Results
A total of 172 datasets entered the analysis. These were distributed
accordingly: 37 HC and 50 patients had baseline data; 15 HC and 34
patients (68%) had data from session 2; 36 patients (72%) had data
from session 3. All cases of dropout were related to issues with
treatment, e.g., the patient was, contrary to initial evaluation, deemed
not suitable for psychotherapy or was rejected due to too low
attendance. Note that for HC, session 2 was not after 10 weeks but after
> 8 weeks, as HC did not participate in treatment.
Demographics and behavioral
measures
All participants were right-handed save for 5 in the HC group and 1 in
the patient group and all participants reported normal hearing.
Diagnoses were distributed accordingly: agoraphobia: 4; depression: 20;
GAD: 5; OCD: 12; PD: 8; and SAD: 1. Seven patients (14%) received no
medication, 34 patients (68%) received one type of medication and the
remaining nine patients (18%) received more than one medication. In
total 86% of patients received at least one psychiatric medication, of
which all received at least one type of selective serotonin re-uptake
inhibitors (SSRI). No patients were treated with anti-psychotic
medication.
Table 2 shows demographics and behavioral measures at baseline for the
two groups. There was no difference between groups in sex or age, nor in
number of Correct and Error trials in the Flanker paradigm. The patient
group had significantly longer reaction times (RT) in both Correct and
Error trials in the Flanker paradigm and to Target stimuli in the AO
paradigm. The mean number of Error trials for each group was high, 53.6
for HC and 47.4 for patients, on average well above the recommended
minimum of 17 trials for reliable (traditional) estimation of the ERN
(Clayson, 2020). However, four patients were below 17 remaining trials
(5, 8, 13 and 16, respectively). Note that in WLS, parameter estimation
is on the total number of trials, which in the Flanker paradigm was well
above 250 trials for all subjects. Upon visual inspection of the grand
average and beta coefficient plots for these subjects, the data and
parameter estimation were deemed to be of sufficient quality, in all
cases showing the characteristic response-locked Flanker triphasic
waveform. Nevertheless, although no empirical value exists, it must be
noted that the more available trials, the more precise the estimation of
variables (C. Pernet et al., 2022).
>>
Table 2 here <<
Psychometrics
Table 3 shows McDonald’s Omega as a measure of internal consistency as
well as results from group comparisons for all self-report
questionnaires at baseline.
>> Table 3 here <<
All psychopathology measures showed good internal consistency (Omega
> 0.7). The patient grouped scored significantly higher
than HC on all items with two exceptions: Positive temperament in MEDI,
where the patient group scored significantly lower than HC, and the
Antagonism personality trait in PID36 where there was no significant
difference between the groups.
Table 4 shows change in psychopathology measures across sessions
assessed using mixed linear models with subject as random factor and
baseline (Session 1) as reference, e.g., (Bates et al., 2015).
>> Table 4 here <<
For MEDI, treatment significantly reduced total score and almost all of
the of sub scale scores. For some dimensions, e.g., Neurotic
Temperament, a reduction from baseline was only significant at week 14
after the end of treatment. For others, e.g., Intrusive Cognitions,
significant and lasting reduction could be measured already at week 10.
Interestingly, Positive Temperament improved significantly at 10 weeks,
but effects diminished to not significant compared to baseline at week
14. Traumatic Re-experiencing was the only symptom dimension in MEDI not
significantly changed by treatment.
Somewhat surprisingly, treatment did not lead to an overall improvement
in PID36 total score. Among the PID36 sub scales, reduction was only in
Detachment.
Finally, both K10 and LPFS
showed significant improvement due to treatment already at 10 weeks.
ERP grand average
waveforms
Figures 1 to 4 show the group-wise 20% trimmed mean of mean weighted
subject-level single-trial ERP data across stimulus types for all
paradigms at baseline. Shaded areas indicate the 95% HDI. Well-known
ERP components are marked on each plot and appear in agreement with the
literature. For the UO ERPs, it is interesting to note that cMMN, the
MMN in the Combined difference wave, is a mixture of fMMN and dMMN in
that both the earlier-detected frequency change as well as the
later-detected duration change are captured in the waveform. As such,
the cMMN has two peaks.
Attended oddball
>>
Figure 1 here <<
Response-locked Flanker
>>
Figure 2 here <<
Stimulus-locked Flanker
>>
Figure 3 here <<
Unattended oddball
>>
Figure 4 here <<
ERP beta coefficients
Figure 5 shows beta time courses at FCz corresponding to stimuli in each
paradigm.
>> Figure 5 here <<
, in LIMO EEG called the adjusted mean, is in itself not a measure of
brain activity but depends on the other beta coefficients which are
modulations around this constant term. Note that the beta coefficient to
Target stimuli eliciting the P3b is more suitably plotted at Pz where it
reaches maximum (see Figure 7 below). Note also that the Correct trial
beta coefficient is positive-going even though the CRN is a
negative-going wave. Finally, note that plots for the UO paradigm are
difference contrasts between deviant and standard beta coefficients.
ERP correlations with
psychometrics
Due to the many correlation analyses (10 ERP models * 4 psychopathology
measures), we present only those for which TFCE detected large
significant regions at the corrected level of 0.1%. Full results at an
uncorrected TFCE of 5% are available in Supplementary materials. Due to
TFCE often detecting many and overlapping significant regions and since
we cannot know which of the voxels in each cluster are significant, we
use visual inspection to describe significant regions in terms of start
and end times and general cortical regions. Throughout the analysis we
interpret effects on ERPs in terms of changes in amplitudes even though
we cannot rule out that some effects are due to differences in peak
latency rather than peak amplitude. That being said, correlations
between higher scores and changes in amplitude within a given time
interval is valid irrespective of whether effects are due to increased
peak latency or reduced peak amplitude within the significant
region . In addition, most significant regions span at least 50 ms,
making it unlikely that the observed effects are due to increases in
peak latency.
K10 Distress Scale (K10)
Figure 5 shows results for K10 assessing general psychological distress.
We found several correlations between K10 and ERPs from the AO and
response-locked Flanker paradigms. There were no significant
correlations between K10 and ERP models from the stimulus-locked Flanker
or UO paradigms at the main analysis level.
>> Figure 6 here <<
For Target stimuli in the AO paradigm, we found a large significant
region from 324 ms to 696 ms covering both frontal, central and parietal
channels. Figure 7 shows the Target stimulus beta along with the
adjusted mean at Pz.
>> Figure 7 <<
This region clearly corresponded to the P3b and the negativet -values at central-parietal and parietal channels, where is more
positive-going than , indicated that a reduced P3b is associated with
higher scores in K10.
For Standard stimuli in the AO paradigm, we found a significant region
from 304 to 372 ms centered at CPz, Pz and POz. This region immediately
succeeds the N2, which is commonly analyzed at more frontal regions. As
such, the significant region does not correspond to a known ERP. To aid
in interpretation, Figure 8 shows the Standard stimulus grand average
and beta time course at Pz.
>> Figure 8 here <<
It can be seen that the significant region corresponds to a negative
peak starting just after 300 ms on the grand average plot (Figure 8,
left). Because is more negative-going than in this region (Figure 8,
right), the positive t -values indicate that decreased or less
negative-going amplitudes at this region correlates with higher scores
in K10.
For Standard stimuli, we also found a large region, not corresponding to
any known ERPs either, starting at 396 ms and ending at 588 ms covering
both frontal, central and parietal channels. Figure 8 shows a
negative-going slow wave at Pz and the positive t -values indicate
that less negative-going amplitudes across this wave correlates with
higher scores in K10.
For Correct trials, we observed a significant region from -16 to 64 ms
at central electrodes, centered at FCz, Cz and CPz. The time range and
involved regions clearly corresponded to the CRN. The negativet- values indicated that higher scores in K10 correlated with a
increased, or more negative-going, . As can be deduced from Figure 5
(top right) and because , a more negative translates to an increased, or
more negative-going, CRN. In other words, an increased CRN
correlated with higher scores in K10.
For Error trials, we observed a significant region from -20 to 56 ms,
more frontal than the corresponding regions for the CRN, centered at Fz,
FCz and Cz. This region clearly corresponded to the ERN and the positivet -values indicated that higher scores in K10 are associated with
a reduced (less negative-going) ERN.
Finally, also for Error trials, we observed a large significant region
from 284 ms to 468 ms, mainly at central-parietal and parietal regions,
and with opposite effects at frontal regions. However, no obvious peak
or wave is shown in neither the grand average plot (Figure 2, right) nor
in the beta coefficient time course plot for Error trials and adjusted
mean (Figure 5, top right). We interpreted this region as a continuation
of the Pe, and the negative t -values indicated that a reduced
late part of the Pe correlates with higher scores in K10.
Level of Personality Functioning Scale
(LPFS)
Figure 8 shows results for LPFS assessing severity of personality
pathology. We found correlations between LPFS and ERPs from the AO,
response-locked Flanker and UO paradigms. There were no significant
correlations with ERPs from the stimulus-locked Flanker at the main
analysis level.
>> Figure 9 here <<
For ERPs from the AO paradigm, we found similar correlations as for K10.
For Target stimuli, we found a large region from 312 ms to 688 ms
covering frontal, central and parietal channels, clearly corresponding
to the P3b. As for K10, reduced (less positive-going) P3b at parietal
channels correlated with increased scores in LPFS. For Standard stimuli,
we found that reduced amplitudes in the same wave covering a large
region - from 312 to 680 ms, at both frontal, central and parietal
channels - correlated with increased scores in LPFS. So did the negative
peak just after 300 ms described for K10 above.
For the response-locked Flanker ERPs, as for K10, an increased CRN and a
reduced ERN correlated with increased scores in LPFS. However, effects
for the CRN were more frontally distributed this time, with centers at
Fz, FCz and Cz.
We also noted a reversal of effects, with positive t -values
correlating with increased scores in parietal regions. However, we also
noted that the effect was absent at parietal channels along the midline,
e.g., CPz and Pz. A plot of the Correct trial beta at P6, where the
effect was strong, did not reveal a CRN-like waveform. As such, results
were not straightforward to interpret. It is possible that these
regional effects reflected activity from the brain processes generating
the CRN, which were then picked up by lateral electrodes through volume
conduction. A similar but weaker effect was observed for the ERN.
For the Combined deviant difference wave from the UO paradigm, we found
a significant region from 156 to 200 ms centered around Fz. This region
corresponded to the cMMN and the negative t -values indicated than
an increased or more negative-going cMMN correlated with higher
scores in LPFS. In addition, we found a significant region from 212 ms
to 256 ms, centered around Fz and FCz. The positive t -values
indicated that an increased combined deviant dP3a11Note
that the d in dP3a denotes the difference wave ERP component
corresponding to P3a. dP3a elicited to one of the three deviant types
is spelled out as such, e.g., frequency deviant dP3a. correlated with
increased LPFS scores.
Multidimensional Emotional Disorder Inventory
(MEDI)
Figure 9 shows results for MEDI assessing symptom dimensions within the
Internalizing spectrum.
>> Figure 9 here <<
For MEDI total scores, in a similar fashion to results for K10 and LPFS,
we found that an increased CRN, a reduced ERN and a reduced P3b
correlated with higher scores in MEDI. Again we found a significant
region corresponding to the above-described late wave in response to
Standard stimuli in the AO paradigm, but the effect was weaker. In
addition, for Error trials we found a significant region from 184 ms to
388 ms centered at Cz and CPz. This region corresponded to Pe and
because is above at this time interval, the negative t -values
indicated that a reduced Pe correlated with higher scores in
MEDI.
Because we found significant correlations for MEDI total score, we also
analysed the MEDI sub scales at the less conservative level of 5%, each
assessing a specific symptom dimension within the Internalizing
spectrum. These results are available in Supplementary materials.
Not surprisingly, at this less conservative level, all of the regional
effects for MEDI total score described above were present and more
pronounced in covering more channels and longer time frames. In
addition, higher scores correlated with a reduced stimulus-locked
Flanker P3b and a reduced duration deviant dP3a from the UO paradigm.
Post-hoc , then, a reduced P3b elicited to Target stimuli in the
AO paradigm correlated with all of the MEDI sub scales.
Similarly, a reduced ERN correlated with higher scores in all MEDI sub
scales except Traumatic Re-experiencing, albeit weakly for Somatic
Anxiety and Avoidance. An increased CRN correlated with higher scores in
Depression and less strongly with higher scores in Avoidance, Social
Anxiety and Somatic Anxiety.
As perhaps could be expected, a reversal of effects was seen for
Positive temperament, which is the only dimension where healthy
comparison subjects scored higher than patients (Table 3). Here we
observed that, e.g., a reduced CRN and, more weakly, an increased ERN
correlated with higher scores.
For Error trials in the response-locked Flanker paradigm, in addition to
the results already described above, we found that a reduced Pe
correlated, more or less strongly, with higher scores in the sub scales
Autonomic Arousal, Avoidance, Depression (the late part of Pe),
Intrusive Cognitions, Somatic Anxiety, Social Anxiety as well as
Traumatic Re-experiencing (weak and the late part of Pe). In addition,
an increased Pc correlated with increased scores in Social
Anxiety.
Post-hoc , we also found significant effects for the ERPs in the
stimulus-locked Flanker paradigm, e.g., N2 and P3b, which did not
survive the conservative level of 0.1%. However, because the P3b in the
stimulus-locked Flanker paradigm falls immediately before button press,
it cannot be reliably analysed due to some trials overlapping.
Therefore, here we consider only results for the N2. Interestingly, for
MEDI sub scales Intrusive Cognitions and Traumatic Re-experiencing areduced N2 correlated with higher scores, whereas for Neurotic
Temperament, an increased N2 correlated with higher scores.
Post-hoc , we also found that a reduced Novelty P300 at CPz
and Pz correlated with increased scores in MEDI Depression.
For ERPs from the UO paradigm, the strongest result was a correlation
between MEDI Avoidance and a reduced (less positive) duration
deviant dP3a and, more weakly, a reduced combined deviant dP3a. A
reduced dP3a also correlated with increased scores in Intrusive
Cognitions (duration deviant) and with increased scores in Traumatic
Re-experiencing (both combined and duration deviants). For the MMN,
correlations were quite specific in that only Social Anxiety correlated
with an increased (more negative) cMMN and more weakly with an
increased fMMN.
Finally, for the N1-P2-N2 complex, which is elicited to both Standard,
Distractor and Target stimuli in varying degrees and with different
overlap and proximity of peaks, results are a bit more difficult to
analyze. Given that little is known about the properties of this wave
complex in terms of, e.g., polarity-reversal, we resort to reporting
that, post-hoc , we found correlations for each of these peaks
with several of the MEDI sub scales (Winkler et al., 2013). The
interested reader is referred to Supplementary materials. Plots of the
beta coefficients at relevant channels can be supplied at request.
Modified Personality Inventory for DSM-5 and ICD-11
(PID36)
Figure 10 shows results for PID36 indexing maladaptive personality trait
dimensions.
>> Figure 10 here <<
Results for PID36 largely mimicked those already described above. We
found that a reduced P3b and ERN and an increased CRN correlated with
higher scores. For Standard stimuli in the AO paradigm, we found the
same regional effects corresponding to reductions in the negative peak
just after 300 ms and the following slow negative wave in parietal
regions.
As for MEDI, since we found significant correlations for the PID36 total
score, post-hoc we also analysed each PID36 sub scale at the
uncorrected 5% level. Again, the correlations found for PID36 total
score were stronger, involving more channels and longer time ranges. A
reduced P3b correlated strongly with increased scores in all sub scales
except for Psychoticism. A corresponding pattern was observed for the
late parietal wave elicited to Standard stimuli in the AO paradigm. Of
the response-locked Flanker ERPs, an increased CRN and a decreased ERN
correlated with higher scores in the same three sub scales: Anankastia,
Detachment and Negative Affect. In addition, an increased CRN correlated
with increased scores in Psychoticism, but only at Cz and CPz.
For Negative Affect, a reduced Pc in frontal-central regions correlated
with higher scores while a reduced Pe in the same regions correlated
with higher scores in Anankastia.
Also for Negative Affect, we found correlations between a reducedNovelty P300 in frontal-central regions and higher scores. We noted
that, along with the results for MEDI Depression described above, this
was the only significant correlation for Novelty P300 in our entire
analysis.
We also observed some interesting correlations for the UO paradigm. For
Anankastia, increases in dMMN and the following duration deviant dP3a,
both centered around Fz and FCz, correlated with higher scores, albeit
weakly. For Antagonism, reductions in cMMN (although only at CPz and Pz)
and dMMN and the following duration deviant dP3a correlated with higher
scores. For Detachment, increased cMMN at Fz correlated with higher
scores. For Disinhibition, increases in all three MMN measures as well
as decreases in all three corresponding dP3a measures correlated with
higher scores. Finally, of opposite direction, reductions in cMMN and
fMMN correlated with higher scores in Negative Affect.
Other than these go-to results, as in the post-hoc analysis of
the MEDI sub scales described above, several correlations involving the
N1-P2-N2 complex were observed. Again we invite the reader to study the
results in the Supplementary materials.