Clinical Psychology; Psychiatry and Mental Health; Biological Psychiatry
Abstract :
[en] Semantic language dysfunction is a hallmark of early psychosis, yet the underlying brain structural correlates are largely unexplored. In particular, it is unclear whether core deficits arise from disruptions to semantic representation, which refers to the stored knowledge of word meanings, or to semantic control, which entails top-down mechanisms that guide the retrieval and selection of context-appropriate semantic information. By dissociating semantic representation-related from semantic control-related performance, we aimed to identify the preferential impairment in early psychosis and its structural correlates in the ventral and dorsal language streams. We investigated N = 120 individuals across the psychosis spectrum: N = 40 individuals with early psychosis, N = 40 individuals with high schizotypy, and N = 40 individuals with low schizotypy. Participants with high and low schizotypy constituted the non-clinical comparison group. All participants completed tasks designed to isolate semantic representation-related and semantic control-related processes. Given the importance of accurate delineation, this study employed meticulous manual fiber tractography of diffusion tensor imaging (DTI) data to ensure reliable evaluation of ventral and dorsal pathway microstructure. Compared to individuals with high and low schizotypy, individuals with early psychosis showed pronounced deficits in semantic control-related performance, while the semantic representation-related measure remained largely intact. Mean diffusivity in the left inferior fronto-occipital fasciculus and left uncinate fasciculus was lower in the early psychosis group than in individuals with schizotypy. In the early psychosis group, fractional anisotropy in the left arcuate fasciculus was negatively correlated with semantic control-related performance, but no DTI measure was associated with the semantic representation-related measure. These results underscore semantic control-related performance as a core deficit in early psychosis and extend the conventional view that semantic processing is subserved primarily by ventral pathways. The arcuate fasciculus appears implicated in semantic control-related processes, indicating a more integrated interplay of dorsal and ventral streams in semantic language processing.
Surbeck, Werner; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland. werner.surbeck@pukzh.ch
Omlor, Wolfgang; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Dannecker, Noemi; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Samuel, Robin ; Department of Social Sciences, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Steiner, Anna; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Fabian, Dominic; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Gasser, Allegra; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Hüppi, Roya ; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Horisberger, Rahel; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Cecere, Giacomo; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Kallen, Nils; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Sarti, Pierfrancesco; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Stämpfli, Philipp; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Scholtes, Félix ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Denier, Niklaus; Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
Bracht, Tobias; Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
Brugger, Peter ; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
Homan, Philipp ; Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland ; Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
This research was supported by grants from the Swiss National Science Foundation (Grant no. 501100001711\u2013191938, to N.D.), the Brain & Behavior Research Foundation (Grant no. 28997, to W.S.), and the OPO Foundation (Grant no. 2020-0075, to W.S., N.D., P.B., and P.H.).
L. Palaniyappan P. Homan M.F. Alonso-Sanchez Language Network Dysfunction and Formal Thought Disorder in Schizophrenia Schizophr. Bull. 49 486 497 36305160
S.R. Marder T.D. Cannon Schizophrenia N. Engl. J. Med. 381 1753 1761 1:CAS:528:DC%2BC1MXitFWktrjF 31665579
Winkelbeiner, S. et al. Decreased blood flow in the right insula and middle temporal gyrus predicts negative formal thought disorder in schizophrenia. Schizophr. Res.201, 432–434 (2018).
M.E. Shenton M.R. Solovay P.S. Holzman M. Coleman H.J. Gale Thought disorder in the relatives of psychotic patients Arch. Gen. Psychiatry 46 897 901 1:STN:280:DyaK3c%2FisFKluw%3D%3D 2489936
M. Kiang M. Kutas Association of schizotypy with semantic processing differences: an event-related brain potential study Schizophr. Res. 77 329 342 15919182
C. Steel D.R. Hemsley A.D. Pickering Associations between schizotypal personality traits and the facilitation and inhibition of the speed of contextually cued responses Psychiatry Res 150 131 140 17287028
S. Uzman Ozbek K. Alptekin Thought disorder as a neglected dimension in Schizophrenia Alpha Psychiatry 23 5 11 36425242
A. Wada et al. Semantic memory disorganization linked to social functioning in patients with schizophrenia Schizophrenia 11 61 40229291 11997020
Y. Matsumoto et al. Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI Schizophr. Bull. 49 498 506 36542452
S.D. Han C.G. Wible Neuroimaging of semantic processing in schizophrenia: a parametric priming approach Int. J. Psychophysiol. 75 100 106 19765623
M. Kubicki et al. An fMRI study of semantic processing in men with schizophrenia Neuroimage 20 1923 1933 1:STN:280:DC%2BD3sngt12quw%3D%3D 14683698
T. Bracht et al. White matter pathway organization of the reward system is related to positive and negative symptoms in schizophrenia Schizophr. Res. 153 136 142 24485586
P.V. Viher et al. White matter correlates of the disorganized speech dimension in schizophrenia Eur. Arch. Psychiatry Clin. Neurosci. 268 99 104 28032254
P.R. Szeszko et al. Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia Neuropsychopharmacology 33 976 984 17581532
M. Cavelti et al. Formal thought disorder is related to aberrations in language-related white matter tracts in patients with schizophrenia Psychiatry Res. Neuroimaging 279 40 50 29861197
M. Cavelti T. Kircher A. Nagels W. Strik P. Homan Is formal thought disorder in schizophrenia related to structural and functional aberrations in the language network? A systematic review of neuroimaging findings Schizophr. Res. 199 2 16 29510928
A.L. Lemaitre G. Lafargue H. Duffau G. Herbet Damage to the left uncinate fasciculus is associated with heightened schizotypal traits: A multimodal lesion-mapping study Schizophr. Res. 197 240 248 29499963
H. Duffau S. Moritz-Gasser E. Mandonnet A re-examination of neural basis of language processing: proposal of a dynamic hodotopical model from data provided by brain stimulation mapping during picture naming Brain Lang. 131 1 10 23866901
S. Moritz-Gasser G. Herbet H. Duffau Mapping the connectivity underlying multimodal (verbal and non-verbal) semantic processing: a brain electrostimulation study Neuropsychologia 51 1814 1822 23778263
G. Herbet S. Moritz-Gasser H. Duffau Direct evidence for the contributive role of the right inferior fronto-occipital fasciculus in non-verbal semantic cognition Brain Struct. Funct. 222 1597 1610 27568379
W. Surbeck et al. Anatomical integrity within the inferior fronto-occipital fasciculus and semantic processing deficits in schizophrenia spectrum disorders Schizophr. Res 218 267 275 31948896
M.A. Ralph E. Jefferies K. Patterson T.T. Rogers The neural and computational bases of semantic cognition Nat. Rev. Neurosci. 18 42 55 1:CAS:528:DC%2BC28XhvFelsbfN 27881854
K. Patterson P.J. Nestor T.T. Rogers Where do you know what you know? The representation of semantic knowledge in the human brain Nat. Rev. Neurosci. 8 976 987 1:CAS:528:DC%2BD2sXhtlalt7rO 18026167
M.F. Alonso-Sanchez R. Limongi J. Gati L. Palaniyappan Language network self-inhibition and semantic similarity in first-episode schizophrenia: A computational-linguistic and effective connectivity approach Schizophr. Res 259 97 103 35568676
M.F. Alonso-Sanchez W. Hinzen R. He J. Gati L. Palaniyappan Perplexity of utterances in untreated first-episode psychosis: an ultra-high field MRI dynamic causal modelling study of the semantic network J. Psychiatry Neurosci. 49 E252 E262 39122409 11318974
E.M. Cocquyt et al. The white matter architecture underlying semantic processing: A systematic review Neuropsychologia 136 107182 31568774
A.S. Dick B. Bernal P. Tremblay The language connectome: new pathways, new concepts Neuroscientist 20 453 467 24342910
P. Sarti et al. An exploratory network analysis to investigate schizotypy’s structure using the ‘Multidimensional Schizotypy Scale’ and ‘Oxford-Liverpool Inventory’ in a healthy cohort Schizophrenia 11 34 40021721 11871301
Rohanian, M. et al. Uncertainty modeling in multimodal speech analysis across the Psychosis Spectrum. arXiv (2025).
Kirchhoff, C. et al. Gender-specific associations of adverse childhood experiences (ACEs) and schizotypal traits - an observational study in healthy young adults. medRxiv (2024).
Omlor, W. et al. Estimating multimodal structural brain variability in schizophrenia spectrum disorders: a worldwide ENIGMA Study. Am. J. Psychiatry, appiajp20230806, https://doi.org/10.1176/appi.ajp.20230806 (2025).
O. Mason G. Claridge The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE): further description and extended norms Schizophr. Res. 82 203 211 16417985
T.R. Kwapil G.M. Gross P.J. Silvia M.L. Raulin N. Barrantes-Vidal Development and psychometric properties of the Multidimensional Schizotypy Scale: A new measure for assessing positive, negative, and disorganized schizotypy Schizophr. Res. 193 209 217 28735642
Scrucca, L., Fraley, C., Murphy, B. & Raftery, A. Model-based Clustering, Classification and Density Estimation Using mclust in R. Chapman and Hall/CRC (2023).
J.F. Veale Edinburgh Handedness Inventory - Short Form: a revised version based on confirmatory factor analysis Laterality 19 164 177 23659650
R.A.I. Bethlehem et al. Brain charts for the human lifespan Nature 604 525 533 1:CAS:528:DC%2BB38XptF2hsLY%3D 35388223 9021021
S.R. Kay A. Fiszbein L.A. Opler The Positive and Negative Syndrome Scale (PANSS) for schizophrenia Schizophr. Bull. 13 261 276 1:STN:280:DyaL2s3ptF2huw%3D%3D 3616518
Deloche, G. & Hannequin, D. Test de dénomination orale d’images: DO 80. Éditions du Centre de psychologie appliquée, Paris (1997).
E.T. McKinnon et al. Types of naming errors in chronic post-stroke aphasia are dissociated by dual stream axonal loss Sci. Rep. 8 30254222 6156587 14352
S. Lehrl G. Triebig B. Fischer Multiple choice vocabulary test MWT as a valid and short test to estimate premorbid intelligence Acta Neurol. Scand. 91 335 345 1:STN:280:DyaK2Mzms1arsw%3D%3D 7639062
K.H. Nuechterlein et al. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity Am. J. Psychiatry 165 203 213 18172019
C.E. Bokat T.E. Goldberg Letter and category fluency in schizophrenic patients: a meta-analysis Schizophr. Res. 64 73 78 14511803
S. Bozeat M.A. Lambon Ralph K. Patterson P. Garrard J.R. Hodges Non-verbal semantic impairment in semantic dementia Neuropsychologia 38 1207 1215 1:STN:280:DC%2BD3cvjvFCrsA%3D%3D 10865096
E. Jefferies M.A. Lambon Ralph Semantic impairment in stroke aphasia versus semantic dementia: a case-series comparison Brain 129 2132 2147 16815878
J.W. Peirce Generating Stimuli for Neuroscience Using PsychoPy Front Neuroinform. 2 10 19198666
P. Hoffman An individual differences approach to semantic cognition: Divergent effects of age on representation, retrieval and selection Sci. Rep. 8 29802344 5970266 8145
Strauss, E., Sherman, E. & Spreen, O. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. Oxford University Press, 3. Edition (2006).
T.N. Tombaugh Trail Making Test A and B: normative data stratified by age and education Arch. Clin. Neuropsychol. 19 203 214 15010086
M. Daseking F. Petermann H.-C. Waldmann Schätzung der allgemeinen Intelligenz mit einer Kurzform der WAIS-IV bei neurologischen Fragestellungen Aktuelle Neurol. 41 349 355
F. Isensee et al. Automated brain extraction of multisequence MRI using artificial neural networks Hum. Brain Mapp. 40 4952 4964 31403237 6865732
Leemans, A, Jeurissen, B, Sijbers, J. & Jones, D. K. ExploreDTI: a graphical toolbox for processing, analyzing and visualizing diffusion MR data. Proceedings of the International Society for Magnetic Resonance in Medicine 17th Annual Meeting April 18-24, 3536, Honolulu, Hawai (2009).
A. Leemans D.K. Jones The B-matrix must be rotated when correcting for subject motion in DTI data Magn. Reson. Med. 61 1336 1349 19319973
P.J. Basser J. Mattiello D. LeBihan Estimation of the effective self-diffusion tensor from the NMR spin echo J. Magn. Reson. B 103 247 254 1:CAS:528:DyaK2cXivVyitL0%3D 8019776
M. Smits L.C. Jiskoot J.M. Papma White matter tracts of speech and language Semin. Ultrasound CT MR 35 504 516 25217302
N. Denier et al. Electroconvulsive therapy induces remodeling of hippocampal co-activation with the default mode network in patients with depression Neuroimage Clin. 38 103404 37068311 10130338
S.S. Panesar F.C. Yeh T. Jacquesson W. Hula J.C. Fernandez-Miranda A Quantitative Tractography Study Into the Connectivity, Segmentation and Laterality of the Human Inferior Longitudinal Fasciculus Front. Neuroanat. 12 47 29922132 5996125
T. Bracht et al. Physical activity is associated with left corticospinal tract microstructure in bipolar depression Neuroimage Clin. 20 939 945 30308380 6178191
R.W. Heinrichs K.K. Zakzanis Neurocognitive deficit in schizophrenia: a quantitative review of the evidence Neuropsychology 12 426 445 1:STN:280:DyaK1czjvVOrtA%3D%3D 9673998
N. Ojeda et al. Verbal fluency in schizophrenia: does cognitive performance reflect the same underlying mechanisms in patients and healthy controls? J. Nerv. Ment. Dis. 198 286 291 20386258
P. Pinelli et al. Delayed verbal reactions are specifically impaired in patients with schizophrenia Int J. Psychophysiol. 37 163 175 1:STN:280:DC%2BD3cvgsVCluw%3D%3D 10832003
R. Chiou E. Jefferies J. Duncan G.F. Humphreys M.A. Lambon Ralph A middle ground where executive control meets semantics: the neural substrates of semantic control are topographically sandwiched between the multiple-demand and default-mode systems Cereb. Cortex 33 4512 4526 36130101
M. Montefinese Semantic representation of abstract and concrete words: a minireview of neural evidence J. Neurophysiol. 121 1585 1587 30785804
S. Kelly et al. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group Mol. Psychiatry 23 1261 1269 1:STN:280:DC%2BC1M7htlGgtA%3D%3D 29038599
E. Plitman et al. Glutamate-mediated excitotoxicity in schizophrenia: a review Eur. Neuropsychopharmacol. 24 1591 1605 1:CAS:528:DC%2BC2cXhtlCjtLzI 25159198 4470624
K. Friston H.R. Brown J. Siemerkus K.E. Stephan The dysconnection hypothesis (2016) Schizophr. Res. 176 83 94 27450778 5147460
L. Palaniyappan A. Al-Radaideh O. Mougin P. Gowland P.F. Liddle Combined white matter imaging suggests myelination defects in visual processing regions in schizophrenia Neuropsychopharmacology 38 1808 1815 23558741 3712891
X. Chang et al. Language abnormalities in schizophrenia: binding core symptoms through contemporary empirical evidence Schizophrenia 8 95 36371445 9653408
U. Ettinger et al. Cognition and brain function in schizotypy: a selective review Schizophr. Bull. 41 S417 S426 25810056 4373634
M.S. Lener et al. White matter abnormalities in schizophrenia and schizotypal personality disorder Schizophr. Bull. 41 300 310 24962608
H.W. Thermenos et al. Altered language network activity in young people at familial high-risk for schizophrenia Schizophr. Res. 151 229 237 1:STN:280:DC%2BC2c7hsVKrtQ%3D%3D 24176576 3987706
J. Fridriksson et al. Revealing the dual streams of speech processing Proc. Natl. Acad. Sci. USA 113 15108 15113 1:CAS:528:DC%2BC28XitVyisrjO 27956600 5206517
A. Roelofs A dorsal-pathway account of aphasic language production: the WEAVER++/ARC model Cortex 59 33 48 25128898
L. Palaniyappan Dissecting the neurobiology of linguistic disorganisation and impoverishment in schizophrenia Semin. Cell Dev. Biol. 129 47 60 1:CAS:528:DC%2BB3MXisVKgur3I 34507903
Y. Pan et al. Acute conceptual disorganization in untreated first-episode psychosis: a combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum J. Psychiatry Neurosci. 46 E337 E346 33904669 8327974
