Cerebellar Effects on Abnormal Psychomotor Function Are Mediated by Processing Speed in Psychosis Spectrum

Alexandra B. Moussa-Tooks1, Jinyuan Liu2, Kristan Armstrong1, Baxter Rogers3, Neil D. Woodward1, Stephan Heckers1
1Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, USA
2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, USA
3Vanderbilt University Institute of Imaging Science, Nashville, USA

Tóm tắt

Psychomotor disturbance has been identified as a key feature of psychotic disorders, with motor signs observed in upwards of 66% of unmedicated, first-episode patients. Aberrations in the cerebellum have been directly linked to sensorimotor processing deficits including processing speed, which may underly psychomotor disturbance in psychosis, though these brain-behavior-symptom relationships are unclear, in part due to within-diagnosis heterogeneity across these levels of analysis. In 339 psychosis patients (242 schizophrenia-spectrum, 97 bipolar with psychotic features) and 217 controls, we evaluated the relationship between cerebellar grey matter volume in the Yeo sensorimotor network and psychomotor disturbance (mannerisms and posturing, retardation, excitement of the Positive and Negative Syndrome Scale [PANSS]), as mediated by processing speed (assessed via the SCIP). Models included intracranial volume, age, sex, and chlorpromazine equivalents as covariates. We observed significant mediation by processing speed, with a small positive effect of the cerebellum on processing speed (ß = 0.172, p = 0.029, d = 0.24) and a medium negative effect of processing speed on psychomotor disturbance (ß = −0.254, p < 0.001, d = 0.60), with acceptable specificity and sensitivity suggesting this model is robust against unmeasured confounding. The current findings suggest a critical role of cerebellar circuitry in a well-established sensorimotor aberration in psychosis (processing speed) and the presentation of related psychomotor phenotypes within psychosis. Establishing such relationships is critical for intervention research, such as TMS. Future work will employ more dimensional measures of psychomotor disturbance and cognitive processes to capture normative and aberrant brain-behavior-symptom relationships and may also determine the magnitude of these relationships within subtypes of psychosis (e.g., disorganized behavior, catatonia).

Tài liệu tham khảo

Cao H, Cannon TD. Cerebellar dysfunction and schizophrenia: from “cognitive dysmetria” to a potential therapeutic target. Am J Psychiatry. 2019;176:498–500. https://doi.org/10.1176/appi.ajp.2019.19050480. Bernard JA, Mittal VA. Cerebellar-motor dysfunction in schizophrenia and psychosis-risk: the importance of regional cerebellar analysis approaches. Front Psychiatry. 2014;5:160. https://doi.org/10.3389/fpsyt.2014.00160. Castle D, Sham P, Murray R. Differences in distribution of ages of onset in males and females with schizophrenia. Schizophr Res. 1998;33:179–83. Moberget T, Ivry RB. Prediction, psychosis and the cerebellum. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:820–31. https://doi.org/10.1016/j.bpsc.2019.06.001. Chrobak AA, Siwek GP, Siuda-Krzywicka K, Arciszewska A, Starowicz-Filip A, Siwek M, Dudek D. Neurological and cerebellar soft signs do not discriminate schizophrenia from bipolar disorder patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;64:96–101. https://doi.org/10.1016/j.pnpbp.2015.07.009. Shinn AK, Roh YS, Ravichandran CT, Baker JT, Ongur D, Cohen BM. Aberrant cerebellar connectivity in bipolar disorder with psychosis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:438–48. https://doi.org/10.1016/j.bpsc.2016.07.002. Walther S, Mittal VA. Motor system pathology in psychosis. Curr Psychiatry Rep. 2017;19:97. https://doi.org/10.1007/s11920-017-0856-9. Gur RC, Calkins ME, Satterthwaite TD, Ruparel K, Bilker WB, Moore TM, Savitt AP, Hakonarson H, Gur RE. Neurocognitive growth charting in psychosis spectrum youths. JAMA Psychiatry. 2014;71:366–74. https://doi.org/10.1001/jamapsychiatry.2013.4190. Grootens KP, Vermeeren L, Verkes RJ, Buitelaar JK, Sabbe BG, van Veelen N, Kahn RS, Hulstijn W. Psychomotor planning is deficient in recent-onset schizophrenia. Schizophr Res. 2009;107:294–302. https://doi.org/10.1016/j.schres.2008.09.032. Nadesalingam N, Chapellier V, Lefebvre S, Pavlidou A, Stegmayer K, Alexaki D, Gama DB, Maderthaner L, von Kanel S, Wuthrich F, Walther S. Motor abnormalities are associated with poor social and functional outcomes in schizophrenia. Compr Psychiatry. 2022;115:152307. https://doi.org/10.1016/j.comppsych.2022.152307. Varambally S, Venkatasubramanian G, Thirthalli J, Janakiramaiah N, Gangadhar BN. Cerebellar and other neurological soft signs in antipsychotic-naive schizophrenia. Acta Psychiatr Scand. 2006;114:352–6. https://doi.org/10.1111/j.1600-0447.2006.00837.x. Walther S, Ramseyer F, Horn H, Strik W, Tschacher W. Less structured movement patterns predict severity of positive syndrome, excitement, and disorganization. Schizophr Bull. 2014;40:585–91. https://doi.org/10.1093/schbul/sbt038. Kaikoushi K, Middleton N, Chatzittofis A, Bella E, Alevizopoulos G, Karanikola M. Socio-demographic and clinical characteristics of adults with psychotic symptomatology under involuntary admission and readmission for compulsory treatment in a referral psychiatric hospital in Cyprus. Front Psychiatry. 2021;12:602274. https://doi.org/10.3389/fpsyt.2021.602274. Clark S, Tannahill A, Calhoun VD, Bernard J, Bustillo J, Turner JA. Weaker cerebello-cortical connectivity within sensorimotor and executive networks in schizophrenia compared to healthy controls: relationships with processing speed. Brain Connect. 2020;10:490–503. https://doi.org/10.1089/brain.2020.0792. Moore DM, D'Mello AM, McGrath LM, Stoodley CJ. The developmental relationship between specific cognitive domains and grey matter in the cerebellum. Dev Cogn Neurosci. 2017;24:1–11. https://doi.org/10.1016/j.dcn.2016.12.001. Bolbecker AR, Westfall DR, Howell JM, Lackner RJ, Carroll CA, O’Donnell BF, Hetrick WP. Increased timing variability in schizophrenia and bipolar disorder. PLoS One. 2014;9:e97964. https://doi.org/10.1371/journal.pone.0097964. Moussa-Tooks AB, Rogers BP, Huang AS, Sheffield JM, Heckers S, Woodward ND. Cerebellar structure and cognitive ability in psychosis. Biol Psychiatry. 2022;92:385–95. https://doi.org/10.1016/j.biopsych.2022.03.013. Brady RO Jr, Gonsalvez I, Lee I, Ongur D, Seidman LJ, Schmahmann JD, Eack SM, Keshavan MS, Pascual-Leone A, Halko MA. Cerebellar-prefrontal network connectivity and negative symptoms in schizophrenia. Am J Psychiatry. 2019;176:512–20. https://doi.org/10.1176/appi.ajp.2018.18040429. Schäppi L, Strik W, Stegmayer K, Vladimirova I, Weiss F, Schoretsanitis G, Alexaki D, Walther S. Inhibitory repetitive transcranial magnetic stimulation to treat psychomotor slowing: a transdiagnostic, mechanism-based randomized double-blind controlled trial. Schizophrenia Bulletin Open. 2020:1. https://doi.org/10.1093/schizbullopen/sgaa020. Morrens M, Hulstijn W, Matton C, Madani Y, van Bouwel L, Peuskens J, Sabbe BG. Delineating psychomotor slowing from reduced processing speed in schizophrenia. Cogn Neuropsychiatry. 2008;13:457–71. https://doi.org/10.1080/13546800802439312.