Journal of Theoretical Biology 473 (2019) 80–94

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Journal of Theoretical Biology

journal homepage: www.elsevier.com/locate/jtb

Neural dynamics in co-morbid schizophrenia and OCD:

A computational approach
Krisztina Szalisznyó a,c,∗, David N. Silverstein b, János Tóth d
a
Department of Neuroscience, Psychiatry, University Hospital, Uppsala University, Uppsala 751 85 Sweden
b
Department of Computational Science and Technology, KTH Royal Institute of Technology, Stockholm, Sweden
c
Computational Neuroscience Group Wigner Research Institute, Hungarian Academy of Sciences Budapest, Hungary
d
Department of Mathematical Analysis, Budapest University of Technology and Economics, Budapest, Hungary

a r t i c l e i n f o a b s t r a c t

Article history: The co-morbidity of obsessive-compulsive disorder (OCD) and schizophrenia is higher than what would
Received 1 July 2018 be expected by chance and the common underlying neuropathophysiology is not well understood. Repet-
Revised 29 January 2019
itive stereotypes and routines can be caused by perseverative thoughts and motor sequences in both of
Accepted 31 January 2019
these disorders. We extended a previously published computational model to investigate cortico-striatal
Available online 6 February 2019
network dynamics. Given the considerable overlap in symptom phenomenology and the high degree of
Keywords: co-morbidity between OCD and schizophrenia, we examined the dynamical consequences of functional
OCD connectivity variations in the overlapping network. This was achieved by focusing on the emergence of
Schizophrenia network oscillatory activity and examining parameter sensitivity. Opposing activity levels are present in
Cortico-striatal network orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) in schizophrenia and OCD. We found that
Computational modeling with over-compensation of the primary pathology, emergence of the other disorder can occur. The oscil-
latory behavior is delicately modulated by connections between the OFC/ACC to the ventral and dorsal
striatum and by the coupling between the ACC and dorsolateral prefrontal cortex (DLPFC). Modulation
on cortical self-inhibition (e.g. serotonin reuptake inhibitor treatment) together with dopaminergic input
to the striatum (e.g. anti-dopaminergic medication) has non-trivial complex effects on the network os-
cillatory behavior, with an optimal modulatory window. Additionally, there are several disruption mech-
anisms and compensatory processes in the cortico-striato-thalamic network which may contribute to the
underlying neuropathophysiology and clinical heterogeneity in schizo-obsessive spectrum disorders. Our
mechanistic model predicts that dynamic over-compensation of the primarily occuring neuropathophysi-
ology can lead to the secondary co-morbid disease.
© 2019 Elsevier Ltd. All rights reserved.

1. Introduction
The prevalence of obsessive-compulsive symptoms (OCS) in
schizophrenia is higher than what would be expected by chance.
The lifetime prevalence for OCD is about 2–3% and approaches 1%
for schizophrenia. The prevalence of OCD has been reported to
be around 16% in a schizophrenia patient group, which is about
7 times higher than without co-morbidity (Krüger et al., 20 0 0).
Moreover, differential diagnoses of compulsive behaviors in con-
temporary psychiatric diagnostic systems are not without contro-
versy (Oulis et al., 2013). In drug-naive schizophrenia, the onset
of obsessive-compulsive symptoms can either precede, be simulta-
neous or develop later than the onset of psychotic symptoms. A
∗
Corresponding author.
E-mail address: krisztina.szalisznyo@neuro.uu.se (K. Szalisznyó).
recent study has found that adolescents with schizophrenia and
OCD needed more antipsychotic doses and the symptomatol-
ogy appears to be more treatment resistant, although the sever-
ity of the schizophrenia was similar between study groups
(Baytunca et al., 2017). OCS can also develop from atypical antipsy-
chotic treatments (Venkatasubramanian et al., 2009).
Cortico-striato-thalamo-cortical pathological circuit dynamics
plays a key role in OCD development. Various pathophysiology,
among them inflammatory processes can give rise to abnormal dy-
namics in this circuit (Attwells et al., 2017). Obsessive-compulsive
disorder is characterized by recurrent intrusive thoughts (obses-
sions) and repetitive behaviors (compulsions). Apart from the
widely accepted models of OCD pathophysiology which mostly
focus on cortico-striatal circuitry, recent neuroimaging evidence
points to critical involvement of the dorsal anterior cingulate
cortex (ACC) and amygdalo-cortical circuitry as well (Milad and
Rauch, 2011). Chamberlain concluded that working memory

https://doi.org/10.1016/j.jtbi.2019.01.038
0022-5193/© 2019 Elsevier Ltd. All rights reserved.
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94 81

dysfunction is much less generalized and pervasive in OCD than
in schizophrenia, and suggested that this difference may be due to
the greater involvement of dorsolateral prefrontal cortex (DLPFC)
in schizophrenia vs. orbitofrontal prefrontal cortex (OFC) in OCD
(Chamberlain et al., 2005). A recent study found that a subgroup
of individuals with ultra high-risk for psychosis with co-existing
OCS might show higher levels of depression, but better work/study
performance and less cognitive deficits in comparison with a sub-
group without OCS (Soyata et al., 2018). Dual impairment of dorso-
lateral and orbitofrontal prefrontal cognitive functions in the OCD-
schizotypal personality disorder population has been suggested
as a predictor of poorer clinical and treatment outcomes (Scotti-
Muzzi and Saide, 2017).
Another recent study demonstrated significant differences in
areas of cognitive processing, selective attention and executive
function in schizophrenia patients who have co-morbid OCD as
an intrinsic part of the illness versus those where the OCD symp-
tomatology was induced by antipsychotic medication (de novo
OCD) (Sahoo et al., 2018). These results further support the clinical
heterogeneity of schizo-obsessive spectrum disorders.
We have extended a previously published computational
model (Rădulescu and Marra, 2017), by taking into account the
functional and structural network changes of the cortico-striato-
thalamo-cortical circuit in the schizo-obsessive population. We
analyzed the effects of orbitofrontal cortex (OFC), ACC, amyg-
dala, thalamus and the ventral tegmental area (VTA) on the
network dynamics. We modified the original model by expand-
ing the striatum to dorsal (D) and ventral (V) parts and by
adding the dorsolateral prefrontal cortex (DLPFC). The brain
region hypo- or hyperactivity and hypo- or hyper- connec-
tivity data were implemented and the effects were analyzed
computationally.
Pathological neurodynamics of OCD and schizophrenia has
been extensively studied using computational and theoretical ap-
proaches (Friston et al., 2014; Maia et al., 2008; Rolls, 2012; Rolls
et al., 2008). Several theoretical works suggested the hypothesis
that attractor networks become too stable in obsessive-compulsive
disorder (Rolls, 2012; Rolls et al., 2008). In these modeling and the-
oretical studies stable fixed-point attractors were assumed and an-
alyzed.
In our current study we considered stable periodic solutions as
pathological attractors for OCD neurodynamics. The underlying as-
sumption is that the periodic orbits give rise to repetitive thoughts
and behavioral patterns. The justification of this assumption is sup-
ported by increased oscillatory activity of OFC and ACC in patients
with OCD (Hou et al., 2012; Zhu et al., 2016).
The clinical observations, human studies and animal experi-
mental evidence were summarized, which underline the functional
and structural changes in OCD, schizophrenia and in case of coex-
isting symptoms (Table 1).

Table 1
Structural and functional changes and connectivity alterations in OCD, schizophrenia (SCH) and schizo-obsessive disease (SCH-OCD),
based on brain imaging studies. Increased and decreased activity or connectivity is denoted by ↑ and by ↓, respectively. All the
references are from human studies. The changes, which were implemented in the model simulations are marked with frames .

Brain region OCD SCH S-O Reference

OFC ↑ Hou et al. (2012); Lv et al. (2017); Zhu et al. (2016)

OFC ↑ Attademo et al. (2016)
OFC ↓ Chamberlain et al. (2008); Remijnse et al. (2006)
OFC ↓ Li et al. (2016); Lui et al. (2015)

OFC ← → V-Striat ↑ Abe (2015); Anticevic et al. (2014); Jung et al. (2013); Nakamae et al. (2014)

OFC ← → D-striat ↓ Jung et al. (2017)

ACC ↑ Gu et al. (2008); Hou et al. (2012); Maia et al. (2008)

dACC ↑ Fitzgerald et al. (2005); Zhang et al. (2017)

ACC ↓ Gu et al. (2008); Radua et al. (2010)
ACC ↓ Adams and David (2007); Fornito et al. (2009); Lui et al. (2015)

rACC-DLPFC ↓ Zhang et al. (2017)

dACC-DLPFC ↑ Milad and Rauch (2011); Schlösser et al. (2010)

ACC ← → DLPFC ↓ Cui et al. (2015)

D-Striat ↓ ↓ Bleich-Cohen et al. (2014)
D-Striat ↓↑ Der-Avakian and Markou (2012)
D-Striat ↑ ↓↑ Gross-Isseroff et al. (2003)
V-Striat ↑ Lv et al. (2017)
V-Striat ↓ Der-Avakian and Markou (2012)
V-Striat ← → ACC ↓ Lin et al. (2017)

V-Striat ← → VTA ↓ Harrison et al. (2009)

V-Striat ← → DLPFC ↓ Harrison et al. (2009)
D-Striat ← → DLPFC ↓ Vaghi et al. (2017)
DLPFC ↓ ↓ Attademo et al. (2016); Bleich-Cohen et al. (2014)
DLPFC ↓ Gu et al. (2008); Levine et al. (1998); Vaghi et al. (2017)
Thal ← → D-V-striat ↑ Jung et al. (2017)
Amyg ← → D-V-striat ↓ Göttlich (2014)
Thal ↑ Lv et al. (2017)
Amyg ↑ Göttlich (2014)
82 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94
1.1. Clinical motivation of the study
Patients with schizophrenia often show obsessive rumina-
tions, repetitive ritualized behavior or stereotypic thoughts during
acute psychosis (Schirmbeck and Zink, 2013). Repetitive manner-
isms of catatonia may phenomenologically overlap with obsessive-
compulsive symptoms, but the relationship is unclear (Hermesh
et al., 1989; Penland et al., 2006). Perseveration is also a fea-
ture of both schizophrenia and OCD. Given the high co-morbidity
of the two disorders and the similarity of certain symptom
phenomenology, we unified in a modeling framework the patho-
logical variations of the possible overlapping network. We took
into consideration altered fluctuation activities mostly based on
resting-state fMRI studies. The amplitude of the low frequency
fluctuations (ALFF) of the blood-oxygen-level dependent (BOLD)
signal is correlated with the local magnitude of neural resting ac-
tivity (Leon et al., 2014; Nugent et al., 2015). We assumed that
the underlying shared neural network pathology can account for
the co-morbidity. Therefore, we incorporated the known network
alterations. We have not distinguished between different clinical
variables and symptoms (e.g. in case of OCD harm-related, check-
ing, religious, symmetry/ordering, contamination/cleaning; e.g. in
case of schizophrenia negative and positive symptom groups), as
the present modeling framework is at a higher level of abstraction.
We focused on the emergence of oscillatory activity and examined
parameter sensitivity.
Spontaneous low-frequency BOLD signal fluctuations (ALFF)
show strong covariations with intracranial electrocorticographic
and local field potential recordings. This was also shown for fluc-
tuations in high-frequency (ie, gamma-band) power (He et al.,
2008; Leopold et al., 2003), thus hemodynamic response fluctua-
tions were tightly correlated to the power of local field potential
(LFP) oscillations in the gamma range (Niessing et al., 2005). An-
other study demonstrated correlations between gamma 50 – 100
Hz band-limited power and the spontaneous fMRI BOLD signal
and these observations were present in both wakefulness and REM
sleep (He et al., 2008). Gamma abnormalities have been shown to
be associated with cognitive and perceptual domains that are im-
paired in schizophrenia (Hoptman et al., 2010).
1.2. OFC hyper- or hypo-activity
OFC plays a distinct role in processing reward, fear and anxiety.
It supports behavioral flexibility and its dysfunction can contribute
to pathological perseveration (Clarke et al., 2008). Altered OFC ac-
tivity reported from clinical and animal model studies in OCD and
schizophrenia patients are summarized in Table 1.
1.2.1. OFC abnormalities in OCD
In a human OCD study a significantly increased ALFF of the
BOLD signal was found in OFC, compared with healthy controls,
which provides supporting evidence of an enhanced OFC sponta-
neous neural activity in OCD etiology (Zhu et al., 2016). Increased
ALFF values in bilateral OFC were positively correlated with over-
all OCD symptom severity (measured by Yale Brown Obsessive-
Compulsive Scale (Y-BOCS) total scores) (Hou et al., 2012). It was
shown that OFC hyperconnectivity stem from a higher oscillation
frequency of neurons within this region (Giménez, 2017). From
EEG analyses, most studies agree that OCD patients in one or both
band(s) (theta and delta bands) have higher power in contrast with
the control groups (Ghaffari et al., 2018). Increases in grey matter
volume were also found of the medial orbitofrontal cortex (mOFC)
and the ventral striatum in OCD patients (Lv et al., 2017).
However, task-induced OFC hypoactivity was described in a
human study and it was suggested that OFC-striatal dysfunc-
tion in OCD is associated with increased resting-state activity
together with decreased responsiveness on cognitive challenge
(Remijnse et al., 2006). Patients with OCD can exhibit reduced
lateral OFC responsiveness during reversal learning, thus reversal-
learning related hypofunction can even be a vulnerability marker
(Chamberlain et al., 2008).
OCD has been linked with serotonergic dysfunction and treated
with serotonin selective reuptake inhibitors (SSRIs). The SSRI treat-
ment modulates top-down inhibitory functions of the OFC. Con-
sistent with reversal learning representing a possible marker of
compulsivity, it was found that 5-hydroxytryptamine (5-HT) deple-
tion in the marmoset prefrontal cortex impaired reversal learning
(Clarke et al., 2004; 2008).
A human study of OCD patients also revealed a reduction
in functional connectivity between the central OFC and dorsal
striatum, but increased functional and structural connectivity be-
tween the OFC and ventral striatal regions (Jung et al., 2017).
Early PET studies reported increased resting-state OFC metabolism
(Baxter et al., 1988), and this region has been shown to be hyper-
connected with the ventral striatum (Anticevic et al., 2014), sug-
gesting a hyperactivation of the ventral affective corticostriatal cir-
cuit (Harrison et al., 2009).
1.2.2. OFC abnormalities in schizophrenia
Experimental evidence for the OFC pathology in schizophrenia
is limited. A recent study revealed that patients with schizophre-
nia had lower ALFF values in the OFC than did control subjects at
baseline (Li et al., 2016). These alterations improved toward nor-
mal levels at 1-year follow-up examinations after treatment. In a
schizophrenia patient group, the degree of ALFF reduction in the
right OFC at baseline was negatively correlated with the magnitude
of the increase in ALFF values (ie, normalization) in this region at
1-year follow-up (Li et al., 2016).
The most commonly accepted hypothesis for schizophrenia sug-
gests that changes in dopaminergic function occur at two sites. 1)
Increased presynaptic dopamine synthesis and altered striatal D2
receptor affinity/expression correlate with the magnitude of posi-
tive symptoms. 2) Decreased D1 receptor neurotransmission in the
prefrontal cortex is proposed to be linked with negative symptoms
(Clarke et al., 2014). OFC innervates the caudate nucleus, projects
directly and indirectly to the midbrain ascending DA systems and
inhibits the ventral tegmental area (VTA) neurons (Clarke et al.,
2014). It seems that altered OFC dopaminergic transmission con-
tributes to the striatal hyperdopaminergic state, thus reduction in
primate OFC dopamine levels elevates dopaminergic levels in the
caudate (Clarke et al., 2014).
The functional normalization of ALFF values in OFC in treated
schizophrenia patients can be interpreted in the context of the
dopamine and serotonin hypotheses (Li et al., 2016). Hypoactiva-
tion in meso-cortical dopaminergic input may reduce activity in
the orbitofrontal cortex. This deficit may respond to 5-HT2A and
D2 receptor antagonism, such that OFC activity may be relatively
normalized (Li et al., 2016).
1.3. Anterior cingulate cortex
The evidence in ACC pathology was summarized both in OCD
and in schizophrenia (Table 1).
1.3.1. ACC pathology in OCD
In OCD, a number of studies show hyperactivation of the dor-
sal ACC (Milad and Rauch, 2011; Schlösser et al., 2010). Compared
with normal controls, patients with OCD presented increased ALFF
in ACC (Hou et al., 2012). It was proposed that hyperactivation of
the dorsal ACC mediates faulty error signals that contribute to the
obsessions or to elevated fear and anxiety observed in OCD (Milad
and Rauch, 2011; Schlösser et al., 2010).
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94 83

Task-induced functional connectivity analysis in OCD patients
showed enhanced connectivity between the dorsal ACC and the
DLPFC, supporting the idea of abnormal error processing in OCD
patients (Schlösser et al., 2010). Increased connectivity between
dorsal ACC and caudate was also observed with resting state fMRI
in OCD patients (Zhang et al., 2017).
1.3.2. ACC pathology in schizophrenia
Studies which describe hypoactivation outnumber studies
which report hyperactivation (Adams and David, 2007). Relative
to the control group, schizophrenia patients showed a significantly
decreased ALFF in the left cingulate gyrus. Hypoactivity of the OFC
and ACC was demonstrated in pathogenesis across different psy-
chotic disorders (Lui et al., 2015).
Salience network dysfunction has been proposed as a mecha-
nistic model for several core symptoms of schizophrenia. Patients
with schizophrenia have an impaired ability to detect erroneous
responses to stimuli and were characterized by hypoactivity in
the rostral ACC compared with healthy participants during error-
eliciting tasks (Friston et al., 2014; Laurens et al., 2003). ACC is
hypoactive during emotional processing in schizophrenia and re-
cent evidence suggests the hypoactive ACC in schizophrenia is cor-
related with negative (and not positive) symptoms (Nelson et al.,
2015).
1.4. Dopaminergic hyper- or hypo-activity and striatum
Pathological modulation from dopamine signaling in the stria-
tum leads to abnormal repetitive behaviors in animals (Wood and
Ahmari, 2015). Dopaminergic inputs to ventral striatum and the
VTA projections to the ventral striatum likely contribute to
selecting and sustaining appropriate behavioral sequences. Hyper-
dopaminergic states can directly contribute to OCD-related com-
pulsivity (Wood and Ahmari, 2015). A rodent study found that
hyper-dopaminergic mutant mice show excessively strong and
rigid manifestations of a complex fixed-action pattern compared
to wild-type mice (Berridge et al., 2005). An experimental primate
study found that bicuculline injections into limbic regions of the
globus pallidus can induce stereotypes (Monteiro and Feng, 2016).
Clinical studies have implicated dysfunction in goal-directed
cortico-striatal pathways in OCD and this dysfunction forces pa-
tients to rely instead on a parallel, habitual system (Gillan et al.,
2011). A recent cognitive model of OCD hypothesizes that activ-
ity of a goal-directed system normally shifts to a second habit-
mediating system (Milad and Rauch, 2011). OCD may result from
dysfunction in the goal-directed response system, thus necessar-
ily increasing the reliance on the habitual responding system
(Gillan et al., 2011).
Second-generation antipsychotic-induced obsessive-compulsive
symptoms are likely to be attributed to the antidopaminergic and
antiserotonergic drug properties (Scotti-Muzzi and Saide, 2017).
These atypical antipsychotic medications have less dopamine D2 -
receptor blockade and more serotonin (5-HT) receptor blockade.
This serotonin receptor blockade, which contributes to the disin-
hibition of dopamine in the frontal cortex, may be clinically effec-
tive in reducing negative symptoms of schizophrenia (Tibbo and
Warneke, 1999).
Patients with OCD showed evidence of reduced functional
connectivity of the dorsal striatum and lateral prefrontal cortex
(Harrison et al., 2009). The same study found an unanticipated ap-
parent loss of functional connectivity between the ventral striatum
regions and the midbrain VTA (Harrison et al., 2009).

Fig. 1. Schematic figure of the cortico-striato-thalamic network used to model pathophysiology in OCD and schizophrenia. Red lines denote excitatory, blue lines inhibitory
and green/brown lines dopaminergic inputs. The dopaminergic effect implemented in the model with a nonlinear term is represented with green arrows and the linear
dopaminergic effect is denoted with brown arrows. The connection between V and D is bidirectional but the ascending spiral indicates the preferred direction between the
ventral and dorsal regions (Haber et al., 20 0 0). Grey circles denote bidirectional couplings, where the valence and the type of neurotransmission is different in the two
opposing directions. (For interpretation of the colors in this figure legend, the reader is referred to the web version of this article.)
84 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94

Table 2 Table 3
Summary of the variables used in various simulation sets, listed alphabetically. Summary of the parameters used in various simulation sets. The first and the
The first and the second column denotes the variables and the corresponding second column denotes parameters and the corresponding connectivity or scal-
brain regions, respectively. ing parameters in the model.

Variables Brain regions Parameters Connectivity

A amygdala b11 O→V

C ACC b12 O→D
D dorsal striatum b2 A → V, D
O OFC e self-inhibition of A
P DLPFC g δ→V
T thalamus h δ → D
V ventral striatum i O, C → A
δ VTA/substantia nigra pars compacta j D→V
k V→D
l self-inhibition of C
m excitatory conn.
2. Methods and materials n self-inhib. D, V, T, P, δ
u C→P
w P→C
2.1. Model description and development
y C → D, V
z self-inhibition of O
We extended the modeling framework specified by μ parameter of the sigmoidal func.
Rădulescu and Marra (2017). The modeled network is schemat-
ically represented in Fig. 1. We modeled neural population
activity and network connectivity based on functional MRI studies ics from the VTA/substantia nigra pars compacta (Rădulescu and
(Rădulescu and Marra, 2017). The variables and the parameters Marra, 2017).
are listed in Tables 2 and 3, respectively. Differences from the
dC
 
original model are denoted in frames throughout the equations. = −lC + m O + T + A + wP + fμ (C, δ ) (2)
The model is a system of ordinary differential equations consisting dt
of the following: Variable C describes the ACC population activity, l is the self-
inhibition parameter of C. P represents DLPFC population activity
dO
= −zO + m(A + T ) + fμ (O, δ ) (1) and w scales the effect of DLPFC on ACC.
dt
dA
Variable O denotes the OFC population activity, parameter z = −eA − i(O + C ) + m(T + δ ) + fμ (A, δ ) (3)
dt
is the self-inhibition, and variables A, T are the amygdala and
thalamus neural population activity, respectively. Parameter m is Parameter e is the self-inhibition of the amygdala population
an excitatory scaling term used to parameterize excitatory con- activity and parameter i scales the inhibitory effect of the OFC and
nections, throughout the model. The term fμ denotes a com- ACC to the amygdala (Rădulescu and Marra, 2017).
plex dopamine modulation described in Eq. (9) (Rădulescu and dT
 
Marra, 2017). The variable δ describes the dopaminergic dynam- = −nT + m O + C + P + A + V + D + f μ (T , δ ) (4)
dt

Fig. 2. Schematic figure of the network changes due to altered activity of the OFC. The figure summarizes the parameter changes studied in simulation set I. The self-
inhibition of the OFC (z), the OFC → V (b11 ), OFC → D (b12 ) connection strengths were analyzed. (For interpretation of the colors in this figure legend, the reader is referred
to the web version of this article.)
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94 85

Variable T is the thalamus population activity, n parameterizes
the self-inhibition of T. V and D are the ventral and the dorsal stri-
atal variables, respectively. The striatum was divided into dorsal
(D) and ventral (V) parts, whereas the original study had only one
striatal region (Rădulescu and Marra, 2017). The analyzed connec-
tivity alterations of these two parts were motivated by the network
pathology between these two regions of the striatum and the cor-
tex in schizophrenia and in OCD.
dV
= −nV + b11 O + jD + b2 A + mT + yC − gδ + fμ (V, δ )
dt
Parameter n is the self-inhibition of V, b11 specifies the OFC ef-
fect on the V, j scales the effect of the dorsal striatum popula-
tion activity to the ventral striatum, b2 parameterizes the amyg-
dala’s effect on the V. Parameter y scales the ACC input to the ven-
tral striatum, g parameterizes the dopaminergic influence from the
VTA.
dD
= −nD + b12 O + b2 A + m(T + P ) + kV + yC − hδ + fμ (D, δ )
dt
Variable D is the dorsal striatal activity, n is the parameter for
the self-inhibition of D. Parameter b12 denotes the OFC effect on
the dorsal striatal activity, parameter k scales the effect of V on D,
h influences the dopaminergic input from the VTA, b2 parameter-
izes the amygdala’s effect on D. Parameter y scales the ACC input
to the dorsal striatum.
brain DA nuclei, we did not include this or projections from the
dorsal striatum to the VTA in the model.
dδ
= −nδ + m(O + C + A + T + V ) (8)
dt
Parameter n scales the self-inhibition of δ .
1
fμ (X, δ ) = (9)
exp(−μ(X − δ )) + 0.5
(5)
The complex dynamics of the modulatory dopamine effect
has been modeled by a sigmoidal function and has been con-
sidered to be proportional to the activity already present in the
target area (Rădulescu and Marra, 2017; Szalisznyó and Müller,
2009). The parameter μ was chosen to be 0.1 in every simula-
tion (Rădulescu and Marra, 2017). One early study suggested that
dopamine increases the signal-to-noise ratio of a postsynaptic neu-
ron (Servan-Schreiber et al., 1990). A connectionist approach of
this idea was implemented by changing the dopaminergic gain of
a sigmoidal activation function (Gershman, 2013; Servan-Schreiber
et al., 1990). The modulatory dopamine effect was also modeled
(6) in our study using a sigmoidal function and is considered to be
proportional to the activity already present in the target area
(Rădulescu and Marra, 2017). It was chosen as not centered to be

dP
= −nP + m(O + T ) + uC + fμ (P, δ ) (7)
dt

Dorsolateral prefrontal cortex was added to the model. The mo-

tivation of this change was that the DLPFC dysfunctions are signif-
icant among the schizophrenia patients. Parameter n denotes the
self-inhibition of P, u scales the effect of the ACC on the DLPFC.
The DLPFC projects mostly to the central striatum and premotor
and motor cortex projects to the dorsolateral striatum (Choi et al.,
2017; Haber et al., 20 0 0). The ventral striatum modulates cog-
nitive and motor striatal areas via the midbrain dopamine cells.
Thus the information flow is following the so called “Haber spiral”,
from ventral-medial to dorsal-lateral striatum (Burton et al., 2015;
Haber, 2016). Although DLPFC sends sparse projections to the mid-

Table 4
Summary of the parameters used in various simulation sets. The parameters,
which were altered in a specific simulation set were denoted with boldface. Note
that all parameters are non-negative, except g and h in simulation IV.

Model parameters Sim.I. Sim.I. Sim.II. Sim. III. Sim. IV.

Fig. 3A. Fig. 3B. Fig. 5. Fig. 7. Fig. 9.

i 2 2 2 2 2
b11 1.2 1.5 1.2 1.2 1.2
b12 0.9–1.2 1.5 1.2 1.2 1.2
b2 1.2 1.2 1.2 1.2 1.2
g 0.7 0.7 0.7 0.7 −1–2
h 0.7 0.7 0.7 0.7 −1–1.4
k 1 1 0.1 9–10 0.1
j 1 1 0.1 11–12 0.1
Fig. 3. Bifurcation analysis of the OFC variable (O) as a function of OFC self-
l 1.4 1.4 0–3 1.4 1.4
inhibition parameter (z). In case of Fig.A the connection between OFC → V was cho-
m 0.7 0.7 0.7 0.7 0.7
sen to be b11 = 1.2, (b12 = 1.2) (I). Then the OFC → V was increased to be b11 = 1.5,
n 1.4 1.4 1.4 2 1.4
(b12 = 1.2) (red direction) (II). Finally the OFC → D was decreased to b12 = 0.9,
e 1.4 1.4 1.4 1.4 1.4
(b11 = 1.2) (blue direction) (III). On Fig.B. both the connections between OFC → V
y 0 0 0–0.6 0 0
and OFC → D were the same b11 = 1.5, b12 = 1.5. The bifurcation analysis demon-
z 0–0.5 0–0.02 1.4 1.4 0–0.2
strates the amplitudes (upper and lower bounds) of the stable limit cycles that
μ 0.1 0.1 0.1 0.1 0.1
emerged from the Hopf bifurcation and the stable or unstable equilibrium curves.
w 0.7 0.7 0–1.7 0.7 0.7
(For interpretation of the colors in this figure legend, the reader is referred to the
u 0 0 0–3 0 0
web version of this article.)
86 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94
zero when x = δ, according to previous modeling studies (Fellous
and Linster, 1998; Hass and Durstewitz, 2011; Servan-Schreiber
et al., 1990). We have not found qualitative differences between
the results, using our version as compared to the original one.
The initial conditions for all variables were chosen to be 0
throughout the study. The parameters are summarized in Table 2.
The parameters used in various simulation sets are summarized in
Table 4.
2.2. Numerics
Simulations were performed on a Thinkpad T420s running the
Ubuntu-16.04 Linux operating system and using XPP simulation
software (version 5.91). The differential equations were solved
using the 4th order Runge–Kutta method, with a step size of
0.05 ms. For the bifurcation analysis the AUTO module of XPP was
used (Ermentrout, 2002).
3. Results
3.1. Orbitofrontal cortex activation
Simulation set I.
OFC self-inhibition
We investigated the effects of altering OFC self-inhibition in our
network model, via altering parameter z (Table 3) (Fig. 2, Fig. 3)
and observed that the OFC self-inhibition influences the system,
such that with low parameter values (low disinhibition level) the
variables exhibit a stable periodic solution (OCD-like behavior). As
the parameter value increased, a more inhibitory effect is intro-
duced and the system finds a stable fixed-point solution (Fig. 3A).
This implies that regulatory processes on the hyperactive OFC can
contribute to decreased oscillatory activity and eventually decreas-
Fig. 4. Schematic figure of the network changes due to altered activity of the ACC. The figure summarizes the parameter changes studied in the simulation set II. The effect
of the ACC self-inhibition and the ACC ← → DLPFC connection strength were analyzed. (For interpretation of the colors in this figure legend, the reader is referred to the
web version of this article.)
ing the OCD symptoms. Overcompensation can generate hypoactive
OFC, which is demonstrated in schizophrenia.
OFC → V and OFC → D projections
According to the literature, patients with OCD have increased
functional and structural connectivity between the OFC → V (Abe,
2015; Jung et al., 2017; Nakamae et al., 2014; Takagi, 2017) regions
but reduced connectivity between the OFC → D (Jung et al., 2017)
(Table 1), (Fig. 2). To investigate the effect of such pathological al-
terations, first the connectivity between the OFC → V regions was
altered via changing the parameter b11 (Fig. 3). With increased b11
values the system finds a stable fixed-point solution at lower z val-
ues, thus the increased OFC → V connectivity prevents the sys-
tem from exhibiting repetitive periodic OCD-like activity (Fig. 3A
II.). We then decreased the connectivity between the OFC → D re-
gions (Jung et al., 2017) by altering parameter b12 (Fig. 2). With de-
creased b12 values the system exhibits stable periodic solutions at
higher z values and it finds a stable fixed-point solution at higher z
values, so the decreased OFC → D connectivity pushes the system
to periodic OCD-like activity (Fig. 3A III.). This suggests that the
decreased OFC → D connectivity (and increased oscillatory activ-
ity) can be compensated for by an increased OFC → V connection
strength.
3.2. The effect of the anterior cingulate cortex activation
Simulation set II.
ACC self-inhibition
Motivated by the pathophysiological hyperactivation of ACC in
OCD patients (Gross-Isseroff et al., 2003; Maia et al., 2008; Mi-
lad and Rauch, 2011) we investigated the effect of self-inhibition
in the ACC (parameter l) (Fig. 4.). There is a parameter regime (in
the l space) in which the system exhibits stable periodic solutions
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94
Fig. 5. Bifurcation analysis of the ACC variable (C) (Fig.A) as a function of ACC self-
inhibition parameter (l). Two dimensional analysis was performed in the (l − u)
(Fig.B) and in the (l − w) parameter space (Fig.C). Bifurcation analysis of the ACC
variable (C) (Fig.D) as a function of ACC → striatum connectivity strength (y)
(Fig.D). (For interpretation of the colors in this figure legend, the reader is referred
to the web version of this article.)
(Figs. 5A and 6A). With higher l values the amplitude of the sta-
ble periodic solution decreases and the frequency of the oscillation
increases (Fig. 6A and B). With higher ACC self-inhibition, the sys-
tem switches to a stable fixed-point solution. Demonstration of the
projections of the phase space and direction fields in various l pa-
rameter values are presented in Fig. 6. The system is able to change
behavior from a stable fixed-point (Fig. 6C) to stable periodic so-
lutions (Fig. 6D). These simulation results imply, that regulatory
processes on the hyperactive ACC can contribute to decreased os-
cillatory activity and eventually decreasing and terminating oscil-
latory activity. Hypoactive ACC (as in schizophrenia) may emerge
as an overcompensation of the primary pathology (Fig. 11).
ACC ← → DLPFC projections
We have studied the effect of coupling strength between the
dorsolateral prefrontal cortex (P) and the anterior cingulate cor-
87
tex (C) and vice versa (parameters w and u). The results show
that with increased coupling strength from the ACC → DLPFC (pa-
rameter u) and back from the DLPFC → ACC (parameter w) the
Hopf bifurcation moves in the l - u and in the l - w space along
the l dimension (Fig. 5B and C). This means that with increased w
and u connection strength values, more self-inhibition of the ACC
is required to shift from periodic solutions to a stable fixed-point
solution (Fig. 5B and C). These results suggest that an emergence of
oscillatory activity in the network can appear due to an increased
connection strength between the ACC and DLPFC, which was de-
scribed in OCD (Milad and Rauch, 2011; Schlösser et al., 2010). The
decreased connectivity in this coupling in schizophrenia might be
due to compensatory processes (Cui et al., 2015).
ACC → striatal projections
The effect of connectivity change between the ACC and the
striatum was also examined. We investigated the effect of cou-
pling strength from ACC to the V, to the D and both (altering
parameter y) (Fig. 4). We found that as the coupling increased
from the ACC to the striatum (both ventral and dorsal), the sta-
ble fixed-point solution did not change qualitatively, but did in-
crease rapidly in a very narrow parameter regime (Fig. 5D). We
have not observed changes in the oscillatory behavior, while al-
tering parameter y. These results may imply that the connection
strength between ACC → V, D influences ACC activity and this in-
fluence is threshold-like, with a steeply changing effect in a very
narrow parameter regime. With a decreased connection strength
between ACC → V, low ACC activity can be present, which was ob-
served in schizophrenia (Lin et al., 2017). When only the coupling
to the V or to the D was increased, we observed the very same
qualitative behavior (figures not presented).
3.3. Changing the intrastriatal projections (V ← → D)
Simulation set III.
We investigated the effects of coupling strength from the ven-
tral to the dorsal part of the striatum (parameter k) (Fig. 2) and the
opposite direction dorsal → ventral via parameter (j). The under-
lying anatomy suggests that the ventromedial striatum projections
terminate throughout an extensive region of the dorsal midbrain,
whereas the dorsolateral striatal projections are relatively limited
to the ventrolateral striatum. Primate studies suggest that in phys-
iological cases the ventral striatal regions influence more the dor-
sal striatal regions via ascending spiraling projections (Haber et al.,
20 0 0). These differences in proportions significantly alter their re-
lationship to the midbrain (Haber et al., 20 0 0). Motivated by the
possible pathophysiological alterations in the Haber spiral we in-
vestigated the altered connectivity in both directions (Haber et al.,
20 0 0).
The results show that there is no qualitative difference in the
case of bidirectional coupling between the dorsal and ventral stria-
tum (Fig. 7A and B). With increased coupling strength, the stable
fixed-point solution changes to stable periodic solutions via a Hopf
bifurcation (Fig. 7A and B). However, the ventral → dorsal cou-
pling (k) strength change does result in a periodic solution at a
lower coupling strength and with a less steep frequency transition.
The dorsal → ventral coupling (j) increase also results in emerging
periodic solutions, but at slightly higher parameter values and with
more abrupt change in a narrower parameter regime. These results
suggest that the V → D and D → V activation patterns have qual-
itatively the same effects. However, the reverse D → V activation
(opposite to the Haber-spiral (Haber et al., 20 0 0)) results in oscil-
latory behavior in a bit higher parameter values, but with more
abrupt changes.
88 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94

Fig. 6. Bifurcation analysis of the ACC variable (C) as a function of ACC self-inhibition parameter (l) (Fig.A). Phase plane and direction fields in the O − C space as a function
of various l parameter values (Fig.B–D). On figure B, l was chosen to be 0.885 (yellow dashed line in the Fig.A), on figure C, l was chosen to be 0.887 (blue dashed line on
Fig.A.) (For interpretation of the colors in this figure legend, the reader is referred to the web version of this article.)

3.4. Altering the dopaminergic effect
Simulation set IV. We modeled the dopaminergic effect on the
ventral and dorsal striatum (Fig. 8). The effect of self-inhibition
change of the OFC was investigated in the network model, while
altering parameter g and h (Fig. 8). The dopaminergic activity in-
fluences the system, such that with negative parameter values the
variables (e.g the OFC) exhibit stable periodic solutions at higher g
and h values. (Note that negative values mean positive influence in
Eqs. (6) and (7) as the dopaminergic terms have negative valence).
As the parameters (g, h) are increased, the system becomes more
excitable, thus the stable fixed-point solution changes to stable pe-
riodic solutions via Hopf bifurcation at lower OFC activity values
(O) (Fig. 9A and B).
The two-dimensional OFC self-inhibition (z) and dopaminergic
influence (both on ventral (g) as well as the dorsal (h) striatum)
were also examined (Fig. 9). With increased OFC self-inhibition the
system changes behavior, such that it looses the periodic oscilla-
tory behavior and exhibits a stable fixed-point solution. The tran-
sition occurs via Hopf bifurcation (Fig. 9C and D).
With low and negative dopaminergic coupling to the V (nega-
tive g values) the system requires lower self-inhibition for reaching
a stable fixed-point solution. However, with increased dopaminer-
gic coupling, higher z values are needed for the transition from
periodic to fixed-point behavior. With a further increased g value,
lower self-inhibition is enough for the transition from a periodic to
stable fixed-point solution. Thus, there is a parameter “window” of
the dopaminergic input to the V, which contributes to more acces-
sible periodic solutions and in this window higher self-inhibition
is needed for reaching a stable fixed-point solution. In the case of
lower or higher values, lower self-inhibition z of the OFC is enough
to reach a stable fixed-point solution (Fig. 9C).
With negative dopaminergic coupling to the D (negative h val-
ues) the system requires higher self-inhibition for reaching the
stable fixed-point solution. However, with increased dopaminer-
gic coupling lower z values are enough for preventing periodic
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94
Fig. 7. Bifurcation analysis of the OFC activity (O) as a function of ventro → dorsal
(k) (Fig.A.) versus dorso → ventral (j) (Fig.B.) striatal connection strength.
solutions. Further increasing the coupling strength, again higher
z values are needed for the transition from periodic to fixed-
point behavior. Interestingly, here also an “optimal window” of the
dopaminergic input to the D was observed, which effectively can
contribute to preventing the periodic solutions. Lower or higher
values require a higher self-inhibition z of the OFC (Fig. 9D).
These results imply that the modulation on the cortical self-
inhibition (e.g. SSRI treatment) together with the dopaminergic in-
put (e.g. anti-dopaminergic medication) have a non-trivial complex
effect, with an optimal modulatory window (Fig. 10).
3.4.1. Predictions
The analysis of the coupling strength between the ventral and
dorsal striatum predicts that by decreasing the ventral → dorsal
coupling it is easier to evoke periodic solutions. The reverse dor-
sal → ventral coupling strength increase the occurance of emerg-
ing periodic solutions at slightly higher parameter values and with
more abrupt change in this narrower parameter regime. It is also
worth noting that anatomically the ventral striatal regions influ-
ence more the dorsal striatal regions via ascending spiraling pro-
jections than vice versa (Haber et al., 20 0 0). The transition from
voluntary goal-directed to habitual behavior has been demon-
strated both in animal as well as in human studies (Everitt and
Robbins, 2013). Our computational modeling results predict that
89
pathological recruitment of cortico-striatal pathways are involved
in OCD and that the hyperactivity is capable of spreading from the
dorsal to the ventral regions. Our simulations suggest that com-
pensatory mechanisms for preventing OCD-like periodic solutions
include decreased OFC → D connectivity, thus it might be that the
neural circuit is able to compensate for increased OFC → V connec-
tivity (Abe, 2015; Jung et al., 2013; Nakamae et al., 2014) by de-
creased OFC → D connection strength (Jung et al., 2017). It appears
that different regions in striatum can compensate for each other
when function in one is disrupted, suggesting that these structures
can work in parallel (Burton et al., 2015).
The literature is controversial regarding ACC activity in OCD,
but studies which found increased ACC activity in OCD (Milad
and Rauch, 2011; Schlösser et al., 2010), outnumber those which
demonstrated decreased activity (Gu et al., 2008; Radua et al.,
2010). Our simulation results show that as ACC self-inhibition
decreased, the system loses a stable fixed-point solution and
exhibits stable periodic solutions (OCD-like activity). Increased
connectivity between ACC and DLPFC also promotes OCD-like
behavior, thus higher self-inhibition of ACC is needed to obtain
a stable fixed-point solution, which is in correspondence with
some findings in OCD patient groups (Schlösser et al., 2010).
Hypoactive ACC in schizophrenia was found to be correlated
with negative symptoms (Nelson et al., 2015) and grey matter
reductions in the ACC precedes psychosis onset in schizophrenia
(Fornito et al., 2009). Our simulation results show that increased
self-inhibition results in ACC hypoactivity, which correlates with
clinical findings in schizophrenia. Bilaterally decreased inferior
V-dACC functional connectivity correlated inversely with overall
symptom severity in first episode schizophrenia (Lin et al., 2017).
Our simulations predict that the connection strength between
the ACC and V, D influences the ACC activity and this influence
is “threshold like”, with a steeply changing effect in a very nar-
row parameter regime. According to our simulation results the
co-morbid set of patients most likely exhibit ACC hyperactivity,
which implies a low correlation with negative symptoms in
schizophrenia.
4. Discussion
Anatomical evidence now indicates that the cortico-striatal
loops are more integrated across the ventral and dorsal striatum as
well as the thalamus and not fully segregated as initially thought.
It seems that there is a dynamic interplay between different stri-
atal regions (Szalisznyó et al., 2017). A hyperdopaminergic state in
the ventral striatum could lead to excessive valuation or repetitive
selection of a behavior and can directly contribute to OCD-related
compulsivity. On the other hand, the classical hyperdopaminergic
state in the mesolimbic pathways is the widely accepted working
hypothesis of the positive symptom development in schizophrenia.
VTA projections to the ventral striatum may be particularly rele-
vant to OCD (Wood and Ahmari, 2015).
Atypical antipsychotic drugs (AAP) are efficient as augmenta-
tion to SSRI in treatment resistant OCD and some of them such as
risperidone or aripiprazole have favorable effects in schizoptypic
OCD, although AAPs can cause induced OCS in schizophrenic pa-
tients (Grillault-Laroche and Gaillard, 2016). The majority of the
available evidence suggests that OCD is associated with a hyper-
dopaminergic state (Perani et al., 2008), but there are also findings
that support a more complex relationship between OCD symp-
tomatology and dopamine. There is: (1) evidence that dopamine
antagonism can also exacerbate symptoms or fail to produce a clin-
ical benefit (Klanker et al., 2013) and (2) imaging data suggest-
ing both increased and decreased dopamine transporter binding
(Klanker et al., 2013).
90 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94

Fig. 8. Schematic figure of the network changes due to altered dopaminergic effects. The figure summarizes the parameter changes studied in the simulation set IV. The
dopaminergic effect implemented with a nonlinear term is represented with green arrows, and the dopaminergic effect denoted with brown arrows. (For interpretation of
the colors in this figure legend, the reader is referred to the web version of this article.)

Fig. 9. Parameter sensitivity analysis of the Hopf bifurcation point as a function of dopaminergic effects on the Ventral (A) and on the Dorsal striatum (B). Co-dimension one
bifurcation analysis in two-dimensional parameter slices (C and D). The Hopf bifurcation point in the two-dimensional OFC self inhibition (z) and the dopaminergic influence
(g) parameter space (C). The Hopf bifurcation point in the two-dimensional OFC self inhibition (z) and the dopaminergic influence (h) parameter space (D). The effect of a
dopamine antagonist from antipsychotic medication (AP) and downregulation of OFC activity from SSRI represented by blue and red arrows, respectively. (For interpretation
of the colors in this figure legend, the reader is referred to the web version of this article.)
 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94 91

Fig. 10. Schematic figure of the cortico-striatal connections in healthy, OCD and schizophrenia models. Pink dashed zone symbolizes the cortical areas which are influenced
by SSRI treatment, while the blue dashed zone denotes the brain areas affected by antipsychotic treatment (AP). (For interpretation of the colors in this figure legend, the
reader is referred to the web version of this article.)

Fig. 11. Schematic representation of the cortico-thalamo-striatal network pathophysiology in schizophrenia and OCD. Each region is marked by both a red and blue dot to
represent contributions to both loops from schizophrenia and OCD, respectively. The red dots and lines denote activity and connectivity changes in schizophrenia. The blue
dots and lines denote activity and connectivity changes in OCD. Dashed lines denote decreased, while solid double lines denote increased connectivity. The dots which are
inside the black octagon have decreased activity in a disease, while the dots outside the black octagon symbolize increased activity in pathological conditions. Fig.B represents
the possible over-compensatory plasticity sites, where the OCD and schizophrenia patients have opposite primary pathology. Red and blue half circle arrows denote possible
compensatory regions in the neural network. The anterior insula (AI) and the alterations in its connections (green) with the OFC and ACC are important neural correlates of
insight in both OCD and schizophrenia (not included in the simulations). (For interpretation of the colors in this figure legend, the reader is referred to the web version of
this article.)

Our findings demonstrate an increase in network excitability
with increased dopaminergic influence on the dorsal and the ven-
tral striatum. For a specific self-inhibition level of the OFC (which
can be related to the level of SSRI treatment), there exists a level
of dopaminergic input to the dorsal striatum, which provides the
optimal window of modulation for the system to switch to a stable
fixed-point solution, preventing OCD-like behavior. On the other
hand, there exists a certain parameter regime for V dopaminer-
gic modulation which prevents most effectively the system from
switching to a stable fixed-point solution, promoting OCD-like be-
havior.
A theoretical study pointed out that reduced inhibition does
not correspond well to any known disturbances in OCD (Maia and
McClelland, 2012). Instead there is more evidence for increased
excitation which is consistent with evidence of glutamatergic
hyperactivity in OCD (Maia and McClelland, 2012). In our cur-
rent study, self-inhibition of the OFC and ACC was decreased to
simulate an imbalance between excitation and inhibition.
92 K. Szalisznyó, D.N. Silverstein and J. Tóth / Journal of Theoretical Biology 473 (2019) 80–94
Clozapine is one of the most effective antipsychotic drugs which
is known to induce obsessive-compulsive effects due to its strong
antiserotonergic properties (Schirmbeck and Zink, 2012). In accor-
dance with this theory, SSRIs and cognitive behavioral therapy
(CBT) have therapeutic effects via altered serotonergic neurotrans-
mission in OCD. 5-HT receptors might modulate the top-down in-
hibitory functions of the OFC and is implicated in compulsive be-
havior.
In the case of both OCD and schizophrenia, opposite activation
levels for ACC and OFC were reported in the literature. We predict
that the network is able to compensate partially for the primary
pathophysiology and over-compensation can contribute to the
emergence of a secondary induced pathological state. For example,
compensatory mechanisms reactive to the neuropathophysiological
changes in schizophrenia causes secondary OCD symptoms and
vice versa (Fig. 11). However, some compensatory processes might
be limited and more confined, which may help to explain that
for example OCD patients who develop schizophrenia are more
difficult to treat.
The diagnostic status of poor insight is ambiguous (Oulis et al.,
2013). It can be either a marker of chronicity of obsessions, or a
marker of delusionality and is a key clinical factor which signifi-
cantly influences therapy and outcome (Oulis et al., 2013). A recent
study found that projections from the right anterior insula (AI) to
the right mOFC are decreased in an OCD group with poor insight,
relative to both healthy controls and OCD with good insight. It was
also indicated that OCD with the good insight group had signifi-
cantly increased functional connectivity between the right AI ← →
left dACC than healthy controls (Fan et al., 2017). Furthermore, an
impaired insula ← → OFC connection was associated with insight
level in schizophrenic patients (Fan et al., 2017). These data suggest
that the connectivity alterations between the AI ← → OFC and AI
← → ACC may be important neural correlates of insight in OCD
and schizophrenia. These connectivity changes are not included in
our current modeling work, but should be examined in a follow-
up study (Fig. 11). Schizophrenia may trigger OCD-like symptoms
via thought checking on positive symptoms and OCD may trigger
schizophrenia-like symptoms via rumination and distraction with
increased prediction errors (Friston et al., 2014).
This study seeks to analyze the clinical and preclinical hu-
man and animal literature in a modeling framework for a deeper
understanding of the underlying neuropathophysiology of schizo-
obsessive co-morbidity. To our knowledge this is the first compu-
tational study which analyzed the neural circuits of this co-morbid
spectrum disorder. There are clear limitations of our study. The
model is phenomenological and gives a mechanistic explanation
for the underlying neurodynamical pathologies. We assumed lin-
earity of excitatory and inhibitory influences between brain areas
and used a single spatio-temporal scale. The model is determin-
istic and the emergence of periodic oscillatory solutions are in-
tended to correlate with the ALFF signals, which are stochastic. Fu-
ture studies must attempt to overcome and expand beyond these
limitations.
In conclusion, our current study reviewed clinical evidence and
some experimental results to provide a mechanistic framework in
a computational model for the underlying neuropathophysiology in
coexisting OCD and schizophrenia symptoms. The model can pre-
dict in which conditions the two states can coexist. The clinical
and animal experimental studies summarized above suggest in-
consistencies. The serotoninergic or dopaminergic signaling patho-
physiology alone does not provide a complete explanatory model
of schizo-obsessive spectrum disorders. Our network model sug-
gests that several additional disruption points and possible com-
pensatory network mechanisms may contribute to a deeper under-
standing of the clinical heterogeneity in schizo-obsessive spectrum
disorders.
Acknowledgements
We wish to thank Tamás Kiss for carefully reading the
manuscript and for useful comments and suggestions. K.Sz. was
supported by the Swedish Medical Association and Medical Train-
ing and Research Agreement (ALF) Funds from Uppsala University
Hospital, FoU and RUFU grants from Uppsala University Hospital
and Uppsala University, Institute of Neuroscience. JT was partially
supported by the National Research, Development and Innovation
Office, Hungary (SNN 125739).
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