Restricted accessResearch articleFirst published online 2022-06
Tracking Positive and Negative Symptom Improvement in First-Episode Schizophrenia Treated with Risperidone Using Individual-Level Functional Connectivity
To improve treatment outcomes of patients with schizophrenia, research efforts have focused on identifying brain-based markers of treatment response. Personal characteristics regarding disease-related behaviors likely stem from interindividual variability in the organization of brain functional systems. This study aimed to track dimension-specific changes in psychotic symptoms following risperidone treatment using individual-level functional connectivity (FC).
Methods:
A reliable cortical parcellation approach that accounts for individual heterogeneity in cortical functional anatomy was used to localize functional regions in a longitudinal cohort consisting of 42, drug-naive, first-episode schizophrenia (FES) patients at baseline and after 8 weeks of risperidone treatment. FC was calculated in individually specified brain regions and used to predict the baseline severity and improvement of positive and negative symptoms in FES.
Results:
Distinct sets of individual-specific FC were separately associated with the positive and negative symptom burden at baseline, which could be used to track the corresponding symptom resolution in FES patients following risperidone treatment. Between-network connections of the fronto-parietal network (FPN) contributed the most to predicting the positive symptom domain. A combination of between-network connections of the default mode network, FPN, and within-network connections of the FPN contributed markedly to the prediction model of negative symptoms.
Conclusion:
This novel study, which accounts for individual brain variation, takes a step toward establishing individual-specific theranostic biomarkers in schizophrenia.
Impact statement
This study revealed a theranostic marker for personalized medicine in schizophrenia and may aid in circuit-specific therapies for this disorder.
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References
1.
AnselmettiS, CavallaroR, BechiM, et al.2007. Psychopathological and neuropsychological correlates of source monitoring impairment in schizophrenia. Psychiatry Res, 150:51–59.
2.
ArgyelanM, CarbonM, GhilardiM-F, et al.2008. Dopaminergic suppression of brain deactivation responses during sequence learning. J Neurosci, 28:10687–10695.
3.
BertolinoA, CaforioG, BlasiG, et al.2004. Interaction of COMT Val108/158 Met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry, 161:1798–1805.
4.
BluhmRL, MillerJ, LaniusRA, et al.2007. Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophr Bull, 33:1004–1012.
5.
BoldingMS, WhiteDM, HadleyJA, et al.2012. Antipsychotic drugs alter functional connectivity between the medial frontal cortex, hippocampus, and nucleus accumbens as measured by H215O PET. Front Psychiatry, 3:105.
6.
BradyR, TandonN, KeshavanM, et al.2017. Negative symptoms of schizophrenia and fronto-parietal circuit dysfunction. Biol Psychiatry, 81:S111.
7.
BrennanBP, DanhongW, MeilingL, et al.2018. Use of an individual-level approach to identify cortical connectivity biomarkers in obsessive-compulsive disorder. Biol Psychiatry Cogn Neuroence Neuroimag, 4:27–38.
8.
BucknerRL, KrienenFM, CastellanosA, et al.2011. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol, 106:2322–2345.
9.
BullmoreET, FrangouS, MurrayRM. 1997. The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia. Schizophr Res, 28:143–156.
10.
CaoB, ChoRY, ChenD, et al.2020. Treatment response prediction and individualized identification of first-episode drug-naive schizophrenia using brain functional connectivity. Mol Psychiatry, 25:906–913.
11.
ChangCC, LinCJ. 2011. LIBSVM: A library for support vector machines. ACM Trans Intell Syst Technol, 2:1–27.
12.
CiricR, WolfDH, PowerJD, et al.2017. Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity. Neuroimage, 154:174–187.
13.
ColeJC, BernackiCG, HelmerA, et al.2015. Efficacy of transcranial magnetic stimulation (TMS) in the treatment of schizophrenia: a review of the literature to date. Innov Clin Neurosci, 12:12.
14.
CreeseI, BurtDR, SnyderSH. 1976. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192:481–483.
15.
da CostaRQM, de Gobbi PortoFH, MarrocosRP. 2013. Dissociation of depression from apathy in traumatic brain injury: A case report. Dement Neuropsychol, 7:312.
16.
DaleAM, FischlB, SerenoMI. 1999. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage, 9:179–194.
17.
DuanX, HuM, HuangX, et al.2020. Effect of risperidone monotherapy on dynamic functional connectivity of insular subdivisions in treatment-naive, first-episode schizophrenia. Schizophr Bull, 46:650–660.
18.
DuboisJ, AdolphsR. 2016. Building a science of individual differences from fMRI. Trends Cogn Sci, 20:425–443.
19.
EmsleyR, RabinowitzJ, MedoriR. 2006. Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry, 163:743–745.
FischlB, SerenoMI, DaleAM. 1999a. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage, 9:195–207.
22.
FischlB, SerenoMI, TootellRB, et al.1999b. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp, 8:272–284.
23.
FristonKJ. 1999. Schizophrenia and the disconnection hypothesis. Acta Psychiatr Scand Suppl, 395:68–79.
24.
FristonKJ, FrithCD. 1995. Schizophrenia: a disconnection syndrome?. Clin Neurosci, 3:89–97.
25.
GómezJLR, BellidoLH, VeguillaMR, et al.2010. Attentional network task performance in schizophrenic patients. Psicothema, 22:664–668.
26.
GordonEM, LaumannTO, AdeyemoB, et al.2017. Individual-specific features of brain systems identified with resting state functional correlations. Neuroimage, 146:918–939.
27.
GuoJ, BiswalBB, HanS, et al.2019. Altered dynamics of brain segregation and integration in poststroke aphasia. Hum Brain Mapp, 40:3398–3409.
28.
HanS, ChenY, ZhengR, et al.2021. The stage-specifically accelerated brain aging in never-treated first-episode patients with depression. Hum Brain Mapp, 42:3656–3666.
29.
JenkinsonM, BannisterP, BradyM, et al.2002. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage, 17:825–841.
30.
JiaW, ZhuH, NiY, et al.2020. Disruptions of frontoparietal control network and default mode network linking the metacognitive deficits with clinical symptoms in schizophrenia. Hum Brain Mapp, 41:1445–1458.
31.
KaneJM. 1999. Pharmacologic treatment of schizophrenia. Biol Psychiatry, 46:1396–1408.
32.
KaySR, FiszbeinA, OplerLA. 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull, 13:261–276.
33.
KomossaK, Rummel-KlugeC, SchwarzS, et al.2011. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev, 1:CD006626.
34.
KongR, LiJ, OrbanC, et al.2019. Spatial topography of individual-specific cortical networks predicts human cognition, personality, and emotion. Cereb Cortex, 29:2533–2551.
35.
KuhnS, MussoF, MobascherA, et al.2012. Hippocampal subfields predict positive symptoms in schizophrenia: first evidence from brain morphometry. Transl Psychiatry, 2:e127.
36.
LaumannTO, GordonEM, AdeyemoB, et al.2015. Functional system and areal organization of a highly sampled individual human brain. Neuron, 87:657–670.
37.
LehmanAF, LiebermanJA, DixonLB, et al.2004. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry, 161(2 Suppl.):1–56.
38.
LeuchtS, CiprianiA, SpineliL, et al.2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet, 382:951–962.
39.
LevyR, DuboisB. 2006. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. Cereb Cortex, 16:916–928.
40.
LiM, WangD, RenJ, et al.2019. Performing group-level functional image analyses based on homologous functional regions mapped in individuals. PLoS Biol, 17:e2007032.
41.
MarzoukT, WinkelbeinerS, AziziH, et al.2019. Transcranial magnetic stimulation for positive symptoms in schizophrenia: A systematic review. Neuropsychobiology, 79:384–396.
MedaSA, GillA, StevensMC, et al.2012. Differences in resting-state fMRI functional network connectivity between schizophrenia and psychotic bipolar probands and their unaffected first-degree relatives. Biol Psychiatry, 71:881.
44.
MillanMJ, FoneK, StecklerT, et al.2014. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol, 24:645–692.
45.
MiyamotoS, MiyakeN, JarskogL, et al.2012. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry, 17:1206–1227.
46.
MuellerS, WangD, FoxMD, et al.2013. Individual variability in functional connectivity architecture of the human brain. Neuron, 77:586–595.
47.
MurphyK, FoxMD. 2017. Towards a consensus regarding global signal regression for resting state functional connectivity MRI. Neuroimage, 154:169–173.
48.
Nagano-SaitoA, LiuJ, DoyonJ, et al.2009. Dopamine modulates default mode network deactivation in elderly individuals during the Tower of London task. Neurosci Lett, 458:1–5.
49.
PalaniyappanL, SimmoniteM, WhiteTP, et al.2013. Neural primacy of the salience processing system in schizophrenia. Neuron, 79:814–828.
50.
RattehalliRD, ZhaoS, LiBG, et al.2016. Risperidone versus placebo for schizophrenia. Cochrane Database Syst Rev, 12:CD006918.
51.
RepovsG, CsernanskyJG, BarchDM. 2011. Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry, 69:967–973.
52.
RollsET, LohM, DecoG, et al.2008. Computational models of schizophrenia and dopamine modulation in the prefrontal cortex. Nat Rev Neurosci, 9:696–709.
53.
RosenbergO, RothY, KotlerM, et al.2011. Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study. Ann Gen Psychiatry, 10:3.
54.
Rotarska-JagielaA, van de VenV, Oertel-KnochelV, et al.2010. Resting-state functional network correlates of psychotic symptoms in schizophrenia. Schizophr Res, 117:21–30.
55.
SambataroF, BlasiG, FazioL, et al.2010. Treatment with olanzapine is associated with modulation of the default mode network in patients with Schizophrenia. Neuropsychopharmacology, 35:904–912.
56.
SarpalDK, ArgyelanM, RobinsonDG, et al.2015a. Baseline striatal functional connectivity as a predictor of response to antipsychotic drug treatment. Am J Psychiatry, 173:69–77.
57.
SarpalDK, RobinsonDG, LenczT, et al.2015b. Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia. JAMA Psychiatry, 72:5–13.
58.
SatterthwaiteTD, VandekarSN, WolfDH, et al.2015. Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms. Mol Psychiatry, 20:1508–1515.
59.
SmithSM, JenkinsonM, WoolrichMW, et al.2004. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 23(Suppl. 1):S208–S219.
60.
TregellasJR. 2014. Neuroimaging biomarkers for early drug development in schizophrenia. Biol Psychiatry, 76:111–119.
61.
WaltonE, HibarDP, van ErpTG, et al.2017. Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium. Acta Psychiatrica Scandinavica, 135:439–447.
62.
WangC, ShiW, HuangC, et al.2017. The efficacy, acceptability, and safety of five atypical antipsychotics in patients with first-episode drug-nave schizophrenia: a randomized comparative trial. Ann Gen Psychiatry, 16:47.
63.
WangD, BucknerRL, FoxMD, et al.2015. Parcellating cortical functional networks in individuals. Nat Neurosci, 18:1853–1860.
64.
WangD, LiM, WangM, et al.2020. Individual-specific functional connectivity markers track dimensional and categorical features of psychotic illness. Mol Psychiatry, 25:2119–2129.
65.
WangY, TangW, FanX, et al.2017. Resting-state functional connectivity changes within the default mode network and the salience network after antipsychotic treatment in early-phase schizophrenia. Neuropsychiatr Dis Treatm, 13:397–406.
66.
Whitfield-GabrieliS, ThermenosHW, MilanovicS, et al.2009. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A, 106:1279–1284.
67.
WoodSJ, YungAR, McGorryPD, et al.2011. Neuroimaging and treatment evidence for clinical staging in psychotic disorders: from the at-risk mental state to chronic schizophrenia. Biol Psychiatry, 70:619–625.
68.
WoodwardND, RogersB, HeckersS. 2011. Functional resting-state networks are differentially affected in schizophrenia. Schizophr Res, 130:86–93.
69.
YeoBT, KrienenFM, SepulcreJ, et al.2011. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol, 106:1125–1165.
70.
YuQ, AllenEA, SuiJ, et al.2012. Brain connectivity networks in schizophrenia underlying resting state functional magnetic resonance imaging. Curr Top Med Chem, 12:2415–2425.
71.
ZhouY, LiangM, JiangT, et al.2007. Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI. Neurosci Lett, 417:297–302.
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