2.3 Work program and proposed research methods
The work program is divided into the following three work packages:
Recruitment of patients and healthy subjects including diagnostic and psychological
assessments as well as assessment of clinical outcome.
Collecting the MR-related (Glx, GABA, RSFC).
Data evaluation and analysis of the results.
Recruitment of patients and healthy subjects Patients will be recruited from routine
admissions to the psychiatric day-hospital. According to our power calculation, we aim to
include at least 120 patients with BPD according to the general and borderline specific
criteria of the alternative DSM-5 Model for Personality Disorders (Section III of DSM 5, p
761ff (APA, 2013), which includes a specific dimensional pattern of impairments in
personality functioning and pathological personality traits for diagnosis.
A total of at least 60 healthy volunteers will be recruited by newspaper advertisement. They
will be examined using a semi-structured interview and self-ratings (SCL-90-R) to assess
current mental status, to exclude personal or first-degree family history of psychiatric
disorders (including substance abuse) or history of neurological or major medical conditions
that might affect brain function.
Description of therapy conditions with/without emotion focused schema therapy interventions:
Deficits in emotion regulation are widely seen as a core pathology in BPD. Hence, quicker and
more intense emotional activation can a priori be expected in every BPD patient. This study
makes use of the fact that some interventions in ST evoke intense emotions (child modes),
e.g. to foster awareness of child's needs, while others aim to establish a "healthy distance"
from overintense emotions to enable adequate parental care (healthy adult mode). With regard
to emotions schema therapy techniques have been divided into therapy relationship,
experiential, cognitive, and behavioral techniques (Fassbinder et al., 2016). Schem therapy
assumes that by using these strategies, the patient's fear of emotions reduces while
willingness to overcome experiential avoidance increases (Fassbinder et al., 2016). This
approach also clarifies "old" (biographically linked) goals of emotion regulation behavior
(now counting as dysfunctional or a strategies of emotional avoidance), now replacing them by
"new" (actual) goals that require and enhance new (functional) emotion regulation behavior.
MR-based investigation protocol
Scheduled acquisitions (scan time including patient positioning up to 1.5h):
High-resolution, T1-weighted 3D whole brain scan using the MP-RAGE sequence TR/TE/TI =
2530/2.7/1100 ms; α = 7°; 176 sagittal slices of 1 mm thickness; FOVAP×HF = 256 × 256
mm²; in-plane matrix: 256 × 256 pixels; acquisition time: 6 min.
Resting state fMRI scan of the entire brain using T2*-weighted EPI; TR/TE = 2520/30 ms;
whole brain coverage with 45 transverse slices (thickness 2.5 mm); FoVAP×LR = 220×210
mm²; in-plane matrix: 88×84 pixels; 240 volumes; TA = 10 min.
1H-MR spectra with MEGA-PRESS sequence in three voxels placed in the aMCC (SN network)
and left and right DLPFC (ECN network).
Manual adjustment of field homogeneity and water suppression (5 min); TR/TE = 2000/68 ms; 256
alternating single acquisitions with subsequent application of frequency-selective RF pulses
at 1.9 ppm and 7.5 ppm, respectively; additional series acquisition of twelve water
non-suppressed single scans with varying echo times (TR = 20 s, TE's = 30, 40, 50, 60, 75,
90, 110, 150, 175, 200, 250, 300 ms), TA = 17 min per voxel; total MRS duration of 50 - 55
min.
Photoplethysmogram (PPG) and respiration recordings during MRI acquisition with 500 Hz using
an MR-compatible polygraph MP150 (BIOPAC Systems Inc., Goleta, CA, USA). Respiratory activity
will be monitored by a strain gauge transducer incorporated in a belt tied around the chest,
approximately at the level of the xiphoid process. The PPG sensor will be attached to the
proximal phalanx of the left index finger.
Analysis of baseline (T0) MRI-data:
Separate analysis for rs-fMRI and 1H-MRS data:
A seed-based correlation analysis will be used to explore the whole-brain RSFC pattern of the
regions being central to the study, i.e., the aMCC and DLPFC. Analysis of variance (ANOVA)
will be applied to test for RSFC differences between patient groups and controls.
The same analyses will be applied to analyze group differences of the local Glx and GABA
concentrations as well as the Glx/GABA balance in aMCC and DLPFC between patients and
controls.
Associations between rs-fMRI and 1H-MRS data:
A linear mixed model analysis will be performed to investigate differences of associations
between RSFC (SN and ECN) and Glx or GABA concentrations at the aMCC and DLPFC between
patients and controls.
Follow-up (T0-T1;T1-T2) analysis of treatment effects on MRI target parameters (RSFC, Glx,
GABA)
Separated analysis for rs-fMRI and 1H-MRS data:
Analysis of variance (ANOVA) for repeated measures will be applied to test for effects of
group belonging (ST-EF, ST-AC, and healthy subjects; ST-EF vs. ST-AC) on changes of RSFC, Glx
and GABA over time, as well as for within-subject changes between T0 and T1, and T1 and T2
scans.
Associations between RSFC and the local Glx and GABA concentrations:
A linear mixed model analysis will be performed to investigate changes after 9 weeks of
treatment (T0 vs. T1) or 6month of catamnesis (T1 vs. T2) of either therapeutic condition
(ST-EF, ST-AC) compared to unspecific changes over time in healthy controls as well as
between treatment groups.
In a first step, this analysis will be performed separately in both treatment groups and
healthy controls and for both neurotransmitters (Glx, GABA) and both spectroscopic and
functional connectivity target regions (aMCC, DLPFC).
In the second (more important) step, potential treatment condition driven differences in the
correlations between metabolic and RSFC parameters will be investigated by applying the same
model including the factor treatment group.
Clinical outcome
Evaluation of changes of core symptoms and their clinical significance:
In a follow-up (T0-T1; T1-T2) analysis of treatment effects, the individual change of each
patient in measures of the primary (Emotion Regulation Inventory, ERI) and secondary
(Borderline Personality Disorder Severity Index - fourth version, BPDSI-IV; Levels of
Personality Functioning Scale, SEFP; Personality Inventory for DSM-5 (Criterion B), PID-5;
Borderline Symptom List (95 Items) BSL-95; Inventory of Interpersonal Problems, IIP-D; Young
Schema Questionnaire (short version), YSQ-S3r, and Schema Mode Inventory (118 item version),
SMI) outcome criteria will be estimated by the Reliable Change Index (RCI) (Wise, 2004) in
each therapeutic condition.
Evaluation of changes in primary and secondary criteria and their clinical significance: In
each therapeutic condition the improvement of each patient in measures of the primary (ERI)
and secondary (BPDSI-IV, SEFP, PID-5, BSL-95, IIP-D, YSQ-S3r, and SMI) outcome criteria will
be estimated by the Reliable Change Index (RCI), which summarizes changes at the level of an
individual in the context of observed changes for the whole sample.
The RCI provides information about the functioning of an individual before/after therapy on
an outcome measure, including the normative information about this measure by dividing the
difference between pre- and post-treatment scores by the standard error (that includes also
the reliability coefficient, not only the standard deviation of the measure). The change will
be considered as being unlikely the product of measurement error (i.e., considered reliable),
if the RCI is greater than 1.96. When the individual has a change score greater than 1.96 it
can be assumed that the individual has improved. More detailed information on RCI scores and
their meaning in each outcome measurement is given in the uploaded material.
Interrelation between clinical outcome parameters and neurobiological findings:
A linear mixed model analysis will be used that includes those MRI-data (RSFC, Glx, GABA)
that have been significantly affected by therapy (T0 vs. T1) and those clinical scores that
reached the highest RCI. The detected significant interactions will be compared between the
ST-EF and ST-AC treatment condition.