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Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age = 32.50, male = 21, female = 13) and 30 subjects with schizophrenia (mean age = 33.07, male = 19, female = 11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60) = 21.19, p < 0.0001). MMP9 levels correlated with negative symptoms in patients (R = 0.39, p = 0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59) = 9.12, p = 0.0040) and right (F(1,59) = 6.49, p = 0.013) hippocampal volumes. Finally, left (R = -0.39, p = 0.034) and right (R = -0.37, p = 0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

Although white matter hyperintensities (WMHs) are quite commonly found incidentally, their aetiology, structural characteristics, and functional consequences are not entirely known. The purpose of this study was to quantify WMHs in a sample of young, neurologically asymptomatic adults and evaluate the structural and functional correlations of lesion load with changes in brain volume, diffusivity, and functional connectivity. MRI brain scan using multimodal protocol was performed in 60 neurologically asymptomatic volunteers (21 men, 39 women, mean age 34.5 years). WMHs were manually segmented in 3D FLAIR images and counted automatically. The number and volume of WMHs were correlated with brain volume, resting-state functional MRI (rs-fMRI), and diffusion tensor imaging (DTI) data. Diffusion parameters measured within WMHs and normally appearing white matter (NAWM) were compared. At least 1 lesion was found in 40 (67%) subjects, median incidence was 1 lesion (interquartile range [IQR] = 4.5), and median volume was 86.82 (IQR = 227.23) mm3. Neither number nor volume of WMHs correlated significantly with total brain volume or volumes of white and grey matter. Mean diffusivity values within WMHs were significantly higher compared with those for NAWM, but none of the diffusion parameters of NAWM were significantly correlated with WMH load. Both the number and volume of WMHs were correlated with the changes of functional connectivity between several regions of the brain, mostly decreased connectivity of the cerebellum. WMHs are commonly found even in young, neurologically asymptomatic adults. Their presence is not associated with brain atrophy or global changes of diffusivity, but the increasing number and volume of these lesions correlate with changes of brain connectivity, and especially that of the cerebellum. • White matter hyperintensities (WMHs) are commonly found in young, neurologically asymptomatic adults. • The presence of WMHs is not associated with brain atrophy or global changes of white matter diffusivity. • The increasing number and volume of WMHs correlate with changes of brain connectivity, and especially with that of the cerebellum.

Background Schizophrenia (SCZ) is a severe and chronic brain disorder that affects about 1% of the world population. It is among the most burdensome illnesses with a serious impact on patients, their families and society. To this day, a lot remains unknown about the neuropathological cause and etiology of SCZ. The prominent two-hit theory postulates that early neurodevelopmental abnormalities interact with a later “second hit” which occurs around symptom onset. Recent research points towards the role of inflammation in pathophysiology of schizophrenia. Matrix metalloproteinase-9 (MMP-9) was recently suggested as a potential key player in both first and second “hit” in the pathology of SCZ. It is considered to not only regulate brain development and synaptic plasticity, but to also mediate neuroinflammation. A point of interest for interaction with neuroinflammatory pathways is the Choroid Plexus (ChP). MMP-9 has been reported to be upregulated in ChP in SCZ. Since ChP regulates CSF production and permeability of the blood-CSF-barrier, MMP-9 upregulation in ChP might lead to its enlargement, as well as enlargement of the lateral ventricles and increased extracellular water volume, all found previously in SCZ. We investigate, for the first time, the relationship between MMP-9 blood plasma concentration and volume of ChP in patients with SCZ compared to healthy controls (HC). Methods We included 66 subjects (25 female = 38%, 41 male = 62%, mean age 32.59 +/- 9.14 years); 32 were patients with SCZ, 34 were HC. ELISA analysis was performed to measure MMP-9 blood concentrations in patients and HC. A whole brain, high-resolution three-dimensional T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence scan was used to collect 240 sagittal slices, field of view = 224 x 224 mm2, 1 mm3 isotropic voxel, TR = 2.3 s, TE = 2.33 ms, flip angle = 8° on a 3T Siemens Magnetom Prisma. Structural T1 images underwent visual quality control, were realigned and parcellated into 176 gray and white matter regions using FreeSurfer software. Preliminary analyses were conducted comparing 1) MMP-9 levels between groups and 2) relating MMP-9 levels to ChP volume utilizing regression analyses. Results Patients with SCZ showed a strong upregulation of MMP-9 compared to HC (patients: 120 ± 60 ng/ml; HC: 60 ± 40 ng/ml; p < 0.0001). Furthermore, linear regression analyses - corrected for age and sex - demonstrated a positive association between concentration of MMP-9 and ChP volumes (left: R2 = .095, p < .01; right: R2 = .084, p < .02). Discussion To our knowledge, our study is the first to present preliminary evidence of an association between brain structure and MMP-9 peripheral upregulation in SCZ. Advanced evaluation of MMP-9 might enhance our understanding of illness cause, enable outcome predictions and paint the way for more individualized psychopharmacotherapy, as MMP-9 might serve as potential pharmacological target. However, further analyses are needed to validate our findings using as neuroanatomically precise methods as possible and to develop MMP-9 biomarkers that would capture central, as opposed to peripheral levels of MMP-9.

Abnormalities in both time processing and dopamine (DA) neurotransmission have been observed in schizophrenia. Time processing seems to be linked to DA neurotransmission. The cognitive dysmetria hypothesis postulates that psychosis might be a manifestation of the loss of coordination of mental processes due to impaired timing. The objective of the present study was to analyze timing abilities and their corresponding functional neuroanatomy in schizophrenia. We performed a functional magnetic resonance imaging (fMRI) study using a predictive motor timing paradigm in 28 schizophrenia patients and 27 matched healthy controls (HC). The schizophrenia patients showed accelerated time processing compared to HC; the amount of the acceleration positively correlated with the degree of positive psychotic symptoms and negatively correlated with antipsychotic dose. This dysfunctional predictive timing was associated with BOLD signal activity alterations in several brain networks, especially those previously described as timing networks (basal ganglia, cerebellum, SMA, and insula) and reward networks (hippocampus, amygdala, and NAcc). BOLD signal activity in the cerebellar vermis was negatively associated with accelerated time processing. Several lines of evidence suggest a direct link between DA transmission and the cerebellar vermis that could explain their relevance for the neurobiology of schizophrenia.

Patients with schizophrenia (SCH) often demonstrate impairment in social-cognitive functions as well as disturbances in large-scale network connectivity. The ventromedial prefrontal cortex (vmPFC) is a core region of the default mode network, with projections to limbic structures. It plays an important role in social and emotional decision-making. We investigated whether resting-state functional connectivity (FC) relates to the cognitive and affective domains of theory of mind (ToM). Twenty-three SCH patients and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging scanning. vmPFC seed connectivity was correlated with behavioral measures assessing ToM domains. SCH performed less well than HCs in both ToM task domains. An analysis of the resting-state FC revealed that SCH had reduced connectivity from the vmPFC to the subcallosal cortex, right amygdala, and right hippocampus as a function of behavioral scores in both ToM domains. Within-group analyses indicated that in HCs, the performance in ToM was positively associated with frontoamygdalar resting-state connectivity, whereas in SCH, the performance in ToM was negatively associated with the frontosubcallosal connectivity. Differences in the pattern of the resting-state frontolimbic connectivity and its associations with performance in ToM tasks between the two study groups might represent a different setup for processing social information in patients with SCH.

Time perception is an essential part of our everyday lives, in both the prospective and the retrospective domains. However, our knowledge of temporal processing is mainly limited to the networks responsible for comparing or maintaining specific intervals or frequencies. In the presented fMRI study, we sought to characterize the neural nodes engaged specifically in predictive temporal analysis, the estimation of the future position of an object with varying movement parameters, and the contingent neuroanatomical signature of differences in behavioral performance between genders. The established dominant cerebellar engagement offers novel evidence in favor of a pivotal role of this structure in predictive short-term timing, overshadowing the basal ganglia reported together with the frontal cortex as dominant in retrospective temporal processing in the subsecond spectrum. Furthermore, we discovered lower performance in this task and massively increased cerebellar activity in women compared to men, indicative of strategy differences between the genders. This promotes the view that predictive temporal computing utilizes comparable structures in the retrospective timing processes, but with a definite dominance of the cerebellum.