Peer review of: Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR (2020)

In this paper, Stein and colleagues use different computational models to relate
effects of schizophrenia and anti-NMDAR encephalitis to serial effects in a
delayed-response task. While they find now difference in actual memory
performance, they do show a difference between three groups at a behavioural
level: while the serial effect of probes is initially repulsive in all groups,
it becomes attractive in healthy controls with increasing delay, less so in the
aNMDAR group, and remains repulsive in the SCZ group. They also show that the
attractive effect shows signs of improving over time with clinical recovery in
the aNMDAR group. Using a network of excitatory and inhibitory neurons, they
then attempt to distinguish NMDAR dysfunction affecting either synaptic
plasiticity, or excitatory-excitatory or excitatory-inhibitory function. They
find that only the first can qualitatively capture the data.
Overall, this is an excellent, well-written and exciting paper. It combines an
 intereseting study design with elegant computational modelling, and addresses an
 important question.
 Issues
- My main concern relates to the impact of medication. This is very strongly
correlated with the group effects, and there are trends in the CPZ equivalents
in both patient groups (I imagine that pooling across the patient groups would
show a significant effect). More information and data is needed to convince me
that these are not pure medication effets. The current analyses and data are
not sufficient in that regard. I should emphasize that the results continue to
be important and relevant, but the impact of these medications need to be
discussed and displayed in more detail.
- I was unsure about the importance of memory-independent repulsive biases in
 the E-I network. How are these important for the overall results?
 - For the symptom correlations, I wonder whether the authors have considered a
 linear mixed effects analysis across groups with factors controlling for
 group.
 - Please clarify if any of these data have been published before
Reviewer #2:
Remarks to the Author:
The manuscript from Stein et al. proposes a nice psychophysical and computational account of
working memory deficits observed in two disorders associated with excitatory-to-inhibitory neural
imbalance, i.e., anti-NMDA-R encephalitis and Schizophrenia. Based on quantitative model-fits with
real data collected during a visuo-spatial delayed-response task (in the two pathological groups plus a
group of healthy controls), the authors argued for the involvement of impaired NMDA-dependent
candidate mechanisms, such as short-term potentiation (STP). The manuscript in well-written and I do
have quite a few comments and suggestions which I hope the authors will find helpful for a revision of
their paper.
1) Schizophrenia (SCZ) and NMDA-R encephalitis (ENC) could greatly differ in terms of underlying
biological mechanisms, and these mechanisms could also vary according to specific clinical
dimensions, so why absolutely trying to find a common mechanism for both disorders (STP here) ?
This should be better justified. For instance, the cognitive dimension was nicely explored here
(through Working Memory deficits), but the two clinical groups seemed to have very limited psychotic
symptoms for instance (Supp Table 1), a dimension which has been related to false inference in
alternative frameworks (Bayesian notably) and could also be involved in the pathophysiology of the
these disorders. Hardly no positive symptoms were observed for ENC patients (only negative ones).
This should be discussed and acknowledged, since patients are explored during relatively stabilized (or
non-acute) states.
2) ENC data seems to be explained qualitatively without disruption of the STP, even though the fit
presented Figure 3 is not so good quantitatively. Could the authors clarify this point ?
3) Regarding Hyp. 1: why would the STP alteration be only on the E-E synapses ? Please clarify in the
main text.
4) Regarding Hyp. 3: A decrease of g_EE would mean a lower E-I ratio, right ? But to my knowledge
and based on the literature, this is not the case for SCZ: please clarify.
5) Regarding the task itself: Was there a preference for a particular direction in the different samples
explored ? The paper seems to only compute the difference between angles, without consideration of
the values of these angles.
6) In the data presented, the behavior seemed less affected in ENC participants than in SCZ
participants compared with CTLs, right ? I was wondering if there was a direct experimental evidence
from the literature (e.g. STP disruption of NMDA-R for ENC vs SCZ), or indirect evidence coming from
behavioral studies for that pattern ?
7) Did the authors find any correlation between the scales provided Supp. Table 2 and the amount of
serial bias ? Please comment and discuss.
8) Minor comments:
a. in Figure 3 g.h.i., please add the experimental data as you did in Figure 1 d.e.f.
b. Suppl. Figure 7: I think there is a mistake in the title: “n-1” instead of “n+1”.
Reviewer #3:
 None