, once forward and once backward. Five seconds of data were
removed at the beginning and the end of recordings to decrease signal
drift. All data were visually inspected to correctly detect R peaks in the
QRS complex. Using the times corresponding to the visually detected R-
peaks, HRV parameters were then calculated with the python package
pyHRV (Gomes et al., 2019). We used the root mean square of the suc-
cessive differences (RMSSD) as the representative HRV index. The
RMSSD is a time-domain index that reects vagal tone and is relatively
free of respiratory inuences, compared to other HRV indexes; it is also
highly correlated with high-frequency (HF) frequency-domain index,
which is most representative of the vagal tone in that index category
(Laborde et al., 2017). The a priori decision of limiting ourselves to only
one HRV index also decreased the number of statistical tests needed,
decreasing the odds of chance ndings.
Statistical analysis
Given the longitudinal nature of the data collection for BDI-II, we
tested for a statistically signicant association between pre-treatment
RMSSD and the BDI-II outcome using a linear mixed effects model,
where the correlation of BDI-II measurements within the same subject
are dealt with by modeling random effects for each subject (i.e.
intercepts and/or slopes). The main xed effects include pre-treatment
RMSSD, and time (dened as continuous). Although the study design
was balanced (i.e., the BDI-II measurements were taken at xed times for
each subject and there were no missing data), given 9 repeated measures
over the course of treatment, we chose to consider time as a continuous
variable to reduce the number of estimated parameters required. In
addition, given that the average BDI over time was curvilinear, we chose
to employ a polynomial trend over time instead of a linear trend.
Baseline demographics and clinical characteristics are located in the
clinical outcomes paper (Miron et al., 2021a). Average pre-treatment
resting heart rate (HR) was 76.9 ±14.0 beats per minute (bpm) and
average RMSSD was 25.0 ±9.8 SD milliseconds (ms) (Fig. 1). As dis-
played in Fig. 2, average BDI-II score decreased from mean (SD) 35.2
(9.2) to 23.6 (10.5) over the 5 days of treatment, and then leveled off
during follow-up, with 24.0 (11.7) at 1 week and 23.5 (13.3) at 4 weeks.
In most cases, subjects showed a decreasing trajectory, while there was
little to no changes in others. BDI-II at the start of treatment varied
considerably across subjects, as did the trajectory of response over time.
In most cases subjects showed a decreasing trajectory, while in other
subjects there was no change or a slight increase over time (Fig. 3).
A t of a linear mixed model with random intercepts and slopes
found that although average BDI-II changed signicantly over time,
these changes were not signicantly associated with pre-treatment
RMSSD. This model assumes the random intercepts and slopes have an
unstructured variance-covariance matrix. Both the variability of in-
tercepts (Z =3.61; p =0.0002) and slopes (Z =2.88; p =0.002) across
subjects was statistically signicant. The between subjects variability
represented 70.7% of the total variability. Time was represented by a
polynomial of degree 2. Both terms were highly statistically signicant.
In other words, the average BDI-II changed signicantly over time. A
cubic term for time was also introduced in the model tting, but it did
not signicantly improve the model t. The effect of pre-treatment
RMSSD was not statistically signicantly associated with average
changes in BDI-II over time (p =0.60). This nding remained when
adjusting for age, sex, and HR, individually and collectively. We provide
a visual representation of the correlation between RMSSD and percent
improvement at each time point in Fig. 4 (highest R
value of 0.0533 at
Day 2).
Fig. 1. Box and whisker plot of pre-treatment HR and RMSSD, bpm =beats per minute, ms =milliseconds.
J.-P. Miron et al.
Journal of Aective Disorders Reports 6 (2021) 100270
Fig. 2. Average observed BDI-II scores over time.
Fig. 3. Linear regression ts of BDI-II scores over time for individual subjects.
J.-P. Miron et al.
Journal of Aective Disorders Reports 6 (2021) 100270
Lastly, the main effect of age on BDI-II improvement reached sta-
tistical signicance (p =0.026). Using a model with time and time
squared for every one-year increase over the average age of 41.3, the
average BDI-II dropped by 0.3. This suggests that older participants had
a greater response to rTMS.
This is the rst study to explore the ability of HRV to predict response
to 1 Hz arTMS of the right DLPFC in MDD. Using a linear mixed effects
model, we did not nd any association between pre-treatment resting
RMSSD and clinical outcomes.
The HRV literature in MDD is complex. Even though initial studies
have consistently demonstrated that MDD patients have reduced HRV
compared to healthy controls (Tabitha A. Tabitha A Iseger et al., 2019),
other ndings have been more heterogeneous. Subsequent studies
focused primarily on assessing if HRV parameters could be used as
treatment response monitoring markers. Some have reported HRV in-
crease after treatment (Udupa et al., 2011, 2007) while others have not
(Brunoni et al., 2013; Tabitha A Tabitha A Iseger et al., 2019). Studies on
R² = 2E-05
0 102030405060
Day 1
R² = 0.0041
0 102030405060
Day 5
R² = 0.0533
0 102030405060
Day 2
R² = 0.0064
0 102030405060
End of Last Day
R² = 0.0047
0 102030405060
Day 3
R² = 0.0105
0 102030405060
1 week
R² = 0.021
0 102030405060
Day 4
R² = 9E-06
0 102030405060
4 weeks
Fig. 4. Correlation between RMSSD in milliseconds (ms) on the horizontal axis and percent improvement on the vertical axis at each time points.
J.-P. Miron et al.
Journal of Aective Disorders Reports 6 (2021) 100270
the use of HRV as a predictive biomarker have had similar mixed results.
In a yoga study in MDD participants (N =17) with partial remission to
antidepressants, Shapiro and colleagues found that remitters had higher
high-frequency (HF) and lower low-frequency (LF) HRV pre-treatment
values compared to non-remitters (David et al., 2007). Subsequently,
Jain and colleagues found a correlation between pre-treatment lower
relative power of very low frequency (VLF) and improvement after
treatment with escitalopram and yoga in two separate trials, although
the signicance was lost after adjusting for age and gender (Jain et al.,
2014). The small sample size and heterogeneity of results make those
studies difcult to interpret. These studies also did not report correction
for multiple comparisons despite the numerous statistical tests examined
for the HRV parameters studied. More recently, two small rTMS studies
did not nd any associations between pre-treatment HRV values and
clinical improvement (Tabitha A Tabitha A Iseger et al., 2019; Udupa
et al., 2007). Lastly and more importantly, a recent large trial (N =
1008) also did not nd an association between pre-treatment RMSSD
and antidepressant response in MDD patients, although they did report
that RMSSD could predict clinical outcomes as a function of anxious
versus nonanxious depression (Kircanski et al., 2018). In our study, we
did not have the ability to reliably measure anxiety using the BDI-II.
Our results thus add to the negative ndings of recent literature in
term of pre-treatment resting HRV as a predictor of clinical outcomes in
MDD. Nonetheless, this does not mean that other cardiac indexes could
not prove useful in this area. For example, the concept of Neuro-Cardiac-
Guided TMS (NCG-TMS) has recently garnered attention and has shown
that rTMS applied to sites near the DLPFC can inuence cardiac activity
(Iseger et al., 2021, 2017; Tabitha A. Tabitha A Iseger et al., 2019;
Tabitha A Tabitha A Iseger et al., 2019; Kaur et al., 2020). In their initial
pilot study, Iseger and colleagues reported a greater HR decrease during
DLPFC (F3/F4) 10 Hz rTMS stimulation in N =10 healthy subjects,
compared to other prefrontal (PFC) (FC3, FC4) and non-PFC (C3, C4, Pz)
areas (Iseger et al., 2017). So far, these ndings have been twice repli-
cated in N =20 (Kaur et al., 2020) and N =28 (Iseger et al., 2021)
healthy participants. A follow-up study done in N =15 MDD partici-
pants showed that HR signicantly decreased more during the rst
minute of active intermittent theta-burst stimulation (iTBS) compared to
sham stimulation (Tabitha A Tabitha A. Iseger et al., 2019). Importantly,
a trend towards an association between HR deceleration and treatment
response was also observed, but the study was not powered to detect
small effects. A larger trial will be needed before any conclusions can be
drawn, but this might suggest that cardiac reactivity to rTMS could be
useful in response prediction. This could represent a paradigm shift,
where efforts should now focus on assessing potential biological effects
during treatment or during a task, instead of at rest. A ‘cardiac hotspot
for rTMS would satisfy the criteria of being simple, practical and suitable
for widespread clinical use, if it can demonstrate robust predictive value
for treatment outcome in MDD.
Lastly, the nding of a positive correlation between age and response
is not new. Even though initial rTMS studies reported decreased effec-
tiveness of rTMS for MDD in late-life depression (LLD) (Fregni et al.,
2006; Manes et al., 2001; Mosimann et al., 2004), recent ndings using
more intensive protocols suggest otherwise (Jodoin et al., 2019; Trevi-
zol et al., 2019). Given the burden of depression in older adults and the
need for novel interventions, future work should explore this potential
marker and treatment in older adults.
This study had several limitations. Given its open-label nature, there
was no sham group allowing for assessment of overall efcacy. Our
modest sample size also could have put us at risk of a type-II error.
Indeed, there was no a priori consideration of statistical power, given the
exploratory nature of this study. We also used an EEG set-up that was not
designed per se for ECG recording. Still, our signal was of good quality
and we did not experience any data loss. We also did not make
participants undergo a clinical ECG to formally exclude any cardiac
abnormalities, even though patients with pre-existing severe cardiac
conditions were excluded. The use of RMSSD as the only representative
index of HRV could be seen as a limitation, given that other studies
reported several other measures. Still, we believe that limiting ourselves
to a single HRV parameter decreases the odds of chance nding. RMSSD
has been reported as a robust HRV parameter that can be captured with a
short recording (unlike the standard deviation of the IBI of normal sinus
beats - SDNN) and is considered the primary time-domain measure used
to estimate the vagally mediated changes reected in HRV (Shaffer
et al., 2014; Shaffer and Ginsberg, 2017). RMSSD is also highly corre-
lated with HF power, which also reect parasympathetic activity, while
being less inuenced by breathing (Shaffer and Ginsberg, 2017). Large
HRV studies in MDD have also used RMSSD as their main HRV param-
eter (Brunoni et al., 2013; Kircanski et al., 2018). Regarding clinical
outcomes, the BDI-II was not validated for daily use and therefore might
not have been sensitive enough to capture rapid clinical changes (Miron
et al., 2021a). In the future, it would be important to use a scale vali-
dated for daily use, such as the 6-item Hamilton Depression Rating Scale
(HAMD-6). Furthermore, the fact that our recording session preceded
the participants rst ever rTMS session could have increased anxiety
levels, and therefore may have had an effect on cardiac activity by
increasing sympathetic tone, although average HR remained in the
normal range. Additionally, we were not able to control for antide-
pressant use given our small sample size and the risk of overtting.
Antidepressants have been reported to decrease HRV, but not in all
studies. HRV decreases were mostly seen with older tricyclic antide-
pressants (TCA), while this was not consistently seen with SSRIs and
more recent antidepressants (Kemp et al., 2012, 2010). Finally, it is
important to note that the ndings of this study pertain specically to 1
Hz right DLPFC stimulation, and may not generalize to other common
protocols such as high-frequency/theta-burst left or bilateral
In conclusion, we did not nd support for the use of pre-treatment
HRV to help predict clinical outcomes to a 1 Hz arTMS course. Our
ndings add to the body of recent negative studies that have also failed
to demonstrate utility of pre-treatment HRV for response prediction in
MDD. However, there remains promise in the potential utility for HRV
with DLPFC rTMS interventions due to the connections with the un-
derlying neurocircuitry. As discussed, future studies should focus on
assessing HRV in response to stimulation or a task instead of at rest.
Another approach could also be to include HRV with other biomarkers in
order to create a composite index from multiples sources, such as what is
being done in the eld of allostatic load (Flier et al., 1998). Other cardiac
indices or approaches (e.g., NCG-rTMS) could also prove useful for
outcome prediction and monitoring. Given the high costs associated
with MDD and the need to prevent chronic depressive states, researchers
must identify reliable and scalable biomarkers so that clinicians can go
beyond the current trial-and-error approach to treating depression.
The authors declare no nancial interests relative to this work. JPM
reports research grants from the Brain & Behavior Research Foundation
NARSAD Young Investigator Award and salary support for his graduate
studies from the Branch Out Neurological Foundation. JS, TP, MH, FM,
LF, HV, VDJ, PL, CLP and RPJ do not report any conict of interest.
ZJD has received research and equipment in-kind support for an
investigator-initiated study through Brainsway Inc and Magventure Inc.
His-work was supported by the Canadian Institutes of Health Research
(CIHR), the National Institutes of Mental Health (NIMH) and the Tem-
erty Family and Grant Family and through the centre for Addiction and
Mental Health (CAMH) Foundation and the Campbell Institute. DMB
J.-P. Miron et al.
Journal of Aective Disorders Reports 6 (2021) 100270
receives research support from CIHR, NIH, Brain Canada and the Tem-
erty Family through the CAMH Foundation and the Campbell Family
Research Institute. He received research support and in-kind equipment
support for an investigator-initiated study from Brainsway Ltd. He is the
site principal investigator for three sponsor-initiated studies for
Brainsway Ltd. He also receives in-kind equipment support from Mag-
venture for investigator-initiated research. He received medication
supplies for an investigator-initiated trial from Indivior. JD reports
research grants from CIHR, the National Institute of Mental Health,
Brain Canada, the Canadian Biomarker Integration Network in Depres-
sion, the Ontario Brain Institute, the Weston Foundation, the Klarman
Family Foundation, the Arrell Family Foundation, and the Buchan
Family Foundation, travel stipends from Lundbeck and ANT Neuro, in-
kind equipment support for investigator-initiated trials from MagVen-
ture, and is an advisor for BrainCheck, TMS Neuro Solutions, and
Restorative Brain Clinics.
JPM lead the project, designed the study, was responsible for data
collection and analyses and wrote the manuscript. TP conducted sta-
tistical analyses and reviewed the manuscript. JS, MH, FM, LF and HV
participated in the study design, data collection, analyses and reviewed
the manuscript. VDJ, PL, CLP, RPJ and ZJD reviewed the manuscript.
DMB and JD supervised the project and reviewed the manuscript.
JPM would like to thank the Brain & Behavior Research Foundation
and the Branch Out Neurological Foundation for their nancial support
of this project. We would also like to thank Terri Cairo, Julian Kwok,
Meaghan Todd, Nuno Ferreira, Thomas Russell and Eileen Lam for their
involvement and organizational support throughout this project.
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Full-text available
Background Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention for major depressive disorder (MDD). Completing a full treatment course, however, is costly and time-consuming. Biomarkers of clinical outcome such as baseline resting-state brain activity measured with electroencephalography (EEG) may spare people futile treatment and conserve limited clinical resources. Additionally, investigating changes in EEG power post-treatment could provide insights into the working mechanism of rTMS. Methods 39 MDD patients received 6 daily sessions of accelerated low-frequency (LF) rTMS over the right dorsolateral prefrontal cortex (DLPFC) for 5 days followed by a tapering course of 25 once-daily sessions. Resting-state EEG and heart rate (HR) measures were acquired immediately before and after a single rTMS session at 3 different timepoints: baseline, one week after the final accelerated session, and upon completion of the tapering course. The primary clinical outcome measure was the Beck Depression Inventory II (BDI-II). Results High relative baseline theta power in prefrontal areas and high baseline HR were associated with poorer clinical outcome. HR decreased acutely at the beginning of the patients’ first rTMS session but this effect was not associated with treatment outcome. Limitations The main limitations were small sample size and a lack of sham and healthy control group. Conclusion Our results suggest that high relative theta power at baseline may be a marker of poorer response to right-sided LF rTMS. If validated, this easily applicable measure could inform rTMS protocol choice for the individual, thereby potentially speeding up patient recovery and saving clinical resources.
Full-text available
Neuro-Cardiac-Guided Transcranial Magnetic Stimulation (NCG-TMS) was studied for its potential to specifically target the frontal-vagal network. Previous research demonstrated that prefrontal stimulation led to significant heartrate slowing. We aimed to replicate these results in a larger sample and extend the findings to investigate dose-response relationships, reproducibility and stimulation frequency (10 Hz and intermittent theta burst (iTBS)). Data of forty-five healthy controls were analyzed, of which 28 received 10 Hz TMS (NCG-TMS) and 27 iTBS (NCG-iTBS; 10 received both protocols) at different stimulation sites according to the 10-20-EEG system. NCG-TMS yielded a relative heartrate deceleration at the F3/4 coil position replicating earlier studies. Both internal consistency and dose-response relationships were found. For NCG-iTBS adverse events were reported and topography for frontal-vagal activation was more lateralised relative to NCG-TMS. These results indicate that we were able to transsynaptically stimulate the frontal-vagal network and that excitability thresholds for the prefrontal cortex may differ relative to motor cortex.
Full-text available
BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility. OBJECTIVE We assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course. METHODS We conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Primary outcomes were response and remission rates on the Beck Depression Inventory-II (BDI-II). RESULTS Response and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at follow-up 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels. CONCLUSION 1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Validation in a randomized trial will be required. TRIAL REGISTRATION Identifier: NCT04376697.
Full-text available
Background: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response. Objective: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS. Methods: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed. Results: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed. Conclusion: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted.
Full-text available
Major Depressive Disorder (MDD) is a psychiatric disorder characterized by high comorbidity with cardiovascular disease. Furthermore, a combination of high heart rate (HR) and low heart rate variability (HRV) has been frequently reported in depressed patients. The present review proposes a frontal-vagal (brain-heart) network that overlaps with functional nodes of the depression network. Moreover, we summarize neuromodulation studies that have targeted key nodes in this depression network, with subsequent impact on heart rate (HR) or heart-rate-variability (HRV), such as the dorsolateral prefrontal cortex (DLPFC), subgenual anterior cingulate cortex (sgACC), and the vagus nerve (VN). Based on the interplay of this frontal-vagal network, we emphasize the importance of including HR and HRV measurements in human depression studies, in particular those that conduct neuromodulation, in order to obtain a better understanding of the pathways that are affected, and we explore the possibilities of using this frontal-vagal interplay as a method for target engagement in neuromodulation treatments. This frontal-vagal network theory opens-up the possibility for individualizing neuromodulation treatments such as rTMS. A recent development called Neuro-Cardiac-Guided TMS (NCG-TMS), was developed based on this theory, and an individual-participant meta-analysis is presented. Four studies provide consistent and replicable support for NCG-TMS as a target engagement method, with consistent HR deceleration during frontal TMS and HR acceleration during motor strip TMS.
Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.
Major depressive disorder (MDD) is one of the disabling diseases in the world-wide, and known to increase cardiac morbidity and mortality. Therefore, previous studies related heart rate variability (HRV) have been conducted to evaluate and diagnose MDD, and to predict treatment outcomes in patient with MDD. We performed an extensive review of the previous peer-reviewed publications associated with this issue, using Pub-Med. In this review article, we introduce the basic concept of HRV and HRV measures, and present several important findings associated with diagnosis and treatment prediction in MDD with using HRV parameters. Furthermore, we discuss the possible underlying mechanism of this phenomenon, and suggest several considerations for the future research.
Background: Heart rate in MDD is often dysregulated, expressed in overall higher heart rates (HR) and lower heart rate variability (HRV). Interestingly, HR decelerations have been reported after stimulation of the DLPFC using rTMS, suggesting connectivity between the DLPFC and the heart. Recently, a new form of rTMS called theta burst stimulation (TBS) has been developed. One form of TBS, intermittent TBS (iTBS), delivers 600 pulses in just 3 min. Objective: To determine whether iTBS aimed at the DLPFC also affects HR, blood pressure and HRV, and whether these cardiac responses at baseline are associated with treatment response. Methods: ECG and blood pressure were recorded during both sham and active iTBS in 15 MDD patients, over 30 sessions. Results: We found a significantly larger HR deceleration for active iTBS, compared to sham, within the first minute of stimulation. Also, a trend towards an association between HR deceleration and treatment response was found, explaining 26% of the variance. Furthermore, several measures of heart rate variability were significantly higher during iTBS stimulation over sessions, compared to sham. Both systolic and diastolic blood pressure, were lower during active iTBS. Conclusion: Active iTBS applied to the DLPFC is able to transsynaptically modulate the autonomic nervous system, in particular the parasympathetic branch, similar to what has been found for conventional rTMS methods. Furthermore, data suggest that the larger the autonomic changes induced at baseline, the better the clinical response after 30 sessions of iTBS.