Global and Specific Cortical Volume Asymmetries in Individuals With Psychosis Risk Syndrome and Schizophrenia: A Mixed Cross-sectional and Longitudinal Perspective

Abstract

Cortical volumetric asymmetry (CVA) has been widely observed in individuals with psychosis, and is associated with etiological risk factors (e.g., genetics, neuromaturation) and treatment response. However, it is unclear whether CVA abnormalities emerge before psychotic illness onset. Understanding whether CVA manifests in clinical high-risk (CHR)—compared with healthy controls and schizophrenia patients (SCZ)—over time may inform our understanding of pathogenic factors. A total of 233 individuals: 73 CHR, 112 healthy controls, and 48 SCZ underwent an MRI and clinical interviews. Ninety-four individuals including healthy volunteers (HV) (n = 49) and CHR (n = 45), completed another scan at 12-months. CVA was compared by lobe in a repeated-measure design across groups, then nested by time in a longitudinal model. CHR and SCZ groups showed reduced global CVA compared with the healthy control groups but the CHR and SCZ group did not differ from each other. A group by lobe interaction indicated the presence of lobe specific reductions in frontal and cingulate CVA. Cingulate CVA was reduced in CHR and SCZ groups compared to HC groups but did not differ from each other. Frontal CVA was reduced in the older healthy controls compared with younger-HC and CHR, but did not differ from the similarly aged SZ group. CVA is similarly impacted in SCZ and CHR groups, potentially reflecting pathogenic processes. Longitudinal analyses provided further support for the neurodevelopmental hypothesis as CHR exhibited longitudinal changes in opposite directions from normative neuromaturation in HV, which was related to increasing risk for psychosis in the CHR.

Introduction

Cortical volumetric asymmetry (CVA) is widely observed in healthy neuromaturation and may reflect the rapid growth of frontal lobe and left lateralized temporal language areas during evolution in humans.^1,2 Theoretically, rapid growth in specific brain regions leads to widespread, general cortical asymmetry as other areas must accommodate or make room for this rapid growth.^1,3 As a result, asymmetries of particular regions are thought to reflect the development of functional localization such as language development, motor development, or handedness, while a general difference in CVA is thought to reflect the competing forces of expansion within a limited space over development.^1,4,5 As a result, individual differences in CVA may reflect alterations in neuromaturation.^1,4,5

In typical human neurodevelopment, CVA also appears to be influenced by hormones during adolescent neuromaturation^1,4,5 and during healthy aging processes.⁶ Given these competing influences, variability in CVA may reflect the cumulative influence of genetics, and abnormal developmental events that are relevant to psychosis vulnerability.^1,4,5,7 Taken together, the relationship between psychosis and CVA abnormalities are consistent with evidence that genetics, hormones, and deviations in early neuromaturation are involved in the etiology of this disorder.^8–10

Individuals with both first-episode and chronic psychosis have shown abnormalities in CVA, defined by a reduced rightward anterior bias and reduced leftward posterior bias cortically.^8–18 In addition to global CVA differences, psychosis is associated with regional differences in CVA.^19,20 This specificity is especially true in subcortical volume asymmetry; psychosis relates to increased rightward bias in amygdala and hippocampus and increased leftward bias in the lateral ventricle.^19,20 This CVA specificity may reflect specific alterations in neural endophenotypes or altered neural connectivity.

CVA may also be sensitive to critical etiological processes in psychosis.²¹ CVA has been related to symptom severity.^22,23 Despite the developmental influences over CVA,⁶ much of the work exploring CVA in psychosis depends on a single timepoint.²¹ Studies that included multiple clinical timepoints, however, found that frontal CVA predicted treatment response to both medication²⁴ and cognitive behavioral therapy.²³ These features highlight the potential for CVA to improve early detection of psychosis, illuminate etiological processes, and identify targets for treatments to likely responders.^23,24

To address this gap in the literature, the current article will examine multiple timepoints. In addition to multiple timepoints, the current article evaluates individuals with low/trait level psychosis vulnerability that, rather than reflecting a disease stage per se, may also illuminate the sensitivity of CVA to accumulating psychosis risk factors when compared with individuals with a psychosis diagnosis. Extant research suggests that reduced CVA reflects the early influence of psychosis risk genes over healthy neuromaturation.^13,15,19,20 However, genetic high-risk (GHR) studies have found both no CVA difference^25,26 and psychosis-like CVA reduction.^15,20,27 Other work on CVA suggests that cortical volumes are sensitive to a culmination of risk, including hormonal and neuromaturational factors,^1,4,6,8–10 that also confer additional vulnerability in addition to genetic risk.^25,26 Furthermore, cortical volume becomes more abnormal as symptom severity increases in early psychosis; ²⁶ as a result individuals who are asymptomatic may obscure the relevance of CVA to pathogenic processes in psychosis.

Unfortunately, less work has focused on CVA in individuals at clinical high-risk for psychosis (CHR), a phenotype that is related to a low-end trait vulnerability for psychosis, where individuals show attenuated positive symptoms and accompanying functional impairment. The few studies that have examined CVA in individuals at CHR have focused on specific CVA in regions of interest, including anterior internal capsule,²⁸ anterior cingulate cortex,^29,30 or olfactory sulcus.²⁹ Although these studies have found that individuals at CHR show CVA similar to schizophrenia patients (SCZ), this focus on a single structure has yielded limited insight into global CVA differences and the scope of specificity in CVA abnormalities. As a result, it remains unclear if overall CVA would be reduced in CHR individuals, similar to individuals with psychosis, or if CVA develops after psychotic disorder onset.

To address these open questions, we have 2 aims: (1) to examine the general and specific CVA differences across different trait levels of vulnerability for psychosis and (2) to examine changes in CVA over time in the risk group. In the first aim, we examine CVA across level of vulnerability including: a CHR group, a SCZ group, and 2 groups of healthy volunteers (HV). HV groups were age-matched to respective research groups, younger-HV are age-matched to CHR and older-HV are age-matched to SCZ, and collected at the both sites. In addition to vulnerability stage groups, CVA will be compared across lobes of the brain (frontal, temporal, parietal, occipital, cingulate). In examining CVA by lobes as a repeated measure, we are able to detect general, global CVA differences between groups (main effect of group) as well as lobe specific differences between groups (group by lobe interactions). We expect that reduced CVA relates to early vulnerability for psychosis, and therefore CVA should be reduced in both the CHR and the SCZ groups. Alternatively, it is also possible that CVA reflects a neurotoxic effect of psychosis, which would result in reduced CVA appearing only in the SCZ group. These cross-sectional analyses provide limited insight into pathogenic processes. Therefore, the current study also includes a longitudinal analyses. In the second aim, a subset of CHR and younger-HV individuals had a second timepoint which was examined for lobes at each timepoints across group (CHR, younger-HV). We expect that the CHR group may show pathogenic processes that are distinct from the typical neuromaturation in younger-HV. If group display differences in CVA changes over time, then follow-up analyses will be conducted within the CHR group to assess whether these changes are related to increasing risk scores.

Methods

Participants

A total of 233 participants (younger-HV = 74, older-HV = 38, CHR = 73, SCZ = 48) were recruited as part of a collaboration between the Intermountain Neuroimaging Consortium sites at the University of Colorado Boulder and the Mind Research Network (Albuquerque, NM) all MRI machines, software, and sequences were identical across sites. Gray matter volume data from these sites have been successfully integrated across sites in previous work,³¹ but have not examined CVA. Also, previous methodological papers suggest that gray matter volume metrics are highly consistent across sites.³² All procedures were reviewed and approved by the local institutional review board at each institution. Participants 18 years old or older gave written consent to participate. For those participants under the age of 18, a parent gave written consent and participants gave written assent. Identifiable subject information was only shared among team members listed on the IRB protocol in accordance with HIPAA. At the New Mexico site, older-HV (n = 38) and individuals with a schizophrenia diagnosis (n = 48) were recruited at the Mind Research Network COBRE ongoing study based in Albuquerque, NM from inpatient and outpatient psychiatric clinics, group homes, referrals from physicians, and advertisements. Patients met criteria for SCZ based on the Structured Clinical Interview for DSM-IV Axis I disorders (SCID) and were confirmed by review of the case file. Exclusion criteria for SCZ patients included head injury, presence of a neurological disorder, and the presence of any contraindication to the magnetic resonance imaging environment. At the University of Colorado Boulder site, younger-HV (n = 74) and CHR (n = 73) samples were recruited to the Adolescent Development and Preventive Treatment (ADAPT) research program. Ninety-four individuals, HV (n = 49) and CHR (n = 45) at the Colorado site completed a second scan about 12 months later. At both sites, exclusion criteria included head injury, presence of a neurological disorder, lifetime substance dependence (as assessed by the SCID), and the presence of any contraindication to the magnetic resonance imaging environment. The presence or lifetime history of an Axis I psychotic disorder were exclusion criteria for CHR participants. Exclusion criteria for healthy volunteers included presence of a psychotic disorder in a first-degree relative. Participants are between ages 12 and 35 (mean [M] = 20.11, standard error of the mean [SEM] = 0.305), and 59.5% of the sample is male. Although the groups are younger at the Colorado site (CHR: 13–22, M = 18.64, SD = 1.78; younger-HV: 12–21 years old, M = 18.24, SD = 2.63) and older at the Mind Research Network (SCZ: 18–34 years old, M = 24.8, SD = 4.53; older-HV: 18–34 years old, M = 26.37, SD = 4.37), there was overlap across sites in the age range and HV groups were similar in age within site. Additionally, both age and collection site were included in the cross-sectional model to account for age or site variance. Forty-five individuals were currently medicated on antipsychotics (CHR = 7, SCZ = 38), in follow-up analyses dosage was not related to asymmetry index, P = .67. Demographic and positive symptom sample characteristics are described in table 1. The Structured Interview for Psychosis Risk Syndromes (SIPRS³³) was used to diagnose CHR syndromes.

Table 1.

Demographic and CVA Metrics by Group

Variables	Younger-HV (n = 74)	CHR (n = 73)	Older-HV (n = 38)	SCZ (n = 48)	Statistics
Demographics
Gender (% male)	43.20%	60.30%	62.15%	83.33%	χ 2 (3) = 18.57, P < .001
Age, M (SD)	18.24 (2.63)	18.64 (1.78)	26.37 (4.37)	24.80 (4.53)	F(3, 227) = 87.47, P < .001
Age range	12–21	13–22	18–34	18–34
% on antipsychotics, CPZ	0% (0)	15.06%, 12.0 mg	0% (0)	93.75%, 357.51 mg
Handedness (% right)	93%	89%	100%	85%	χ 2 (3) = 6.91, P = .07
Symptoms
Positive, M (SD)	—	11.97 (0.53)		15.27 (0.77)
Negative, M (SD)	—	10.12 (0.84)		15.39 (0.91)
Cortical volume asymmetry
Overall	0.02 (0.17)	−0.43 (0.17)	0.349 (0.27)	−0.341 (0.29)	F(2, 222) = 4.15, P = .02
Model estimated mean (SEM)
Group by lobe interaction
Sample mean (SD)a					F(8, 888) = 4.67, P < .001
Frontal CVA	−0.297 (1.23)	−0.475 (1.05)	−1.29 (1.80)	−0.897 (1.52)
Cingulate CVA	−1.79 (6.16)	−3.46 (4.198)	−0.09 (5.57)	−3.67 (6.73)
Over two timepoints	HV (n=74)	CHR (n=73)
Overall
Model estimated mean (SEM)	0.48 (0.28)	−0.51 (0.25)			F(2, 76) = 4.18, P = .04
Baseline	0.67 (0.27)	−0.61 (0.26)			F(2, 76) = 4.97, P = .03
Follow-up (12 month)	0.30 (0.27)	−0.41 (0.26)

^aThe described effects below (i.e., Frontal CVA and Cingulate CVA) refer effects in the sample mean rather than model derived means as in the line above (the model derived mean accounts for variance by region as well as accounting for variance related to sex, age, and collection site).

Clinical Assessments

All subjects were administered the Structured Clinical Interview for DSM-IV Axis I disorders (SCID). The SCID was administered to diagnose psychotic disorders in the SCZ group, and to rule out a psychosis diagnosis for the CHR and HV groups, as well as to assess history of mood and anxiety disorders. The SIPRS was administered to CHR and HV participants in order to diagnose CHR subjects and rule out symptoms in HV. For the SCZ group, symptom ratings were completed using the Positive and Negative Syndrome Scale (PANSS³⁴). Risk was assessed at both timepoints using the NAPLS-2 risk calculator³⁵ in the CHR group; the progression of risk in a larger sample and the methods followed were previously reported.³⁶

MRI Acquisition and Processing

Images were acquired with a 3-Tesla Siemens Tim Trio magnetic resonance imaging scanner (Siemens Healthineers, Erlangen, Germany) using a standard 12-channel head coil. Structural images were collected with a T1-weighted 3D magnetization prepared rapid gradient multi-echo sequence (sagittal plane; repetition time (TR) = 253 ms; echo times (TE) = 1.64, 3.5, 5.36, 7.22, and 9.08 ms; GRAPPA parallel imaging factor 2; 1 mm³ isotropic voxels, 192 interleaved slices; FOV = 256 mm; flip angle = 7°, time = 6:03 min). A T2 weighted acquisition (axial oblique aligned with anterior commissure-posterior commissure line; TR = 3720 ms; TE = 89 ms; GRAPPA parallel imaging factor 2; 0.9 mm × 0.9 mm voxels; FOV = 240 mm; flip angle: 120°; 77 interleaved 1.5 mm slices; time = 5:14) was collected to check for incidental pathology. MRI technologists identified possible image quality issues and forwarded images of concern to radiologists for a formal review. MRI data were visually inspected for quality of gray matter segmentation and motion artifacts.³⁷ Region of interest gray matter volumes were calculated in Freesurfer v.6.0,³⁸ using the Desikan atlas³⁹ to define of lobe volumes (frontal, temporal, occipital, parietal, and cingulate), see figure 1A. For each lobe an asymmetry index was calculated as a ratio of left and right hemisphere volumes {[(right − left)/(right + left)] × 100}.^{23,25,38–40} In this asymmetry index, a positive value indicates that right cortical volume is greater than the left cortical volume (a rightward bias), and a negative value indicates that the left cortical volume is greater than the right cortical volume (a leftward bias).

Fig. 1.

Cortical volume asymmetry across the psychosis spectrum: model corrected group differences (A) are graphed in the right panel with error bars depicting standard error of the mean and regional definition of lobes are depicted on the right on a sample average brain surface; significant group by lobe interactions are depicted in the frontal (B) and cingulate (C) lobes, which are graphed in the right panel with error bars depicting standard error of the mean and regional definitions are depicted in the left panel on a sample average brain surface.

Results

Participants

Our sample included 233 participants (younger-HV = 74, CHR = 73, older-HV = 38, SCZ = 48; table 1). There were significant differences in sex by group, χ ²(3) = 18.57, P < .001, such that there were fewer women in the CHR and SCZ groups. There was also a significant difference in age between groups, F(3, 227) = 87.47, P < .001. Age differed significantly across sites (Ps < .001), but not within sites (Ps < .12). In other words, group difference in age was driven by the SCZ group and older-HV being significantly older than the CHR (P < .001) and younger-HV groups (P < .001), but the CHR and younger-HV group did not differ significantly from each other (P = .88), and the SCZ did not differ from the older-HV (P = .125). The majority of the sample self-identified as right handed (91.4%), there was no significant difference in handedness across groups (CHR, young-HV, SCZ, older-HV), χ ²(3) = 6.91, P = .08. There is a group difference, χ ²(1) = 6.30, P = .012, if the CHR and SCZ are combined and compared with the healthy volunteers (older, younger); consistent with prior reports of an increase in left-handedness in psychosis risk.⁴¹ To explore the impact of handedness, all analyses were also conducted without left handed individuals, which did not impact the magnitude or direction of the resulting effects. All following analyses accounted for the effect of age and sex of all subjects.

Cortical Volume Asymmetry Group Analyses

Asymmetry index was compared across groups (younger-HV = 74, CHR = 73, older-HV = 38, SCZ = 48) as a between-subject factor across lobes (frontal, temporal, parietal, occipital, cingulate) and as a repeated within-subject factor accounting for age, collection site, and sex, table 1. For the younger-HV and CHR groups, only the first timepoint was included in the cross-sectional analyses. There was a significant effect of group, F(2, 222) = 4.15, P = .02, consistent with global CVA differences. Post hoc analyses of global CVA showed that the CHR group (M = −0.43, SEM = 0.172) CVA indices were reduced compare to the young HV group (P = 0.04, M = 0.02, SEM = 0.17). In the SCZ group (M = −0.341, SEM = 0.29) CVA indices were also reduced compared with older-HV group M = 0.35, SEM = 0.27 (P = .04). Across sites, CHR showed reduced CVA indices compared with older-HV (P = .03), but the CHR group did not differ from the SCZ CVA (P = .84). Finally, the SCZ group showed decreased CVA indices compared to the younger-HV though not significantly so (P = .32), figure 1A. There was also a significant lobe by group interaction, F(8, 888) = 4.67, P < .001, indicating that there were lobe-specific group differences in the frontal and cingulate CVA. In the frontal CVA, the CHR (M = −0.554, SEM = 0.175) group did not significantly differ from the younger-HV (P = .398, M = −0.363, SEM = 0.177). The SCZ group (Ps > .190, M = −0.855, SEM = 0.295) did not significantly differ from any other group. Across sites, the CHR group did differ from the older healthy control group (P = .036, M = 0.756, SEM = 0.357). The younger HV also significantly differed from the older-HV (P = .010), figure 1B. In the cingulate CVA, the CHR group (M = −3.62, SEM = 0.76) reduced compared with younger-HV (P = .068, M = −1.83, SEM = 0.768) though not significantly so. Cingulate CVA was significantly reduced in the SCZ group (P = .002, M = −4.380, SEM = 1.280), compared with the older-HV group (M = 0.440, SEM = 1.19). Across site, the CHR group did not differ from SCZ groups (P = .638). CHR CVA also reduced compared to older-HV (P = .009), figure 1C. There were no other significant main or interactive effects of sex, site, or age, Ps > .26.

Cortical Volume Asymmetry Over Time

Asymmetry index was compared across groups (HV = 49, CHR = 45) as a between-subject factor and for each timepoint (baseline and one year follow up) across lobes (frontal, temporal, parietal, occipital, cingulate) as a nested repeated within-subject factor accounting for age and sex, table 1. There was a significant main effect of group indicating the presence of global CVA differences across both timepoints, F(1, 76) = 4.18, P = .04, ${\eta }_{\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{t}\mathrm{i}\mathrm{a}\mathrm{l}}^2$ = .052, such that the CHR group showed an average leftward bias across lobes and timepoints (M = −0.51, SEM = 0.25) compared with the HV group (M = 0.48, SEM = 0.26), table 1. There was also a significant group by timepoint interaction, F(1, 360) = 4.97, P = .03, ${\eta }_{\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{t}\mathrm{i}\mathrm{a}\mathrm{l}}^2$ = .061, such that rightward bias decreased in the HV group (baseline: M = 0.67, SEM = 0.27, follow-up: M = 0.30, SEM = 0.27) and leftward bias decreased in the CHR group (baseline: M = −0.61, SEM = 0.26, follow-up: M = −0.41, SEM = 0.26) over time, figure 2. There were no other significant main or interactive effects of sex or age, Ps > .10.

Fig. 2.

Cortical volume asymmetry in CHR over time. (A) Regional definition of lobes are depicted on the right on a sample average brain surface with error bars depicting standard error of the mean B. Model corrected group differences are graphed in the right panel C. Model corrected mean change in cortical volume asymmetry index by change in risk score over time.

Cortical Volume Asymmetry Related to Change in Risk for Psychosis

To assess the possibility that changes in CVA was related to increasing risk for developing psychosis, asymmetry index was compared baseline NAPLS-2 risk scores as a between-subject factor for each timepoint (baseline and 1 year follow-up) across lobes (frontal, temporal, parietal, occipital, cingulate) as a nested repeated within-subject factor accounting for age and sex in the CHR group. There was no significant main effects of NAPLS risk score, F(1, 41) = .35, P = .56, but there is a significant interactive effect of change in NAPLS risk score related to asymmetry over time, F(1, 41) = 6.51, P = .014, ${\eta }_{\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{t}\mathrm{i}\mathrm{a}\mathrm{l}}^2$ = .14, r_partial = .37; such that increased risk was related to decreased leftward bias.

Discussion

In the present study, there were both general and specific differences in CVA across the various levels of vulnerability to psychosis. In the cross-sectional analyses, CHR and SCZ groups showed reduced overall rightward bias compared with older and younger-HV groups, but the CHR group did not differ from the SCZ group, which may indicate that CVA reflects a general vulnerability to psychosis. In addition to a global reduction in CVA in clinical groups, there was a group by lobe interaction, which may indicate lobe-specific group differences in asymmetry (i.e., cingulate and frontal lobes). Notably, these analyses may indicate emerging specificity in the CHR group, which did not significantly differ from the younger-HV or SCZ group, but did differ significantly from the older-HV group. In separate longitudinal analyses, the CHR had consistently reduced CVA compared with the HV across both timepoints. Additionally, the group by timepoint interaction indicated that CVA changed in opposing directions over time—CHR showed decreased leftward bias and HV showed typical neuromaturation decreased rightward bias over time.⁶ Within the CHR group, the greater decrease in CVA leftward bias (i.e., aberrant neuromaturation) related to increased risk for psychosis over the same time period. Taken together, there was a global difference in CVA for CHR and SCZ groups. Additionally, CHR appeared to exhibit emerging specificity of CVA differences, continued reductions in CVA over time, and pathogenic development of CVA related to increasing risk for psychosis over time.

Abnormal CVA in the SCZ group compared with (both younger and older) HV is consistent with previous findings in psychosis^8–15 and in first-episode psychosis.^22,24,41 Similarly, decreased CVA in the CHR group relative to the HV group is consistent with some studies of individuals at GHR for psychosis^15,20 that have also found that reduced CVA. CVA is sensitive to a culmination of genetics, neuromaturational, and hormonal factors, and so these inconsistencies²¹ in GHR findings may be driven by neurodevelopmental and hormonal influences over CVA.^1,4,5 Additionally, cortical volumes are normal in GHR before symptom onset, but tend to become abnormal as symptoms present over time, which is further consistent with the current longitudinal analyses.²⁶ The current findings of leftward bias in the CHR group are consistent with the possibility that CVA reflects diathesis (e.g., development, hormones, experience). Critically, the current study detected global CVA differences that had yet to be examined in the CHR literature, which has focused on specific regions of theoretical interest.^28–30 Finally, given that CVA abnormalities predict treatment responsivity in past studies of psychosis, future research should explore the utility of CVA in targeting CHR individuals with relevant treatments.^23,24

The vulnerability for psychosis group by lobe interaction highlighted lobe-specific differences in CVA; both the CHR and SCZ groups showed greater leftward bias in the cingulate compared with older-HV but not younger-HV. Similarly, the greater leftward bias in the cingulate lobe for individuals with SCZ compared to the HV group has been previously reported in the literature.³⁰ Frontal CVA abnormalities in psychosis are well established in previous research of psychosis.^{11,13–15,19,20,22–24,43} It is notable, however, that studies in early psychosis found no differences in frontal CVA,⁴³ as in the current article where the SCZ group did not differ from older (age-matched) HV. However, the current article did find that frontal volumes distinguish healthy older adults from younger-HV and CHR, which may reflect co-occurring the frontal neuromaturation processes,⁴⁴ rather than psychosis course progression as no similar interaction was observed in the longitudinal analyses.

Prior studies in psychosis have focused on frontal CVA, however, considerably fewer prior work has examined cingulate CVA, often instead focusing on frontal, temporal, and occipital volumes alone.^{11,13–15,19,20,22–24,43} The present findings suggest more work should consider the inclusion of the cingulate when modeling CVA in psychosis. The CHR group significantly differed from the younger and older-HV in terms of cingulate as in prior CVA studies.^17,29,30 It is noteworthy that these prior research restricted CVA analyses to anterior portions of the cingulate cortex, whereas the current study defined the region of interest as the cingulate lobe^17,29,30; at the whole cingulate level the CHR group still showed evidence of emerging specificity in significantly differing from the HV groups but not from SCZ groups. Finally, it is important to note that individuals at CHR did not significantly differ from individuals with SCZ, and CVA may reflect a marker of psychosis risk that may not vary by the presence of psychosis onset/progression.

The CHR group did not significantly differ from the younger-HV group in frontal and cingulate CVA, which highlights several possibilities regarding the role of CVA in the etiology of psychosis. CVA reflects the confluence of genetic, neuromaturational, and hormonal influences.¹ In such a case, the greater abnormality in the SCZ group may reflect a larger risk burden or diathesis (e.g., genetic, neuromaturational, hormonal) compared with the CHR group. This hypothesis is consistent with evidence that CVA becomes more abnormal as symptom severity increases²⁶ in frontal and cingulate regions. Unfortunately, this final possibility, cannot be answered in the current cross-sectional design, and emphasizes the need for CVAs to be examined longitudinally in CHR and SCZ individuals.

Longitudinal analyses compared CHR and HV over a 1-year period and provided insight into how CVA may change over time. The main effect of group suggested that group reductions in global CVA in the CHR group were maintained over a 12-month period and that reduced CVA may be a stable endophenotype of risk for psychosis. Additionally, this analysis revealed a group by timepoint interaction, which suggested that CVA changed in opposing directions over time in the CHR and HV groups. Both groups show a decrease over time in overall bias, that is, HV showing less rightward bias and CHR showing decreased leftward bias, which may reflect a regression to the mean over time, but these groups remain significantly different. Previous psychosis studies also found that psychosis patients remained significantly different from controls in terms of asymmetry, but that individuals with psychosis showed a reduction in anomalies over a 2-year follow up period.²¹ Furthermore, a reduction in leftward bias, as the current study observed in the HV group, has been established in the literature as a typical neuromaturational trajectory.⁶ And so, the deviations from the normal neuromaturation of CVA in the CHR group may reflect pathogenic processes. The magnitude of this change in CVA was related to increased risk for psychosis over the same period. Furthermore, the reduction in anomalous asymmetry over time is consistent with a previous study of psychosis.²¹ Taken together, the reduction in leftward bias in the CHR group is consistent with prior work in psychosis patients²¹ and may reflect a distinct deviation from expected CVA development related to increasing risk for psychosis.⁶

This study showed great promise, but there are still limitations and future directions to consider. One such limitation is that the current study was underpowered to fully explore the impact of sex. Although the current study accounted for sex effects in our models, future studies with larger sample sizes and more longitudinal timepoints (including those at an earlier age) will be necessary to more definitely address questions relating to sex-CVA and sex-neurodevelopmental questions. As such, although the present study does introduce several important new findings, the effects of sex on CVA remains an open question. This study is comparable to other CVA group analyses where sample sizes ranged from 20 to 84 individuals,^{11–15,20,22–30,40,42} but future work would benefit from increased sample sizes. Furthermore, CVA can be calculated in existing large data sets to explore un answered questions, including: explore the potential for CVA to detect distinct psychosis subgroups, serve as a biomarker to improve risk calculators, and corroborate the current findings. These larger sample sizes would allow future studies to explore the nuance of continuous variables account of the impacts of medication dosage, symptoms and age on CVA, which remain an open question. Questions also remain regarding the functional and symptom outcomes related to changes in CVA, which should be assessed in future studies. Additionally, there were limited number of CHR individuals were diagnosed with a psychotic disorder at the 1-year follow-up (n = 7) and the rate of future conversion is unknown. To address these questions, future studies should include larger longitudinal samples of individuals with varying vulnerability for psychosis, to explore how CVA relates to vulnerability for psychosis. This would help clarify the relationship of CVA to conversion to psychosis and over psychosis progression. Finally, while the current metric was established by prior literature,^{23,25,38–40} there is significant room for methodological development in the assessment of CVA. Future studies should investigate new alternatives to assess CVA.

Funding

This work was supported by the National Institutes of Mental Health (Grant R01s. MH094650, MH112545–01, MH103231, MH112545, MH094650, R21/R33MH103231, and R21MH110374) and Centre of Biomedical Research Excellence (COBRE) (5P20RR021938/P20GM103472 and F32MH102898-01).