. Author manuscript; available in PMC: 2026 Oct 18.

Published in final edited form as: Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Apr 25;11(9):1091–1100. doi: 10.1016/j.bpsc.2025.04.009

Presence, Severity, and Functional Associations of Incomplete Hippocampal Inversion in 22q11.2 Deletion Syndrome

David Roalf ^1,², Ally Atkins ³, Adam Czernuszenko ⁴, Margaret K Pecsok ⁵, Donna M McDonald-McGinn ^6,^7,^8,⁹, J Eric Schmitt ¹⁰, Maxwell J Roeske ¹¹, Sarah Hopkins ^12,^13,¹⁴, Phoebe Freedman ^15,¹⁶, Aaron Alexander-Bloch ^17,¹⁸, Jenna Schabdach ¹⁹, Benjamin Jung ²⁰, T Blaine Crowley ²¹, R Sean Gallagher ^22,²³, Daniel E McGinn ²⁴, Paul J Moberg ^25,²⁶, Kosha Ruparel ^27,²⁸, Russell T Shinohara ²⁹, Bruce I Turetsky ³⁰, Lauren White ^31,³², Elaine H Zackai ^33,^34,³⁵, Ruben C Gur ^36,³⁷, Raquel E Gur ^38,³⁹

¹Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

²Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

³Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

⁴Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

⁵Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

⁶22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

⁷Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

⁸Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

⁹Division of Human Biology and Medical Genetics, Sapienza University of Rome, Rome, Italy

¹⁰Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

¹¹Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

¹²22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

¹³Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

¹⁴Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

¹⁵Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

¹⁶Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

¹⁷Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

¹⁸Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

¹⁹Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²⁰Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²¹22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²²Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

²³Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²⁴22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²⁵Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

²⁶Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²⁷Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

²⁸Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

²⁹Penn Statistics in Imaging and Visualization Endeavor, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³⁰Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³¹Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³²Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

³³22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

³⁴Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

³⁵Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³⁶Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³⁷Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

³⁸Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

³⁹Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

All authors critically reviewed the article’s content and approved the final version for publication.

^✉

Address correspondence to David Roalf, Ph.D., at roalf@pennmedicine.upenn.edu.

Roles

David Roalf: Writing, editing, and approval of the final version of this article, Conceptualized, designed the research, Performed statistical analyses, wrote the first draft of the article

Ally Atkins: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments, Performed statistical analyses

Adam Czernuszenko: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments, Performed statistical analyses

Margaret K Pecsok: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments, Performed statistical analyses

Donna M McDonald-McGinn: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

J Eric Schmitt: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Maxwell J Roeske: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Sarah Hopkins: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Phoebe Freedman: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Aaron Alexander-Bloch: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Jenna Schabdach: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Benjamin Jung: Writing, editing, and approval of the final version of this article

T Blaine Crowley: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

R Sean Gallagher: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Daniel E McGinn: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Paul J Moberg: Writing, editing, and approval of the final version of this article, Conceptualized, designed the research

Kosha Ruparel: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments, Performed statistical analyses

Russell T Shinohara: Writing, editing, and approval of the final version of this article, Performed statistical analyses

Bruce I Turetsky: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Lauren White: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Elaine H Zackai: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Ruben C Gur: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

Raquel E Gur: Writing, editing, and approval of the final version of this article, Prepared the assessment tools, performed aspects of the MRI experiments

PMCID: PMC13676297 NIHMSID: NIHMS2209056 PMID: 40288750

Abstract

BACKGROUND:

The hippocampus is smaller and functionally disrupted in individuals with 22q11.2 deletion syndrome (22q11DS), but the cause remains unclear. During gestational weeks 20 to 30, an inversion in the dentate gyrus and cornu ammonis occurs. This process can go awry, resulting in incomplete hippocampal inversion (IHI). In the general population, IHI is more common in the left hemisphere than the right hemisphere; however, its prevalence, severity, and functional impact in 22q11DS remain unexplored. Investigating IHI in 22q11DS could uncover morphological hippocampal abnormalities linked to neuropsychiatric and neurocognitive symptoms.

METHODS:

Using 3T structural magnetic resonance imaging data, the presence and severity of IHI were assessed in individuals with 22q11DS (n = 108) and healthy comparison participants (HCs) (n = 633). Total and subregional hippocampal volumes, psychopathology, and hippocampal-based memory were evaluated.

RESULTS:

IHI prevalence was significantly higher in individuals with 22q11DS compared with HCs in both the left (63% vs. 30%, p < .001) and right (29% vs. 8%, p < .001) hemispheres. IHI severity was also greater in participants with 22q11DS (p < .001) bilaterally. IHI influenced hippocampal volume differences, with left IHI primarily affecting the head (p < .01) and tail (p < .001) and right IHI affecting only the tail (p < .001). In exploratory analyses within participants with 22q11DS, left IHI presence was linked to poorer face memory (p < .05) but not to psychopathology.

CONCLUSIONS:

These findings highlight a high prevalence of hippocampal morphological alterations in 22q11DS, which are associated with memory performance. Earlier developmental and longitudinal studies are needed to clarify the role of IHI in 22q11DS sequelae.

22q11.2 deletion syndrome (22q11DS), a contiguous gene deletion syndrome, is the most common cause of DiGeorge syndrome as well as several previously described clinical conditions and is the second most common chromosomal abnormality in humans (1). 22q11DS is a genetic condition caused by deletion of a small segment of the long arm of chromosome 22. It results in heterozygous loss of ~50 genes, and its clinical manifestations range from palatal abnormalities, congenital heart disease, immunodeficiency, and hypoparathyroidism to a spectrum of neuropsychiatric disorders. The latter include schizophrenia with a high prevalence of negative symptoms and early onset during childhood and adolescence, together with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, epilepsy, and early-onset Parkinson’s disease (1,2). In addition, 22q11DS has been associated with several volumetric brain abnormalities (3,4) and alterations of the hippocampus (3,5,6). Previous studies of 22q11DS have reported smaller bilateral hippocampal volumes (7,8), with focal deficits in the body of the hippocampus (9) and alterations in hippocampal shape dependent on deletion length (7). Alterations of hippocampal structure are linked to difficulties with working memory, long-term memory, and spatial memory (10,11). Moreover, the hippocampus shows altered functional and structural connectivity with other brain regions such as the prefrontal cortex, thereby likely affecting cognitive processes and emotion regulation. Smaller hippocampal volume and altered function may contribute to the increased risk of psychiatric disorders in individuals with 22q11DS, particularly psychosis, anxiety, and depression (12–16). Given the pervasiveness of hippocampal abnormalities in 22q11DS, it is likely that these structural abnormalities begin early in development, possibly in utero, and contribute to neurodevelopmental deficits that become more evident as an individual ages. However, there have been few studies of the morphological variation of the hippocampus.

Incomplete hippocampal inversion (IHI), also called hippocampal malrotation (17), is a neuroanatomical variation in the structure of the hippocampus that can be observed using brain imaging (18,19). Normally, during fetal development, the hippocampus undergoes a process called inversion, where it rotates and folds to form its characteristic C-shape within the medial temporal lobe (20). In cases of IHI, this inversion process does not fully complete, leading to morphological differences in the hippocampal shape and orientation (21). In IHI, the hippocampus may appear flatter, more rounded, or less curved. IHI is typically most prominent in the left hemisphere, leading to asymmetry between the two hippocampi (22). IHI also leads to altered positioning such that the hippocampus may appear anatomically higher or misaligned compared with its expected location. Finally, IHI is typically accompanied by a less well-developed collateral sulcus, which separates the hippocampus from adjacent brain regions.

Generally, IHI is considered a benign anatomical variant that does not necessarily lead to clinical symptoms, because unilateral IHI appears in approximately 20% of individuals. However, IHI has been linked to various neurological conditions, including epilepsy, which is common in 22q11DS; prolonged febrile seizures (23); and an increased risk of psychiatric conditions (24). In particular, IHI has been associated with specific changes in the hippocampus in schizophrenia (21,24), suggesting that differences in hippocampal morphology in schizophrenia can be attributed to an anatomical variant that arises during the perinatal period, long before the emergence of the clinical phenotype. Given the higher incidence of psychopathology, including schizophrenia, in 22q11DS, it is plausible that individuals with 22q11DS have a higher prevalence of IHI. To date, one study (25) has measured IHI, previously referred to as hippocampal malrotation in 22q11DS, and found that 64% of participants (9/14) had a unilateral IHI, a 3fold increase over the general population. Six of these participants were also affected with schizophrenia, with or without epilepsy. Two other studies have reported single cases of 22q11DS participants with IHI (2,26) and schizophrenia, one with adult onset (26) and the other with childhood onset (2). Overall, these studies and case reports have been conducted with small samples of participants with 22q11DS, even smaller when considering psychopathology, and thus there is still limited data on the effect of IHI on schizophrenia in 22q11DS.

Here, we measured the presence and severity of IHI in a large sample of participants with 22q11DS and healthy comparison participants (HCs). In addition, we measured the total and subfield volumes of the hippocampus to determine whether IHI had global or local effects on hippocampal volume. Finally, we compared psychopathology and memory performance in 22q11DS participants with and without IHI. We hypothesized that 1) IHI would be more prevalent and severe in participants with 22q11DS compared with HCs; 2) IHI would ubiquitously affect hippocampal volume; and 3) IHI would be more prevalent or severe in 22q11DS participants with more psychopathology and poor memory performance.

METHODS AND MATERIALS

Participants

This study included 108 individuals with 22q11DS. Magnetic resonance imaging (MRI) and clinical data from 84 individuals with 22q11DS were collected by the 22q and You Center at the Children’s Hospital of Philadelphia (CHOP) in collaboration with the Brain Behavior Laboratory at the University of Pennsylvania (Penn). MRI data from an additional 24 individuals with 22q11DS were curated from a clinical database in the Department of Radiology at CHOP. Data from the clinic were included to broaden ascertainment and harmonize research and clinical data. Participants with 22q11DS had a confirmed chromosome 22q11.2 deletion using fluorescence in situ hybridization, comparative genomic hybridization, multiplex ligation-dependent probe amplification, or single nucleotide polymorphism microarray (27). A total of 633 HCs were recruited from the Penn-CHOP Lifespan Brain Institute (LiBI) and Brain Behavior Laboratory at Penn Medicine. They were not tested for 22q11DS because the diagnosis of this syndrome is generally made early in life due to the associated malformative features. Therefore, healthy individuals who lack the typical clinical manifestations of 22q11.2 are not routinely tested for it (28). Additional participant characteristics are detailed in Table 1.

Table 1.

Demographic Comparisons for Participants With 22q11DS and HCs

	22q11DS, n = 108	HC, n = 633	p Value
Age, Years			.11
Mean (SD)	20.0 (8.69)	18.6 (9.18)
Median (IQR)	17.5 (8–52)	17.0 (8–51)
Sex, n (%)			.81
Female	53 (49.1%)	322 (50.9%)
Male	55 (50.9%)	311 (49.1%)
Race, n (%)			<.001
Black	10 (9.3%)	209 (33.0%)
Other	13 (12.0%)	62 (9.8%)
White	85 (78.7%)	362 (57.2%)

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22q11DS, 22q11.2 deletion syndrome; HC, healthy comparison participant.

Participants from the 22q and You Center and LiBI provided informed consent/assent, and the study procedures were approved by the institutional review boards at CHOP and Penn. Data from the Department of Radiology were part of a study (29) that was reviewed by the CHOP Institutional Review Board and determined to be exempt from additional oversight because it consisted of secondary analyses of preexisting clinical data.

Structural MRI

All MRI data were collected on 3T Siemens scanners at CHOP or Penn. All structural images used in the current study were acquired using a magnetization-prepared rapid acquisition gradient-echo (MPRAGE) T1-weighted sequence at high spatial resolution. Most MRI data (84/108 scans, 77.7%) from participants with 22q11DS and all data from HCs were collected as part of a research protocol on the same scanner at Penn (3T Siemens Tim Trio) and acquired using a similar MPRAGE sequence (30–32). These individuals were routinely followed at the 22q and You Center at CHOP for medical evaluation and were recruited for an MRI research study because of their 22q11DS diagnosis. The remainder of the 22q11DS data (24/108 scans, 22.3%) were collected as part of a clinical protocol on Siemens scanners within the Department of Radiology at CHOP (see the Supplement for additional details and Figure S1). Clinical MRI data were restricted to 3T MRI scanners that used a harmonized MPRAGE sequence that was deployed at CHOP in 2008 for routine brain MRI examinations. The most common indications for clinical MRI were 22q11DS (11/23), headaches (7/23), follow-up for Chiari I malformation (5/23), and developmental delay (4/23). Some individuals were referred based on the presence of several of these indications. Notably, although the prevalence of idiopathic seizures is elevated in patients with 22q11DS (33), suspected seizures led to clinically indicated MRI in only 3 individuals with 22q11DS. Clinical scans whose neuroradiology reports detailed large artifacts due to motion or dental hardware, mentions of brain surgery, or disorders associated with tumor growth were excluded (29). Details for all MPRAGE protocols used in this study are provided in Supplemental Methods.

Image Processing of the Hippocampus

Cortical and subcortical reconstruction of the T1-weighted image was performed for all participants using FreeSurfer version 7.1.1 (34). FreeSurfer’s automated hippocampal segmentation was used to further parcellate the hippocampus into its subfields (35). This software uses a probabilistic atlas built with ultra-high-resolution ex vivo MRI data to produce an automated segmentation of the hippocampal substructures. Volumes of the whole hippocampus and its head, body, and tail were extracted for analysis. As in previous work, all T1 images underwent automated quality assurance using FreeSurfer’s Euler statistic (36). Euler values closer to zero indicate higher quality data.

Assessment of IHI

The approach and criteria used to determine the presence and severity of IHI were based on published methods (22,24), with modifications to facilitate semiautomated landmarking. All ratings were completed in native space, and binary masks of the hippocampus, perirhinal cortex, subiculum, and dentate gyrus were overlaid on the raw T1-weighted image to aid in landmarking morphological features used in IHI scoring (Figure 1). All criteria were obtained in the coronal view for both the left and right hippocampus using ITK-SNAP (37). IHI criteria are summarized in Supplemental Methods.

Figure 1. — IHI was measured using T1-weighted MRI scans in native space **(A)**. T1-weighted MRIs were analyzed using FreeSurfer **(B)** to extract hippocampal volume. Hippocampal subfield segmentation **(C)** was performed using FreeSurfer to provide landmarks for manual measurement of IHI criteria (C1, C2, C3, C5). Regions shown include red = CA1 body, blue = subiculum body, green = CA3 body, purple = presubiculum body, light blue = granule cell and molecular layers of the dentate gyrus body, yellow = peririhinal cortex. Additional details are provided in the Supplement. CS, collateral sulcus; IHI, incomplete hippocampal inversion; MRI, magnetic resonance imaging; OTS, occipitotemporal sulcus.

Initial training of raters (AA, AC) was done in consultation with a board-certified neuroradiologist (JES), a cognitive neuroscientist (DR), and a neuropsychiatrist (MJR) with previous IHI rating experience. Data from 62 individuals were used to evaluate interobserver reproducibility for AA and AC using the kappa statistic (38). Discrepancies were resolved through consensus. Cohen’s kappa indicated moderate-to-substantial interobserver reliability in both the left (kappa = 0.77; z = 9.30, p < 1.38 × 10⁻²⁰) and right (kappa = 0.70; z = 4.31, p < 1.65 × 10⁻⁵) hippocampus that differed significantly from zero, which is consistent with published findings (22,24). Raters were blinded to the diagnostic group when assessing IHI. Raters AC and AA evaluated IHI for all 108 participants with 22q11DS, and scores were aggregated. AA rated IHI for 316 HCs, and AC rated IHI for 317 HCs. Two IHI measures were derived for the left and right hippocampus: IHI presence was defined as an IHI score ≥3.75 (22), and IHI severity was defined as the total IHI score, which could range from 0 to 10.

Assessment of Psychopathology in 22q11DS

Psychopathology was completed through one of several assessments (see Supplemental Methods for additional details). The presence of the following diagnoses were determined for all participants with 22q11DS: ADHD, anxiety, schizophrenia, and prodromal psychosis. In addition, overall adaptive functioning was assessed using the Global Assessment of Functioning (39). These measures were only available for the 22q11DS research sample.

Hippocampal-Based Memory Assessment

Participants with 22q11DS completed the Penn Computerized Neurocognitive Battery (40,41), which includes several hippocampal-based memory measures. Specifically, we assessed performance in verbal (Penn Word Memory Test), spatial (Visual Object Learning Test), and face (Penn Face Memory Test) memory. Details on these test procedures have been published elsewhere (42,43), are presented in Supplemental Methods, and are available at https://webcnp.med.upenn.edu/explore-tests.html.

Statistical Analysis

Data were compared across groups using t tests and χ² tests, as appropriate. The prevalence of IHI in participants with 22q11DS and HCs was compared using χ² tests for each hemisphere. The severity of IHI scores in the groups was compared using a linear mixed model with IHI score as the dependent variable and diagnosis (22q11DS, HC), hemisphere (right, left), and the interaction between diagnosis and hemisphere as the fixed effects. Sex, age, and estimated total intracranial volume were included as covariates and participant as the random effect. To determine the effect of IHI on hippocampal volume and subfield volumes (head, body, tail), independent linear mixed models were used assessing subfield volume as the dependent variable and diagnosis (22q11DS, HC); hemisphere (right, left); IHI (0, 1); and the interaction between diagnosis, hemisphere, and IHI score as the fixed effects. Sex, age, and estimated total intracranial volume were included as covariates, and participant was included as the random intercept. Post hoc comparisons were completed using the least squares means approach (lsmeans). Significance values were set at α = .05, and only effects that survived false discovery rate correction for multiple comparisons are reported. Exploratory associations between IHI and the presence of psychopathology and hippocampal-based memory performance in participants with 22q11DS were examined using Fisher’s exact tests and 1-way analyses of variance where appropriate. Sensitivity analyses were implemented using harmonized hippocampal volumes; harmonization was completed using neuroComBat (44,45). All statistics were computed in R (version 4.3.1).

RESULTS

There were no differences in mean age or sex distribution between participants with 22q11DS and HCs (Table 1). There was a higher proportion of White individuals in the 22q11DS group than in the HC group. Age (F_1,736 = 6.81, p < 9.25 × 10⁻³) and diagnosis (F_1,736 = 7.39, p < 6.69 × 10⁻³) affected data quality, as measured via FreeSurfer’s Euler number. Data quality was higher in older adults, and participants with 22q11DS (−45.16 ± 22.12) had better quality assurance metrics than HCs (−54.18 ± 26.05).

The Presence and Severity of IHI Are Higher in 22q11DS

Participants with 22q11DS had more frequent IHI in both left (χ²₁ = 63.78, p < 1.38 × 10⁻¹⁵; 63% vs. 30%) and right (χ²₁ = 37.89, p < 7.48 × 10⁻¹⁰; 29% vs. 8%) hemispheres compared with HCs (Figure 2A, B). The analysis model of IHI severity, measured by the total IHI score, showed an interaction between group and hemisphere (F₁,₇₃₉ = 13.59, p < 2.43 × 10⁻⁴). Specifically, IHI severity was higher in the left than in the right hemisphere in both participants with 22q11DS (t₇₃₉ = 7.79, p < .001) and HCs (t₇₃₉ = 9.21, p < .001), but the difference between the groups was more pronounced in the left (t₁₃₇₁ = 9.17, p < .001) than the right (t₁₃₇₁ = 4.73, p < .001) hemisphere (Figure 2). Follow-up analysis of the individual criteria scores showed that all criteria scores in the left hemisphere were higher in participants with 22q11DS compared with HCs, while only criterion 1 and criterion 2 were higher in the right hemisphere in participants with 22q11DS compared with HCs (Tables S1 and S2). In addition, the presence of bilateral IHI was significantly higher (χ²₂ = 90.61, p < 2.2 × 10⁻¹⁶) in participants with 22q11DS (19%) compared with HCs (4%).

Figure 2. — The presence and severity of IHI were higher in participants with 22q11DS than in HCs. IHI was more prevalent (binary presence = green, absence = red) in both the left **(A)** and right **(B)** hippocampus in participants with 22q11DS (top row) compared with HCs (bottom row). Severity of IHI scores **(C)** was higher in participants with 22q11DS compared with HCs in both the left and right hippocampus. * indicates false discovery rate-corrected p < .05. 22q11DS, 22q11.2 deletion syndrome; HC, healthy comparison participant; IHI, incomplete hippocampal inversion.

Compared with the participants with 22q11DS who completed the research protocol, those who were scanned using the clinical MRI protocol showed higher rates of left (χ²₄ = 4.43, p < .03) but not right (χ²₁ = 0.10, p < .75) hippocampal IHI. In the clinical 22q11DS sample, 83% of individuals had a left IHI compared with 57% in the research sample. The clinical sample had higher severity scores in the left (t₁₈₀ = 3.10, p = .01) but not in the right (p = .37) hippocampus compared with HCs (Figure S2).

The Presence of IHI Differentially Affects Hippocampal Volume in 22q11DS

Participants with 22q11DS had smaller bilateral hippocampal volumes compared with HCs (F_1,736 = 16.81, p = 4.59 × 10⁻⁵). However, when IHI presence was included as an additional factor, there was a significant 3-way interaction between diagnosis, hemisphere, and IHI (F_1,866 = 5.77, p = .01) (Figure 3). Post hoc comparisons indicated that in the presence of a left IHI, participants with 22q11DS had smaller left hippocampus (t₁₂₂₆ = 3.44, p < 6.0 × 10⁻⁴) compared with HCs, but right hippocampus volume did not differ between the groups in the presence of a right IHI (p = .37). In the absence of an IHI, participants with 22q11DS had significantly smaller left (t₁₃₄₇ = 2.90, p < .004) and right (t₁₀₂₅ = 4.90, p < .001) hippocampi compared with HCs. Participants with 22q11DS from the clinical and research samples did not differ in hippocampus volume (Figure S3). Harmonizing hippocampal volume data using neuroComBat did not alter these results (Supplemental Results).

Figure 3. — Hippocampal volume differences between participants with 22q and HCs differed based on the presence or absence of an IHI. When there was no IHI, volume differences were present bilaterally (left panel). Volume differences were significant in the presence of a left IHI but not a right IHI. * indicates false discovery rate-corrected p < .05. 22q, 22q11.2 deletion syndrome; HC, healthy comparison participant; IHI, incomplete hippocampal inversion; n.s., not significant.

IHI Effects on Hippocampal Subregions

Follow-up analyses of hippocampal subregional volume indicated that in the presence of a left IHI, the head (t₁₂₈₄ = 2.40, p < .01) and tail (t₁₄₀₂ = 5.41, p < 3.0 × 10⁻⁴), but not the body, of the hippocampus were smaller in participants with 22q11DS compared with HCs. In the presence of a right IHI, groups differed only in the volume of the tail (t₁₀₇₄ = 5.50, p < 3.0 × 10⁻⁴). In the absence of a left IHI, only the ipsilateral hippocampal tail (t₁₄₀₂ = 4.93, p < 3.0 × 10⁻⁴) differed in volume, while the absence of a right IHI resulted in a hippocampal volume difference between participants with 22q11DS and HCs in the head (t₁₀₇₄ = 3.62, p < 3.0 × 10⁻⁴), body (t₁₁₆₁ = 4.12, p < 1.0 × 10⁻⁴), and tail (t₁₀₈₃ = 4.29, p < 3.0 × 10⁻⁴) (Figure 4). Harmonizing hippocampal volume data using neuroComBat did not alter these results (Supplemental Results).

Figure 4. — Hippocampal subregion volume between participants with 22q and HCs differed based on the presence or absence of an IHI. The presence of an IHI affected hippocampal volume of the head (left panel) and tail (right panel) but not the body (middle panel) in 22q. * indicates false discovery rate-corrected p < .05. 22q, 22q11.2 deletion syndrome; HC, healthy comparison participant; IHI, incomplete hippocampal inversion; n.s., not significant.

IHI Has a Limited Association With Psychopathology in 22q11DS

Rates of IHI in 22q11DS participants with ADHD, anxiety, psychosis, and prodromal psychosis are shown in Tables 2 and 3. The presence of left or right IHI was not associated with the presence of any psychopathological condition assessed in the current study.

Table 2.

Presence of IHI in 22q11DS Participants With Comorbid ADHD, Schizophrenia, Anxiety, and Risk for Psychosis in the Left Hippocampus

	No IHI, n = 33	IHI, n = 48	Overall, n = 81
ADHD
No	17 (51.5%)	28 (58.3%)	45 (55.6%)
Yes	16 (48.5%)	20 (41.7%)	36 (44.4%)
Schizophrenia
No	30 (90.9%)	43 (89.6%)	73 (90.1%)
Yes	3 (9.1%)	5 (10.4%)	8 (9.9%)
Anxiety
No	12 (36.4%)	18 (37.5%)	30 (37.0%)
Yes	21 (63.6%)	30 (62.5%)	51 (63.0%)
Risk for Psychosis
No	15 (45.5%)	21 (43.8%)	36 (44.4%)
Yes	18 (54.5%)	27 (56.3%)	45 (55.6%)

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Values are presented as n (%). Clinical data were only available for a subset of participants with 22q11DS.

22q11DS, 22q11.2 deletion syndrome; ADHD, attention-deficit/hyperactivity disorder; IHI, incomplete hippocampal inversion.

Table 3.

Presence of IHI in 22q11DS Participants With Comorbid ADHD, Schizophrenia, Anxiety, and Risk for Psychosis in the Right Hippocampus

	No IHI, n = 58	IHI, n = 23	Overall, n = 81
ADHD
No	33 (51.5%)	12 (58.3%)	45 (55.6%)
Yes	25 (48.5%)	11 (41.7%)	36 (44.4%)
Schizophrenia
No	51 (90.9%)	22 (89.6%)	73 (90.1%)
Yes	7 (9.1%)	1 (10.4%)	8 (9.9%)
Anxiety
No	20 (36.4%)	10 (37.5%)	30 (37.0%)
Yes	38 (63.6%)	13 (62.5%)	51 (63.0%)
Risk for Psychosis
No	25 (45.5%)	11 (43.8%)	36 (44.4%)
Yes	33 (54.5%)	12 (56.3%)	45 (55.6%)

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Values are presented as n (%). Clinical data were only available for a subset of participants with 22q11DS.

22q11DS, 22q11.2 deletion syndrome; ADHD, attention-deficit/hyperactivity disorder; IHI, incomplete hippocampal inversion.

Association of IHI With Hippocampal-Based Memory Performance

Exploratory comparisons of memory performance in the 22q11DS cohort with and without IHI revealed a significant difference in face memory between participants with and without a left IHI (F_1,74 = 4.67, p = .03). Participants with an IHI performed worse than those without an IHI (Tables 4 and 5). No other memory test showed an association with IHI in participants with 22q11DS.

Table 4.

Exploratory Analysis Found That 22q11DS Participants With a Left Hemisphere IHI Had Poorer Face Memory Performance Than Those With No IHI

	No IHI, n = 36	IHI, n = 48	p Value
Verbal Memory
Mean (SD)	35 (±2.8)	33 (±4.8)	.15
Missing, n (%)	16 (44.4%)	19 (39.6%)	–
Spatial Memory
Mean (SD)	13 (±2.2)	13 (±2.5)	.63
Missing, n (%)	4 (11.1%)	3 (6.3%)	–
Face Memory
Mean (SD)	25 (±3.4)	24 (±3.7)	.03
Missing, n (%)	3 (8.3%)	3 (6.3%)	–

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22q11DS, 22q11.2 deletion syndrome; IHI, incomplete hippocampal inversion.

Table 5.

Exploratory Analysis Found No Relationship Between Right Hemisphere IHI and Memory in 22q11DS Participants

	No IHI, n = 61	IHI, n = 23	p Value
Verbal Memory
Mean (SD)	34 (±3.4)	32 (±5.7)	.25
Missing, n (%)	24 (39.3%)	11 (47.8%)	–
Spatial Memory
Mean (SD)	13 (±2.4)	13 (±2.3)	.50
Missing, n (%)	6 (9.8%)	1 (4.3%)	–
Face Memory
Mean (SD)	24 (±3.7)	24 (±3.8)	.73
Missing, n (%)	5 (8.2%)	1 (4.3%)	–

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22q11DS, 22q11.2 deletion syndrome; IHI, incomplete hippocampal inversion.

DISCUSSION

This study highlights significant differences in the presence, severity, and effects of IHI in individuals with 22q11DS compared with HCs. IHI was more frequent and severe in individuals with 22q11DS, particularly in the left hemisphere. IHI severity scores were elevated in both hemispheres in individuals with 22q11DS, with the left hemisphere consistently showing greater dysmorphology. Hippocampal volume analyses revealed a complex interaction between IHI, hemisphere, and diagnosis. Specifically, left IHI was associated with smaller left hippocampus volume in participants with 22q11DS compared with HCs, whereas right hippocampal volume did not differ between participants with 22q11DS and HCs with a right IHI. In the absence of IHI, the 22q11DS cohort exhibited bilateral reductions in hippocampal volume compared with HCs. Subregion analyses of the hippocampus indicated that the presence of left IHI primarily impacted the hippocampal head and tail, while the presence of right IHI resulted in volume differences only in the tail. Despite these structural differences, IHI showed limited associations with psychopathology in participants with 22q11DS; however, left IHI was linked to poorer face memory performance. These findings underscore the complex role of IHI in shaping hippocampal morphology and cognitive function in individuals with 22q11DS, with implications for understanding neural and cognitive vulnerabilities in this population.

The current findings highlight the pronounced morphological abnormalities in midline structures of the head and brain associated with 22q11DS. While healthy individuals exhibited hippocampal malrotation (IHI) at rates consistent with previous studies (17,22,24,46–48), the prevalence of IHI in individuals with 22q11DS was remarkably high. Our findings are consistent with the only other study on hippocampal malrotation in 22q11DS, which reported a prevalence of 64% (25); however, our sample size was 10 times larger. Notably, nearly 20% of individuals with 22q11DS in our study showed IHI in both the left and right hippocampus, underscoring significant structural abnormalities in this population. Additionally, IHI was more prevalent in clinical MRI records (83%) than in research participants (57%), suggesting that more severe or medically complex cases of 22q11DS may be associated with higher rates of IHI. These findings strongly suggest that deletion of the 22q11.2 region frequently results in IHI. The neuronal mechanisms that underlie IHI in 22q11DS remain unclear, but many 22q11DS-related genes are expressed in the brain throughout development and into maturity (49). The observed morphological alterations in the hippocampus may stem from the heterozygous deletion of multiple genes within the 22q11.2 region, some of which play crucial roles during key neurodevelopmental windows (50). For example, recent research has shown that a 2-fold reduction in Hira gene expression leads to altered neuronal morphology in primary hippocampal cultures (51). While it is likely that IHI originates early in embryogenesis, the precise timing and developmental trajectory of these abnormalities require further investigation. Future studies that use translational models and in vivo analyses are necessary to better understand the underlying mechanisms and developmental timing of IHI in 22q11DS.

The clinical significance of IHI remains poorly understood. Previous research in 22q11 DS found IHI to be prevalent in both patients with and without epilepsy (25). However, in the current study, few participants with 22q11DS underwent MRI due to suspected seizure disorders. While some evidence (47,52) suggests that IHI may contribute to epileptogenesis in conjunction with other structural abnormalities, no direct causal relationship has been identified, and IHI alone is unlikely to account for the development of seizure disorders. Despite robust levels of ADHD, anxiety, and risk for psychosis in the 22q11DS sample, we did not observe a difference in the presence of IHI in participants with these comorbid conditions. Previous studies of idiopathic schizophrenia have indicated an elevated presence of IHI (21,24,48), but there were only 8 22q11DS individuals with schizophrenia in the current study, which might have limited our ability to detect an effect. In addition, we could not assess comorbid neurodevelopmental and neuropsychiatric conditions in the clinically derived sample, where IHI was more prevalent. Hippocampal abnormalities including heterotopia, dysplasia, and IHI are higher in patients with developmental delay (52) and ASD (52), including those with duplications of 15q11.2–13 (53,54). But systematic assessment of IHI in other genetically based neurodevelopmental disorders has been limited. Nonetheless, the presence of IHI may render individuals with 22q11DS more vulnerable to hippocampal-related dysfunction. Our exploratory analyses found that IHI was associated with deficits in facial memory, indicating a potential link between IHI and disrupted neurocognitive function in 22q11DS. This preliminary finding suggests that IHI may contribute to specific cognitive impairments; the relationship between IHI and neuropsychological outcomes requires more systematic investigation. Future research could focus on elucidating the functional implications of IHI in 22q11DS to better understand its role in hippocampal dysfunction, psychopathology, and cognitive functioning.

IHI was differentially related to hippocampal volume in individuals with 22q11DS and HCs, with significant interactions observed between diagnosis, hemisphere, and IHI presence. When left IHI was present, individuals with 22q11DS showed lower left hippocampal volume, while the right hippocampus remained unaffected; in the absence of IHI, both hippocampi were significantly smaller in participants with 22q11DS across hippocampal subregions. Subregion analysis revealed that left IHI was associated with lower volumes in the hippocampal head and tail, while right IHI primarily affected the tail. These findings confirm lower hippocampal volumes in 22q11DS and suggest that subregions of the left and right hippocampus are differentially affected by IHI. Previous research showed that patients with 22q11DS exhibited lower volumes in all hippocampal subfields except for CA2/3 (55), located in the hippocampal body—a subregion that our findings suggest is not significantly affected by IHI. Complex shape analyses have also identified hippocampal differences in 22q11DS, with shape alterations being influenced by the size of the deletion; larger A-D deletions are associated with more extensive changes than smaller A-B deletions (8). Furthermore, disruptions in hippocampal excitatory/inhibitory balance, as indicated by altered levels of glutamate and GABA+ (gamma-aminobutyric acid), have been reported (56), which may be the result of significant changes in hippocampal morphology. The origins of these volume, shape, and neurometabolic abnormalities remain unclear, but it is plausible that early embryological disruptions in hippocampal development represent a first hit that triggers structural and functional consequences. Comprehensive studies on early hippocampal development are needed to better understand these mechanisms.

While our study found a higher prevalence of IHI in patients with 22q11DS than in HCs, several limitations must be noted. We combined MRI data from research and clinical sources with slightly different protocols; although T1-weighted imaging is robust, our results remained the same after data harmonization, and our data quality was high, excluding lower resolution scans and younger individuals might have omitted relevant morphological features. Nevertheless, incorporating clinically acquired MRIs reduces selection bias by broadening study inclusion, unlike many 22q11DS studies that recruit based on strict criteria. Our observed IHI rate in HCs was higher than some previous reports (22,24), possibly due to demographic differences or our semiautomated methodology that uses individual-specific FreeSurfer landmarks in native space rather than standardized warping. We believe that the assessment of morphological brain features should be completed in native space, because warping data to a standardized brain space may hinder the use of individualized hippocampal landmarks that facilitate accurate manual ratings. Future improvements in automated IHI assessments may standardize these measurements, better enabling analysis of larger datasets in a reproducible manner (57,58). Developmental stage may also influence results; although the hippocampus is largely developed by early childhood (59), ongoing maturation into adulthood warrants longitudinal study, especially because our younger clinical sample showed higher left-hemisphere IHI prevalence. Finally, the absence of data on psychopathology or cognitive performance in the clinical sample represents a limitation in understanding the broader clinical context of these findings, and the use of updated clinical practice recommendations is strongly advised (16,60) to aid in the incorporation of clinical and research data. Future studies should integrate rich neurocognitive phenotyping and explore genome-wide modifiers to clarify the functional impact of IHI in 22q11DS.

Conclusions

Our findings reveal that IHI is more frequent and severe in individuals with 22q11DS than in HCs and has significant effects on hippocampal structure, particularly in the presence of left IHI. While IHI had minimal associations with psychopathology, its impact on hippocampal morphology and face memory performance highlights its potential role in shaping cognitive and neural vulnerabilities in 22q11DS.

Supplementary Material

NIHMS2209056-supplement-1.pdf^{(333.4KB, pdf)}

Supplementary material cited in this article is available online at https://doi.org/10.1016/j.bpsc.2025.04.009.

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institute of Mental Health (Grant Nos. MH120174 and MH119185 [to DR]; MH119219 and U01 MH119738 [to REG]; and MH117014 [to RCG]), the Dowshen Program for Neuroscience at the University of Pennsylvania, and the Lifespan Brain Institute.

We thank the patients and families who participated in this study.

Footnotes

Participants provided informed consent/assent, and the study procedures were approved by the institutional review boards at CHOP and the University of Pennsylvania. Participants’ privacy and confidentiality were ensured at every stage of the study. We confirm that all methods were performed in accordance with the relevant guidelines and regulations.

Presented at the 13th Biennial International 22q11.2 Scientific Conference, July 2024, Obidos, Portugal.

The data generated and/or analyzed during the current study are available. Please contact the corresponding author with questions and considerations regarding data sharing upon reasonable requests.

SH reports consulting fees from Bristol Myers Squibb (unrelated) and from Nobias Therapeutics.

All other Sauthors report no biomedical financial interests or potential conflicts of interest.

Contributor Information

David Roalf, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Ally Atkins, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Adam Czernuszenko, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Margaret K. Pecsok, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Donna M. McDonald-McGinn, 22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Human Biology and Medical Genetics, Sapienza University of Rome, Rome, Italy.

J. Eric Schmitt, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Maxwell J. Roeske, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.

Sarah Hopkins, 22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Phoebe Freedman, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Aaron Alexander-Bloch, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Jenna Schabdach, Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Benjamin Jung, Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

T. Blaine Crowley, 22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

R. Sean Gallagher, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Daniel E. McGinn, 22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Paul J. Moberg, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Kosha Ruparel, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Russell T. Shinohara, Penn Statistics in Imaging and Visualization Endeavor, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Bruce I. Turetsky, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Lauren White, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Elaine H. Zackai, 22q and You Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Ruben C. Gur, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Raquel E. Gur, Neurodevelopment & Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

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Supplementary Materials

NIHMS2209056-supplement-1.pdf^{(333.4KB, pdf)}

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Presence, Severity, and Functional Associations of Incomplete Hippocampal Inversion in 22q11.2 Deletion Syndrome

David Roalf

Ally Atkins

Adam Czernuszenko

Margaret K Pecsok

Donna M McDonald-McGinn

J Eric Schmitt

Maxwell J Roeske

Sarah Hopkins

Phoebe Freedman

Aaron Alexander-Bloch

Jenna Schabdach

Benjamin Jung

T Blaine Crowley

R Sean Gallagher

Daniel E McGinn

Paul J Moberg

Kosha Ruparel

Russell T Shinohara

Bruce I Turetsky

Lauren White

Elaine H Zackai

Ruben C Gur

Raquel E Gur

Roles

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSIONS:

METHODS AND MATERIALS

Participants

Table 1.

Structural MRI

Image Processing of the Hippocampus

Assessment of IHI

Figure 1.

Assessment of Psychopathology in 22q11DS

Hippocampal-Based Memory Assessment

Statistical Analysis

RESULTS

The Presence and Severity of IHI Are Higher in 22q11DS

Figure 2.

The Presence of IHI Differentially Affects Hippocampal Volume in 22q11DS

Figure 3.

IHI Effects on Hippocampal Subregions

Figure 4.

IHI Has a Limited Association With Psychopathology in 22q11DS

Table 2.

Table 3.

Association of IHI With Hippocampal-Based Memory Performance

Table 4.

Table 5.

DISCUSSION

Conclusions

Supplementary Material

ACKNOWLEDGMENTS AND DISCLOSURES

Footnotes

Contributor Information

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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