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Energy Delivered by Subthalamic Deep Brain
Stimulation for Parkinson Disease Correlates
With Depressive Personality Trait Shift
Francesca Mameli, PsyD
1,a
; Fabiana Ruggiero, PsyD
1,a
;
Michelangelo Dini, PsyD
2
; Sara Marceglia, PhD
3
; Marco Prenassi, PhD
3
;
Linda Borellini, MD
1
; Filippo Cogiamanian, MD
1
; Elena Pirola, MD
1
;
Luigi Gianmaria Remore, MD
1
; Giorgio Fiore, MD
1
; Maria Rita Reitano, PsyD
4
;
Natale Maiorana, PhD
2
; Barbara Poletti, PhD
5
; Marco Locatelli, MD, PhD
1
;
Sergio Barbieri, MD, PhD
1
; Alberto Priori, MD, PhD
2,4
;
Roberta Ferrucci, PhD
2,4
ABSTRACT
Objectives: Despite the large amount of literature examining the potential influence of subthalamic nucleus deep brain stim-
ulation (STN-DBS) on psychiatric symptoms and cognitive disorders, only a few studies have focused on its effect on personality.
We investigated the correlation between total electrical energy delivered (TEED) and the occurrence of depressive traits in
patients with Parkinson disease (PD) after one year of DBS.
Materials and Methods: Our study involved 20 patients with PD (12 women, mean [±SD] age 57.60 ± 7.63 years) who underwent
bilateral STN-DBS, whose personality characteristics were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-
2), according to the core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD) procedure.
Results: We found that despite a marked improvement in motor functions and quality of life after 12 months, patients showed a
significant increase in MMPI-2 subscales for depression (D scale and Depression scale) and in other content component scales
(low self-esteem, work interference, and negative treatment indicators). Interestingly, only the TEED on the right side was
inversely correlated with the changes in scale D (r
s
=−0.681, p=0.007), whereas depressive traits did not correlate with disease
duration, levodopa equivalent daily dose (LEDD) reduction, patient’s age, or severity of motor symptoms.
Conclusions: Our preliminary observations indicate that despite the excellent motor outcome and general improvement in
quality of life, DBS treatment can result in patients poorly adjusting to their personal, familiar, and socio-professional life. Different
influences and multiple factors (such as TEED, intra/postsurgical procedure, coping mechanisms, and outcome expectations) may
affect depressive traits. Further advances are expected to improve stimulation methods.
Keywords: Deep brain stimulation, depression, Parkinson disease, personality trait, total electrical energy delivered
Conflict of Interest: Francesca Mameli, Roberta Ferrucci, Sergio Barbieri, Sara Marceglia, Filippo Cogiamanian, and Alberto Priori
are stakeholders of Newronika Spa. The remaining authors reported no conflict of interest.
Address correspondence to: Roberta Ferrucci, PhD, Aldo Ravelli Center, University of Milan, Via A. di Rudinì 8, 20142, Milan, Italy. Email: roberta.ferrucci@unimi.it
1
Foundation IRCCS Ca’Granda Ospedale Maggiore Policlinico, Department of Neuroscience and Mental Health, Milan, Italy;
2
“Aldo Ravelli”Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, Milan, Italy;
3
Department of Engineering and Architecture, University of Trieste, Trieste, Italy;
4
Neurology Unit I, San Paolo University Hospital, ASST Santi Paolo e Carlo, Milan, Italy; and
5
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
a
Indicates equal contribution.
For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please see the journal’sGuide
for Authors.
Source(s) of financial support: This study was partially supported by the Italian Ministry of Health (Ricerca Corrente RC 2020–2021 grant number 01).
Ethics approval: This study was approved by the Foundation IRCCS Ca’Granda Policlinico Review Board, Milan, Italy, ID number: 2236-55/11.
Neuromodulation: Technology at the Neural Interface
Received: October 21, 2021 Revised: December 9, 2021 Accepted: January 7, 2022
hiips://doi.org/10.1016/j.neurom.2022.01.004
www neuromodulationjournal.org © 2022 International Neuromodulation Society. Published by Elsevier Inc.
All rights reserved.
Neuromodulation 2022; -:1–9
1
INTRODUCTION
Deep brain stimulation (DBS) has emerged as one of the most
effective treatment modalities for Parkinson disease (PD). There is
impartial evidence that alleviation of motor symptoms is associated
with a considerable improvement in quality of life in patients with
PD and predominant nonaxial motor symptoms, or long-term
complications from medical treatment.
1
Subthalamic nucleus-DBS (STN-DBS) has been established as an
effective surgical treatment for motor fluctuations in PD. In general,
the DBS procedure also has a positive effect on behavioral outcomes
and on quality of life of patients.
2
Interestingly, there is a significant
heterogeneity in the observed pre- vs postsurgical modifications in
depression scores, which also seems to be modulated by two related
factors: disease duration and Unified Parkinson Disease Rating Scale
(UPDRS) score.
3
Several large cohort studies found that the average
severity of depressive symptoms was reduced post-DBS when
considering the whole cohort. Others studies found no significant
effect in either direction,
4
or small increases in symptom severity.
5
This heterogeneity suggests that although DBS may not neces-
sarily induce depressive symptoms, a small but consistent minority
of patients who undergo DBS may be at heightened risk of
emotional or mood decline.
6
Therefore, after 20 years of STN-DBS
use, a better understanding of the mechanisms behind changes in
mood and other behavioral effects is still needed to enable a rational
management and improve clinical outcomes.
7
Despite the large amount of literature discussing the influence of
STN-DBS on psychiatric symptoms (ie, apathy, depression, anxiety,
and mania) and on cognitive disorders (ie, decrease in verbal
fluency), few studies have quantitatively examined its effect on
personality. Clinicians described personality changes in PD following
STN-DBS, including irritability, impulsivity, and impaired decision-
making.
8,9
Interesting studies touch upon the psychologic effects of
DBS, focusing on issues such as impulsivity,
10
psychologic variables
relevant to neuroethics,
11
acute and enduring psychiatric and
neuropsychiatric changes,
7,12
and measurement of other complex
changes.
13
Some of these articles reviewed research that assessed
variables relevant to the field of personality psychology, such as
behavioral disorders
14
and personality disorders
15
; however, none of
the studies focused primarily on personality traits after DBS.
16
The interpretation of studies on behavioral changes following
the implantation of STN electrodes for DBS is complex. Several
factors may contribute to the neuropsychiatric outcomes or
changes in personality after surgery: Dopaminergic treatment
modifications, psychosocial presurgical status, personality traits,
and postsurgical coping mechanisms may each play a distinct role
in determining the psychologic well-being of patients who
underwent DBS.
3
Although the psychiatric effects of noninvasive
brain stimulation such as transcranial direct current stimulation are
clear, with quantifiable effects depending on the amount of current
delivered,
17
little is known about how the specific amount of cur-
rent delivered through STN-DBS can affect psychiatric symptoms.
Because STN-DBS targets a limbic-system–related region, which
receives fibers projecting from the anterior cingulate cortex and
descending to the ventral pallidum,
18
current spread to the limbic
areas may contribute to the emergence of various neuropsychiatric
symptoms.
19
The purpose of this study was to investigate the impact of DBS
on the personality profile of 20 patients with PD, after 12 months of
neurostimulation treatment. To further characterize this issue, we
investigated the correlation between total electrical energy deliv-
ered (TEED) and the occurrence of personality trait shift in patients
with PD after one year of DBS. Deriving quantitative measures of
electrical stimulation could help to better understand the afore-
mentioned heterogeneous effects of DBS on personality and
behavior. Recent studies have found that TEED correlates with STN
firing rate
20
and clinical motor effects.
3
Therefore, we aimed to
assess the presence of correlations between TEED and behavioral
outcomes. Finally, because it is commonly recognized that psy-
chologic suffering is mostly expressed in women, we also analyzed
the presence of possible sex differences.
MATERIALS AND METHODS
Patients
We included 20 patients with PD (12 women, [mean ± SD] age
57.60 ± 7.63 years) who underwent bilateral DBS lead implantation
into the STN. All patients were screened at the Center for Move-
ment Disorders of Foundation IRCCS Ca’Granda Ospedale Mag-
giore Policlinico in Milan, Italy, by a team of experienced
neurologists, neurosurgeons, and neuropsychologists, through
appropriate diagnostic tests.
21
None of the patients exhibited signs
of dementia (Montreal Cognitive Assessment [MoCA] score: mean
25.82 ± 2.85). The demographic and clinical characteristics of the
groups are summarized in Table 1.
The study was performed according to the Declaration of Hel-
sinki and approved by the local institutional review board, and
informed consent was obtained for each patient.
Surgical Procedure
All surgical procedures were performed by a Parkinson dedicated
neurosurgical team of the Center for Movement Disorders of Foun-
dation IRCCS Ca’Granda Ospedale Maggiore Policlinico in Milan.
The surgical procedure performed in all patients consisted of the
two-stage procedure described by Levi et al.
22
In the first stage,
bilateral intracerebral leads were implanted under local anesthesia
in awake patients. Bilateral STN targeting and trajectories were
elaborated on preoperative magnetic resonance imaging (MRI)
fluid-attenuated inversion recovery, volumetric T2- and T1-
weighted sequences with gadolinium. A stereotactic computed
tomography (CT) scan, performed immediately before surgery with
a Cosman-Roberts-Wells stereotactic frame (Radionics [Integra,
Plainsboro, NJ]) placed on the head of the patient, was combined
with MRI in a dedicated workstation (Istereotaxy, Brainlab, Kapel-
lenstrat, Germany). The recording microelectrodes (FHC Inc, Bow-
doin, ME) were placed, and their position was tested by recording
neurophysiological activity. Final leads (Model 3389 [Medtronic Inc,
Minneapolis, MN]) were subsequently implanted. A CT scan was
performed on all patients at the end of the surgical procedure. The
second stage was performed under general anesthesia and con-
sisted of the placement of a lead extender and an implantable
pulse generator. This procedure was generally scheduled within
seven days after the lead placement. Patients were subsequently
discharged, and the stimulation was turned on three to six weeks
later, during a second hospitalization.
Motor and Psychologic Assessment
Motor disabilities were assessed with UPDRS-III-Motor part.
23
Before surgery, motor score was obtained both in a “medication-
off”condition, following a 12-hour overnight withdrawal of
MAMELI ET AL
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All rights reserved.
Neuromodulation 2022; -:1–9
2
dopaminergic medication, and in a “medication-on”condition, after
the intake of an L-dopa dose. The L-dopa dosage was assessed for
each patient to induce an optimal motor response during preop-
erative clinical testing. After 12 months, the motor score was
obtained in a “stimulation-on”and “medication-on”condition.
To assess the psychologic profile, we selected validated and
standardized psychologic instruments, according to presurgical
psychologic screening procedures based on the core assessment
program for surgical interventional therapies in Parkinson’s
disease (CAPSIT-PD) guidelines.
21
To rate symptoms of depres-
sion, we administered the Montgomery-Asberg Depressive Rating
Scale (MADRS),
24
a validated semistructured interview used to
measure depressive symptoms and to assess treatment efficacy in
PD.
25
A ten-item questionnaire evaluates core symptoms of
depression (nine of ten items are self-reported, and one is based on
the rater’s observation during the interview). The diagnostic cutoff
was established at >19, according to the CAPSIT-PD guidelines.
21
Personality characteristics were assessed using the Minnesota
Multiphasic Personality Inventory-2 (MMPI-2), a self-report yes/no
questionnaire widely used to assess adult psychopathology.
26
We
analyzed ten clinical scales: 1) hypochondriasis (Hs), 2) depression
(D), 3) hysteria (Hy), 4) psychopathic deviate (Pd), 5) masculinity-
femininity (Mf), 6) paranoia (Pa), 7) psychasthenia (Pt), 8) schizo-
phrenia (Sc), 9) hypomania (Ma), and 10) social introversion (Si); and
15 clinical subscales: 1) anxiety (ANX), 2) fears (FRS), 3) obsessive-
ness (OBS), 4) depression (DEP), 5) health concerns (HEA), 6) bizarre
mentation (BIZ), 7) anger (ANG), 8) cynicism (CYN), 9) antisocial
practices (ASP), 10) type A behavior (TPA), 11) low self-esteem (LSE),
12) social discomfort (SOD), 13) family problems (FAM), 14) work
interference (WRK), and 15) negative treatment indicators (TRT).
Raw scale scores were converted to T-scores with a mean of 50 and
a standard deviation of 10. T-scores greater than 65 are suggestive
of psychopathology.
Disease-specific quality of life was rated with the Parkinson
Disease Questionnaire-8 (PDQ-8),
27
a short-form version derived
from the PDQ-39 questionnaire designed to assess aspects of
functioning and well-being of patients with PD across eight
dimensions of daily living, including relationships, social situations,
and communication.
Finally, in addition to the psychodiagnostic tests, we adminis-
tered a cognitive screening through the MoCA to exclude the
presence of cognitive deficits.
TEED Estimation
TEED per second through the STN-DBS electrodes was estimated
using the Koss formula.
28,29
The stimulation parameters and the
contact impedance were read at 12 months after DBS, and TEED
values were calculated separately for the left and right STN (Left-
TEED: left STN TEED; RightTEED: right STN TEED). To better estimate
the total energy administered to the patient in one year following
the DBS, the TEED values calculated at six and 12 months were
summed together (LeftTEED total and RightTEED total). The later-
ality of PD motor symptoms was used to select a single lateralized
value of TEED for every patient (LateralityTEED).
Statistical Analysis
The statistical analysis was carried out using the MATrix LABo-
ratory (Matlab) software version 9.3.0.713579 (R2017b, The Math-
Works, Inc, Natick, MA).
MMPI-2, MADRS, and PDQ-8 scales were analyzed as indepen-
dent samples and tested for normal distribution. The one-sample
Table 1. Demographic and Clinical Characteristics.
Patient Side onset Sex Age range
(years)
Disease
duration
(years)
LEDD MoCA
score
UPDRS
OFF-MED
pre-DBS
UPDRS
ON-MED
pre-DBS
UPDRS
OFF-MED
ON-STIM
post-DBS
UPDRS
ON-MED
ON-STIM
post-DBS
1 Left F 60–69 15 1122 19.98 40 18 25 12
2 Right F 60–69 17 859 28.98 44 15 30 25
3 Left M 50–59 11 1203 30.00 35 16 23 15
4 right F 50–59 11 1117 23.52 39 16 19 13
5 Left F 40–49 8 675 25.15 48 10 17 6
6 Left F 50–59 9 632 24.52 54 16 39 20
7 Left M 40–49 12 1208 27.65 41 23 22 11
8 Left M 60–69 10 1290 24.98 18 11 22 16
9 Left F 50–59 11 1480 26.52 20 4 12 12
10 Left M 60–69 15 875 22.98 35 16 18 10
11 Right F 50–59 10 818 24.52 40 11 18 10
12 Left M 50–59 12 935 26.52 45 24 23 11
13 Left F 60–69 7 832 23.98 25 11 16 12
14 Left F 50–59 5 1015 27.65 36 21 25 23
15 Left M 70–79 19 1280 27.11 41 19 21 20
16 Right F 40–49 9 793 24.52 37 14 23 14
17 Left F 50–59 10 882 29.65 46 14 34 28
18 Left F 40–49 6 1554 30.28 38 18 13 10
19 Left M 60–69 11 1838 21.52 54 20 35 12
20 Left M 60–69 11 1979 24.98 47 14 25 10
Mean ± SD 16 left 12 women
8 men
57.60 ± 7.63 10.95 ± 3.49 1119.35 ± 369.05 25.75 ± 2.78 39.15 ± 9.62 15.55 ± 4.78 23.00 ± 7.11 14.50 ± 5.77
OFF-MED, medication “off”condition; ON-MED, medication “on”condition; ON-STIM, stimulation “on”condition; OFF-STIM, stimulation “off”condition.
PERSONALITY TRAIT SHIFT AFTER DBS
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Kolmogorov-Smirnov test (p<0.05) showed that psychologic
clinical scale scores were not normally distributed. Therefore, a
nonparametric paired Wilcoxon signed ranked test (p<0.05) was
used; effect size is reported as r.
We then evaluated the correlation (Spearman coefficient)
between demographic and clinical characteristics (age, disease
duration, levodopa equivalent daily dose [LEDD], and MMPI-2
scores [change from baseline]).
To establish whether there was an association between the total
energy delivered in one-year DBS and psychologic outcomes in
those scales/subscales that were showing a significant difference
between pre-DBS and 12-month follow-up, we correlated the score
change from baseline with the total TEED values using Spearman
coefficient (r
s
) because of the small sample size. The change was
calculated as follows:
diff score =12-month FUP score−pre-DBS score (1)
where 12-month FUP score is the score at 12-month follow-up,
and pre-DBS score is the value before DBS. Bonferroni correction
was applied (α=0.01).
Changes at follow-up also were calculated for PDQ-8 and LEDD,
using the same formula. As a further control, total TEED values at
12-month follow-up in patients both treated and nontreated with
antidepressants were compared through a nonparametric Kruskal-
Wallis test (p<0.05). All values are means ± SD.
RESULTS
After 12 months of DBS, patients showed significant changes in
MMPI-2 scales (Fig. 1). More specifically, we observed higher scores
in the D scale (pre-DBS mean: 56.05 ± 9.01; 12-month mean:
61.90 ± 10.31; p=0.015, r=0.54), DEP scale (pre-DBS mean:
51.20 ± 11.01; 12-month mean: 56.40 ± 13.43; p=0.009, r=0.58),
LSE scale (pre-DBS mean: 54.70 ± 10.81; 12-month mean: 58.90 ±
10.78; p=0.023, r=0.51), WRK scale (pre-DBS mean: 52.80 ± 10.87;
12-month mean: 57.00 ± 12.29; p=0.002, r=0.69), and TRT scale
showed a significant trend (pre-DBS mean: 55.05 ± 13.24; 12-month
mean: 59.75 ± 11.25; p=0.025, r=0.50). Other MMPI-2 scales did
not change before and 12 months after DBS (Table 2). We did not
find any difference between male and female patients. Detailed
results are reported in Table 3.
Further analyses were conducted on the MMPI-2 (D, DEP, LSE,
WRK, and TRT scales) correlating the change from baseline scores
with age, disease duration, UPDRS total motor score, and LEDD; no
correlations were found (Table 4).
PDQ-8 assessment for 18 patients was significantly different
between pre-DBS and 12-month follow-up (pre-DBS vs post-DBS
[mean ± SD] =40.15 ± 14.80 vs 30.73 ± 17.88; p=0.011). Specif-
ically, PDQ-8 score improved for 13 (72.2%) patients, remained
unchanged for one, and worsened for four (22.2%). Based on the
cutoffs for minimal clinically important difference reported in the
literature,
30
we observed a significant improvement in ten (55.6%)
patients, whereas three (16.7%) showed significant worsening of
symptoms.
Finally, we did not find significant differences between pre-DBS
and after 12-month follow-up in MADRS scale assessment (pre-
DBS vs post-DBS [mean ± SD] =8.18 ± 3.84 vs 9.22 ± 7.21, p=
0.977) and in MoCA test (25.75 ± 2.78 vs 24.64 ± 3.13, p=0.231).
After DBS, we observed a 40% improvement in UPDRS scores in
the “medication-off”condition (pre-DBS vs post-DBS [mean ± SD] =
39.15 ± 9.62 vs 23.00 ± 7.30; Z =−3.79; p<0.001), but no signif-
icant change in the “medication-on”condition (15.55 ± 4.78 vs
14.53 ± 5.93; Z =−0.73; p=0.483).
TEED Analysis After 12 Months
When we looked at the correlation between the changes in
MMPI-2 scores after 12-month DBS and the amount of energy
delivered to the tissue in one year, we found that only the energy
on the right side was inversely correlated with the changes in D-
depression (r
s
=−0.681, p=0.007), as shown in Figure 2.
In addition, we did not observe significant correlations between
TEED and age (TEED right: r
s
=0.121, p=0.680; TEED left:
r
s
=−0.075, p=0.799), disease duration (TEED right: r
s
=0.024, p=
0.934; TEED left: r
s
=−0.033, p=0.910), and PDQ-8 score change
(TEED right: r
s
=0.247, p=0.395; TEED left: r
s
=−0.216, p=0.459).
Furthermore, the group of patients treated with antidepressants
showed a lower LateralityTEED at the 12-month follow-up than
patients not treated with antidepressants (LateralityTEED in
patients treated with antidepressants [mean ± SD] =24.51 ± 9.22
μJs
−1
,N=6; in patients not treated with antidepressants =39.83 ±
14.67 μJs
−1
,N=11, p=0.035).
There were no significant differences between men and women
in TEED to the right (p=0.240) or left (p=0.438) STN.
We did not find significant correlations between TEED and
UPDRS score delta either in the “medication-off”(right side:
r
s
=−0.207, p=0.477; left side: r
s
=0.157, p=0.593) or the
“medication-on”(right side: r
s
=0.075, p=0.799; left side: r
s
=
0.064, p=0.828) condition.
DISCUSSION
Our results showed that despite a marked reduction in parkin-
sonian symptoms and consequent improvement in quality of life,
patients showed a shift in scales measuring depression (D, DEP,
Figure 1. Significant changes of MMPI-2 scales between pre-DBS and post-
DBS (12-month follow-up) scores. Data are presented as mean and SE. Aster-
isks denote statistically significant differences (after Bonferroni correction, p<
0.025) at follow-up (Wilcoxon signed ranks test; *p<0.025, **p<0.01).
MAMELI ET AL
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Neuromodulation 2022; -:1–9
4
WRK, TRT, and LSE), characterized by an overall moderate wors-
ening of symptoms, denoted by higher scores. Interestingly, TEED
to the right STN correlated negatively with depression score delta
between pre- and post-DBS. This means that patients who received
less energy to the right STN showed a greater increase in depres-
sion scores, and patients who received more energy showed a
smaller increase in depression scores. We did not find any signifi-
cant correlation between TEED to the left STN and depression score
delta. MMPI score changes after DBS did not correlate with disease
duration, LEDD reduction, patient’s age, or severity of motor
symptoms.
Evidence of the different involvement of the two hemispheres in
depression comes from lesion studies where stroke patients with
an injury to the left prefrontal cortex showed a worsening of
depressive symptoms.
31
In addition, functional MRI studies showed
that patients with major depressive disorder present an imbalance
in interhemispheric activation, consisting in hypoactivation of the
left dorsolateral prefrontal cortex (DLPFC) and hyperactivation of
the right DLPFC.
32,33
Accordingly, noninvasive neuromodulation
studies observed improvements of depressive symptoms obtained
by facilitating left DLPFC excitability and inhibiting the right
DLPFC.
34
Moreover, a classical study by Lozano et al (2008)
35
demonstrated that targeting the subgenual cingulate cortex (BA
25) in DBS for drug-resistant depression led to normalization of the
hypoactivity in the DLPFC because of the strong connections
existing between BA 25 and DLPFC. Even if classical models of
frontostriatal circuits take into consideration the limbic circuit
underlying connections between the basal ganglia, the medial
orbitofrontal cortex, and the anterior cingulate cortex,
36
a recent
study by Irmen et al (2020)
37
showed that the worsening of
depression following STN-DBS in patients with PD may be caused
by the influence of STN-DBS on the DLPFC. The authors combined
volume tissue activation based on individual electrode recon-
struction with connectome normative data to describe the effects
of stimulation on depression depending on the site of stimulation.
They observed that left STN-DBS leads to hypoactivation of the left
DLPFC and consequently to worsening of depression. The negative
correlation between the amount of TEED delivered to the right STN
and the worsening of depression observed in this study may
therefore be linked to the inhibitory effect of STN-DBS on the right
DLPFC. Conversely, it is possible that in our sample, higher TEED
caused greater inhibition to the right DLPFC, leading to smaller
depression score delta between pre- and post-DBS and therefore
less severe worsening of depression. Nevertheless, it is important to
consider other possibilities. For example, some authors hypothe-
sized that the STN might not present such a distinct functional
segregation, thus suggesting that differences in electrode place-
ment and current diffusion might explain the different behavioral
effects observed in each patient.
38
In this context, Serranová et al
(2019)
39
have recently demonstrated that electrodes positioned
more posteriorly in the motor component of the STN activate
subpopulations of neurons responding to emotional stimuli. Higher
TEED might therefore translate into greater current diffusion, which
could mean that limbic STN regions also were stimulated, in
Table 2. MMPI-2 Scales Comparison.
MMPI-2 scales Pre-DBS T1 pValue*
Mean SD Mean SD
Base
Hs 58.85 10.25 61.40 9.65 0.305
D 56.05 9.01 61.90 10.31 0.015
Hy 59.60 12.01 57.85 9.28 0.519
Pd 49.25 8.79 52.30 13.03 0.147
Mf 53.50 13.65 54.10 10.85 1.000
Pa 49.75 14.07 54.35 9.18 0.393
Pt 52.40 13.73 55.45 11.73 0.067
Sc 56.20 12.74 58.00 11.20 0.213
Ma 52.20 13.50 53.95 11.00 0.527
Si 54.15 10.37 56.95 9.67 0.132
Content
ANX 53.50 10.05 54.30 10.40 0.522
FRS 52.85 8.16 53.75 9.56 0.670
OBS 51.50 13.58 53.05 11.46 0.348
DEP 51.20 11.01 56.40 13.43 0.009
HEA 61.60 10.04 60.50 7.98 0.711
BIZ 53.35 9.77 53.35 9.75 0.472
ANG 47.30 11.22 49.25 10.87 0.306
CYN 54.15 10.70 55.50 11.26 0.979
ASP 48.30 16.96 51.15 9.56 0.861
TPA 51.10 10.82 50.05 9.49 0.448
LSE 54.70 10.81 58.90 10.78 0.023
SOD 52.70 8.01 55.70 9.65 0.047
FAM 50.95 11.09 52.30 10.22 0.491
WRK 52.80 10.87 57.00 12.29 0.002
TRT 55.05 13.24 59.75 11.25 0.025
*Significance level of a Wilcoxon signed-rank test. In bold: significant
differences after Bonferroni correction (p<0.025).
Table 3. Differences Between Men and Women in MMPI-2 Scales Score
Change After DBS.
MMPI-2 scales Women Men pValue*
Mean SD Mean SD
Base
Delta Hs 0.58 12.40 5.50 6.76 0.395
Delta D 2.50 7.40 10.88 10.72 0.096
Delta Hy −3.25 13.92 0.50 8.73 0.536
Delta Pd 0.67 7.61 6.63 10.70 0.245
Delta Mf 0.17 14.19 1.25 15.16 0.354
Delta Pa 0.25 6.88 11.13 25.92 0.533
Delta Pt 3.50 8.59 2.38 9.69 0.787
Delta Sc 3.00 9.25 0.00 6.68 0.728
Delta Ma 2.33 9.62 0.88 14.62 0.877
Delta Si 5.08 6.88 −0.63 8.60 0.113
Content
Delta ANX −0.42 4.44 2.63 6.80 0.333
Delta FRS 1.08 7.45 0.63 4.27 0.876
Delta OBS 2.00 6.28 0.88 9.61 0.756
Delta DEP 3.92 7.56 7.12 8.56 0.462
Delta HEA −0.33 10.43 −2.25 8.68 0.698
Delta BIZ −1.17 7.02 1.75 11.45 0.787
Delta ANG 2.33 8.17 1.37 4.60 0.846
Delta CYN 1.67 11.64 0.88 8.01 0.969
Delta ASP 7.00 19.35 −3.37 7.17 0.081
Delta TPA −1.92 7.56 0.25 8.75 0.938
Delta LSE 5.08 6.84 2.88 8.27 0.485
Delta SOD 3.75 7.59 1.87 4.64 0.728
Delta FAM 1.75 6.05 0.75 9.65 0.588
Delta WRK 3.75 4.20 4.88 7.02 1.000
Delta TRT 6.33 7.69 2.25 10.51 0.418
*Significance level of a Mann-Whitney Utest.
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addition to the targeted motor regions. Accordingly, studies have
shown a greater mood/apathy improvement with additional
ventral stimulation of the STN.
40
In this study, the STN target was
localized both radiologically and electrophysiologically using MRI,
microelectrode recording, and macrostimulation. Postsurgery MRIs
were systematically performed in patients and did not reveal any
misplacement. However, future studies willing to further disclose
the possible effects on nonmotor STN areas should adopt more
precise neuroimaging measurements (eg, tractography).
Moreover, from a surgical point of view, reports have raised the
possibility that the procedure may have deleterious effects on
certain aspects of mood regulation. Fiber tracts involved in the
neural control and regulation of mood are altered.
41
According to
the hypothesis that STN regulates not only motor but also asso-
ciative and limbic cortico-subcortical circuits, the STN could have a
direct effect on mood by way of its connections.
42
Neuroimaging
findings indicating a change of activity in sections of the cingulate
cortex during STN stimulation may support these hypotheses.
43
In our sample, patients who were treated with antidepressants
showed lower LateralityTEED (ie, TEED in the contralateral hemi-
spheric with regard to the onset side of motor symptoms). Because
most of our sample had a left motor onset, LateralityTEED reflects
primarily the TEED to the right STN. This reinforces the link between
changes in depressive traits after DBS and TEED to the right STN.
When interpreting our results, we also must consider that
changes in depressive traits could be attributed to a hypo-
dopaminergic syndrome.
7
In fact, the pathological STN neuronal
activity observed in PD leads to motor, cognitive, and emotional
inhibition; deafferentation stimulation of the STN by DBS can
reverse such behavioral inhibition. The release of this brake allows
motor improvement. Conversely, the notable reduction in anti-
parkinsonian drug dose allowed by motor improvement can unveil
mesolimbic hypodopaminergic behaviors such as apathy, anxiety,
or depression.
7
However, in our sample, the changes in LEDD did
not correlate with a worsening in depressive symptoms, which
means that the change in depressive trait score, measured with the
MMPI-2, could be correlated directly with the effects of the current
spread produced by the DBS.
In addition, the shift observed in scales that measure low self-
esteem and work difficulties may suggest that this phenomenon
also is linked to psychologic and social factors. This issue has
been already described in the literature. Studies indicate that
there is often a contrast between the improvement in motor
disability and the difficulties experienced by patients with PD in
reintegrating into a normal familial and social life: Some patients
are unexpectedly dissatisfied, whereas others become apathetic
and are therefore confronted with familial conflicts and malad-
justment at work.
44,45
Nevertheless, the causes of the observed
discrete changes in the behavior of operated patients remain
unclear.
In this study, depressive trait levels increased after DBS treatment
when considering MMPI-2 scales, whereas no differences were
observed at the two successive MADRS depression assessments.
Differences between such instruments could help clarify the con-
flicting evidence. In particular, MMPI-2 is a self-report assessment
tool, but MADRS is a clinician-administered scale; these two
approaches are intended to be complementary and to provide
different and useful information, relevant for depression clinical
diagnosis and prognosis.
46
It is possible that patients reported the
presence of more severe depressive symptoms in the self-evaluation
Table 4. Correlations Between Age, Illness Duration, TEED, UPDRS, and MMPI-2 Scales.
Variable Statistics Delta D Delta DEP Delta LSE Delta WRK Delta TRT
Age r
s
0.035 −0.03 0.064 −0.235 −0.290
p0.882 0.899 0.788 0.318 0.215
Disease duration r
s
0.355 0.117 0.096 −0.029 0.198
p0.125 0.624 0.687 0.903 0.402
Total TEED (right) r
s
−0.681 0.161 0.200 0.065 −0.015
p0.007 0.583 0.492 0.826 0.958
Total TEED (left) r
s
0.238 −0.018 −0.356 −0.432 −0.244
p0.413 0.952 0.212 0.123 0.401
LEDD difference (post-DBS −pre-DBS) r
s
−0.407 −0.133 0.048 −0.067 0.202
p0.075 0.577 0.842 0.780 0.394
UPDRS delta (medication-on) r
s
−0.412 −0.089 0.023 −0.254 0.047
p0.080 0.717 0.924 0.293 0.847
UPDRS delta (medication-off) r
s
−0.112 0.142 0.099 0.087 0.140
p0.648 0.562 0.686 0.724 0.568
In bold: Statistically significant correlations. Significant differences after Bonferroni correction (p<0.01).
Figure 2. Rank correlation between total TEED estimate on the right STN side
after 12 months and MMPI-2 D score difference between pre- and post-DBS
(Delta D). Delta D, MMPI-2 depression (clinical scale) score change at follow-
up (positive values represent higher scores at follow-up, and therefore worse
depression).
MAMELI ET AL
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Neuromodulation 2022; -:1–9
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questionnaire (MMPI-2) than in the evaluation conducted by the
clinician (MADRS). Some studies, in fact, found that neurologists
failed to recognize depressive and anxious symptoms in people with
PD during routine office visits, >50% of the time.
47,48
When inter-
preting this discrepancy, it is also useful to consider the possibility of
an underestimation by the neurologist or an overestimation of the
patient’s own emotional experience. Finally, both instruments serve
different purposes (personality assessment vs evaluation of the
severity depressive symptoms), which means we must consider
these results separately and very carefully.
Indeed, patients least accepting of their disease might be more
willing to undergo DBS, and they would be more prone to disap-
pointment if DBS fails to meet their expectations. Expectations
should never be unrealistic, and the caring team should ensure not
only that patients fully understand the risks and potential benefits
of the DBS but also that it will not stop the neurodegenerative
progression of the disease.
Accounting for these social and psychologic factors is of the
highest importance during the preoperative evaluation for DBS
and must be included in the multidisciplinary team discussion.
The outcome on mood symptoms is highly variable, and it likely
depends on multiple factors; this underlines the importance of
the patient selection process for a positive outcome.
49
The
screening of patients eligible for DBS could be done by the
administration of MADRS and MMPI-2, per CAPSIT-PD guide-
lines.
21
Because of the complexity of psychiatric phenomena, it
would be advisable to take a cautious approach by including
psychiatric evaluation by interview for a better selection of
patients who score close to the pathological cutoffs in MADRS
and MMPI-2.
Collectively, our preliminary observations showed that despite
the excellent motor outcome and the improvement in quality of
life, DBS treatment can result in poor adjustment of patients to
their personal, family, and socio-professional life. It is still unclear
whether this is a purely reactive response to a new situation or a
direct consequence of the surgical procedure.
Despite the insights obtained from this study, caution is
required for the following reasons. First, we must underline that
this is a preliminary study with a small sample size, which limits
the generalizability of our results; therefore, future studies with
larger sample sizes are needed. Secondly, we failed to collect data
on the prevalence and severity of apathy from all patients, so we
cannot rule out an influence of apathy on our results. Different
influences and multiple factors, such as intra/postsurgical pro-
cedure, genetic factors, coping mechanisms, outcome expecta-
tions, stressful life events, and supporting factors may affect
depressive traits.
The correlation analyses performed in this study highlight a
relationship between the amount of energy delivered by DBS and
the change in depression after one year but do not allow us to
establish the directionality of this association.
This study encourages broader research programs focused on
increasing our knowledge of the effect of TEED on mood and
behavioral traits. Further studies should implement longer follow-
ups to clarify the duration of the potential stimulation effects on
patients’mood. Future studies also should consider implementing
a controlled experimental design to establish whether there is a
causal link between TEED and changes in depressive traits. More
generally, a multidisciplinary approach to patient care is highly
recommended, including psychosocial preparation during the
preoperative phase and postoperative follow-up. This is necessary
to help patients and their entourage to deal with expectations and
potential limitations of DBS treatment, the effectiveness of which
remains unquestionable.
Authorship Statements
Francesca Mameli, Fabiana Ruggiero, and Roberta Ferrucci
participated in the conceptualization, methodology, writing,
review, and editing of the manuscript. Michelangelo Dini, Sara
Marceglia, and Marco Prenassi participated in the data curation,
formal analysis, writing, review, and editing of the manuscript.
Linda Borellini, Filippo Cogiamanian, Elena Pirola, Luigi Gianmaria
Remore, Giorgio Fiore, and Marco Locatelli participated in the
clinical management of patients, writing, review, and editing of the
manuscript. Alberto Priori and Sergio Barbieri participated in
the conceptualization, funding acquisition, and supervision. Maria
Rita Reitano, Natale Maiorana, and Barbara Poletti participated in
the methodology, writing, review, and editing of the manuscript.
All authors approved the final version of the manuscript.
How to Cite This Article
Mameli F., Ruggiero F., Dini M., Marceglia S., Prenassi M.,
Borellini L., Cogiamanian F., Pirola E., Remore L.G.,
Fiore G., Reitano M.R., Maiorana N., Poletti B., Locatelli M.,
Barbieri S., Priori A., Ferrucci R. 2022. Energy Delivered by
Subthalamic Deep Brain Stimulation for Parkinson Dis-
ease Correlates With Depressive Personality Trait Shift.
Neuromodulation 2022; -:1–9.
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COMMENTS
This article reveals evidence of behavioral consequences from STN-
DBS among patients with PD. The authors compare psychologic
consequences, including personality, between pre- and post-
intervention and found change in depressive personality trait, but
depressive symptoms were not different. Methods and data analyses
were well prepared; however, applications were limited according to
small sample size and study design. To summarize, this article could be
a pilot study for further larger controlled experimental studies in the
future.
Daruj Aniwattanapong, MD
Bangkok, Thailand
***
This article highlights the important topic of behavioral outcomes
following DBS in patients with PD. The results of the study imply a cor-
relation between the increase of the depressive traits as measures by the
MMPI-2 and the total amount of current delivered to the right STN.
Johanna Philipson, MS
Umeå, Sweden
***
STN-DBS is an established effective therapy for motor deficits
observed in patients with PD. A prevalent side effect of this approach
is the worsening of depression symptoms that can hinder overall
MAMELI ET AL
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Neuromodulation 2022; -:1–9
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therapeutic benefits. The study by Mameli et al investigates the cor-
relation of total electrical energy delivered (TEED) in STN-DBS with
changes in scale measures of personality trait, particularly associated to
depression. Data were collected and interpreted thoroughly. Conclu-
sions are limited because of the small sample size, but the authors
adequately recognize this among other limitations of the this study.
The scientific community will greatly benefit from this study.
Suelen Boschen de Souza, PhD
Rochester, NY, USA
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9
