Hippocampal Commissure Research Articles

Malformations of the Cerebral Commissures

AbstractMalformations of the cerebral commissures are abnormalities involving the structures which connect the brain hemispheres. The main cerebral commissures are the anterior commissure, the hippocampal commissure, and the corpus callosum, which is the largest and best known of the three and connects the neocortex of the two cerebral hemispheres. Commissures of more reduced extension are the posterior commissure and the habenular commissure. They derive embryologically from the same structure, the commensurate plate. Any interference in the embryological development of the brain commissures may cause an anomaly of all the three commissures or of a single commissure, as well as any combination of anomalies of each of them.Each of these three commissural traits may be absent, isolated, or in combination. The abnormality of the commissures, in addition, can be complete or partial, with dysplasia of the meninges, with multicystic dysplasia of the interhemispheric meninges, in the context of Aicardi syndrome or with the presence of interhemispheric lipomas.The complete agenesis of the commissures (“classic” form) is the most common form and encompasses more than a third of the cases. In complete agenesis, by definition, both the corpus callosum and the hippocampal commissure are totally absent.Anomalies of the commissural structures associated with dysplasia of the meninges include the agenesis of the corpus callosum with interhemispheric cysts (a complex spectrum of clinical and neuroradiological conditions characterized by the associated presence of an interhemispheric cyst formed by communicating cavities) and the agenesis of commissures with interhemispheric lipomas that are usually located in the subarachnoid space.Genes responsible for axonal migration to the commissural plate and those responsible for crossing and connections with the neurons of the contralateral hemisphere are multiple, so that malformations of the cerebral commissure/corpus callosum can be found in numerous malformative syndromes with other multiple associated abnormalities.

Disruption of awake sharp-wave ripples does not affect memorization of locations in repeated-acquisition spatial memory tasks.

Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through space. However, it is unclear if awake replay impacts immediate future behavior, gradually creates and stabilizes long-term memories over a long period of time (hours and longer), or enables the temporary memorization of relevant events at an intermediate time scale (seconds to minutes). In this study, we aimed to address the uncertainty around the timeframe of impact of awake replay by collecting causal evidence from behaving rats. We detected and disrupted sharp wave ripples (SWRs) - signatures of putative replay events - using electrical stimulation of the ventral hippocampal commissure in rats that were trained on three different spatial memory tasks. In each task, rats were required to memorize a new set of locations in each trial or each daily session. Interestingly, the rats performed equally well with or without SWR disruptions. These data suggest that awake SWRs - and potentially replay - does not affect the immediate behavior nor the temporary memorization of relevant events at a short timescale that are required to successfully perform the spatial tasks. Based on these results, we hypothesize that the impact of awake replay on memory and behavior is long-term and cumulative over time.

Structural interhemispheric connectivity defects in mouse models of BBSOAS: Insights from high spatial resolution 3D white matter tractography

White matter (WM) tract formation and axonal pathfinding are major processes in brain development allowing to establish precise connections between targeted structures. Disruptions in axon pathfinding and connectivity impairments will lead to neural circuitry abnormalities, often associated with various neurodevelopmental disorders (NDDs). Among several neuroimaging methodologies, Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) technique that has the advantage of visualizing in 3D the WM tractography of the whole brain non-invasively. DTI is particularly valuable in unpinning structural tract connectivity defects of neural networks in NDDs. In this study, we used 3D DTI to unveil brain-specific tract defects in two mouse models lacking the Nr2f1 gene, which mutations in patients have been proven to cause an emerging NDD, called Bosch-Boonstra-Schaaf Optic Atrophy (BBSOAS). We aimed to investigate the impact of the lack of cortical Nr2f1 function on WM morphometry and tract microstructure quantifications. We found in both mutant mice partial loss of fibers and severe misrouting of the two major cortical commissural tracts, the corpus callosum, and the anterior commissure, as well as the two major hippocampal efferent tracts, the post-commissural fornix, and the ventral hippocampal commissure. DTI tract malformations were supported by 2D histology, 3D fluorescent imaging, and behavioral analyses. We propose that these interhemispheric connectivity impairments are consistent in explaining some cognitive defects described in BBSOAS patients, particularly altered information processing between the two brain hemispheres. Finally, our results highlight 3DDTI as a relevant neuroimaging modality that can provide appropriate morphometric biomarkers for further diagnosis of BBSOAS patients.

Spatial and amplitude dynamics of neurostimulation: Insights from the acute intrahippocampal kainate seizure mouse model.

Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode's placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure-like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy.

Direct interhemispheric cortical communication via thalamic commissures: a new white matter pathway in the primate brain.

Cortical neurons of eutherian mammals project to the contralateral hemisphere, crossing the midline primarily via the corpus callosum and the anterior, posterior, and hippocampal commissures. We recently reported and named the thalamic commissures (TCs) as an additional interhemispheric axonal fiber pathway connecting the cortex to the contralateral thalamus in the rodent brain. Here, we demonstrate that TCs also exist in primates and characterize the connectivity of these pathways with high-resolution diffusion-weighted MRI, viral axonal tracing, and fMRI. We present evidence of TCs in both New World (Callithrix jacchus and Cebus apella) and Old World primates (Macaca mulatta). Further, like rodents, we show that the TCs in primates develop during the embryonic period, forming anatomical and functionally active connections of the cortex with the contralateral thalamus. We also searched for TCs in the human brain, showing their presence in humans with brain malformations, although we could not identify TCs in healthy subjects. These results pose the TCs as a vital fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations.

Retrovirus-Derived RTL/SIRH: Their Diverse Roles in the Current Eutherian Developmental System and Contribution to Eutherian Evolution.

Eutherians have 11 retrotransposon Gag-like (RTL)/sushi-ichi retrotransposon homolog (SIRH) genes presumably derived from a certain retrovirus. Accumulating evidence indicates that the RTL/SIRH genes play a variety of roles in the current mammalian developmental system, such as in the placenta, brain, and innate immune system, in a eutherian-specific manner. It has been shown that the functional role of Paternally Expressed 10 (PEG10) in placental formation is unique to the therian mammals, as are the eutherian-specific roles of PEG10 and PEG11/RTL1 in maintaining the fetal capillary network and the endocrine regulation of RTL7/SIRH7 (aka Leucine Zipper Down-Regulated in Cancer 1 (LDOCK1)) in the placenta. In the brain, PEG11/RTL1 is expressed in the corticospinal tract and hippocampal commissure, mammalian-specific structures, and in the corpus callosum, a eutherian-specific structure. Unexpectedly, at least three RTL/SIRH genes, RTL5/SIRH8, RTL6/SIRH3, and RTL9/SIRH10, play important roles in combating a variety of pathogens, namely viruses, bacteria, and fungi, respectively, suggesting that the innate immunity system of the brain in eutherians has been enhanced by the emergence of these new components. In this review, we will summarize the function of 10 out of the 11 RTL/SIRH genes and discuss their roles in eutherian development and evolution.

The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus.

We studied changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus. Rats under urethane anesthesia were implanted with stimulating electrodes in the ventral hippocampal commissure and dMSA and a recording electrode in the CA1 area of the hippocampus. We found that high-frequency stimulation (HFS) of the dMSA led to the induction of long-term potentiation in the synapses formed by the ventral hippocampal commissure on the hippocampal CA1 neurons. One hour after dMSA HFS, we collected the dorsal and ventral hippocampi on both the ipsilateral (damaged by the implanted electrode) and contralateral (intact) sides and analyzed the expression of genes by qPCR. The dMSA HFS led to an increase in the expression of bdnf and cyr61 in the ipsilateral hippocampi and egr1 in the ventral contralateral hippocampus. Thus, dMSA HFS under the conditions of degeneration of the cholinergic neurons in the medial septal area prevented the described increase in gene expression. The changes in cyr61 expression appeared to be dependent on the muscarinic M1 receptors. Our data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.

CA3-CA1 long-term potentiation occurs regardless of respiration and cardiac cycle phases in urethane-anesthetized rats.

Breathing and heartbeat synchronize to each other and to brain function and affect cognition in humans. However, it is not clear how cardiorespiratory rhythms modulate such basic processes as synaptic plasticity thought to underlie learning. Thus, we studied if respiration and cardiac cycle phases at burst stimulation onset affect hippocampal long-term potentiation (LTP) in the CA3-CA1 synapse in urethane-anesthetized adult male Sprague-Dawley rats. In a between-subjects design, we timed burst stimulation of the ventral hippocampal commissure (vHC) to systole or diastole either during expiration or inspiration and recorded responses throughout the hippocampus with a linear probe. As classical conditioning in humans seems to be most efficient at expiration-diastole, we also expected LTP to be most efficient if burst stimulation was targeted to expiration-diastole. However, LTP was induced equally in all four groups and respiration and cardiac cycle phase did not modulate CA1 responses to vHC stimulation overall. This could be perhaps because we bypassed all natural routes of external influences on the CA1 by directly stimulating the vHC. In the future, the effect of cardiorespiratory rhythms on synaptic plasticity could also be studied in awake state and in other parts of the hippocampal tri-synaptic loop.

BILATERAL SYNCHRONIZATION OF HIPPOCAMPAL THETA-OSCILLATIONS <i>IN VITRO</i>

Hippocampal theta oscillations are pivotal for hippocampal functions of spatial navigation, learning and memory. In the behaving animals in vivo, hippocampal theta oscillations display bilateral synchronization. Internally generated oscillations in the theta frequency range have also been described in the intact hippocampus preparation in vitro. How theta oscillations are synchronized between the left and right hippocampi remains elusive, however. We used preparation of the intact hippocampi interconnected by the ventral hippocampal commissure prepared from juvenile and adult mice and rats in vitro. Local field potentials and multiunit activity were recorded using extracellular electrodes from the pyramidal cell layer and stratum radiatum of the left and right hippocampi. Neuronal network activity in the left and right hippocampi was organized in theta oscillations, which strongly modulated neuronal firing of CA1 neurons. Both neuronal activity and field potential theta oscillations showed high levels of bilateral synchronization. Theta oscillations persisted on both sides, but their bilateral synchronization was eliminated after surgical cut of the ventral hippocampal commissure. Thus, theta oscillations are synchronized in the left and right hippocampi in vitro, and their bilateral synchronization is provided by the ventral commissural connections.

Transportation Stress Increases Fos Immunoreactivity in the Paraventricular Nucleus, but Not in the Nucleus of the Hippocampal Commissure in the Pekin Duck, Anas platyrhynchos domesticus.

Commercial poultry undergo transportation during their life, and the effects of transportation can negatively impact poultry production and welfare. In order to maintain physiological homeostasis, the hypothalamic-pituitary-adrenal axis (HPA) works to respond to stressors. Previous studies by others have shown contradictory effects of transportation on corticosterone release. However, recent studies from our lab and by others have shown that cortisol may also be an important hormone in the avian HPA. The purpose of our current study was to determine the effects of transportation stress on the stimulation of brain nuclei that regulate the HPA in birds, and on glucocorticoid (GC) secretion. To test this hypothesis, we collected blood and brain samples from developer drakes and hens (N = 10 per sex/time point): 24 h prior to transportation, immediately after transportation, 24 h after transportation, and 1 week after transportation. Serum GC levels and fos immunocytochemistry (ICC) within the nucleus of the hippocampal commissure (NHpC) and paraventricular nucleus (PVN) were measured. Data were analyzed using a two-way ANOVA. Post hoc analysis was completed using a Fisher's PLSD with a p < 0.05 considered significant. We observed a sex difference (p < 0.05) in both corticosterone and cortisol secretion in Pekin ducks, although neither GC showed a significant increase in secretion associated with transportation. However, we did observe a significant (p < 0.05) increase in fos-like immunoreactivity for 24 h in the PVN, but not in the NHpC. Further studies are required to determine the specific role that GCs play in the avian stress response and the short-term stressors that could have long-term physiological effects on birds.

Interaction between the hypothalamo-pituitary-adrenal and thyroid axes during immobilization stress.

The location of corticotropin-releasing hormone receptor 2 (CRH-R2) on thyrotropes within the avian anterior pituitary (APit) and its activation by different stressors indicate a possible communication between hypothalamo-pituitary-adrenal (HPA) and thyroid (HPT) axes. Therefore, an experiment was designed to 1) compare the timing of major components of the HPT axis to those of the HPA axis; 2) address whether stressors activating the HPA axis may simultaneously upregulate components of the HPT axis. Blood, brain, and APit were sampled from chicks prior to stress (control) and 15, 30, 60, 90, and 120min following immobilization (IM) stress. The nucleus of the hippocampal commissure (NHpC) and paraventricular nucleus (PVN) were cryo-dissected from brains for RT-qPCR. Gene expression of thyrotropin-releasing hormone (TRH) and its receptors (TRH-R1 and TRH-R3), urocortin3 (UCN3), deiodinase 2 (D2), and the second type of corticotropin-releasing hormone (CRH2) within the NHpC and PVN was measured. Additionally, gene expression of TRH receptors, thyroid stimulating hormone subunit beta (TSHβ), and D2 was determined in the APit and corticosterone assayed in blood. In brains, a significant upregulation in examined genes occurred at different times of IM. Specifically, UCN3 and CRH2 which have a high affinity to CRH-R2 showed a rapid increase in their mRNA levels that were accompanied by an early upregulation of TRHR1 in the NHpC. In the APit, a significant increase in gene expression of TSHβ and TRH receptors was observed. Therefore, results supported concurrent activation of major brain and APit genes associated with the HPA and HPT axes following IM. The initial neural gene expression originating within the NHpC resulted in the increase of TSHβ mRNA in the APit. Specifically, the rapid upregulation of UCN3 in the NHpC appeared responsible for the early activation of TSHβ in the APit. While sustaining TSHβ activation appeared to be due to both CRH2 and TRH. Therefore, data indicate that CRH-producing neurons and corticotropes as well as CRH- and TRH-producing neurons and thyrotropes are activated to produce the necessary energy required to maintain homeostasis in birds undergoing stress. Overall, data support the inclusion of the NHpC in the classical avian HPA axis and for the first time show the concurrent activation of the HPA axis and components of the HPT axis following a psychogenic stressor.

Simultaneous Cellular Imaging, Electrical Recording and Stimulation of Hippocampal Activity in Freely Behaving Mice.

Hippocampal sharp-wave ripple activity (SWRs) and the associated replay of neural activity patterns are well-known for their role in memory consolidation. This activity has been studied using electrophysiological approaches, as high temporal resolution is required to recognize SWRs in the neuronal signals. However, it has been difficult to analyze the individual contribution of neurons to task-specific SWRs, because it is hard to track neurons across a long time with electrophysiological recording. In this study, we recorded local field potential (LFP) signals in the hippocampal CA1 of freely behaving mice and simultaneously imaged calcium signals in contralateral CA1 to leverage the advantages of both electrophysiological and imaging approaches. We manufactured a custom-designed microdrive array and targeted tetrodes to the left hippocampus CA1 for LFP recording and applied electrical stimulation in the ventral hippocampal commissure (VHC) for closed-loop disruption of SWRs. Neuronal population imaging in the right hippocampal CA1 was performed using a miniature fluorescent microscope (Miniscope) and a genetically encoded calcium indicator. As SWRs show highly synchronized bilateral occurrence, calcium signals of SWR-participating neurons could be identified and tracked in spontaneous or SWR-disrupted conditions. Using this approach, we identified a subpopulation of CA1 neurons showing synchronous calcium elevation to SWRs. Our results showed that SWR-related calcium transients are more disrupted by electrical stimulation than non-SWR-related calcium transients, validating the capability of the system to detect and disrupt SWRs. Our dual recording method can be used to uncover the dynamic participation of individual neurons in SWRs and replay over extended time windows.

Human Fetal Brain Magnetic Resonance Imaging (MRI) Tells Future Emergence of Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which can result from a range of observed symptoms pertaining to social, emotional, and cognitive processing difficulties especially regarding communication of their own feelings, opinions, and thoughts with others. Although a diagnosis received by 1 in 68 children in the United States, a cause for autism is still unknown. Both genetic and environmental factors during prenatal and postnatal development are believed to account for the emergence of ASD. It is known that early treatment improves language and cognitive abilities later. However, currently, the earliest diagnosis of ASD can be made only around 18 months of age. It is critical to be aware of an altered initial brain anatomy in ASD for better predicting what aspects of brain function will likely preferentially and precociously deteriorate, which would allow for potentially earlier/better prevention and treatment. We hypothesized that prospective ASD patients will show region‐specific abnormalities in developmental stages. We have used retrospective clinical brain MRI of the fetuses who were diagnosed as ASD in later age to obtain earliest MRI‐based regional volumetric biomarkers. Thirty‐nine fetuses (mean age 24.87 ± 5.05 gestational week [GW]) were included in this study (9 prospective ASD patients, 20 neurotypical controls, 6 non‐ASD controls with neurological comorbidities observed in the prospective ASD patients, and 4 non‐ASD controls with non‐neurological comorbidities observed in the prospective ASD patients. After preprocessing, the images were segmented automatically with an atlas‐based automated anatomical labeling method. A set of three‐factor ANOVA was performed for lobar and regional comparisons of the segmented brain regions. The insula/insular lobe showed statistically significantly larger volume in ASD than that in all three control groups in the lobar comparison. In the regional comparison, the ASD group had statistically significantly larger amygdala, hippocampal commissure, and insula compared to the non‐ASD controls with neurological and non‐neurological comorbidities. Our results suggest that an increased volume of the insula/insular lobe may be a strong prenatal MRI biomarker that could predict the emergence of ASD later in life. The larger amygdala and hippocampal commissure could be additional biomarkers for identifying such prospective ASD patients.

De Novo GLI3 Pathogenic Variants May Cause Hypotonia and a Range of Brain Malformations Without Skeletal Abnormalities

BackgroundGLI3 encodes a zinc finger transcription factor that plays a role in the sonic hedgehog pathway. Germline pathogenic GLI3 variants are associated with Greig cephalopolysyndactyly and Pallister-Hall syndromes, two syndromes involving brain malformation and polydactyly. MethodsWe identified patients with pathogenic GLI3 variants and brain malformations in the absence of polydactyly or other skeletal malformation. ResultsTwo patients were identified. Patient #1 is a 4-year-old boy with hypotonia and global developmental delay. Brain MRI showed a focal cortical dysplasia, but he had no history of seizures. Genetic testing identified a de novo likely pathogenic GLI3 variant: c.4453A>T, p.Asn1485Tyr. Patient #2 is a 4-year-old boy with hypotonia, macrocephaly, and global developmental delay. His brain MRI showed partial agenesis of the corpus callosum, dilatation of the right lateral ventricle, and absent hippocampal commissure. Genetic testing identified a de novo pathogenic GLI3 variant: c.4236_4237del, p.Gln1414AspfsTer21. Neither patient had polydactyly or any apparent skeletal abnormality. ConclusionsThese patients widen the spectrum of clinical features that may be associated with GLI3 pathogenic variants to include hypotonia, focal cortical dysplasia, and other brain malformations, in the absence of apparent skeletal malformation. Further study is needed to determine if GLI3 pathogenic variants are a more common cause of focal cortical dysplasia or corpus callosum agenesis than presently recognized.

Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain

During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities.

Normal Growth, Sexual Dimorphism, and Lateral Asymmetries at Fetal Brain MRI.

Background Tools in image reconstruction, motion correction, and segmentation have enabled the accurate volumetric characterization of fetal brain growth at MRI. Purpose To evaluate the volumetric growth of intracranial structures in healthy fetuses, accounting for gestational age (GA), sex, and laterality with use of a spatiotemporal MRI atlas of fetal brain development. Materials and Methods T2-weighted 3.0-T half-Fourier acquired single-shot turbo spin-echo sequence MRI was performed in healthy fetuses from prospectively recruited pregnant volunteers from March 2013 to May 2019. A previously validated section-to-volume reconstruction algorithm was used to generate intensity-normalized superresolution three-dimensional volumes that were registered to a fetal brain MRI atlas with 28 anatomic regions of interest. Atlas-based segmentation was performed and manually refined. Labels included the bilateral hippocampus, amygdala, caudate nucleus, lentiform nucleus, thalamus, lateral ventricle, cerebellum, cortical plate, hemispheric white matter, internal capsule, ganglionic eminence, ventricular zone, corpus callosum, brainstem, hippocampal commissure, and extra-axial cerebrospinal fluid. For fetuses younger than 31 weeks of GA, the subplate and intermediate zones were delineated. A linear regression analysis was used to determine weekly age-related change adjusted for sex and laterality. Results The final analytic sample consisted of 122 MRI scans in 98 fetuses (mean GA, 29 weeks ± 5 [range, 20-38 weeks]). All structures had significant volume growth with increasing GA (P < .001). Weekly age-related change for individual structures in the brain parenchyma ranged from 2.0% (95% CI: 0.9, 3.1; P < .001) in the hippocampal commissure to 19.4% (95% CI: 18.7, 20.1; P < .001) in the cerebellum. The largest sex-related differences were 22.1% higher volume in male fetuses for the lateral ventricles (95% CI: 10.9, 34.4; P < .001). There was rightward volumetric asymmetry of 15.6% for the hippocampus (95% CI: 14.2, 17.2; P < .001) and leftward volumetric asymmetry of 8.1% for the lateral ventricles (95% CI: 3.7, 12.2; P < .001). Conclusion With use of a spatiotemporal MRI atlas, volumetric growth of the fetal brain showed complex trajectories dependent on structure, gestational age, sex, and laterality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Rollins in this issue.

Transection of the ventral hippocampal commissure impairs spatial reference but not contextual or spatial working memory.

Plasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus provides such a balance via hemispheric lateralization, with the left hemisphere dominant in providing plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric convergence of input from these pathways is essential for integrating spatial memory stored in the left CA3 with navigational working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent navigational working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing navigational working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.

The human dorsal hippocampal commissure: Delineating connections across the midline using multi-modal neuroimaging in major depressive disorder

Reclining on the lyra of the fornix, the dorsal hippocampal commissure (DHC) facilitates communication between the left and right hippocampi. Despite being a key commissural fiber bundle of the hippocampus, the DHC remains relatively underexplored in humans. Using high-resolution T1 and T2 magnetic resonance imaging in conjunction with High Angular Resolution Diffusion Imaging and Constrained Spherical Deconvolution tractography, we investigated if there are differences between the DHC of a sample of 54 healthy controls and 38 patients diagnosed with Major Depressive Disorder (MDD). After isolating the DHC using an anatomically derived protocol, segmented volumes of the left and right temporal pole, amygdala, hippocampus and parahippocampal gyrus extracted. In both controls and MDD patients, DHC fibers were spread across each of these four regions, with the parahippocampal gyri contributing the most to the volume of this white matter tract. Furthermore, diffusion metrics showed no effect of aging or sex on the integrity of the DHC in either group. This study is the first to investigate the DHC in MDD and the first to demonstrate that the DHC connects with the amygdala and temporal pole on both sides of the brain. Our data shows that the human DHC, rather than simply connecting the left and right hippocampi, allows connections between each hippocampus and the contralateral temporal pole, amygdala and parahippocampal gyrus. This suggests that the human temporal lobe, and the parahippocampal gyrus, may exert more influence on the contralateral limbic system via the DHC than previously thought.

P2. Unsupervised anomaly detection for diagnosing brain disorders from EEG recordings – Results from a rodent epilepsy model

We present a general machine learning (ML) framework for diagnosing brain disorders using EEG recordings. It could detect any systematic deviations from the baseline (BL) EEG recordings. We test the approach using a rodent model of an acquired mesial temporal lobe epilepsy (mTLE) via electrical perforant pathway stimulation (PPS) [1] followed by usually a latent period of several weeks of epileptogenesis (EPG) progression without any seizures. Identifying ongoing EPG during this latent period prior to the first spontaneous seizure might enable early intervention. Previous supervised approaches have proven that deep neural networks can distinguish intracranial EEG signals between the BL period prior to PPS and the EPG period after PPS [2]. Here, we formulate the problem as an unsupervised anomaly detection task, which allows learning the statistics of the input data without the need for any labels as in supervised approaches. Specifically, we first train an autoencoder (AE) to learn to encode EEG data from the BL period. We then apply the trained AE on data from the EPG period. We expect that activity patterns systematically deviating from those observed during BL should be characterized by higher reconstruction errors (REs). Indeed, our results show that REs averaged over one hour gradually increase as a function of time after the PPS (Fig. 1). We also find that the distribution of REs from the BL and the EPG phases are significantly different (Fig. 1B). EEG segments with particularly high REs exhibit spikes and high frequency oscillations (Fig. 1B, right inset). Interestingly, there are an increased large number of segments with unusually low REs (Fig. 1B, left inset), which exhibits EEG slowing and delta rhythm (1.5–3 Hz). In conclusion, we showed that unsupervised ML with AEs allows the automatic detection of systematic drifts in brain activity, which may facilitate rapid EEG recordings for early diagnosis of brain disorders and open the door for early interventions. References Costard, L.S., Neubert, V., Venø, M.T., Su, J., Kjems, J., Connolly, N.M., Prehn, J.H., Schratt, G., Henshall, D.C., Rosenow, F. and Bauer, S., 2019. Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression. Brain Stimulation, 12(6), pp. 1390-1401. Lu, D., Bauer, S., Neubert, V., Costard, L.S., Rosenow, F. and Triesch, J., 2020, September. Towards Early Diagnosis of Epilepsy from EEG Data. In Machine Learning for Healthcare Conference (pp. 80-96). PMLR. Fig. 1. A. The reconstruction error evolution throughout the whole recording period of rat #1B. The distribution of the reconstruction errors from the BL and the EPG phases from the recordings of rat #1. We also show some typical EPG segments whose reconstruction errors are below the 10th percentile and over the 90th percentile, highlighted with a solid and a dashed black box, respectively. Other stimulated rats show a similar trend.

Glass-brain mapping provides an adjunct tool for structural analysis in mouse models of neurodevelopmental disease

Neurodevelopmental disorders are complex diseases with genetic and environmental factors shaping brain architecture. Here we undertook a proof of concept study to investigate brain structure using a glass-brain clearing and 3D-mapping workflow at high-resolution. Whole brain and sub-structure analysis included the genetic developmental and epileptic encephalopathy mouse model of Dravet syndrome (DS). In addition, we included the Black and Tan BRachyury (BTBR) mouse strain, which has acknowledged major and minor structural anomalies. Ex vivo P16 mouse brains were cleared using a modified solvent-based clearing method. The high-quality autofluorescence signal from light-sheet imaging provided unambiguous anatomical feature determination including the barrel-like regions of the cortex and absence of corpus callosum in BTBR mice. BTBR volume estimates were consistent with previous reports showing reduced hippocampal commissure volume. An automated image registration and statistical analysis pipeline was used to compare the control and DS model groups. Glass-brain images were registered to the scalable Allen Brain Atlas and annotations transformed into native space, with 20 μm isotropic voxels. Overall, glassbrain mapping provided a high-resolution measure of the premature mouse brain anatomy. We report novel structural changes in the DS model, which are consistent with cognitive and behavioural co-morbidities reported in this neurodevelopmental disease model.