Striatal Functional Hypoconnectivity in Schizophrenia Negative Symptoms: Longitudinal Findings

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Abstract Submission 

Tal Geffen¹, Samyogita Hardikar², Jonathan Smallwood³, Mariia Kaliuzhna⁴, Fabien Carruzzo⁴, Teresa Katthagen¹, Stefan Kaiser⁵, Florian Schlagenhauf^1,6

¹Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Berlin, Germany, ²Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neurology,, Leipzig, Germany, ³Department of Psychology, Queen’s University, Ontario, Canada, ⁴University of Geneva, Clinical and Experimental Psychopathology Laboratory, Faculty of Medicine, Geneva, Switzerland, ⁵Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Basel, Basel, ⁶Bernstein Center for Computational Neuroscience, Berlin, Germany

Tal Geffen  
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Berlin, Germany

Samyogita Hardikar  
Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neurology,
Leipzig, Germany

Jonathan Smallwood  
Department of Psychology, Queen’s University
Ontario, Canada

Mariia Kaliuzhna  
University of Geneva, Clinical and Experimental Psychopathology Laboratory, Faculty of Medicine
Geneva, Switzerland

Fabien Carruzzo  
University of Geneva, Clinical and Experimental Psychopathology Laboratory, Faculty of Medicine
Geneva, Switzerland

Teresa Katthagen  
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Berlin, Germany

Stefan Kaiser  
Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals
Basel, Basel

Florian Schlagenhauf  
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy|Bernstein Center for Computational Neuroscience
Berlin, Germany|Berlin, Germany

Negative symptoms like apathy and diminished expression are persistent challenges in schizophrenia (SZ), with limited treatment options and significant impacts on daily life [1]. Research in this area has been limited, and functional connectivity findings are heterogeneous. SZ is linked to striatal abnormalities, especially in reward and motivation processes [2]. Here we investigate whole-brain connectivity of striatal subregions in schizophrenia patients (SZP) in a longitudinal rsfMRI study across two centers with the aim of discovering striatal connectivity aberrations as potential biomarkers of negative symptoms in SZP.

Participants in the longitudinal study were assessed at baseline (T1) and at three months (T2) with 9.8 minutes rsfMRI, and at nine months (T3) for clinical follow-up, only for SZ patients (SZP). The study was conducted in Berlin and Geneva. Assessments included the Brief Negative Symptom Scale (BNSS; 3) and the Brief Assessment of Cognition in Schizophrenia (BACS; 4). We investigated seed-to-whole brain rsfMRI connectivity using the functional division of the striatum into associative (STR_Asoc: cognition), limbic (STR_Limb: motivation), and sensorimotor (STR_Sens: locomotion) regions [5] via CONN toolbox v.19.c [6]. First (A), we assessed group differences between SZP and controls for all six bilateral striatal seeds. Associations with cognition/negative symptoms were tested with Pearson correlation clusters with significant group differences. Furthermore (B), within the SPZ group, separate group-level GLMs were used with the three negative symptoms sub-scales as independent variables to identify regions relevant for symptoms outside areas displaying group differences. Lastly (C), within SZP we used a GLM to predict negative symptoms at T3 with striatal connectivity measures from T1. The re-test stability of connectivity measures after three months (T2) was assessed using intraclass correlation ICC(2,1) for clusters showing group differences (A) and clusters associated with negative symptoms in SZP (B). FWE correction was used at the cluster and voxel level, and Bonferroni correction for multiple comparisons for the number of seed regions.

SZP with severe psychotic symptoms (PANSS positive > 4) were excluded; all SZP had stable symptoms. 143 participants (77 SZP/66 age, sex, and parental education matched healthy controls, HC) completed rsfMRI. At T2, 111 participants (56 SZP/55 HC) were involved, and 60 SZP completed clinical measures at T3. At T1, 11 clusters showed hypoconnectivity in SPZ compared to HC. Connectivity measures from four of these clusters showed above moderate re-test stability (ICC(2,1)>0.3) over three months, indicating stable hypoconnectivity of STR_Asoc and STR_Sens with frontal, parietal, and cerebellar areas (Fig.1). Notably, hypoconnectivity between bilateral STR_Asoc and the right Superior Frontal Gyrus (SFG_r) [for both seeds: T(139) ≤-5.86, pFWE*6<0.001; ICC(2,1)≥0.44, n=111] correlated positively with cognition in SZP [r(73)=0.26, p=0.03]. Analysis B revealed hypoconnectivity between STR_Sens_r and the right Superior Parietal Lobule (SPL_r) in SZP, associated with stronger BNSS diminished expression severity [T(74)=-5.13, pFWE*18= 0.023; ICC(2,1)=0.32, n=56]. Analysis C showed that connectivity between STR_Sens_r and SPL_r at T1 could predict stronger BNSS diminished expression severity nine months later [T(57)= -3.7, p<0.001] (Fig.2).

Our study aimed to identify robust striatal connectivity aberrations linked to negative symptoms. We found that hypoconnectivity between STR_Sens_r and SPL_r in SZP, related to diminished expression at T1, was stable from T1 to T2 and could predict symptoms nine months later across two centers. This suggests that such a connectivity pattern is worth further investigation as a potential biomarker. Additionally, the association of cognitive and symptom measures with the relevant functional striatal sub-parcels strengthens the validity of our findings.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Emotion and Motivation Other

Connectivity (eg. functional, effective, structural)

fMRI Connectivity and Network Modeling

Task-Independent and Resting-State Analysis ²

Cognition

Computational Neuroscience

FUNCTIONAL MRI

Psychiatric

Schizophrenia

Other - Striatum