Functional Connectivity Changes in the Prefrontal-thalamic- cerebellar Circuit in Adolescents with First-Episode Schizophrenia

doi:10.21203/rs.3.rs-4964386/v1

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Functional Connectivity Changes in the Prefrontal-thalamic- cerebellar Circuit in Adolescents with First-Episode Schizophrenia

https://doi.org/10.21203/rs.3.rs-4964386/v1

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Background

The role of functional connectivity (FC) changes in the prefrontal-thalamic-cerebellar circuit in schizophrenia has received widespread attention. Currently, domestic and international studies on this circuit have focused on adults, while the FC of this circuit in the brains of adolescent patients with schizophrenia (AOS) has been less reported.

Methods

We recruited 124 subjects who underwent resting-state functional magnetic resonance imaging scans at baseline, using key brain regions in the prefrontal-thalamic-cerebellar circuit as seed regions, to investigate the FC in AOS versus healthy controls. The FC of this loop was compared with that of the whole brain in healthy controls.

Results

Compared to healthy controls, patients with AOS had reduced FC between the medial prefrontal cortex (mPFC) and precuneus and between the posterior cerebellar lobe and middle temporal gyrus. Reduced FC in patients with AOS was associated with positive symptom scores and with some cognitive scales.

Conclusions

There are FC abnormalities in the prefrontal-thalamic-cerebellar circuit, precuneus, and temporal lobe in AOS. These abnormalities appear in the early stages of schizophrenia, independent of medication, and are characteristic of the disorder.

Prefrontal-thalamus-cerebellum circuit

Functional connectivity

Early-onset adolescent schizophrenia

Cognitive function

Schizophrenia(SZ) is one of the most common psychiatric disorders seen in clinical practice. As a disabling illness that often lasts for long periods of time, SZ severely affects the quality of life of patients and their families and adversely affects the social environment and the health care system(1), making it a serious global public health problem. There are several hypotheses to explain the etiology of SZ, among which the neurodevelopmental disorder hypothesis is more widely accepted. Therefore, studies of functional brain activity may be more helpful in elucidating the etiology and pathogenesis of SZ.

The neurodevelopmental disorder hypothesis proposes that abnormal neurodevelopment resulting from combinations of multiple genetic risk loci leads to early synaptic structural alterations, which may result in abnormal information processing and thus increased susceptibility to SZ(2). A neurodevelopmental model refined on this basis has since shown that dysregulation of inflammation and immune responses can lead to abnormal proliferation or differentiation of nerves, resulting in excessive pruning of synapses, which impairs synaptic plasticity and myelin sheath formation, and thus brain development(3). This model is supported by evidence of excessive synaptic pruning in some early childhood patients with SZ, such as the presence of reduced prefrontal gray matter volume, segregation of the occipital cortex and reduced neuronal numbers, and diminished connectivity in various regions of the brain(4,5), and thus abnormal neurodevelopment may be correlated with the prevalence of SZ.

Many studies have reported abnormal cerebral blood flow in the prefrontal-thalamic-cerebellar circuit in patients with SZ(6). Although brain networks show activation of the prefrontal-thalamic-cerebellar circuit in recall tasks, patients with SZ show abnormal activation(7). Subsequently, studies of patients with SZ in the early stages of the disease demonstrated imbalances in prefrontal, cerebellar, and thalamic distributions of cortical and subcortical circuits(8). Since then, a large number of neuroimaging studies have provided extensive support for this view, suggesting that abnormalities in the prefrontal-thalamic-cerebellar circuit play an important role in the pathogenesis of SZ(9,10). Whereas anatomically the cerebellum and prefrontal cortex are connected in a bidirectional manner(8), the thalamus receives signals from the cerebellum, sends inputs and projections to the prefrontal cortex, and then signals are returned to the cerebellum through the pontine nuclei of the brainstem, forming a closed loop(11).

Functional magnetic resonance imaging (fMRI) is an important tool for exploring brain functions(12). Assessment of functional connectivity (FC) is the most established method for studying the activity of brain regions, which reveals the FC between different brain regions by measuring the correlation between them. Networks are a hot topic in fMRI research. These correspond to different regions in the brain and are closely related to each other. Altered FC between brain networks may be an important pathological mechanism in SZ(13,14) and may also explain the occurrence of psychotic symptoms in SZ(15). Adolescent SZ, as a specific subtype,

is important for studying brain network connectivity in SZ. However, current fMRI studies in adolescent SZ have failed to elucidate the causal relationship between specific interactions in brain networks associated with the prefrontal-thalamic-cerebellar circuit and adolescent SZ.

In previous studies of patients with SZ, dysfunction of the prefrontal-thalamic-cerebellar circuit has been suggested to potentially affect patients' social activities as well as their ability to learn and work. However, more studies have focused on chronic and medicated patients with SZ, but medication and long-term disease progression may introduce many confounding factors, leading to a lack of reliability in the final results. Therefore, we propose the hypothesis that patients with SZ have abnormal FC between the prefrontal-thalamic-cerebellar loop and the whole brain, which is considered to be a characteristic manifestation of the disease, appearing early in the course of SZ, independent of medication.

Study subjects

A total of 124 participants were recruited to this study, including 60 newly diagnosed untreated adolescents with SZ from the Department of Psychiatry of the Second Affiliated Hospital of Xinxiang Medical University as the patient group, and 64 adolescent volunteers from multiple communities in Xinxiang City as the healthy control (HC) group. Screening was based on inclusion and exclusion criteria, and general information and fMRI data were collected. Both groups were evaluated for cognitive status using the MATRICS Consensus Cognitive Battery (MCCB) scale. For patients with early-onset SZ, the severity of mental symptoms was evaluated using the Positive and Negative Symptom Scale (PANSS).

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical College. The subjects and their families were consented by an informed consent process that was reviewed by the Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical College.and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki.The subjects and their families were provided with detailed information about the research purpose, methods, and potential risks, and were informed that they could terminate their participation at any time if they felt uncomfortable during the study period.

Image acquisition

A 3.0T MR machine (Siemens Medical Systems, Erlangen, Germany) was used to perform MR scans on all participants to acquire imaging data. A gradient echo planar imaging (EPI) sequence was used for resting-state MRI data acquisition with a scan time of 4.8 × 105 ms. The acquisition parameters were as follows: repetition time/echo time (TR/TE): 2000/30 ms, matrix: 64 × 64, number of layers: 33, layer interval: 0.6 mm, the field of view: 220×220 mm2, flip angle: 90°, number of acquisitions: 240, voxel size: 3.44 × 3.44 × 4 mm3.

fMRI preprocessing

On the Matlab R2015b (Mathworks, Natick, MA, USA) platform, DPABI software (16)was used for fMRI data preprocessing (Chao Gan&Yu Feng, 2010). Raw data files were converted from DICOM format to NIFTI format. The imaging data from the first 5 time points were discarded. The remaining 235-time points of data were processed during the next step of testing. The middle layer was used as the standard to perform time correction on the scanned images at each time point. Data with head movement greater than 2 mm or a rotation angle greater than 2° in any direction for head movement correction were discarded. Using the EPI template as the standard, in the Montreal Neurological Institute (MNI) space, images of all subjects were analyzed using 3 × 3 × 3 mm3 voxels resampling. The 6 mm full width at half peak (FWHM) Gaussian smoothing was used to check the image for spatial smoothing. A de-linear trend was performed. Regression covariance analysis was then performed on Friston-24 motion parameters, cerebrospinal fluid, white matter signal, and other inner ear interference signals. Other spectral interferences were excluded using 0.01‒0.1 Hz band-pass filtering.

FC analysis

As described in previous studies(17,18), three regions along the prefrontal-thalamic-cerebellar circuit loop, each with a radius of 3 mm, were defined as the seed regions for FC analysis (see Table 1). Pearson correlation coefficients (r values) between these eight seed regions and whole brain voxels were calculated and then converted to z values using the Fisher transform.

Table 1

Seed sites in the prefrontal-thalamic-cerebellar circuit
Cluster Location	MNI coordinate
Cluster Location	x	y	z
Left Medial prefrontal cortex	10	40	−2
Right Medial prefrontal cortex	0	50	2
Left Thalamus	-3.5	-23	4.5
Right Thalamus	4	-24	9
Left cerebellum (inferior semi-lunar Lobule)	-6	-76	-43
Right cerebellum (inferior semi-lunar Lobule)	9	75	43
Left cerebellum(Posterior)	-32	-79	-31
Right cerebellum(Posterior)	29	78	32

Statistical analysis

The FC analysis was performed on the pre-processed images using DPABI software to derive FC between the region of interest and the whole brain. Demographic data and cognitive functions of the two groups of subjects were analyzed using SPSS 26 software. A t-test was performed on the FC results from the two groups of subjects using SPM8 software. (Age and gender were excluded as covariates. Mean FD was excluded. The GRF method was used to correct the results.) The relationship between PANSS scores and cognitive test scores and FC of brain areas in early-onset adolescent SZ patients was analyzed using RESTplus software. FC values were correlated with clinical symptom scores and cognitive function scores in the patient group by Pearson correlation coefficients. The sensitivity and specificity of the FC results obtained were analyzed using subject working characteristic curves.

Demographic and clinical characteristics

A total of 60 patients with early-onset SZ (AOS) and 64 HCs were recruited to this study. Ten patients and four HCs were excluded due to excessive head movements (head movement translation > 2 mm and/or head rotation movement > 2°) during MRI scanning, and two other patients were also excluded due to incomplete data. Therefore, 48 were included in the AOS group and 60 in the HC group to complete the study. The differences between the two groups in terms of gender and education were not statistically significant (P > 0.05), but the differences in terms of age were statistically significant (P = 0.006, P < 0.05), as shown in Table 2.

FC between two groups

The FC of the left mPFC with the left and right precuneus (PCu) was significantly reduced in the AOS compared to the HC group. The right mPFC was significantly different from the right PCu in HCs. When the right posterior cerebellar lobe was used as the region of interest, there was a significant reduction in FC with the right mPFC in the AOS compared to the HC group (voxel level, P < 0.001, cluster level, P < 0.05, GRF corrected) (see Table 2 and Fig. 1).

Table 2

**Subjects' basic information and clinical characteristics**
	AOS(n = 48)	HC(n = 60)	t/X²	P
Age (year)	14.77 ± 14.77	15.70 ± 1.465	2.828	0.006
Sex (M/F)	17/31	18/42	0.357	0.554
Education(year)	8.85 ± 2.212	9.23 ± 1.663	0.994	0.322
Duration of the illness (month)	5.05 ± 5.515	-	-	-
PANSS, positive score	23.08 ± 5.57	-	-	-
PANSS, negative score	22.52 ± 6.75	-	-	-
PANSS, general score	38.08 ± 7.82	-	-	-
PANSS, total score	85.62 ± 14.55	-	-	-
Note: AOS refers to adolescent patients with SZ; HC refers to healthy controls; PANSS refers to positive and negative symptom scales.

Table 3

FC differences between the two groups
Anatomical regions	Voxel	Peak (MNI)			t value
Anatomical regions	Voxel	X	Y	Z	t value
Decreased in patients with AOS
L Precuneusa	15	-12	-54	48	-3.9103
R Precuneusa	62	6	-57	48	-4.8174
R Precuneusb	19	6	-57	45	-4.6201
R TemPoral-Midc	63	-6	-15	12	-4.1752
Note: a Left medial prefrontal cortex (mPFC) seed regions; b Right medial prefrontal cortex (mPFC) seed regions; c Right posterior cerebellar seed region; voxel level P < 0.001; cluster significance: P < 0.05, corrected. MNI, Montreal Neurological Institute. L, Left; R, Right.

Relationship between brain function and psychopathology

Correlations between FC and PANSS scores in the AOS group were analyzed to evaluate the relationship between symptoms and brain function. Positive symptoms on the PANSS scale were negatively correlated when the seeds were located in the left mPFC (r=-0.286, P = 0.048; see Fig. 2). There was no significant correlation between other FC and PANSS total or subscale scores in the patient group (P > 0.05).

Relationship between brain function and cognition

FC between the left mPFC and left PCu in the AOS group was positively correlated with the Symbolic Encoding Scale (r = 0.316, P = 0.029), the Maze Scale (r = 0.309, P = 0.033), and the Category Fluency Test Scale (P = 0.285, P = 0.050). FC between the right posterior cerebellar lobe and the right middle temporal gyrus was positively correlated with the simple visuospatial memory test (BVMT) (r = 0.355, P = 0.013; see Fig. 3).

Subject characteristic curve analysis

According to the FC results, the ROC curve of four variables was plotted. The results showed that the area under the curve of the left mPFC and the right anterior cuneiform lobe was 0.852, with sensitivity (68.33%) and specificity (91.67%). The area under the curve of the left mPFC and the right anterior cuneiform lobe was relatively high, which had the best diagnostic value (see Fig. 4).

In this study, we explored the issue of abnormal FC in the prefrontal-thalamic-cerebellar loop in AOS and correlations with symptoms and cognition. Compared with HCs, in the AOS group brain regions involved in abnormal loop connections mainly included temporal and cuneiform regions, with abnormal FC in the left medial prefrontal and right anterior PCu being sensitive indicators. In addition, we observed a correlation between positive symptoms of SZ, cognitive decline, and abnormal loop connections. This suggests that the early onset of SZ is closely related to the dysfunction of brain networks.

Our observation of reduced FC from the right posterior cerebellar lobe to the right middle temporal gyrus in the AOS group provides a new basis for impaired brain network connectivity early in the pathogenesis. The temporal lobe is the main region of the brain that processes auditory information and is associated with memory and emotion. In patients with SZ, changes in brain activity in the temporal lobe region have been well documented. In the early stages of the disease, there is a significant reduction in the perfusion of gray matter structures in the temporal cortex(19). There are also abnormalities in gray matter volume and structure in the temporal lobe(20). Mwansisya et al. analyzed whole brain FC in the resting state and there were significant abnormalities in the brain connectivity of the inferior temporal gyrus(21). In a study of low frequency fluctuation amplitude (ALFF) in patients with SZ, elevated ALFF was seen in the temporal lobe(22). As research has evolved, abnormal FC from the left temporal lobe to the prefrontal and cerebellar lobes has been proposed in patients with SZ(23). This is partially consistent with the results of the present study, but the results of the present study still support the hypothesis of neurodevelopmental disorders in SZ, adding further to the hypothesis. The inconsistent consideration of the results may be related to the difficulty in identifying the exact time point of developmental changes in a single cross-sectional study.

We also found functional breaks in the PCu in the patient group. The PCu is a key region of the resting default mode network (DMN). Early imaging studies have shown that the PCu/posterior cingulate cortex (PCC) plays an important role in cognitive activities related to self-processing(24). Franson et al. found that the PCu/PCC may be the only node in the resting default network that interacts directly with other nodes(25). Together with the PCC, the PCu plays an important role in collecting and distributing information, has the greatest metabolic activity at rest, and is also implicated in consciousness and short-term memory recall(26). Animal studies have demonstrated the importance of the PCu for environmental orientation(27). Previous studies have shown reduced FC between the prefrontal lobes and the Pcu in people at genetic risk for SZ(28). Connectivity between prefrontal regions and the PCu is also impaired in adults with SZ(28,29). This is consistent with the conclusion reached in the present study that this loop is associated with reduced FC to PCu in patients with SZ. Some studies have also shown that FC with PCu is increased in this loop(23). In addition, some studies have reported that the PCu in the DMN has abnormally high FC at rest(30,31), both of which were found in the studies by Mingoia(32) and Ongur et al(33). Despite the differences in findings, most studies support the neurodevelopmental disorder hypothesis. Thus, disruption of the PCu prefrontal-thalamic-cerebellar loop connections early in the disease may be a qualitative problem in SZ, and the PCu has an important role in the pathogenesis of SZ(34).

Alterations in resting-state brain activity(35) in patients with SZ, such as abnormalities in spontaneous neural activity or altered FC, are strongly associated with deficits in clinical symptoms(36). Increased connectivity in the PCu is associated with memory and self-perception processes(37). Consistent with our findings that positive symptom scale scores in the AOS group were associated with dysfunctional connectivity between the prefrontal-thalamic-cerebellar circuit loops and the PCu, the abnormal neural activity in the PCu may contribute to early clinical symptoms and may play an important role in disease progression in patients with SZ. Moreover, the pathomechanisms of SZ in adolescents may be associated with the prefrontal-thalamic-cerebellar circuit loops, and PCu FC is related. Meanwhile, under the characteristic curve analysis, we concluded that the relatively high areas under the curves of the left medial mPFC and the right PCu have the best diagnostic value and can be used as an entry point for the early diagnosis of SZ.

Cognitive dysfunction is an unavoidable clinical manifestation in patients with SZ and can be observed even in the early stages of the disease or when there are mild psychotic symptoms. Our study found that patients with AOS scored differently from controls on all six cognitive tests, except for the domain fluency test, and these differences were statistically significant. Patients with AOS showed significant cognitive deficits on several test items, and patients had extensive cognitive dysfunction in the primary stages of the disease, a finding that is consistent with previous studies(38–40).

Temporal lobe damage is strongly associated with memory loss. A previous study found that neurophysiological interactions between the right PCC and other brain regions in a word fluency task were concentrated in the temporal lobe in the normal group, whereas diffuse interactions were found in patients with SZ(41). Altered temporal lobe FC in patients with SZ is closely related to cognitive activity(42). Our study further validates the finding that impaired temporal lobe FC in patients with SZ correlates with the presence of memory. The PCC is involved in introspection and memory, and impaired FC is associated with situational memory processes(43). The maze test is commonly used to assess subjects' executive function and inhibitory interference(44), and executive control is usually more impaired in patients with SZ than in other functions(45), so the maze test may provide a clearer assessment of impaired abilities in patients with SZ. Our study found a significant correlation between the maze test and impaired PCC FC in patients with AOS, and thus, impaired PCC FC in patients with AOS is associated with impaired executive function. However, a large-sample study in 2018 assessed cognitive functioning in patients with SZ by means of the MCCB scale, which showed that environmental and genetic factors also have an impact on cognitive functioning in patients with SZ(46). Therefore, we researchers need to rule out the influence of other factors based on these studies when conducting research on brain function.

There are several limitations to the current study; the inclusion criteria for this study did not have a gender restriction, but no definitive conclusions have been drawn as to whether the pathogenesis of AOS is related to gender factors. Future research needs to add separate studies of male or female patients to further fill these gaps. In addition, whether the impaired connectivity of frontal anterior thalamic-cerebellar circuits in AOS is a specific early manifestation of SZ needs to be followed up. In addition, small sample sizes, many confounding factors, and studies involving only cross-sections may have some implications.

In medication naïve patients with SZ, abnormal FC of the prefrontal-thalamic-cerebellar loop with the PCu and temporal lobes is not associated with medication and is a characteristic manifestation of the disease. At the same time, dysfunctional connectivity of the PCC in AOS correlates with clinical psychiatric symptoms. The abnormal FC between the left mPFC and the right PCu has high diagnostic value in SZ, and whether it can be used as a biomarker in the early stage of SZ disease needs to be further explored in future studies.

Ethical Approval

Competing interests

The authors have no competing interests or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Fundind

This study was supported by grants from the National Natural Science Foundation of China (to LX-L: U22A20304; to WQ-L: 82171498), the Natural Science Foundation of Henan Province (to YZ: 202300410318;), the Science and Technology Research Project of Henan Province (to YZ: 242102310026), the Medical Science and Technology Research Project of Henan Province (to YZ: LHGJ20190479; to HS: LHGJ20210543), the Key Laboratory of Biological Psychiatry of Henan Province (to YZ: ZDSYS2020003), Key Research and Development Projects of Henan Province (241111312800 to WL).

Author Contribution

YCS: Data curation, Formal analysis, Visualization, Writing – original draft. HYZ: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. ZYW and WYH: Data curation, Formal analysis, Visualization. YQZ: Formal analysis, Methodology, Visualization. SZ: Conceptualization, Methodology. YP: Data curation, Formal analysis, ethodology. HS and GY: Formal analysis, Supervision, Visualization. HS: Data curation, Project administration. YFY: Resources, Supervision. WQL: Supervision, Visualization, Funding acquisition.YZ: Conceptualization, ethodology, Supervision, Writing – review & editing. LXL: Conceptualization, Methodology, Funding acquisition.All authors reviewed the manuscript.

Acknowledgement

The authors thank the patients, their families, and the healthy volunteers for their participation, as well as the physicians and technicians who helped us collect clinical data in the Second Affiliated Hospital of Xinxiang Medical University. We thank the International Science Editing (http://www.internationalscienceediting.com) for editing our manuscript. The authors have declared that there are no conflicts of interest in relation to the subject of this study.All experimental protocols were approved by the designated agency and/or licensing board. Confirm that informed consent has been obtained from all subjects and/or their legal guardians.

Availability of data and materials

This manuscript does not report data generation or analysis.

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Functional Connectivity Changes in the Prefrontal-thalamic- cerebellar Circuit in Adolescents with First-Episode Schizophrenia

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Abstract

Background

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Results

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Background

Methods

Study subjects

Image acquisition

fMRI preprocessing

FC analysis

Statistical analysis

Results

Demographic and clinical characteristics

FC between two groups

Relationship between brain function and psychopathology

Relationship between brain function and cognition

Subject characteristic curve analysis

Discussion

Conclusion

Declarations

Ethical Approval

Competing interests

Fundind

Author Contribution

Acknowledgement

Availability of data and materials

References

Additional Declarations

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