Intrinsic Infant Hippocampal Function Supports Inhibitory Processing.

Impaired cerebral inhibition is commonly observed in neurodevelopmental disorders and may represent a vulnerability factor for their development. The hippocampus plays a key role in inhibition among adults and undergoes significant and rapid changes during early brain development. Therefore, the structure represents an important candidate region for early identification of pathology that is relevant to inhibitory dysfunction. To determine whether hippocampal function corresponds to inhibition in the early postnatal period, the present study evaluated relationships between hippocampal activity and sensory gating in infants 4-20 weeks of age (N = 18). Resting-state functional magnetic resonance imaging was used to measure hippocampal activity, including the amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF. Electroencephalography during a paired-stimulus paradigm was used to measure sensory gating (P50). Higher activity of the right hippocampus was associated with better sensory gating (P50 ratio), driven by a reduction in response to the second stimulus. These findings suggest that meaningful effects of hippocampal function can be detected early in infancy. Specifically, higher intrinsic hippocampal activity in the early postnatal period may support effective inhibitory processing. Future work will benefit from longitudinal analysis to clarify the trajectory of hippocampal function, alterations of which may contribute to the risk of neurodevelopmental disorders and represent an intervention target.

Anterior hippocampal dysfunction in early psychosis: a 2-year follow-up study.

BACKGROUND: Cross-sectional studies indicate that hippocampal function is abnormal across stages of psychosis. Neural theories of psychosis pathophysiology suggest that dysfunction worsens with illness stage. Here, we test the hypothesis that hippocampal function is impaired in the early stage of psychosis and declines further over the next 2 years. METHODS: We measured hippocampal function over 2 years using a scene processing task in 147 participants (76 individuals in the early stage of a non-affective psychotic disorder and 71 demographically similar healthy control individuals). Two-year follow-up was completed in 97 individuals (50 early psychosis, 47 healthy control). Voxelwise longitudinal analysis of activation in response to scenes was carried out within a hippocampal region of interest to test for group differences at baseline and a group by time interaction. RESULTS: At baseline, we observed lower anterior hippocampal activation in the early psychosis group relative to the healthy control group. Contrary to our hypothesis, hippocampal activation remained consistent and did not show the predicted decline over 2 years in the early psychosis group. Healthy controls showed a modest reduction in hippocampal activation after 2 years. CONCLUSIONS: The results of this study suggest that hippocampal dysfunction in early psychosis does not worsen over 2 years and highlight the need for longer-term longitudinal studies.

Incomplete hippocampal inversion in schizophrenia: prevalence, severity, and impact on hippocampal structure.

Incomplete hippocampal inversion (IHI) is an anatomical variant of the human brain resulting from an arrest in brain development, especially prevalent in the left hemisphere. We hypothesized that IHI is more common in schizophrenia and contributes to the well-known hippocampal structural differences. We studied 199 schizophrenia patients and 161 healthy control participants with 3 T MRI to establish IHI prevalence and the relationship of IHI with hippocampal volume and asymmetry. IHI was more prevalent (left hemisphere: 15% of healthy control participants, 27% of schizophrenia patients; right hemisphere: 4% of healthy control participants, 10% of schizophrenia patients) and more severe in schizophrenia patients compared to healthy control participants. Severe IHI cases were associated with a higher rate of automated segmentation failure. IHI contributed to smaller hippocampal volume and increased R > L volume asymmetry in schizophrenia. The increased prevalence and severity of IHI supports the neurodevelopmental model of schizophrenia. The impact of this developmental variant deserves further exploration in studies of the hippocampus in schizophrenia.

Manual segmentation of the human bed nucleus of the stria terminalis using 3T MRI.

The bed nucleus of the stria terminalis (BNST)-a small gray matter region located in the basal forebrain-has been implicated in both anxiety and addiction based on compelling evidence from rodent and non-human primate studies. However, the BNST's small size and proximity to other gray matter regions has hindered non-invasive study in human subjects using standard neuroimaging methods. While initial studies have benefitted from a BNST mask created from a single human subject using a 7T scanner, individual variability is likely-especially in patient populations-thus a manual segmentation protocol is needed. Here we report on the development of a reliable manual segmentation protocol performed on 3T MRI images using a scanning sequence that provides high gray matter/white matter/cerebrospinal fluid contrast. Inter- and intra-rater reliabilities, measured in 10 healthy individuals, demonstrate that the protocol can be reliably implemented (intra-rater Dice similarity coefficient≥0.85, inter-rater≥0.77). This BNST tracing protocol provides the necessary foundation for future 3T MRI studies of the BNST in healthy controls and patient populations.

Meta-analytic connectivity modeling reveals differential functional connectivity of the medial and lateral orbitofrontal cortex.

The orbitofrontal cortex (OFC) is implicated in a broad range of behaviors and neuropsychiatric disorders. Anatomical tracing studies in nonhuman primates reveal differences in connectivity across subregions of the OFC, but data on the connectivity of the human OFC remain limited. We applied meta-analytic connectivity modeling in order to examine which brain regions are most frequently coactivated with the medial and lateral portions of the OFC in published functional neuroimaging studies. The analysis revealed a clear divergence in the pattern of connectivity for the medial OFC (mOFC) and lateral OFC (lOFC) regions. The lOFC showed coactivations with a network of prefrontal regions and areas involved in cognitive functions including language and memory. In contrast, the mOFC showed connectivity with default mode, autonomic, and limbic regions. Convergent patterns of coactivations were observed in the amygdala, hippocampus, striatum, and thalamus. A small number of regions showed connectivity specific to the anterior or posterior sectors of the OFC. Task domains involving memory, semantic processing, face processing, and reward were additionally analyzed in order to identify the different patterns of OFC functional connectivity associated with specific cognitive and affective processes. These data provide a framework for understanding the human OFC's position within widespread functional networks.

Enhanced visual cortical activation for emotional stimuli is preserved in patients with unilateral amygdala resection.

Emotionally arousing pictures induce increased activation of visual pathways relative to emotionally neutral images. A predominant model for the preferential processing and attention to emotional stimuli posits that the amygdala modulates sensory pathways through its projections to visual cortices. However, recent behavioral studies have found intact perceptual facilitation of emotional stimuli in individuals with amygdala damage. To determine the importance of the amygdala to modulations in visual processing, we used functional magnetic resonance imaging to examine visual cortical blood oxygenation level-dependent (BOLD) signal in response to emotionally salient and neutral images in a sample of human patients with unilateral medial temporal lobe resection that included the amygdala. Adults with right (n = 13) or left (n = 5) medial temporal lobe resections were compared with demographically matched healthy control participants (n = 16). In the control participants, both aversive and erotic images produced robust BOLD signal increases in bilateral primary and secondary visual cortices relative to neutral images. Similarly, all patients with amygdala resections showed enhanced visual cortical activations to erotic images both ipsilateral and contralateral to the lesion site. All but one of the amygdala resection patients showed similar enhancements to aversive stimuli and there were no significant group differences in visual cortex BOLD responses in patients compared with controls for either aversive or erotic images. Our results indicate that neither the right nor left amygdala is necessary for the heightened visual cortex BOLD responses observed during emotional stimulus presentation. These data challenge an amygdalo-centric model of emotional modulation and suggest that non-amygdalar processes contribute to the emotional modulation of sensory pathways.

Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial.

Hippocampal hyperactivity is a novel pharmacological target in the treatment of schizophrenia. We hypothesized that levetiracetam (LEV), a drug binding to the synaptic vesicle glycoprotein 2 A, normalizes hippocampal activity in persons with schizophrenia and can be measured using neuroimaging methods. Thirty healthy control participants and 30 patients with schizophrenia (28 treated with antipsychotic drugs), were randomly assigned to a double-blind, cross-over trial to receive a single administration of 500 mg oral LEV or placebo during two study visits. At each visit, we assessed hippocampal function using resting state fractional amplitude of low frequency fluctuations (fALFF), cerebral blood flow (CBF) with arterial spin labeling, and hippocampal blood-oxygen-level-dependent (BOLD) signal during a scene processing task. After placebo treatment, we found significant elevations in hippocampal fALFF in patients with schizophrenia, consistent with hippocampal hyperactivity. Additionally, hippocampal fALFF in patients with schizophrenia after LEV treatment did not significantly differ from healthy control participants receiving placebo, suggesting that LEV may normalize hippocampal hyperactivity. In contrast to our fALFF findings, we did not detect significant group differences or an effect of LEV treatment on hippocampal CBF. In the context of no significant group difference in BOLD signal, we found that hippocampal recruitment during scene processing is enhanced by LEV more significantly in schizophrenia. We conclude that pharmacological modulation of hippocampal hyperactivity in schizophrenia can be studied with some neuroimaging methods, but not others. Additional studies in different cohorts, employing alternate neuroimaging methods and study designs, are needed to establish levetiracetam as a treatment for schizophrenia.

Smaller anterior hippocampal subfields in the early stage of psychosis.

Hippocampal volume is smaller in schizophrenia, but it is unclear when in the illness the changes appear and whether specific regions (anterior, posterior) and subfields (CA1, CA2/3, dentate gyrus, subiculum) are affected. Here, we used a high-resolution T2-weighted sequence specialized for imaging hippocampal subfields to test the hypothesis that anterior CA1 volume is lower in early psychosis. We measured subfield volumes across hippocampal regions in a group of 90 individuals in the early stage of a non-affective psychotic disorder and 70 demographically similar healthy individuals. We observed smaller volume in the anterior CA1 and dentate gyrus subfields in the early psychosis group. Our findings support models that implicate anterior CA1 and dentate gyrus subfield deficits in the mechanism of psychosis.

Relationship between functional connectivity and weight-gain risk of antipsychotics in schizophrenia.

BACKGROUND: The mechanisms by which antipsychotic medications (APs) contribute to obesity in schizophrenia are not well understood. Because AP effects on functional brain connectivity may contribute to weight effects, the current study investigated how AP-associated weight-gain risk relates to functional connectivity in schizophrenia. METHODS: Fifty-five individuals with schizophrenia (final N = 54) were divided into groups based on previously reported AP weight-gain risk (no APs/low risk [N = 19]; moderate risk [N = 17]; high risk [N = 18]). Resting-state functional magnetic resonance imaging (fMRI) was completed after an overnight fast ("fasted") and post-meal ("fed"). Correlations between AP weight-gain risk and functional connectivity were assessed at the whole-brain level and in reward- and eating-related brain regions (anterior insula, caudate, nucleus accumbens). RESULTS: When fasted, greater AP weight-gain risk was associated with increased connectivity between thalamus and sensorimotor cortex (pFDR = 0.021). When fed, greater AP weight-gain risk was associated with increased connectivity between left caudate and left precentral/postcentral gyri (pFDR = 0.048) and between right caudate and multiple regions, including the left precentral/postcentral gyri (pFDR = 0.001), intracalcarine/precuneal/cuneal cortices (pFDR < 0.001), and fusiform gyrus (pFDR = 0.008). When fed, greater AP weight-gain risk was also associated with decreased connectivity between right anterior insula and ventromedial prefrontal cortex (pFDR = 0.002). CONCLUSIONS: APs with higher weight-gain risk were associated with greater connectivity between reward-related regions and sensorimotor regions when fasted, perhaps relating to motor anticipation for consumption. Higher weight-gain risk APs were also associated with increased connectivity between reward, salience, and visual regions when fed, potentially reflecting greater desire for consumption following satiety.

Accurate Confidence and Bayesian Interval Estimation for Non-centrality Parameters and Effect Size Indices.

Reporting effect size index estimates with their confidence intervals (CIs) can be an excellent way to simultaneously communicate the strength and precision of the observed evidence. We recently proposed a robust effect size index (RESI) that is advantageous over common indices because it's widely applicable to different types of data. Here, we use statistical theory and simulations to develop and evaluate RESI estimators and confidence/credible intervals that rely on different covariance estimators. Our results show (1) counter to intuition, the randomness of covariates reduces coverage for Chi-squared and F CIs; (2) when the variance of the estimators is estimated, the non-central Chi-squared and F CIs using the parametric and robust RESI estimators fail to cover the true effect size at the nominal level. Using the robust estimator along with the proposed nonparametric bootstrap or Bayesian (credible) intervals provides valid inference for the RESI, even when model assumptions may be violated. This work forms a unified effect size reporting procedure, such that effect sizes with confidence/credible intervals can be easily reported in an analysis of variance (ANOVA) table format.

Hippocampal Network Dysfunction in Early Psychosis: A 2-Year Longitudinal Study.

Background: Hippocampal abnormalities are among the most consistent findings in schizophrenia. Numerous studies have reported deficits in hippocampal volume, function, and connectivity in the chronic stage of illness. While hippocampal volume and function deficits are also present in the early stage of illness, there is mixed evidence of both higher and lower functional connectivity. Here, we use graph theory to test the hypothesis that hippocampal network connectivity is broadly lowered in early psychosis and progressively worsens over 2 years. Methods: We examined longitudinal resting-state functional connectivity in 140 participants (68 individuals in the early stage of psychosis, 72 demographically similar healthy control individuals). We used an anatomically driven approach to quantify hippocampal network connectivity at 2 levels: 1) a core hippocampal-medial temporal lobe cortex (MTLC) network; and 2) an extended hippocampal-cortical network. Group and time effects were tested in a linear mixed effects model. Results: Early psychosis patients showed elevated functional connectivity in the core hippocampal-MTLC network, but contrary to our hypothesis, did not show alterations within the broader hippocampal-cortical network. Hippocampal-MTLC network hyperconnectivity normalized longitudinally and predicted improvement in positive symptoms but was not associated with increasing illness duration. Conclusions: These results show abnormally elevated functional connectivity in a core hippocampal-MTLC network in early psychosis, suggesting that selectively increased hippocampal signaling within a localized cortical circuit may be a marker of the early stage of psychosis. Hippocampal-MTLC hyperconnectivity could have prognostic and therapeutic implications.

Evaluation of resampling-based inference for topological features of neuroimages.

Many recent studies have demonstrated the inflated type 1 error rate of the original Gaussian random field (GRF) methods for inference of neuroimages and identified resampling (permutation and bootstrapping) methods that have better performance. There has been no evaluation of resampling procedures when using robust (sandwich) statistical images with different topological features (TF) used for neuroimaging inference. Here, we consider estimation of distributions TFs of a statistical image and evaluate resampling procedures that can be used when exchangeability is violated. We compare the methods using realistic simulations and study sex differences in life-span age-related changes in gray matter volume in the Nathan Kline Institute Rockland sample. We find that our proposed wild bootstrap and the commonly used permutation procedure perform well in sample sizes above 50 under realistic simulations with heteroskedasticity. The Rademacher wild bootstrap has fewer assumptions than the permutation and performs similarly in samples of 100 or more, so is valid in a broader range of conditions. We also evaluate the GRF-based pTFCE method and show that it has inflated error rates in samples less than 200. Our R package, pbj , is available on Github and allows the user to reproducibly implement various resampling-based group level neuroimage analyses.

Incomplete Hippocampal Inversion: A Neurodevelopmental Mechanism for Hippocampal Shape Deformation in Schizophrenia.

BACKGROUND: Shape analyses of patients with schizophrenia have revealed bilateral deformations of the anterolateral hippocampus, primarily localized to the CA1 subfield. Incomplete hippocampal inversion (IHI), an anatomical variant of the human hippocampus resulting from an arrest during neurodevelopment, is more prevalent and severe in patients with schizophrenia. We hypothesized that IHI would affect the shape of the hippocampus and contribute to hippocampal shape differences in schizophrenia. METHODS: We studied 199 patients with schizophrenia and 161 healthy control participants with structural magnetic resonance imaging to measure the prevalence and severity of IHI. High-fidelity hippocampal surface reconstructions were generated with the SPHARM-PDM toolkit. We used general linear models in SurfStat to test for group shape differences, the impact of IHI on hippocampal shape variation, and whether IHI contributes to hippocampal shape abnormalities in schizophrenia. RESULTS: Not including IHI as a main effect in our between-group comparison replicated well-established hippocampal shape differences in patients with schizophrenia localized to the CA1 subfield in the anterolateral hippocampus. Shape differences were also observed near the uncus and hippocampal tail. IHI was associated with outward displacements of the dorsal and ventral surfaces of the hippocampus and inward displacements of the medial and lateral surfaces. Including IHI as a main effect in our between-group comparison eliminated the bilateral shape differences in the CA1 subfield. Shape differences in the uncus persisted after including IHI. CONCLUSIONS: IHI impacts hippocampal shape. Our results suggest IHI as a neurodevelopmental mechanism for the well-known shape differences, particularly in the CA1 subfield, in schizophrenia.

Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study.

Neuroimaging studies have revealed hippocampal hyperactivity in schizophrenia. In the early stage of the illness, hyperactivity is present in the anterior hippocampus and is thought to spread to other regions as the illness progresses. However, there is limited evidence for changes in basal hippocampal function following the onset of psychosis. Resting state functional MRI signal amplitude may be a proxy measure for increased metabolism and disrupted oscillatory activity, both consequences of an excitation/inhibition imbalance underlying hippocampal hyperactivity. Here, we used fractional amplitude of low frequency fluctuations (fALFF) to test the hypothesis of progressive hippocampal hyperactivity in a two-year longitudinal case-control study. We found higher fALFF in the anterior and posterior hippocampus of individuals in the early stage of non-affective psychosis at study entry. Contrary to our hypothesis of progressive hippocampal dysfunction, we found evidence for normalization of fALFF over time in psychosis. Our findings support a model in which hippocampal fALFF is a marker of psychosis vulnerability or acute illness state rather than an enduring feature of the illness.

The Medical Segmentation Decathlon.

International challenges have become the de facto standard for comparative assessment of image analysis algorithms. Although segmentation is the most widely investigated medical image processing task, the various challenges have been organized to focus only on specific clinical tasks. We organized the Medical Segmentation Decathlon (MSD)-a biomedical image analysis challenge, in which algorithms compete in a multitude of both tasks and modalities to investigate the hypothesis that a method capable of performing well on multiple tasks will generalize well to a previously unseen task and potentially outperform a custom-designed solution. MSD results confirmed this hypothesis, moreover, MSD winner continued generalizing well to a wide range of other clinical problems for the next two years. Three main conclusions can be drawn from this study: (1) state-of-the-art image segmentation algorithms generalize well when retrained on unseen tasks; (2) consistent algorithmic performance across multiple tasks is a strong surrogate of algorithmic generalizability; (3) the training of accurate AI segmentation models is now commoditized to scientists that are not versed in AI model training.

Stable habituation deficits in the early stage of psychosis: a 2-year follow-up study.

Neural habituation, the decrease in brain response to repeated stimuli, is a fundamental, highly conserved mechanism that acts as an essential filter for our complex sensory environment. Convergent evidence indicates neural habituation is disrupted in both early and chronic stages of schizophrenia, with deficits co-occurring in brain regions that show inhibitory dysfunction. As inhibitory deficits have been proposed to contribute to the onset and progression of illness, habituation may be an important treatment target. However, a crucial first step is clarifying whether habituation deficits progress with illness. In the present study, we measured neural habituation in 138 participants (70 early psychosis patients (<2 years of illness), 68 healthy controls), with 108 participants assessed longitudinally at both baseline and 2-year follow-up. At follow-up, all early psychosis patients met criteria for a schizophrenia spectrum disorder (i.e., schizophreniform disorder, schizophrenia, schizoaffective disorder). Habituation slopes (i.e., rate of fMRI signal change) to repeated images were computed for the anterior hippocampus, occipital cortex, and the fusiform face area. Habituation slopes were entered into a linear mixed model to test for effects of group and time by region. We found that early psychosis patients showed habituation deficits relative to healthy control participants across brain regions, and that these deficits were maintained, but did not worsen, over two years. These results suggest a stable period of habituation deficits in the early stage of schizophrenia.

BNST and amygdala connectivity are altered during threat anticipation in schizophrenia.

In schizophrenia, impairments in affect are prominent and anxiety disorders are prevalent. Neuroimaging studies of fear and anxiety in schizophrenia have focused on the amygdala and show alterations in connectivity. Emerging evidence suggests that the bed nucleus of the stria terminalis (BNST) also plays a critical role in anxiety, especially during anticipation of an unpredictable threat; however, previous studies have not examined the BNST in schizophrenia. In the present study, we examined BNST function and connectivity in people with schizophrenia (n = 31; n = 15 with comorbid anxiety) and controls (n = 15) during anticipation of unpredictable and predictable threat. A secondary analysis tested for differences in activation and connectivity of the central nucleus of the amygdala (CeA), which has also been implicated in threat anticipation. Analyses tested for group differences in both activation and connectivity during anticipation of unpredictable threat and predictable threat (p < .05). Relative to controls, individuals with schizophrenia showed stronger BNST-middle temporal gyrus (MTG) connectivity during unpredictable threat anticipation and stronger BNST-MTG and BNST-dorsolateral prefrontal connectivity during predictable threat anticipation. Comparing subgroups of individuals with schizophrenia and a comorbid anxiety disorder (SZ+ANX) to those without an anxiety disorder (SZ-ANX) revealed broader patterns of altered connectivity. During unpredictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions of the salience network (insula, dorsal anterior cingulate cortex). During predictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions associated with fear processing (insula, extended amygdala, prefrontal cortex). A secondary CeA analysis revealed a different pattern; the SZ+ANX group had weaker CeA connectivity across multiple brain regions during threat anticipation compared to the SZ-ANX group. These findings provide novel evidence for altered functional connectivity during threat anticipation in schizophrenia, especially in individuals with comorbid anxiety.

Automated, open-source segmentation of the Hippocampus and amygdala with the open Vanderbilt archive of the temporal lobe.

Examining volumetric differences of the amygdala and anterior-posterior regions of the hippocampus is important for understanding cognition and clinical disorders. However, the gold standard manual segmentation of these structures is time and labor-intensive. Automated, accurate, and reproducible techniques to segment the hippocampus and amygdala are desirable. Here, we present a hierarchical approach to multi-atlas segmentation of the hippocampus head, body and tail and the amygdala based on atlases from 195 individuals. The Open Vanderbilt Archive of the temporal Lobe (OVAL) segmentation technique outperforms the commonly used FreeSurfer, FSL FIRST, and whole-brain multi-atlas segmentation approaches for the full hippocampus and amygdala and nears or exceeds inter-rater reproducibility for segmentation of the hippocampus head, body and tail. OVAL has been released in open-source and is freely available.

Relational Memory in the Early Stage of Psychosis: A 2-Year Follow-up Study.

BACKGROUND: Relational memory, the ability to bind information into complex memories, is moderately impaired in early psychosis and severely impaired in chronic schizophrenia, suggesting relational memory may worsen throughout the course of illness. METHODS: We examined relational memory in 66 early psychosis patients and 64 healthy control subjects, with 59 patients and 52 control subjects assessed longitudinally at baseline and 2-year follow-up. Relational memory was assessed with 2 complementary tasks, to test how individuals learn relationships between items (face-scene binding task) and make inferences about trained relationships (associative inference task). RESULTS: The early psychosis group showed impaired relational memory in both tasks relative to the healthy control group. The ability to learn relationships between items remained impaired in early psychosis patients, while the ability to make inferences about trained relationships improved, although never reaching the level of healthy control performance. Early psychosis patients who did not progress to schizophrenia at follow-up had better relational memory than patients who did. CONCLUSIONS: Relational memory impairments, some of which improve and are less severe in patients who do not progress to schizophrenia, are a target for intervention in early psychosis.

Cognitive motor impairments and brain structure in schizophrenia spectrum disorder patients with a history of catatonia.

There is growing interest in understanding the behavioral and neural mechanisms of catatonia. Here, we examine cognition and brain structure in schizophrenia spectrum disorder (SSD) patients with a history of catatonia. A total of 172 subjects were selected from a data repository; these included SSD patients with (n = 43) and without (n = 43) a history of catatonia and healthy control subjects (n = 86). Cognitive functioning was assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) and brain structure was assessed using voxel-based morphometry (VBM) in the CAT12 toolbox. SSD patients with a history of catatonia showed worse performance on tests of verbal fluency and processing speed compared to SSD patients without such a history, even after controlling for current antipsychotic and benzodiazepine use. No differences were found between patients with and without a history of catatonia in terms of brain structure. Both patient groups combined showed significantly smaller grey matter volumes compared to healthy control subjects in brain regions consistent with prior studies, including the anterior cingulate, insular, temporal, and medial frontal cortices. The results highlight a cognitive-motor impairment in SSD patients with a history of catatonia. Challenges and limitations of examining brain structure in patients with a history of catatonia are discussed.