Cognitive Reappraisal Training Targeting Emotion Circuits As a Therapeutic Intervention in Borderline Patients
Phase: NA
Conditions: Borderline Personality Disorder
Sponsor: Icahn School of Medicine at Mount Sinai

Cognitive Reappraisal Training Targeting Emotion Circuits As a Therapeutic 
Intervention in Borderline Patients  
PI: Harold W Koenigsberg, MD
NCT04967222
Document Date: 2-12-2025

1
Cognitive Reappraisal Training Targeting Emotion Circuits As a Therapeutic Intervention 
in Borderline Patients
PI: Harold W. Koenigsberg, M.D.
Research Protocol, version May 2021
RESEARCH STRATEGY 
A. Significance
     A.1.   Borderline Personality Disorder and its Treatment Challenges 
Borderline Personality Disorder (BPD) is a prevalent and enduring psychiatric condition 
found in approximately 2% to 5.9% of the population [1, 2] and 20% of hospitalized psychiatric 
patients. Suicide rates of approximately 10% have been reported [3]. One of the most prominent 
clinical features of BPD is extreme mood shifts [4-6] occurring in response to external 
social/emotional events [7-9]. The emotional instability in BPD contributes to many of the most 
disabling, even life-threatening, symptoms of the disorder, including suicidality, outbursts of 
intense anger, and seriously impaired role functioning [10]. The severity of the BPD symptom 
profile, its prevalence, chronicity and high burden upon health care services [11-13] make the 
development of effective and accessible treatment for BPD a high priority. Although several 
psychological treatments show promise [1417] and medications are of value in ameliorating 
certain specific symptoms [18, 19], no medications are currently indicated to treat the BPD 
syndrome [19] and extant psychological treatments have small effect sizes, are resource 
intensive and of limited availability [20, 21]. The development of new treatment approaches is 
therefore essential. Neuroimaging is useful in treatment development to identify neural 
mechanisms underlying key symptoms, guide targeted treatments and assess their impacts.  
     A.2.   Cognitive Reappraisal as Therapeutic Focus 
 Intense, unstable or prolonged emotional reactions to psychosocial events characterize 
BPD, contributing to high levels of distress, disturbed relationships and impaired role 
functioning. Reducing affective instability (AI) in BPD is important to the successful treatment of 
the disorder because of the central role of AI in BPD’s most disabling and life-threatening 
symptoms [4, 5, 10]. Thus, the enhancement of emotion regulation is central to the treatment of 
BPD. A growing body of research has characterized the dynamics of emotion regulation [22]. A 
number of classes of regulation strategies have been described, including changing the 
situation (e.g., avoiding stressful situations), attentional redeployment (e.g., diverting attention 
away from the stressor), cognitive change, and modulating one’s emotional response (e.g., 
suppressing the expression of emotion) [23-25]. Cognitive change in particular is one of the 
most highly adaptive and versatile classes of regulation strategies, with cognitive reappraisal 
(CR) representing a particularly valuable strategy for implementing cognitive change [25]. CR 
entails re-construing a situation in such a way as to alter its emotional valence.  
Two CR tactics have been described as a means of operationalizing reappraisal [26, 27]. 
The first, distancing, is a strategy in which the subject construes the emotional situation as 
psychologically distant – i.e. calmly, objectively, and not emotionally relevant personally, or far 
away in time or place, so as to reduce its negative valence. This is the mechanism, for example, 
which underlies the “clinical distancing” that enables an emergency room physician to function 
effectively even in the face of intensely upsetting situations. The second is reinterpretation – a 
strategy in which the subject creates a different (e.g., more benign) narrative for a situation to 
change its valence (e.g. re-conceptualizing bad performance on a test as a “learning 
opportunity”, rather than as a marker of failure) [28] [26, 27].  
Effective Date: 2/12/2025
End Date:5/27/2025

2
Overall, cognitive reappraisal has been demonstrated to be a particularly effective 
strategy. Individuals who use cognitive reappraisal, in comparison to other regulation strategies, 
show a better sense of well-being, enhanced social relationships, better memory and less 
cardiovascular sympathetic arousal [25, 29, 30]. In particular, the distancing tactic of CR had the 
largest effect size (d=.45) [31] of various emotion regulation strategies examined [22]. Further, a 
direct comparison of distancing and reinterpretation CR tactics has shown that longitudinal 
training in distancing uniquely yields significant reductions in perceived stress in daily life [26].  
We have previously shown that BPD patients show impairments in cognitive reappraisal 
associated with anomalous neural activation when attempting to reappraise-by-distancing (see 
C.1.3.1. for previous results). They fail to engage the top-down cortical regions typically 
employed by healthy subjects (HCs) and do not downregulate amygdala activity as HCs do [32]. 
This observation motivated us to explore whether BPD patients could be trained to enhance the 
effectiveness of cognitive reappraisal-by-distancing, the central aim of our recently completed 
NIMH funded study (R01 MH077813). In this study, we demonstrated that with 5 sessions of 
focused cognitive reappraisal-by-distancing (CRD) training, BPD patients were able, when 
reappraising negative pictures (vs. just looking), to reduce activity (p=0.03, one-tailed) in the 
picture induced negative emotion signature (PINES) network, a whole-brain pattern derived 
through machine learning that is sensitive and specific to picture induced negative emotion [33].  
PINES activation increases monotonically with subjectively reported levels of negative emotion. 
This network is more sensitive and specific for emotional reactions to negative pictures than 
other regions associated with negative emotion alone, such as the amygdala, insula, salience 
network and default mode network.  In addition to the decreased PINES response, we found 
that, behaviorally, subjects showed a decrease in ratings of negative valence after training (p 
<0.03).  
This body of work convinced us to pursue development of focused cognitive reappraisal 
training as a novel approach to the treatment of BPD, either as a stand-alone treatment or in 
concert with evidence-based treatments for BPD. To accomplish this objective, we propose the 
current R61/R33 study. In the R61 phase, the proposed study will develop and manualize an 
enhanced form of focused cognitive reappraisal training, building upon the model explored in 
our previous work, will confirm that the manualized treatment can be delivered adherently, will 
demonstrate that this treatment influences targeted behavioral measures and specific 
hypothesized circuits, and will identify an optimal dose for the treatment. Should we 
demonstrate that the intervention can significantly influence activity in the targeted neural 
circuits, we will proceed to examine the R61determined optimal dose in the R33 phase of the 
study. In this phase, we will confirm that the treatment can be delivered reliably with good 
therapist adherence and patient acceptance, and will examine whether the treatment will have a 
beneficial effect on clinical outcome measures, including measures of overall BPD symptom 
score, affective lability, mood, impulsivity, and perceived stress. In addition this phase will allow 
us to replicate, in a new sample, that the treatment influences the target neural networks 
identified in the R61 phase, and to test whether change in clinical outcome measures correlate 
with changes in target circuit activation and behavioral reappraisal response. We will also 
examine the near-term durability of the treatment effect by re-assessing the clinical outcome 
measures 1 and 4 months after the end of the treatment.  
Effective Date: 2/12/2025
End Date:5/27/2025

3
A.3. From Proximal Target Engagement to Symptom Change: Modeling the Effects of 
Treatment  
The ultimate objective of the proposed treatment for BPD is to reduce the disabling 
symptoms of the disorder that 
contribute to personal distress, 
interpersonal impairments and 
social role dysfunction. These key 
symptoms include affective 
instability, unstable patterns of 
relating to others, impulsivity, 
inappropriate anger, self-destructive 
behaviors and inconsistent 
experience of self in terms of 
values, goals and beliefs. Affective 
instability, the tendency for emotions 
to be excessively reactive to events, 
rapidly shifting from one emotion 
state to another, reaching high 
levels of intensity and being slow to 
return to baseline, is an especially 
critical symptom of BPD. We have 
previously shown that many of the 
symptoms of BPD, including suicidal 
threats, gestures and acts, inappropriate anger, chronic emptiness and identity disturbances, 
are correlated with affective instability [10].  
Hence we 
propose 
a treatment that directly aims to reduce affective instability 
by enhancing the emotion regulation skill of cognitive reappraisal (CR). From moment to 
moment, the effective use of CR should reduce the intensity with which negative stimuli are 
experienced and reduce activity in the PINES network. On the basis of the findings from our 
previous study (see A.2. above and C.1.3.3. below), we predict that CR training will lead to: 1) 
reduced PINES activation during negative picture reappraisal and 2) a reduction in behavioral 
ratings of negative valence (improved reappraisal success). Of the two, we expect that neural 
response will be the more sensitive measure of the proximal training effect because it is less 
subject to demand expectations and reporting bias.  
Our prior work demonstrated that with 5 sessions of CR training, subjects reduced their 
negative ratings of aversive pictures not only when reappraising, but also when simply looking 
at the negative pictures. This suggests that as reappraisal is repeatedly practiced, it becomes 
automatically utilized even when not explicitly directed. We therefore expect that CR techniques 
will generalize beyond the treatment setting and be implicitly activated as subjects contend with 
emotionally stressful events in their daily lives (Fig. 1). This will lead to a decrease in affective 
instability and a consequential decrease in the BPD symptoms linked to affective insatiability: 
suicidal threats gestures and acts, inappropriate anger, chronic emptiness and boredom, and 
identity disturbances.  These hypotheses will be explicitly tested in the R33 phase.  
     A.4. Studies of Cognitive Reappraisal Enhancement 
 A number of recent studies have examined the degree to which individuals can be 
trained to enhance cognitive reappraisal. These studies employed a variety of training 
Effective Date: 2/12/2025
End Date:5/27/2025

4
techniques including: longitudinal mentor guided training in the lab, smart-phone based home 
practice focusing on daily life events, and practice providing counseling to others using 
reappraisal, delivered over an internet platform. The duration of training varied from one to three 
weeks, with session frequencies ranging from every 3 to 5 days to daily. Five of the seven 
studies examined healthy subjects [26, 34-37] and one each examined those with social anxiety 
[38] or high levels of neuroticism [29]. Most studies focused upon the reinterpretation tactic, but 
in their study of healthy subjects, Denny et al [26] compared training in reinterpretation and in 
distancing. They reported a robust reduction in self-reported negative affect relative to the 
control condition in both the distancing and reappraisal training conditions, with the effect in the 
distancing group greater than in the reappraisal group. Moreover, the distancing group showed 
a decrease in perceived stress following training. Overall, training in CR across these various 
studies appeared to be effective and was associated with symptom improvement. None of 
these studies examined BPD and only one defined a group based upon a clinical symptom [38]. 
While we are unaware of any studies, other than our own preparatory work (see C.1.33), 
directly examining the effect of focused CR training on neural activity, one study examined 
regional BOLD activity as a predictor of outcome in cognitive-behavioral treatment (CBT) of 
subjects with generalized anxiety disorder and panic disorder [39]. The authors report that, 
during a task in which subjects were instructed to “keep up” or “reduce” their emotional 
reactions, which the authors characterize as a reappraisal task, activation in the right 
hippocampus and left uncus during “keep up”, and in the left transverse temporal gyrus, left 
anterior insula, right and left superior temporal gyrus, left supramarginal gyrus, left precentral 
gyrus, left superior frontal gyrus, and right substantia nigra during “reduce” predicted, using a 
random forest model, outcome to CBT treatment. Goodman and colleagues [40] reported that 
BPD patients who received 12-months of Dialectical Behavior Therapy (DBT) showed reduced 
amygdala activation to emotional pictures and an improvement in total score in the self-reported 
Difficulties in Emotion Regulation Scale (DERS, [41]). One component of DBT is the 
development of emotion regulation skills, although cognitive reappraisal is not explicitly taught. 
Nevertheless this study provides some support for the hypothesis that CR training may be 
valuable for BPD patients. The current proposed study will, however, test the hypothesis that 
focused CR training, as a highly targeted intervention, may shorten the time to clinical change.  
 Although these findings are highly encouraging, there are some important limitations to this 
literature. Few studies used objective measures of reappraisal utilization and effectiveness, 
instead relying primarily on self-reports. One of these studies involving assessment of neural 
activity showed that repeated CR-by-distancing training uniquely attenuated amygdala activity 
one week following training [37], but that study was confined to healthy subjects and examined 
massed CR practice over two days, rather than longitudinal training. Critically for the current 
application, are no reports of CR-specific treatments that have been manualized and 
there is no data on optimal dose. Further, significantly, no CR training study has examined 
BPD, the paradigmatic condition of emotional dysregulation. Thus, several important 
knowledge gaps remain: 1) can patients with BPD be trained to improve their ability to 
regulate emotion and improve symptoms and functional outcome by targeted CR 
training, 2) what are the neural mechanisms by which CR is enhanced through focused 
training, and 3) what is the optimal form of such training in terms of technique and dose? 
Addressing these knowledge gaps, the present study is positioned to translate cognitive 
reappraisal training into an addition to the therapeutic armamentarium for BPD, efficiently 
targeted to known mechanisms of emotion regulation, and impacting the key symptom domains 
of BPD. It may also have wider application to other disorders marked by affective instability.  
Effective Date: 2/12/2025
End Date:5/27/2025

5
B.   Innovation 
 
The proposed study is highly innovative in several respects. First, it is the only study to 
develop and test a new treatment for BPD that is based upon the highly adaptive emotion 
regulatory strategy of cognitive reappraisal. Further, it is the only study to test this treatment 
intervention on a proximal target defined on the basis of predicted neural and behavioral 
markers of cognitive reappraisal, i.e. reduced activation of signature negative affect neural 
circuits, increased activation of top-down emotion control circuits and behavioral measures of 
reappraisal success. This provides a sensitive test of the effectiveness of the intervention and 
can confirm that clinical benefits arise from theoretically understood mechanisms. This also will 
be the first study to examine the effect of reappraisal training upon clinical symptoms and 
perceived stress in BPD patients, the paradigmatic disorder of emotion dysregulation. In fact, to 
our knowledge, this is the only study to examine the efficacy of reappraisal training in any 
clinical diagnostic group. Finally this proposal is the first to develop a manual for the reliable 
delivery of training in cognitive reappraisal.  
Effective Date: 2/12/2025
End Date:5/27/2025

6
C. Approach   
C.1    Prior Work 
C.1.1  Studies of the Phenomenology of 
Affective Instability in BPD. Our group has 
pursued a research program focused on 
understanding the nature of affective instability 
and emotion regulation in BPD. We have 
characterized its phenomenology in BPD [42], 
examined its relationship to the suicidality and 
interpersonal dysfunction in the disorder [10]  
and contrasted affective instability in BPD to that 
of bipolar disorder [43]. We have continued to 
further refine the affective instability construct 
[44]. 
C.1.2.  Neuroimaging Studies of Passive 
Emotion Processing in BPD.  We contrasted 
patterns of BOLD activation between 19 BPD 
patients and 17 HC subjects while they passively 
viewed emotional images [45]. When viewing 
negative International Affective Pictures System 
(IAPS) pictures 
compared to rest, BPD patients showed greater 
activity than HCs in the amygdala, fusiform 
gyrus, primary visual areas, superior temporal 
gyrus (STG) and premotor areas (Fig 1), 
whereas healthy controls showed greater activity 
in the insula, middle temporal gyrus and 
dorsolateral prefrontal cortex. 
C.1.3.  Neuroimaging Studies of Emotional 
Dysregulation in Borderline Patients  To 
understand 
the 
basis for 
the 
emotional dysregulation in BPD, we conducted a 
study (R01MH077813) examining two 
hypotheses: (1) that BPD patients were emotionally dysregulated because they could not 
effectively bring to bear the common and highly adaptive emotion regulating mechanism of 
cognitive reappraisal by distancing (see A.2.), and (2) that BPD patients were emotionally 
dysregulated because they could not habituate as healthy subjects could, to repeated 
encounters with negative emotional stimuli. 
C.1.3.1. (1) Neuroimaging Studies of Reappraisal by Distancing in BPD. The first 
goal of this previous R01 study was to compare neural activation between BPD and HC 
subjects and the psychopathological control group of AvPD patients as they employed CRD 
when viewing aversive emotional pictures. We published findings contrasting 18 BPD patients 
and 16 HC’s [32]. When distancing compared to looking, BPD patients did not activate the 
dorsal ACC (dACC) and intraparietal sulci (IPS) as strongly as HC’s 
Effective Date: 2/12/2025
End Date:5/27/2025

7
(Fig. 2), did not downregulate the amygdala to the extent that HC’s 
did and activated the superior temporal 
sulcus (STS) and superior frontal 
gyrus more strongly than HC’s. This 
study was the first imaging study, to 
our knowledge, to contrast cognitive 
reappraisal processes in BPD patients 
and healthy controls. To determine 
whether the effects we observed were 
characteristic of personality disorders 
in general or more specific to BPD, we 
included the AvPD group in the 
comparison (19 BPD, 20 AvPD and 18 HC’s). Examination of the 
effect of distancing (vs. looking) in amygdala when viewing aversive images showed a 
significant Condition (distance vs. look) Χ Group interaction (F(2,54)=4.85, p=.01).  Post hoc 
tests demonstrated that for HC’s there was significantly less amygdala activity when distancing 
vs. looking (F(1,18)=9.05, p=.008) and for AvPD’s the effect was in the same direction but less 
marked (F(1,19)=3.66, p=.07), while BPD’s do not show a reduction in amygdala activity 
(F(1,17)=1.20, NS) (Fig. 3). Correspondingly, in the ACC (4,34,22) we found the greatest 
increase in activation from looking to distancing in HC’s, the least in BPD’s, with AvPD’s 
intermediate (Fig. 4).  
Fig 4.  Anterior Cingulate
(Distance - Look) Activation 
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
HC
AvPD
BPD
Group
Regression Weights (beta)
Fig 3.  Amygdala Activation When Looking 
vs. Distancing (Negative Pictures)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
HC
AvPD
BPD
Group
Regression Weights (Beta)
Looking
Distancing
Effective Date: 2/12/2025
End Date:5/27/2025

8
C.1.3.2. (2) Neuroimaging Studies of Habituation to Single Repeat Viewing in BPD vs 
HC’s.  Our second goal in this study was to determine whether there are differences between 
BPD, AvPD and HC subjects in the degree to which neural networks habituate or sensitize to 
emotional stimuli. We found [46] in a sample of 19 BPD subjects, 23 AvPD subjects, and 25 HC 
subjects that, as hypothesized, only the HC subjects habituated to repeated viewing of the 
aversive pictures showing reduced negative affect ratings (t=2.71,df=24,p<0.01, one-tailed). 
HC’s, but not BPDs showed increased activity of the dorsal anterior cingulate cortex (dACC) 
when viewing repeat vs novel 
aversive pictures (156 voxel cluster, 
p<.05, k=150, FWE, Fig.5). 
Importantly, activation in this region 
was negatively correlated with 
affective instability (ALS score) for 
HC and BPD patients (r=-.038, 
p >0.04 and r=-0.56, p<0.01, one-
tailed, respectively, Fig. 6).  
C.1.3.3. Preparatory Studies of Reappraisal Training in BPDs 
Having demonstrated that BPD patients could not down-regulate 
amygdala activity and could not engage top-down regulatory 
networks as healthy volunteers could when attempting cognitive 
reappraisal-by-distancing (see C.1.3.1 above and [47]), we carried 
out a study (R01 MH077813) to determine whether focused 
training could enhance reappraisal in BPD, examining neural 
circuits implicated in reappraisal. BPD subjects (N=19), and healthy volunteers (HC; N=18) 
performed a cognitive reappraisal-by-distancing task 5 times: at baseline while fMRI images 
were acquired, then for three additional training sessions, and again on a 5th session when fMRI 
images were once again acquired. The sessions were separated by 2-3 days each. The 
reappraisal-by-distancing task, similar to the task to be employed in the present proposal (see 
more detailed description below), comprised 3 conditions presented in random order, in 
which subjects received the instruction either: 1) to apply reappraisal-by-distancing when 
viewing negative emotional pictures (Reappraise-Negative Condition; RNeg), 2) to simply look 
at a negative picture, self-monitoring feelings induced by the picture (Look-Negative Condition; 
LNeg), or 3) to simply look at a neutral picture, self-monitoring the feelings present (Look-Neural 
Condition; LNeu). Following each picture presentation, the subject 
was prompted to rate how negative they were feeling on a scale 
from 1 (least negative) to 5 (most negative), after they carried out 
the instruction. A total of 90 trials (30 each condition) were 
presented each day, with different pictures each day. We selected 
pictures that involved interpersonal interactions. The reappraisal 
training carried out each day consisted of two parts and followed a 
standardized script. First the subjects read a brief description of the 
distancing strategy written in lay language and were encouraged to 
discuss their understanding of the strategy and ask questions of the 
experimenter. Subjects practiced distancing with several pictures, describing their thought 
process to the experimenter and receiving feedback to help shape their performance. Second, 
Fig. 5.  BPD patients fail to increase 
dorsal anterior cingulate activity to 
repeat viewings of negative images
Fig. 6. Affective 
instability inversely 
correlates with dorsal 
anterior cingulate activity 
for HCs 
Effective Date: 2/12/2025
End Date:5/27/2025

9
they performed the distancing tactic on 20 practice pictures before beginning the 3-condition 
reappraise by distancing task described above.  
Analysis of the behavioral data demonstrated a decrease from baseline to session 5 in negative 
valence ratings in the BPD group in the Look-Negative as well as the Reappraise-Negative 
condition, suggesting the possibility that the effect of reappraisal training carried over to the 
Look condition, even without conscious intention. This observation is particularly encouraging in 
terms of training generalizability, since it suggests that training in distancing may facilitate its 
automatic engagement, without need for deliberate intent. We found (see fig 7) that the total 
negative valence ratings for RNeg and LNeg showed a significant decrease post-training (p< 
0.05, twotailed). In terms of neural activity, we hypothesized that effective reappraisal of 
negative affective pictures would result in a downregulation of activity in a network known to 
represent a sensitive and specific neural 
signature responsive to viewing aversive 
negative pictures, the PINES network [33]. We 
found that, as expected, after reappraisal training 
BPD patents showed decreased PINES activity 
when reappraising (vs. looking) relative to pre-
training, with a large effect size (d=0.73, p<0.03, 
one-tailed; see Fig. 8). Thus, we found that with 
5-days of reappraisal-by-distancing training BPD 
patients were able to significantly improve their 
ability to downregulate activity in the brain 
network activated by negative emotion, and behaviorally to reduce how negatively they rated 
aversive pictures. 
C.2.  Overall Design 
The present proposal follows the R61/R33 experimental medicine model to refine and test a 
proposed clinical intervention for BPD patients, training in reappraisal-by-distancing, in terms of 
its ability to influence hypothesized neural and behavioral targets and, once that is established, 
to demonstrate its ability improve clinically relevant outcome measures.  
C.2.1.  R61 Phase.  Specifically, in the R61 phase we will determine whether reappraisal 
training will have an effect upon hypothesized proximal neural targets (see below) and 
behavioral measures (assessed by means of our imaging task; C.2.6.), further develop our 
treatment manual and will test 3 doses of the treatment with BPD patients -- treatment delivered 
2 times a week for 2, 4 and 6-weeks. The reappraise-treatment condition will be contrasted with 
a control condition (C.2.7.2). Therapist’s adherence to the manual will be assessed.  
Based upon an extensive body of research on the neural correlates of cognitive 
reappraisal [48-50], we expect reappraisal training focused upon down-regulating reactions to 
negative emotional pictures to influence the neural pattern that reflects processing of negative 
emotional pictures, the PINES signature. The PINES is a particularly appropriate target, 
because it has been shown to vary monotonically with subjective emotion ratings and has been 
shown to be specific to picture induced negative emotion [33]. Moreover, we found in our 
preparatory study (C.1.3.3) that reappraisal training was associated with a significant reduction 
in activation of this region. Hence our milestone for R61 success will be based upon change in 
the PINES network (see C.2.2). Although not specified as milestones, we will also examine 
Effective Date: 2/12/2025
End Date:5/27/2025

10
ROI’s identified in the reappraisal literature: the amygdala, and the top-down control regions: 
the ventrolateral prefrontal cortex (VLPFC), the dorsolateral prefrontal cortex (DLPFC), the 
dorsomedial prefrontal cortex (DMPFC), the dorsal anterior cingulate cortex (dACC), and the 
posterior parietal cortex (PPC) [48]. In addition, we will examine behavioral reappraisal success. 
The effect of reappraisal training upon all of these targets will be monitored at baseline and at 
weeks 2, 4 and 6 by means of our fMRI reappraisal task (see C.2.6. below).  
C.2.2.  Milestones to Proceed to R33 Phase and Optimal Dose Determination. We have 
selected milestones for the present study, cognizant of the need to achieve a balance: criteria 
sufficiently stringent to insure that a target-based treatment is genuine on the one hand, yet 
which also guards against discarding an important treatment advance on the other. Ultimately, 
the goal of reappraisal training is to improve subject’s ability to reduce their negative emotional 
reactions to aversive cues, which we expect (and will test in the R33 phase) to improve their 
ability to handle stress and to reduce the clinical symptoms of BPD. We hypothesize that such 
clinical improvements would be associated with an improved ability to downregulate activity in 
the negative emotion responsive brain regions. As described above, with training, we expect to 
see an improvement in downregulation of the PINES network response to negative pictures. 
Our prior studies (see C.1.3.3) suggest that the neuroimaging measures are more sensitive to 
change than the behavioral measures – the effect size of 5days of training on PINES activity 
was large (d =0.73), while the effect on behavioral ratings of negative valence, though 
significant, was small (d=0.15). We did not see an increase in activity of the top-down control 
regions with training in the BPD, although after training the BPD’s maintained activity in these 
regions at baseline levels in contrast to HC’s whose activity decreased, possibly because of 
increased efficiency. Thus it is possible that, unlike HC’s, BPD’s do not have the ability to 
upregulate these regions, but rather bring about decreased PINES activity through 
enhancement of “bottom-up” regulatory processes. These questions require further exploration.
The milestone to proceed to the R33 phase is based on a statistically significant 
difference between the experimental and the control conditions. Should all three doses be found 
to be significantly superior to the control condition, the dose that shows the largest effect size 
will be considered for the R33 phase. Among doses with similar or same effect size the one that 
requires the fewer number of weeks will be selected.  
C.2.3.  R33 Phase.  In this phase we will examine, in a new sample of BPD patients, the effect 
of the optimal treatment dose (R61) upon clinically relevant symptom measures of BPD. In 
addition, using the same techniques as in the R61 phase we will repeat assessment of the 
effect of treatment upon PINES network activation, activation of the top-down control regions 
and behavioral measures of negative valence during reappraisal, (see C.2.5). This component 
of the R33 phase specifically addresses reproducibility as a priority in this research 
design. We will obtain subjective reports, using established measures (e.g. DERS and ERQ, 
see C.3.3), of the extent to which specific emotion regulation strategies, including reappraisal-
by-distancing, were used by each subject at baseline and following treatment. We will record 
drop-out rates and obtain subjective measures of treatment acceptability and relevance by the 
subjects and monitor therapist adherence to the manual. To assess short-term durability of 
treatment, we will obtain re-assessment of the clinical measures one and four months after 
treatment completion. These R33 phase measures will enable us to assess the clinical 
effectiveness and feasibility of the treatment and to replicate the neural and behavioral effects 
Effective Date: 2/12/2025
End Date:5/27/2025

11
identified in the R61 phase in a distinct population. Finally, we will examine whether change in 
the targeted neural processes is correlated with clinical symptom change.  
C.2.4.   Overview of the Treatment and Control Conditions in the R61 and R33 phases 
The same treatment and control conditions will be used in both R61 and R33 phases, differing 
only in dose delivered. In the R61 phase, three doses – 2, 4, and 6 weeks --   of 2 times a week 
treatment and control 
sessions will be studied. In the R33 phase the 6-week dose will be employed. In the R61 phase, 
all subjects will be seen for 6-weeks, with the full battery of assessments, including fMRI 
imaging, carried out at baseline and the 2, 4, and 6 week time points. We considered the 
alternative model in which separate subject cohorts receive 2, 4 and 6 weeks of treatment. 
However, we believe that any possible benefit to be gained by having subgroups with the 3 pre-
designated treatment durations, is outweighed by the increased power and opportunity for 
within subject comparisons available in the single cohort 6-week staged-dosing model that we 
will use.  
The reappraisal-by-distancing treatment (described in section C.2.7.1 below) is an 
extension of the method developed by Ochsner [51] and employed by our group in two 
published studies [32, 52] and three R01 grant studies. Our group is experienced in these 
methods, having trained over 60 subjects in the distancing strategy. The treatment control 
condition will be Downregulate (CD), an alternative regulation strategy (see C.2.7.2), well-
matched to the experimental condition [22, 23]. Subjects in both conditions will practice an 
emotion regulation task: either reappraisal-by-distancing or the control task, while viewing 
emotional pictures 2 sessions a week for 2- , 4- or 6-weeks. They will receive the same battery 
of behavioral and task-based imaging assessments at the 2-, 4, and 6-week points. Subjects in 
both treatment and control groups will view the same number pictures and have the same 
number of contact hours with the trainer.  
Effective Date: 2/12/2025
End Date:5/27/2025

12
C.2.5.  The imaging tasks During fMRI imaging subjects from both treatment and control 
groups will carry out a task assessing their neural and behavioral responses to instructions to 
down-regulate negative emotions by either 
distancing, or expressive suppression.  The 
imaging task is one that we have considerable 
experience with, having employed it in 
published work [47, 53] and over the last ten 
years in three R01 studies. It is modeled after 
that of [51]. Subjects will be asked to view 
affective pictures under 3 conditions: 1) look at 
neutral pictures, 2) look at negative pictures, and 3) regulate reactions to negative pictures. 
Each picture will be shown for 10 seconds and preceded with an instruction (“Look” or 
“Regulate”), which will appear on the screen for 2 seconds. Subjects will be told that when they 
see the “Regulate” instruction, they should employ reappraisal-by-distancing (treatment group) 
or downregulate (active control group). The “Look” instruction will be paired with neutral and 
negative pictures; “Regulate” with negative pictures only, since an instruction to emotionally 
down-regulate reactions to neutral pictures would be confusing. The order of the 
instruction/picture pairings will be randomized. Each picture is followed by a rating screen at 
which time subjects rate the valence of their reaction to the picture after carrying out the 
instruction on a 9-point scale (from -4 to 4) using an fMRI compatible slider. The rating screen 
will appear for 4 sec followed by an inter-trial screen that will be present for a jittered 2 – 6 sec. 
There will be 40 trials for each of the 3 conditions for a total of 40 minutes, divided into 4 runs 
of 10 minutes each.  
Prior to the baseline imaging task scan, subjects are familiarized with the 2 instructional 
conditions by the experimenter, using standardized scripts for the treatment and control 
conditions.  Subjects in both conditions will be instructed that in the “Look” condition, they 
should simply look at the picture and be aware of whatever spontaneous emotions arise. For 
those in the CRD treatment group, training for the “Regulate” condition consists of two parts. 
First, the subjects will read a brief description of the distancing strategy.  The following 
description of the strategy in lay language is presented: “view the photos in a very neutral way, 
knowing that you are not personally involved, and/or imagine that the pictured events 
happened far away or a long time ago. As you view each pictured event, what is important is 
that you cut all personal ties to the event in a way that any negative emotional reaction is 
decreased as much as possible.” In our experience, BPD subjects readily understand the 
strategy explained in this way. Subjects will next practice distancing to a series of IAPS slides, 
not subsequently used in the scanning sessions. The experimenter will have the subject 
describe aloud how he/she implements distancing, slide-by-slide, and will assist the subject to 
shape effective strategies. The subject will next practice the distancing task in a block of 20 
trials presented outside the scanner on a laptop computer. The training for subjects in the 
downregulate (CD) control group will be the same, except that subjects will be instructed that 
when they see the “Regulate” prompt they should use whatever emotion regulation strategy 
works for them to reduce their negative feelings. As for the treatment group subjects, the 
researcher will shape their behavior in 5 trials, having them draw upon their experience, and 
they will practice for 20 trials outside the scanner before beginning the imaging task. Subjects 
will be specifically instructed not to close their eyes or look away from the images in any of the 
conditions. 
+
2 s
10 s
4 s
2 – 6 s
Instruc on
Instruc on:
●LOOK
●REGULATE
Picture
Display
Rate Emo on
-4
0
+4
Image Presenta on
Ra ng
Inter-trial Interval
Neutral
or
Nega ve
+
Effective Date: 2/12/2025
End Date:5/27/2025

13
C.2.6.  Distancing-Training and Downregulate Control Condition in R61 and R33 Phases 
 
Training in distancing and in the suppression-control condition will be the same in both 
R61 and R33 phases, except that in the R33 phase only a single dose, the optimal dose 
(number of sessions) determined in the R61 phase will be employed.  
C.2.6.1.  Cognitive Reappraisal-by- Distancing (CRD) Training.  We present here a 
brief summary of Distancing Training, which is more fully described in our treatment manual 
(see Appendix). Training is carried out in two 45 minute sessions a week. In the initial session, 
the experimenter reviews the description of distancing (see C.2.6.) and explains that the training 
sessions are designed to help the subject become efficient in using emotion regulation-by-
distancing, emphasizing that it is an important skill to develop since it can be helpful in dealing 
with distressing situations in daily life. Subjects will then engage in an interactive distancing 
practice to 5 negative emotion pictures. In this practice, the trainer asks the subject to describe 
their thought process as they carry out the distancing task, using this opportunity to engage 
collaboratively with the subject, making suggestions (drawn from those in the treatment manual) 
to enhance the process, e.g. “Try looking at the scene from a neutral position, distancing as 
though you are a newspaper reporter collecting information for a story.” In each session, 
following this period of guided instruction, subjects intensively practice, by viewing 40 negative 
pictures on the laptop, distancing to 20 and carrying out the “look’ instruction to 20. This laptop 
practice is similar to imaging task described above (C.2.6.), except that it does not include the 
Look-Neutral condition.  In order to foster carryover of the developing distancing skill beyond the 
lab, subjects will be encouraged in each session to watch for emotional situations in their daily 
life where the distancing strategy might be useful. Ten to 15 minutes of each session will be 
allocated for a review of those real-world situations, considering whether distancing is the 
optimal strategy and how it might be employed. This CRD training program is based upon the 
model that we employed to train 60 subjects in our prior R01 study, modified by an increase in 
the number of sessions and adding generalization to real-world situations component.  
 
C.2.6.2  Control Downregulate (CD)  Condition.  We addressed a number of 
considerations to identify a control condition that would be credible and well-matched to the 
experimental condition, would be neutral in its neural and behavioral effects and would not be 
detrimental to subjects. We chose a condition in which subjects are told we will help them build 
upon their own natural way of downregulating negative feelings to disturbing situations by giving 
them focused practice, using negative pictures, during a training period. See the control 
treatment manual (see Appendix) for fuller description.  While we appreciate that this control 
condition has the drawback of heterogeneity, the fact that it draws upon what our symptomatic 
subjects are already doing speaks the the neutrality of its effect. We will monitor the strategies 
subjects are actually using by asking them to report the specific strategies they use. Our 
concern over the heterogeneity is also mitigated by the fact that many successful BPD 
psychotherapy research studies have used the heterogeneous 
“treatment-as-usual” control condition successfully. 
Like CRD training, CD training is carried out in two 45-minute sessions a week. It will involve 
viewing the same negative and neutral pictures on a laptop and comparable contact and 
engagement with a trainer, as in the reappraisal training condition. Moreover, the fMRI task for 
the CD condition parallels that of the training condition, incorporating the same set of neutral 
and negative pictures and cognitive demands. In the first session, subjects are instructed that 
they will learn how to regulate negative emotions by getting practice with the strategies that 
come naturally to them. Each session will follow the same structure as the CRD training, with 
description of the CD strategy, practice and behavior shaping with 5 negative pictures, 
independent practice with 20 look-negative and 20 suppress-negative trials, and discussion of 
use of the technique in real world settings. 
Effective Date: 2/12/2025
End Date:5/27/2025

14
C.3.   Design Considerations 
C.3.1.   Choice of Affect-Induction Stimuli.  Pictures employed in the fMRI tasks and the 
training tasks will be negative and neutral valence images from the International Affective 
Pictures System (IAPS [55]) and the Nencki Affective Pictures system (NAPS;[56]), stimuli 
widely used in emotion research, which have normed valence and arousal ratings. The 
assignment of images to scan day (baseline, 2-,4-,or 6- weeks in R61 or baseline and endpoint 
in R33) and the assignment of negative images to the look or regulate conditions will be 
counterbalanced among subjects. 
C.3.2.   Choice of Regions of Interest for Imaging Analyses.  We will assess negative 
reactivity by examining activation of the Picture Induced Negative Emotion Signature (PINES) 
network. We selected this network because its activation has been demonstrated to be specific 
to and monotonically proportional to subjective reactions to the negative picture stimuli we are 
employing. Moreover, it has been shown to outperform the three ROI’s, the amygdala, insula 
and ACC, and seven whole brain networks, including the salience, default and somatomotor 
networks, commonly associated with negative affect [33]. Although PINES network activation is 
our primary neural outcome measure, we will also separately examine activity in each of the 
above specific ROI’s and in the salience, default and somatosensory networks. Although not 
primary outcome measures, we will also examine the effect of training upon the top-down 
control regions implicated in cognitive reappraisal that have been highlighted in the meta-
analysis by Buhle et. al. [48]: the dorsolateral prefrontal cortex (dlPFC), the ventrolateral PFC 
(vlPFC), the posterior dorsomedial PFC (dmPFC) and the posterior parietal cortex (PPC).  
C.3.3   Outcome Measures.  R61: The primary outcome measure will be change in PINES 
network activity. Other outcome measures will be change in activity in the top-down control 
regions described above and in behavioral valence ratings of the image stimuli during 
reappraisal. R33: The primary outcome measure will be change in BPD symptomatology (total 
score in the Zanarini Rating Scale for Borderline Personality, self-report (ZAN-BPD, [57])). 
Secondary outcome measures will be the ZAN_BPD sector scores, Affective Lability Scale total 
(ALS, [58], Perceived Stress Scale (PSS; [59]),Difficulty in Emotion Regulation Scale Scores 
(DERS; [41]), Beck Depression Scale score (BDI) and State-Trait Anxiety Scale Score (STAXI).  
C.3.4 Rationale for Eye Gaze and Pupilometry Measures. Eye gaze direction will be 
assessed in both R61 and R33 phases to determine whether changes in BOLD activity during 
regulate conditions are associated with diversion of gaze [60] away from emotionally salient 
portions of the pictures. Change in pupil diameter (regulate-look) will be recorded during each 
scan, as an index of cognitive effort [61]. 
    C.4.0 Specific Design and Methods 
C.4.1    Subject Inclusion and Exclusion Criteria for R61 and R 33 Phases  
C.4.1.1  Inclusion Criteria. Male and female BPD subjects 18 to 55 years old meeting 
criteria for DSM-5 Borderline Personality Disorder and not meet criteria for Schizotypal 
personality disorder (SPD). Subjects meeting criteria for a non-IV substance use disorder more 
than 6 months prior to enrollment will not be excluded. Subjects meeting criteria for past PTSD 
will not be excluded unless they are currently experiencing symptoms. All subjects will be free of 
psychotropic medications for 2 weeks (6 weeks for fluoxetine) and will not be in current 
psychotherapy. We will monitor our recruitment rate every three months during the course of the 
R61 and R33 phases and should extrapolation of these rates suggest that we will not meet our 
recruitment goals we are prepared to liberalize the inclusion criteria to allow patients who are 
currently taking psychotropic medications or are in psychotherapy, so long as there has been no 
change in mediation or psychotherapy over the preceding two months. In this case, medication 
type and dosage and psychotherapy type and duration will be recorded and available for 
Effective Date: 2/12/2025
End Date:5/27/2025

15
subsequent analyses. Educational level will be recorded and will be available as a covariate in 
the analyses. Subjects will be medically healthy.  
C.4.1.2. Exclusion Criteria. Subjects will not meet criteria for Schizotypal Personality 
Disorder (SPD). SPD is excluded to avoid a possible confound from the restricted affect that 
characterizes SPD. BPD subjects will not meet DSM-5 criteria for past or present bipolar I 
disorder, schizophrenia, schizoaffective disorder, substance dependence, organic mental 
syndromes, head trauma, CNS neurological disease, or seizure disorder. Subjects currently 
meeting DSM-5 criteria for PTSD will be excluded, unless they are in remission or not currently 
experiencing symptoms. Subjects currently meeting criteria for major depressive disorder will 
also be excluded (except as described above). However, since depression is commonly 
associated with BPD (Koenigsberg et al., 1999), too stringent a depression exclusion criteria 
would yield a clinically atypical BPD sample. For this reason, BPD patients with Axis I 
depressive disorders other than major depression and those with a past history of major 
depression, will not be excluded. Suicidal subjects will not be excluded, unless referral to a 
higher level of care is deemed clinically necessary by the evaluating clinician. Subjects must not 
have met criteria for a substance use disorder for 6 months prior to entry into the study. All 
subjects must be free of significant medical illness. They may not have a pacemaker, surgical 
clips, any metallic implants, or shrapnel fragments that would contraindicate MRI scanning. 
Pregnant women will be excluded.
C.4.2. Sample Size, Recruitment and Assessment 
C.4.2.1 Sample Size. R61 Phase: (see Power Analysis C.4.5.1).  49 BPD subjects will be 
recruited each for the training and control groups to acquire  39 subjects in each group allowing 
for a 20% loss for drop out and fMRI movement artifact. R33 Phase:  65 BPD subjects will be 
recruited each for the training and control groups to obtain 51 subjects per group, allowing for 
20% loss.  
Effective Date: 2/12/2025
End Date:5/27/2025

16
C.4.2.2  Recruitment: 
Subjects will be recruited 
by newspaper, radio, 
and social media  
advertisements and by 
referral from the 
psychiatry outpatient 
department at Mount 
Sinai Medical Center, the 
Center for the Intensive 
Treatment of Personality 
Disorders at Mount Sinai 
West,  and the Bronx VA 
Medical Center. We are 
confident that we can 
meet recruitment goals 
for both R61 and R33 as 
our Mood and 
Personality Disorders 
Research Program at 
Mount Sinai, which has 
been engaged in 
neurobiological research 
studies of BPD for over 
30 years, has extensive 
experience in recruiting 
borderline personality 
disorder patients for 
research. Recently we 
have augmented our 
recruitment strategy by 
including additional clinical sites and by engaging an experienced research recruitment 
company, Bump Digital Marketing (Toronto, Ontario), to develop targeted website ads and a 
recruitment landing page for our studies.     (See 2.5 Recruitment and Retention Plan for 
detailed recruitment strategy.) 
C.4.2.3.   Assessments     All subjects receive the diagnostic, medical, self-report assessments 
and ratings indicated in Table 1. Assessors will be blind to training assignment. Research 
diagnoses (DSM-5) are made by means of semi-structured interviews, the SADS and SID-P, 
administered by experienced interviewers (masters or doctoral level clinical psychologists). We 
have achieved an interrater reliability kappa of .81 for diagnosing BPD.  
C.4.2.4. Sex as a biological variable. Based on prior experience we expect to recruit 
equal numbers of males and females. We will examine the effect of gender upon all 
findings.  
C.4.3   Procedures for Individual Subjects 
 
C.4.3.1  Timeline of Procedures. For both R61 and R33 Phases: Following consent, 
subjects will be seen for an initial session for baseline clinical interviews and self-report 
Effective Date: 2/12/2025
End Date:5/27/2025

17
instruments (Table 1). Subjects will receive a medical evaluation (see Table 1) and will be 
randomized (1:1) to CRD training or CD control conditions using a randomization scheme in 
random blocks of 2, 4 and 6.  An online, electronic randomization system will be implemented by 
the study statistician. The medical evaluation will take place at the Clinical Research Unit (CRU) 
(1468 Madison Avenue, 1st floor). This will include routine blood tests (complete blood count, 
metabolic and electrolyte panel, thyroid function tests, and a routine urinalysis. The urine drug 
screen will be administered in our office (1399 Park Avenue) on the day of your Medical 
Evaluation. On a separate day, subjects will carry out the baseline imaging task (see C.2.6). For 
R61 Phase: Within about 2 weeks of baseline scan, subjects will begin the manualized CRD-
training or control CD training, which will continue for 6 weeks. At 2-, 4- and 6- weeks, subjects 
will receive an fMRI scan similar to the baseline scan (different image sets will be employed for 
each scan, counterbalanced for sequence among scans across subjects) and the assessment 
measures as indicated in Table 1. For R33 Phase: The procedures will be as in the R61 phase 
except that training will last for 6 weeks. Following the last session, subjects will receive the 
termination assessments, including fMRI, as indicated in Table 1. Subjects will return 
approximately 1- and 4- months after their last session for follow-up (see Table 1). 
 C.4.3.2  Regulation-Training Procedures, Adherence Assessment and Refinement of 
the Treatment Manuals for both R61 and R33 Phases 
Regulation-training (for CRD and CD) will be carried out, guided by the appropriate training 
manual (see appendix for manuals). It will be carried out by a clinical psychologist, who will be 
instructed in the manualized treatments by HWK or BTD (authors of the treatment manuals). All 
treatment sessions will be video and audio recorded. The treatment sessions will be done in 
person via the approved e-prime program, and remotely via the approved PowerPoint slides 
Teleconference supervision for the trainers will be available from HWK or BTD. To assess 
adherence, one random session will be recorded from 20% of the treatments for review by HWK 
or BTD (see adherence rating scale in appendix to training manual) and additional supervision 
will be provided if low adherence (defined by consensus of HWK and BTD) is identified. The 
Specific Aim R61-1 of training manual development will be achieved by periodic reviews 
conducted by HWK and BTD with the training psychologist, at 4 month intervals, at which 
time proposed modifications of the manuals will be considered.  
     C.4.4. Addressing Missed Sessions and Premature Drop-out 
We will implement a number of measures to minimize drop out over the 6-week training 
period. These include careful planning of a session schedule that is optimally convenient for the 
subject, educating the subject about the importance of regular attendance and telephoning 
subjects after missed sessions to encourage attendance at the next session and to troubleshoot 
factors that might interfere with attendance. (See also section 2.5 Recruitment and Retention 
Plan)  
C.5.    Behavioral Data Analysis 
 
C.5.1 R61 Phase.  Analyses for Aims R61-2a and R61-2b are described in image 
analysis (C.6.4, below). Aim R61-2c: Data will be checked for normality and appropriate 
transformations will be applied to normalize them. Data analysis will primarily use linear mixed 
models, incorporating fixed effects for Training Group (CRD and ES), Session, and Trial Type 
(Look Neutral, Look Negative, and Regulate Negative), and their interactions, as well as a 
random effect consisting of an intercept for each participant. We will examine additional models 
that incorporate and estimate random-effects slope variance across participants on the time 
effect (i.e., Session). Outcome variables will be repeated measures in self-reported negative 
affect and reappraisal success (defined as the Look Negative minus Regulate Negative 
behavioral valence rating at each Session). Although we do not anticipate large differences in 
Effective Date: 2/12/2025
End Date:5/27/2025

18
baseline characteristics between the groups, given that the trial is randomized, we will include 
variables that are strongly unbalanced at baseline (p< 0.01) as covariates in our models.  
     C.5.2 R33 Phase. Aim R33-1: The primary outcome measure is the Zanarini total score 
(ZTS;[57]). We compare the change in ZTS from baseline to end of treatment (EOT) between 
groups by mixed effect models with group, time and their interaction as fixed effects. A similar 
analysis will be carried out for the additional outcome measures specified in C.3.3. (Table 1), 
using the Holm’s procedure for correction for multiple comparisons. Aim R33-2: The analysis 
will be as for R61 Aims R61-2 a,b and c. Aim R33-3: The analysis is described in imaging 
analysis section C.6.3. Aim R33-4: As above, we will use linear mixed models to examine 
change in ZTS as the outcome variable. Bonferroni corrections will be applied for multiple 
clinical outcome measures. P-values throughout will be 0.05, two tailed. All analyses will be 
conducted according to the intent-to-treat principle for both the R61 and the R33 phase. As a 
sensitivity analysis we will also consider models that adjust for the number of sessions actually 
received. Missing data will be assumed as MAR. Under this assumption, a mixed model 
approach that uses all available information will yield reasonable estimates of the effect sizes.   
   C.6.    Image Acquisition and Analysis 
   C.6.1  Image Acquisition. Participants will all be scanned 4 times in the R61 Phase 
(0, 2, 4, 6 weeks) or 2 times in the R33 Phase (Baseline, End-of-Treatment [EOT]) using the 
same 3 Tesla Siemens Skyra MRI system equipped with a 16-channel head coil. For each scan 
session, 4 series of 550 T2*-weighted images will be acquired during the 4 runs of the emotion 
regulation task using a multi-band echo-planar imaging sequence sensitive to the blood 
oxygenation level-dependent (BOLD) signal (multi-band factor = 7; repetition time = 1200 ms; 
echo time = 35 ms; flip angle = 60º; field of view = 228 mm2; matrix = 108 × 108; slice thickness 
= 2.1 mm; 70 slices). A high-resolution anatomical image will be acquired with a T1-weighted 
magnetization-prepared rapid gradient echo (MP-RAGE) sequence.
C.6.2  Image Preprocessing.  The 4 time series of T2*-weighted images acquired 
during the emotion regulation task at each time point will be separately motion corrected and co-
registered to the respective MP-RAGE image. Time series with more than 1 voxel of motion (≥ 
2.1 mm) or rotation (≥ 2.1°) will be discarded. Next, to optimize the images for cross-session 
contrasts of treatment effects, the week 2, week 4, and week 6 time series will be separately co-
registered to the week 0 series (R61) and the EOT time series will be co-registered to the 
baseline series (R33). The coregistered sets of time series will then be jointly normalized to the 
Montreal Neurological Institute template and smoothed with a 6-mm Gaussian kernel. C.6.3   
First-Level Modeling of Individual Treatment Effects. General linear models (GLM) will be 
conducted individually for each participant to jointly fit the week 0, 2, 4, and 6 time series (R61) 
or the baseline and EOT time series (R33). Beta weights will be fit to regressors for the 3 trial 
events of interest (Look Neutral, Look Negative, and Regulate Negative) and 2 trial events of no 
interest (Instruction, Rating), as well as 6 motion parameters [62], convolved with the 
hemodynamic response function [63]. Appropriate linear contrasts will be applied to the beta 
weights for Regulate Negative events minus Look Negative events in week 2, week 4, and week 
6 (all versus week 0) in the R61 phase and EOT versus baseline in the R33 phase. The 
resultant contrast maps represent the effects of treatment on whole-brain activation for emotion 
regulation. To estimate the effect of treatment specifically on PINES network activation, the 
contrast maps will be scaled by the PINES weight map (downloaded from 
Chang_PLoSBiology_PINES) by calculating the voxel-wise dot product of the two maps. The 
effect of treatment on neural activation in emotion-specific regions (e.g., amygdala) and top-
down control regions (e.g., dlPFC) will be modeled using the unweighted contrast maps together 
with masks derived from the “aal.002” atlas for automatic anatomic labeling [64] and the meta-
analysis conducted by Buhle et. al. [48]. 
Effective Date: 2/12/2025
End Date:5/27/2025

19
C.6.4  Second-Level Analysis of Group Differences in Treatment Effects. Random-
effects GLM will use two-sample t-tests to compare the neural effects of reappraisal-by-
distancing (CRD) and control training. The 3 contrast maps (weeks 2, 4, 6) for each participant 
in the R61 phase and the EOT versus baseline contrast map for each participant in the R33 
phase will be entered as dependent variables in separate GLM in which gender, age, education 
level, and pre-treatment ALS score will serve as covariates. The speculative purpose of the 
R61/R33 mechanism justifies setting the alpha level at a relatively liberal value of p<0.05 and a 
cluster threshold of 50 contiguous voxels. The hypothesized effects of treatment would be 
supported by findings of significant reductions in PINES activation for emotion regulation in the 
CRD training compared to the CD control training condition at either weeks 2, 4, or 6 or at EOT. 
The decision to proceed to the R33 phase is based on finding a statistically significant difference 
in  reduction in PINES activation between the CRD and control conditions. EOT versus baseline 
contrast maps for all participants in the R33 phase will be entered into a GLM that will use 
multiple regression to test for differential changes in activation in the regions of interest 
associated with improvement on clinical outcome variables for distancing training compared to 
the control condition. The 3 regressors will include: (1) % change in clinical outcome variable; 
(2) dichotomous treatment type variable; and (3) an interaction term (i.e., product), which 
identifies activation change related to differential response to the two treatments. The 
regressors will be centered on zero. 
C.7. Power Analyses:  
R61 Phase: The primary outcome measures are decreases from baseline in PINES network 
activity in the REGULATE (vs. LOOK) conditions in CRD training vs. the CD condition at the 2-, 
4-, and 6-week treatment doses. A significant effect at any dose will meet milestone criteria. In 
our previous work (see C. 1.3.3 above), we obtained a strong effect size of d = 0.73 for 5 days 
of training. We will, however, power the current study at a more moderate power of d = .65 to 
increase our detection sensitivity. We can achieve this at α = 0.05 (two– tailed), power = 0.80 
with an n = 39 per group (G-Power 3.1). R33 Phase: The primary outcome measure for the R33 
is the effect of CRD-training upon BPD relevant symptoms, assessed by the Zanarini Rating 
Scale (see C.4.2.3). A meta-analysis of randomized controlled clinical trials of psychotherapy for 
BPD reported an effect size of 0.56 for seven stand-alone trials employing BPD-relevant 
outcomes [65]. Powering to detect an effect size of 0.56 with a power of 0.80 at two-tailed α = 
0.05 requires 51 subjects per group.  
      
C.8  Potential Study Complications and Alternative Outcomes 
R61 or R33:  Recruitment Shortfall: We will closely monitor the rate of subject recruitment. If the 
rate at the 3- or 6-month time points, extrapolated, suggests that the recruitment goals will not 
be met, we will implement the measures described in section 2.5 (Recruitment and Retention 
Plan), including, modifying exclusion criteria to allow entry of subjects currently on psychotropic 
medication and /or in psychotherapy, provided that dose or session frequency has not changed 
in the prior 2 months. Treatment will be recorded and entered as a covariate in analyses. R61: 
Alternative Outcomes: It is possible that, contrary to our hypothesis, CRD-, will not be superior 
to CD-training in reducing PINES activity. While such a finding would not meet milestone 
criteria, this observation would motivate future research to further explore the active features of 
CD (as well as nonspecific factors) in the treatment of BPD. 
D. Resource Sharing Plan
Data obtained in this study will be shared via the National Database for Clinical Trials 
related to Mental Illness. Upon study enrollment the following information will be collected to 
permit generation of a GUID for each participant: sex, first name, last name, middle name, date 
of birth, and city/municipality of birth. Submission of descriptive/ raw data will be accomplished 
semi-annually and other data will be submitted upon publication or conclusion of the study. A 
Effective Date: 2/12/2025
End Date:5/27/2025

20
plain language description of the data sharing plan will be incorporated into the informed 
consent. Descriptive data will be submitted to the NDCT semiannually (January 15 and July 15) 
and will be checked for accuracy before submission and after submission. All other data will be 
provided at the time of publication or at the end of the grant, whichever comes first. We will 
share positive and negative results specific to the study cohorts. We will disseminate findings 
from this study via publications in peer-reviewed journals and presentations at national and 
international meetings. We will make our treatment manuals available to interested clinicians. In 
addition we will present our findings to lay borderline advocacy groups such as TARA and 
Emotions Matter, groups with which we currently have ongoing relationships.
E. Sources of Materials
Diagnostic and assessment information is obtained by interviews of the subject by 
trained clinicians and raters and by the use of standardized rating questionnaires. Medical 
assessment involves a history and physical examination of the subject as well as blood 
samples, urine samples, an EKG and a chest x-ray if indicated. Brain anatomic information is 
obtained by an MRI scan and functional brain activity by an fMRI scan conducted by our group. 
Eye gaze and pupilometry data is obtained using the NordicNeuroLab, (Milwaukee, WI) eye 
gaze fMRI compatible system. All of this material will be obtained specifically for research 
purposes.
F. Potential Risks
No short-term risks have been reported for MRI. Some people have claustrophobic 
reactions in the MRI scanners. An individual will be present to reassure the subject and aid in 
relaxing, but should the subject wish, the MRI scanning can be stopped immediately. Because 
of possible risks from metallic objects in the scanner magnetic field, subjects with surgical clips 
or metallic prostheses (such as artificial hip or knee), a pacemaker or any metal implants or 
shrapnel in the body, may not participate in the study. The effect of fMRI scanning upon the 
fetus has not been studied. Consequently pregnant women will not be permitted to participate in 
the study. There are no known risks associated with eye gaze measurement. Subjects may 
experience distress when viewing some negative-valence emotional pictures, but such distress 
is expected to be transient. The negative-valence emotional pictures used in this study are 
comparable to those seen in newspaper or television news programs. The blood drawing 
carried out as part of the medical screening has the small risk of bruising or infection at the site. 
The cognitive training programs of cognitive reappraisal-by-distancing (CRD) and the control 
downregulate condition (CD) are not expected to have adverse effects, however it is possible 
that subjects will become more upset or experience exacerbations of symptoms, or 
inappropriate apply regulation strategies during the course of the treatment. Training sessions 
will be video and audio recorded. There is the risk of embarrassment if there is a breach of 
confidentiality with respect to personal information included in study assessments or the video 
recordings of training sessions. All of the above are research risks, as these procedures are not 
part of treatment.
F.1 Adequacy of Protection against Risks
F.1.1 Recruitment and Informed Consent
Subjects who express interest in the study will receive a phone pre-screening evaluation, 
followed by a screening evaluation by Dr. Koenigsberg (PI) or a designated colleague. 
Research-eligible candidates will approached by a research MD or a delegate trained by him for 
consent to participate. Consent will be obtained after the potential subject has expressed 
interest in participating and after the study has been explained to the subject by the researcher. 
Consents will be obtained at the Icahn School of Medicine at Mount Sinai or the James J Peters 
VA Medical Center in a private office setting by the principal investigator or a delegate approved 
by the Mount Sinai and/or JJPVA IRBs. After the protocol is described to the subject and the 
subject’s questions are answered, the subject will be asked to summarize the procedures that 
he/she will undergo and to describe 2 risks involved in the study to confirm understanding. A 
Effective Date: 2/12/2025
End Date:5/27/2025

21
checklist will be used for this purpose by the person obtaining consent. Informed consent will be 
documented by means of an informed consent form approved by the Mount Sinai and/or James 
J Peters VA IRBs and signed by the subject and the researcher who obtains the consent. BPD 
subjects are cognitively intact and have no impairment in reality testing, however, if there is any 
doubt about a BPD subject’s capacity to give consent, a psychiatrist independent of the study 
will assess the subject to determine whether they understand the study and can give informed 
consent.
F.1.2 Protection against Risks
Should a subject become anxious or have a claustrophobic reaction in the scanner, a 
member of the research team will be available to reassure them and aid them in relaxing. 
Subjects will be informed that the scanning will be stopped immediately should they wish it. 
Subjects are prescreened at two points in time – when they sign the informed consent and 
again just prior to scanning – to insure they have no metallic implants. Women will receive a 
pregnancy test to exclude subjects who are pregnant.  Trained technicians will draw blood, 
using sterile technique to minimize risk of bruising or infection the structural MRI scans of all 
subjects will be routinely reviewed by a neuroradiologist at the Mount Sinai Hospital and 
subjects will be informed of clinically significant incidental findings. If indicated, we will refer 
them for medical or neurological follow-up. 
A number of protections are implemented to minimize psychological risks. At the time of 
initial rating, subjects will be routinely screened for suicidal ideation, employing the Columbia 
Suicide Severity Rating Scale (C-SSRS). If present, the subject will be assessed by a research 
psychiatrist or clinical psychologist and, as clinically indicated, will be referred for treatment or 
emergent evaluation and treatment. If there is no clinical indication for emergent treatment or 
referral, subjects with suicidal ideation will not be excluded. Subjects will also be provided with a 
24-hour emergency phone number to contact one of our research psychiatrists at any time 
during the course of the study. The CRD and CD training will be carried out by a clinical 
psychologist and procedures for handling any emergent crises are incorporated in the treatment 
manuals. These include reassessment with the Columbia Suicide Rating Scale, consultation 
with a study psychiatrist, referral for additional treatment, or for emergency evaluation. To 
minimize adverse reactions to the images employed in the study, subjects will be informed of 
the general nature of the negative pictures prior to participation and told that they may ask any 
image to be turned off at any time in the study. An individual will be present to provide 
reassurance for subjects who find any pictures upsetting. 
Serious adverse events and any harm to a subject that is, in the opinion of the 
investigator, unexpected and at least probably related to the research procedures will be 
reported to the Mount Sinai and James J Peters VA Medical Center IRB’s within 5 days and 
other adverse events as required by the IRB’s. All adverse events will be reported to study Data 
Safety Monitoring Board (DSMB, see below) and to the NIH in the annual progress report. The 
principal investigator will monitor all adverse events continuously throughout the study. 
The following procedures will be employed to protect confidentiality: Data, including session 
recordings, will be stored in locked cabinets and password-protected computer files. No 
published reports will identify any subject individually. Each subject will be assigned a coded 
identifier that will be used to associate stored data with each subject. Subjects’ names will be 
entered initially on the telephone screening forms when subjects inquire about the study. These 
names will then be removed from the forms and replaced with a coded identifier. Subsequent 
questionnaires and forms will not have identifiers that can be linked to the subject other than the 
coded identifier. Diagnostic interviewers will only enter coded identifiers on their notes and 
forms. The only forms that will contain the subjects names and identifying information will be the 
consent forms which will be stored separately in a locked file and in the research chart (if the 
patient has a medical chart at Mount Sinai or the James J Peters VA Medical Center a copy will 
also be placed in that chart), and the medical screening examination and medical lab tests 
Effective Date: 2/12/2025
End Date:5/27/2025

22
which will be stored separately in a locked file in the research office and in the Clinical Research 
Center (CRC). The list associating subject’s names with coded identifiers will be maintained 
separately from the data and in a locked file. 
F.1.3 Potential Benefits of the Proposed Research to Human Subjects and Others 
By determining whether BPD patients can be trained to use the cognitive reappraisal 
strategy of distancing to more effectively control their negative reactions to aversive stimuli and 
to normalize their neural activity when employing this strategy, this study can provide proof of 
concept that reappraisal-by-distancing training can help BPD patients better regulate their 
emotions. This would provide a neurobiological rationale for the use of cognitive distancing 
training as a novel approach in the psychotherapy of BPD. In providing information directly 
relevant to psychotherapeutic practice, this study may enhance the treatment of BPD, a 
prevalent and difficult to treat disorder. The research will not be of immediate benefit to the 
participants (apart from the benefits of thorough psychiatric and medical evaluations). Since 
risks involved in this study are small, and the potential benefit in the treatment BPD is 
substantial, the benefit to risk ratio is favorable.
F.1.4 Data and Safety Monitoring Plan. A Data and Safety Monitoring Plan will be 
implemented for this study. A central component of this plan will be A Data Safety and 
Monitoring Board (DSMB), which will consist of 3 experienced clinicians, independent of the 
present study, who will meet every 6 months to review risks and adverse events. The DSMB 
may recommend modifications to the study design to address any possible safety issues. In the 
event of safety issues deemed unaddressable, the DSMB may recommend study closure. In 
addition to the planned 6 month reviews, DSMB may also been convened at any time at the 
discretion of the study investigators or institutional review board, should urgent safety concerns 
arise. 
Data quality and security will be monitored on a continuous basis by the data 
management research coordinator. Interim reviews of the imaging and physiological data will be 
conducted quarterly to insure data integrity. **Any data collected remotely will be through 
HIPAA-Compliant Zoom accounts to ensure the protection of participants personal information** 
G. Dissemination Plan for both the R61 and R33 Phase
This study will be registered under ClinicalTrials.gov as outlined in the NIMH policy.
Results information will be submitted to ClinicalTrials.gov following the timelines of the policy. 
Results from the study will also be disseminated via presentation at national meetings and 
submitted for publication in peer-reviewed journals. The informed consent for this study will 
include a specific statement indicating posting of clinical trial information at ClinicalTrials.gov.
The Icahn School of Medicine at Mount Sinai has an internal policy in place to insure clinical 
trials registration and results reporting are in compliance with policy requirements.
H. Compensation
The compensation for the control condition is:
Session
Length
Compensation
Screening Interview
1 hr
$25
Clinical Interview
2-3 hr
$40
2 Questionnaire Packets
~1 hr per packet
$25 for each packet
Consent & Medical Evaluation 
Visit
1 hour
Not compensated for – can 
keep results of medical 
evaluation
Behavioral Battery
1 hour
$40
Training day + baseline fMRI 
session
2 hour (1 hr training, 1 hour 
fMRI)
$100
Week 1-Week 6
45 minutes, twice a week for 
6 weeks
No charge for the training 
sessions
Effective Date: 2/12/2025
End Date:5/27/2025

23
Training 
in 
Cognitive 
Reappraisal 
by 
Distancing 
with clinical psychologist 
End of Week 6 fMRI + 
behavioral battery check in
2 hour (15 min refresher, 45 
min battery, 1 hour fMRI) 
$100
1 and 4 month follow-up
1-2 hours each
$40 for each session
Total of 20 visits over 6-8 
weeks
23 ~ 25 hours
$435
The compensation for the training condition is
Session
Length
Compensation
Screening Interview
1 hr
$25
Clinical Interview
2-3 hr
$40
2 Questionnaire Packets
~1 hr per packet
$25 for each packet
Consent & Medical Evaluation 
Visit
1 hour
Not compensated for- can 
keep results of medical 
evaluation
Behavioral Battery
1 hour
$40
Training day + baseline fMRI 
session
2 hour (1 hr training, 1 hour 
fMRI)
$100
Week 1-Week 6
Training 
in 
Cognitive 
Reappraisal 
by 
Distancing 
with clinical psychologist 
45 minutes, twice a week for 
6 weeks
No charge for the training 
sessions
End of Week 6 fMRI + 
behavioral battery check in
2 hour (15 min refresher, 45 
min battery, 1 hour fMRI) 
$100
1 and 4 month follow-up
1-2 hours each
$40 for each session
Total of 20 visits over 6-8 
weeks
23 ~ 25 hours
$435
I. COVID considerations
During COVID-19 we would like to implement remote and social distancing measures to 
ensure staff and participant safety. The first two screening interviews and clinical assessments 
can be done over HIPAA-Compliant Zoom. If the participant has to come in person, they will be 
provided with a lab laptop and HIPAA-Compliant Zoom and placed in a separate room as the 
coordinator or clinical psychologist in order to social distance. 
The consent form can be done on iOpen and the coordinator goes through the consent 
form with the participant over HIPAA-Compliant Zoom. If the participant has to come in person, 
they can use paper consent but will still social distance by using HIPAA-Compliant Zoom on a 
lab laptop. All self-report questionnaires can be done on Qualtrics for a remote option, or in 
person on paper in separate rooms. 
**For training days with the clinical psychologist, clinical training can be done in person 
or over a HIPAA-Compliant Zoom. Training done in person will be via the approved e-prime 
program, and remote sessions will be via the approved power point** 
fMRI sessions, these cannot be done remotely as they require lab equipment, but we 
can social distance by communicating over HIPAA-Compliant Zoom in separate rooms.  
Effective Date: 2/12/2025
End Date:5/27/2025

24
Effective Date: 2/12/2025
End Date:5/27/2025