Introduction
What is Schizophrenia?
Schizophrenia is a severe mental illness characterized by symptoms along three separate dimensions. People with positive symptoms might have experiences beyond the usual, such as hearing voices, while people experiencing negative symptoms describe a lack of usual experiences, such as a lack of motivation (1). Some people also have cognitive symptoms, leading to difficulties with mental actions needed to master everyday life. In this domain, particularly episodic memory is affected, describing an impaired ability to recall life events (2). Given this wide range of symptoms, it does not come by surprise that schizophrenia is one of the main causes of disability worldwide (3), particularly leading to high rates of unemployment and difficulties in maintaining close social relationships (from here onwards referred to as functioning) (4). To diminish the burden of schizophrenia, it is therefore important to identify factors leading to poor functioning.
A Neurocognitive Model of Schizophrenia?
Negative symptoms directly lead to poorer functioning (5, 6), and are affected by other factors, which, in turn, impacts functioning . For example, social cognition, the ability to process social information in the context of social interactions, leads to poorer functioning by first leading to an increase in negative symptoms (7, 8). Likewise, episodic memory is impaired across all stages of psychosis, from before the onset of symptoms through to enduring stages of the illness (2, 9, 10). Poorer episodic memory performance in females has been shown to lead to poorer functioning by first increasing negative symptoms (11). In addition, this effect of episodic memory on negative symptoms is exerted through  reductions in social cognition (12), establishing a temporal sequence from episodic memory toward social cognition, negative symptoms, and functional outcome. Recent research has further found a possible foundation for this sequence in the brain, by showing that a reduction in connectivity of the hippocampus, a brain region crucial to memory and social cognitive processes, predicts higher negative symptoms, through a reduction of episodic memory (13). Based on this combined literature, we thus hypothesized a model, in which there is a sequential development from hippocampal dysconnectivity to episodic memory, social cognition and negative symptoms, ultimately leading to poorer functional outcome in psychosis. As schizophrenia is further expressed very differently across individuals (14-19) with some showing less severe deficits than others, we hypothesized this development for a subgroup of people diagnosed with schizophrenia only.
Methods
We sampled data from two independent datasets collected at the Douglas Research Centre, Montréal, Canada. 55 individuals with a first-episode psychosis and 53 controls were included from the first dataset, while 108 people with with multi-episode psychosis and 66 controls were included from the second dataset. To then see whether we would be able to identify a sequential development from the brain to functioning in a subgroup of people with schizophrenia, we used a machine-learning algorithm called Subtype and Stage Inference (SuStaIn) (20). SuStaIn can identify groups of individuals based on a similar illness patterns, and was therefore in the unique position to see whether a subgroup of individuals with schizophrenia would first show signs of a reduced connectivity of the hippocampus, followed by impaired episodic memory, poorer social cognition, higher negative symptoms and poorer functioning, while another subgroup would not show such a development. We thus applied z-score SuStaIn to these variables in a sample of people with first-episode psychosis and multi-episode psychosis, as the first implementation, to our knowledge, of SuStaIn in a model of psychiatry that spans the brain, cognition, symptoms and functioning.
Results
SuStaIn identified three subgroups of people with schizophrenia. The first subgroup (Subtype 0) did not show any reductions in hippocampal connectivity, memory, social cognition, functioning or higher symptoms. A second subgroup (Subtype 1) however showed deficits in episodic memory, social cognition and functioning as well as higher negative symptoms, while the third subgroup (Subtype 2) showed reduced hippocampal connectivity and deficits in episodic memory (Figure a). When looking at the temporal development of Subtype 1 and Subtype 2, we saw two different progression patterns. Subtype 1 showed reduced episodic memory first, followed by reductions in social cognition, higher negative symptoms, poorer functioning and then reduced hippocampal connectivity (Figure b). Subtype 2 however showed such a reduction in hippocampal connectivity first, followed by poorer episodic memory, social cognition, functioning and then higher negative symptoms (Figure c).
Note. In a) we see the differences between subtypes, ** indicates that the difference is significant at p < .001, while * indicate that the difference is significant at p < .05. Figures b) and c) show the development of both subtypes over time, with blue squares indicating one z-score deviation from mean values, pink squares indicating two z-score deviations from mean values, and red indicating three z-score deviations from mean values.
Discussion
We saw that individuals with schizophrenia mostly show a development from impaired episodic memory to impaired social cognition, higher negative symptoms and to poorer functioning. Both identified subtypes showed similar behavioural pattern, but the role of the brain was distinct. For most people, hippocampal connectivity follows last. However, a smaller group of people did show a reduction in hippocampal connectivity which preceded those behavioural changes. We thus provide first evidence in favour of our proposed model, and further show how important it is to look at different patient groups within schizophrenia.
While the hippocampus seems to play a central role in leading the disease progression in Subtype 2, there might be other factors responsible for leading the progression in Subtype 1. One possibility stems from the specific way that we measured hippocampal connectivity. While we looked at brain structure, there are other MRI measures which can capture additional types of tissue or even brain activity (13). Such additional measures could potentially reveal that other aspects of the hippocampus lead the disease progression in Subtype 1. The disease pattern in Subtype 1 might also be driven by a different brain region, with the amygdala as a potential candidate, due to its involvement in social cognition and its relationship to negative symptoms in addition to the hippocampus (21, 22).
Our findings are further of particular importance for the characterisation of schizophrenia. We saw that patient with first- and multi-episode psychosis were grouped into the same subtypes, suggesting that their performance on our variables is similar despite their different stages in the progression of schizophrenia. Our work, thus, complements traditional clinical staging models (23) to better characterize the development within each clinical stage. A machine-learning algorithm which models increases and decreases simultaneously, which is more in line with the clinical manifestation of schizophrenia (24), might be even better suited to address our model.
Conclusion
We provide first evidence for a comprehensive disease progression model of psychosis, in which hippocampal dysconnectivity precedes impairments in episodic memory, social cognition, functioning and higher negative symptoms in a subtype of individuals with schizophrenia. Future research should look at different measures of hippocampal connectivity and other brain regions, while considering the fluctuating nature of clinical presentations in psychosis through more sophisticated machine-learning algorithms.
References
1.     American Psychiatric Association. Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). American Psychiatric Association2013.
2.        Heinrichs RW, & Zakzanis, K. K. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12(3):426.
3.        Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017;390(10100):1211-59.
4.        Lepage M, Bodnar, M., & Bowie, C. R. Neurocognition: clinical and functional outcomes in schizophrenia. The Canadian Journal of Psychiatry. 2014;59(1):5-12.
5.        Milev P, Ho B-C, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry. 2005;162(3):495-506.
6.        Devoe DJ, Braun A, Seredynski T, Addington J. Negative symptoms and functioning in youth at risk of psychosis: a systematic review and meta-analysis. Harvard review of psychiatry. 2020;28(6):341.
7.        Kharawala S, Hastedt C, Podhorna J, Shukla H, Kappelhoff B, Harvey PD. The relationship between cognition and functioning in schizophrenia: A semi-systematic review. Schizophrenia Research: Cognition. 2022;27:100217.
8.        Lin CH, Huang, C. L., Chang, Y. C., Chen, P. W., Lin, C. Y., Tsai, G. E., & Lane, H. Y. Clinical symptoms, mainly negative symptoms, mediate the influence of neurocognition and social cognition on functional outcome of schizophrenia. Schizophrenia research. 2013;146(1-3):231-7.
9.        Valli I, Tognin, S., Fusar-Poli, P., & Mechelli, A. Episodic memory dysfunction in individuals at high-risk of psychosis: a systematic review of neuropsychological and neurofunctional studies. Current pharmaceutical design. 2012;18(4)(443-458).
10.      Mesholam-Gately RI, Giuliano, A. J., Goff, K. P., Faraone, S. V., & Seidman, L. J. Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology. 2009;23(3):315.
11.      Buck G, Lavigne, K. M., Makowski, C., Joober, R., Malla, A., & Lepage, M. Sex differences in verbal memory predict functioning through negative symptoms in early psychosis. Schizophrenia bulletin. 2020 46(6):1587-95.
12.      Raucher-Chéné D, Thibaudeau, E., Sauvé, G., Lavigne, K. M., & Lepage, M. Understanding others as a mediator between verbal memory and negative symptoms in schizophrenia-spectrum disorder. Journal of Psychiatric Research. 2021;143:429-35.
13.      Makowski C, Lewis JD, Khundrakpam B, Tardif CL, Palaniyappan L, Joober R, et al. Altered hippocampal centrality and dynamic anatomical covariance of intracortical microstructure in first episode psychosis. Hippocampus. 2020;30(10):1058-72.
14.      Green MF, Bearden CE, Cannon TD, Fiske AP, Hellemann GS, Horan WP, et al. Social cognition in schizophrenia, part 1: performance across phase of illness. Schizophrenia bulletin. 2012;38(4):854-64.
15.      Rocca P, Galderisi S, Rossi A, Bertolino A, Rucci P, Gibertoni D, et al. Social cognition in people with schizophrenia: a cluster-analytic approach. Psychological Medicine. 2016;46(13):2717-29.
16.      Strauss GP, Horan WP, Kirkpatrick B, Fischer BA, Keller WR, Miski P, et al. Deconstructing negative symptoms of schizophrenia: avolition–apathy and diminished expression clusters predict clinical presentation and functional outcome. Journal of psychiatric research. 2013;47(6):783-90.
17.      Sauvé G, Malla A, Joober R, Brodeur MB, Lepage M. Comparing cognitive clusters across first-and multiple-episode of psychosis. Psychiatry Research. 2018;269:707-18.
18.      Uren J, Cotton SM, Killackey E, Saling MM, Allott K. Cognitive clusters in first-episode psychosis: Overlap with healthy controls and relationship to concurrent and prospective symptoms and functioning. Neuropsychology. 2017;31(7):787.
19.      Lewandowski K, Sperry S, Cohen B, Öngür D. Cognitive variability in psychotic disorders: a cross-diagnostic cluster analysis. Psychological medicine. 2014;44(15):3239-48.
20.      Young AL, Marinescu, R. V., Oxtoby, N. P., Bocchetta, M., Yong, K., Firth, N. C., … & Alexander, D. C. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference. Nature communications. 2018;9(1):1-16.
21.      Guimond S, Mothi SS, Makowski C, Chakravarty MM, Keshavan MS. Altered amygdala shape trajectories and emotion recognition in youth at familial high risk of schizophrenia who develop psychosis. Translational Psychiatry. 2022;12(1):1-8.
22.      Makowski C, Bodnar M, Shenker J, Malla A, Joober R, Chakravarty M, et al. Linking persistent negative symptoms to amygdala–hippocampus structure in first-episode psychosis. Translational Psychiatry. 2017;7(8):e1195-e.
23.      McGorry PD, Purcell R, Hickie IB, Yung AR, Pantelis C, Jackson HJ. Clinical staging: a heuristic model for psychiatry and youth mental health. Medical Journal of Australia. 2007;187(S7):S40-S2.
24.      Ventura J, Subotnik KL, Gitlin MJ, Gretchen-Doorly D, Ered A, Villa KF, et al. Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later. Schizophrenia Research. 2015;161(2-3):407-13.