Longitudinal assessment of ventricular volume trajectories in early-stage schizophrenia: evidence of both enlargement and shrinkage.

BACKGROUND: Lateral ventricular enlargement represents a canonical morphometric finding in chronic patients with schizophrenia; however, longitudinal studies elucidating complex dynamic trajectories of ventricular volume change during critical early disease stages are sparse. METHODS: We measured lateral ventricular volumes in 113 first-episode schizophrenia patients (FES) at baseline visit (11.7 months after illness onset, SD = 12.3) and 128 age- and sex-matched healthy controls (HC) using 3T MRI. MRI was then repeated in both FES and HC one year later. RESULTS: Compared to controls, ventricular enlargement was identified in 18.6% of patients with FES (14.1% annual ventricular volume (VV) increase; 95%CI: 5.4; 33.1). The ventricular expansion correlated with the severity of PANSS-negative symptoms at one-year follow-up (p = 0.0078). Nevertheless, 16.8% of FES showed an opposite pattern of statistically significant ventricular shrinkage during ≈ one-year follow-up (-9.5% annual VV decrease; 95%CI: -23.7; -2.4). There were no differences in sex, illness duration, age of onset, duration of untreated psychosis, body mass index, the incidence of Schneiderian symptoms, or cumulative antipsychotic dose among the patient groups exhibiting ventricular enlargement, shrinkage, or no change in VV. CONCLUSION: Both enlargement and ventricular shrinkage are equally present in the early stages of schizophrenia. The newly discovered early reduction of VV in a subgroup of patients emphasizes the need for further research to understand its mechanisms.

Frequency of brain ventricular enlargement among patients with diabetes mellitus.

AIMS: To determine the prevalence of dilated ventricles and concomitant high blood glucose measures. METHODS: We retrieved blood glucose measures from the emergency department database and selected a subgroup of individuals having both the radiological marker Evans' index (EI) values and blood glucose measures. RESULTS: Out of 1221 consecutive patients submitted to axial Computed Tomography scans, a blood glucose measure was detected in 841 individuals. 176 scans (21 %) showed an EI > 0.30. According to the blood glucose categorization, diabetic patients were 104 (12 %), 25 of them (24 %) were dilated (mean EI 0.33). The age difference between dilated and not-dilated ventricles is about ten years in not-diabetic participants, whereas it is five years in diabetic participants. The age difference between dilated and not-dilated ventricles is about 10 years in diabetic men, whereas it zero in diabetic women. CONCLUSIONS: Pathological ventricular enlargement is more frequent in men and in the elderly. In diabetic patients (especially women), the cerebral ventricles enlarge faster than in non-diabetic individuals. Age, sex, and diabetes may interact in determining how cerebral ventricle size changes over time, especially in diabetic women, making routine brain imaging advisable in these patients after the age of 70 years.

White matter paramagnetic rim and non-rim lesions share a periventricular gradient in multiple sclerosis: A 7-T imaging study.

BACKGROUND: Paramagnetic rim white matter (WM) lesions (PRL) are thought to be a main driver of non-relapsing multiple sclerosis (MS) progression. It is unknown whether cerebrospinal fluid (CSF)-soluble factors diffusing from the ventricles contribute to PRL formation. OBJECTIVE: To investigate the distribution of PRL and non-rim brain WM lesions as a function of distance from ventricular CSF, their relationship with cortical lesions, the contribution of lesion phenotype, and localization to neurological disability. METHODS: Lesion count and volume of PRL, non-rim WM, leukocortical lesion (LCL), and subpial/intracortical lesions were obtained at 7-T. The brain WM was divided into 1-mm-thick concentric rings radiating from the ventricles to extract PRL and non-rim WM lesion volume from each ring. RESULTS: In total, 61 MS patients with ⩾1 PRL were included in the study. Both PRL and non-rim WM lesion volumes were the highest in the periventricular WM and declined with increasing distance from ventricles. A CSF distance-independent association was found between non-rim WM lesions, PRL, and LCL, but not subpial/intracortical lesions. Periventricular non-rim WM lesion volume was the strongest predictor of neurological disability. CONCLUSIONS: Non-rim and PRL share a gradient of distribution from the ventricles toward the cortex, suggesting that CSF proximity equally impacts the prevalence of both lesion phenotypes.

Disruption of Cerebellar Granular Layer as a Consequence of Germinal Matrix Intraventricular Hemorrhage in Extreme Prematurity: An Acute Direct Mechanism Too?

Cerebellum is an important brain structure for the future development of motor, cognitive, and behavioral abilities in children. This structure undergoes its most significant growth during the third trimester of pregnancy. Prematurity gathers several risk factors for cerebellar impairment and underdevelopment, and among them is ventricular dilatation following germinal matrix intraventricular hemorrhage (GMH-IVH). In this report, we illustrate how this prevalent complication associated with prematurity may induce secondary cerebellar cortical damage. A premature male born by an emergency Caesarean section displayed massive GMH-IVH at brain ultrasound performed after three hours of extrauterine life and died after 18 hours of life, despite maximized vital support. We report a postmortem histopathological specimen of the cerebellar cortex showing the disruption of the external granular layer (EGL) by hemorrhagic content flowing from the supratentorial ventricles into the fourth ventricle and cisterna magna. The expansion of the ventricular system and the presence of blood in the lateral ventricles can cause inflammation and damage to the cerebellar gyri. Experimental models have shown a thinning of the EGL, suggesting that blood surrounding the cerebellum has a harmful action. Additionally, a sudden influx of cerebrospinal fluid from the lateral ventricles may directly contribute to cerebellar damage, indicating that this may be another way in which the cerebellar gyri are impaired during acute severe GMH-IVH. This is the first histopathologically confirmed case of acute disruption in the cerebellar cortex during a GMH-IVH in a premature baby.

Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits.

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.

Evaluation of a Fully Automated Method for Ventricular Volume Segmentation Before and After Shunt Surgery in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Determination of the ventricle size in idiopathic normal pressure hydrocephalus (iNPH) is essential for diagnosis and follow-up of shunt results. Fully automated segmentation methods are anticipated to optimize the accuracy and time efficiency of ventricular volume measurements. We evaluated the accuracy of preoperative and postoperative ventricular volume measurements in iNPH by a magnetic resonance imaging (MRI)-based licensed software for fully automated quantitative assessment. METHODS: Forty-eight patients diagnosed with iNPH were retrospectively analyzed. All patients received a ventriculoperitoneal shunt and had symptom grading and routine MRI preoperatively and 3-6 months postoperatively. Ventricular volumes, generated by fully automated T1-weighted imaging volume sequence segmentation, were compared with semiautomatic measurements and routine radiologic reports. The relation of postoperative ventricular size change to clinical response was evaluated. RESULTS: Fully automated segmentation was achieved in 95% of the MRIs, but showed various rates of 8 minor segmentation errors. The correlation between both segmentation methods was very strong (r >0.9) and the agreement very good using Bland-Altman analyses. The ventricular volumes differed significantly between semiautomated and fully automated segmentations and between preoperative and postoperative MRI. The fully automated method systematically overestimated the ventricles by a median 15 mL preoperatively and 14 mL postoperatively; hence, the magnitudes of volume changes were equivalent. Routine radiologic reports of ventricular size changes were inaccurate in 51% and lacked association with treatment response. Objectively measured ventricular volume changes correlated moderately with postoperative clinical improvement. CONCLUSIONS: A fully automated volumetric method permits reliable evaluation of preoperative ventriculomegaly and postoperative ventricular volume change in idiopathic normal pressure hydrocephalus.

Intraventricular central neurocytoma molecularly defined as extraventricular neurocytoma: a case representing the discrepancy between clinicopathological and molecular classifications.

Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN.

Fetal-onset Alexander disease with radiological-neuropathological correlation.

Alexander disease is a leukodystrophy caused by mutations in the GFAP gene, primarily affecting the astrocytes. This report describes the prenatal and post-mortem neuroimaging findings in a case of genetically confirmed, fetal-onset Alexander disease with pathological correlation after termination of pregnancy. The additional value of fetal brain magnetic resonance imaging in the third trimester as a complementary evaluation tool to neurosonography is shown for suspected cases of fetal-onset Alexander disease. Diffuse signal abnormalities of the periventricular white matter in association with thickening of the fornix and optic chiasm can point towards the diagnosis. Furthermore, the presence of atypical imaging findings such as microcephaly and cortical folding abnormalities in this case broadens our understanding of the phenotypic variability of Alexander disease.

High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction.

INTRODUCTION: The aim of this study was to evaluate genetic risk factors in term-born children with antenatal periventricular hemorrhagic infarction (PVHI), presumed antenatal periventricular venous infarction and periventricular hemorrhagic infarction in preterm neonates. METHODS: Genetic analysis and magnetic resonance imaging were performed in 85 children: term-born children (≥36 gestational weeks) with antenatal periventricular hemorrhagic infarction (n = 6) or presumed antenatal (n = 40) periventricular venous infarction and preterm children (<36 gestational weeks) with periventricular hemorrhagic infarction (n = 39). Genetic testing was performed using exome or large gene panel (n = 6700 genes) sequencing. RESULTS: Pathogenic variants associated with stroke were found in 11 of 85 (12.9%) children with periventricular hemorrhagic infarction/periventricular venous infarction. Among the pathogenic variants, COL4A1/A2 and COL5A1 variants were found in 7 of 11 (63%) children. Additionally, 2 children had pathogenic variants associated with coagulopathy, whereas 2 other children had other variants associated with stroke. Children with collagenopathies had significantly more often bilateral multifocal stroke with severe white matter loss and diffuse hyperintensities in the white matter, moderate to severe hydrocephalus, moderate to severe decrease in size of the ipsilesional basal ganglia and thalamus compared to children with periventricular hemorrhagic infarction/periventricular venous infarction without genetic changes in the studied genes (P ≤ .01). Severe motor deficit and epilepsy developed more often in children with collagenopathies compared to children without genetic variants (P = .0013, odds ratio [OR] = 233, 95% confidence interval [CI]: 2.8-531; and P = .025, OR = 7.3, 95% CI: 1.3-41, respectively). CONCLUSIONS: Children with periventricular hemorrhagic infarction/periventricular venous infarction have high prevalence of pathogenic variants in collagene genes (COL4A1/A2 and COL5A1). Genetic testing should be considered for all children with periventricular hemorrhagic infarction/periventricular venous infarction; COL4A1/A2 and COL5A1/A2 genes should be investigated first.

Establishment of Age- and Sex-Specific Reference Cerebral Ventricle Volumes.

BACKGROUND: The diagnosis of hydrocephalus is dependent on clinical symptoms and radiographic findings including ventriculomegaly. Our goal was to generate a data set of ventricular volume utilizing non-pathologic computed tomography (CT) scans for adults to help define reference ventricle size. METHODS: We performed a retrospective analysis of non-contrast head CTs for adults at a single institution to identify patients who had undergone imaging and did not have a diagnosis of hydrocephalus, history of ventriculoperitoneal shunting, or treatments for hydrocephalus. A convolutional neural network was trained on hand-segmented scans from a variety of age ranges and then utilized to automate the segmentation of the entire data set. RESULTS: Ventricles on 866 CT scans were segmented to generate a reference range of volumes for both male and female individuals ranging in age from 18-99 years. The generated data were binned by age ranges. CONCLUSIONS: We have developed a convolutional neural network that can segment the ventricles on CT scans of adult patients over a range of ages. This network was used to measure the ventricular volume of non-pathologic head CTs to produce reference ranges for several age bins. This data set could be utilized to aid in the diagnosis of hydrocephalus by comparing potentially pathologic scans to reference ventricular volumes.

Novel concepts in the pathogenesis of hydrocephalus.

PURPOSE: Hydrocephalus is a multifactorial neurological disorder and one of the most common neurosurgical conditions characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain's ventricles. It can result in dilatation of the ventricular system caused by the inadequate passage of CSF from its point of production within the ventricles to its point of absorption into the systemic circulation. Recent findings on the genetics and molecular studies of hydrocephalus have the potential to improve treatment and quality of life. METHODS: Review of literature on the novel studies of the pathogenesis of hydrocephalus. CONCLUSION: Molecular studies on the pathogenesis of hydrocephalus have provided a means to improve the treatment and follow-up of patients with hydrocephalus.

Morphological evaluation of the normal and hydrocephalic third ventricle on cranial magnetic resonance imaging in children: a retrospective study.

BACKGROUND: Third ventricle morphological changes reflect changes in the ventricular system in pediatric hydrocephalus, so visual inspection of the third ventricle shape is standard practice. However, normal pediatric reference data are not available. OBJECTIVE: To investigate both the normal development of the third ventricle in the 0-18-year age group and changes in its biometry due to hydrocephalus. MATERIALS AND METHODS: For this retrospective study, we selected individuals ages 0-18 years who had magnetic resonance imaging (MRI) from 2012 to 2020. We included 700 children (331 girls) who had three-dimensional (3-D) T1-weighted sequences without and 25 with hydrocephalus (11 girls). We measured the distances between the anatomical structures limiting the third ventricle by dividing the third ventricle into anterior and posterior regions. We made seven linear measurements and three index calculations using 3DSlicer and MRICloud pipeline, and we analyzed the results of 23 age groups in normal and hydrocephalic patients using SPSS (v. 23). RESULTS: Salient findings are: (1) The posterior part of the third ventricle is more affected by both developmental and hydrocephalus-related changes. (2) For third ventricle measurements, gender was insignificant while age was significant. (3) Normal third ventricular volumetric development showed a segmental increase in the 0-18 age range. The hydrocephalic third ventricle volume cut-off value in this age group was 3 cm3. CONCLUSION: This study describes third ventricle morphometry using a linear measurement method. The ratios defined in the midsagittal plane were clinically useful for diagnosing the hydrocephalic third ventricle. The linear and volumetric reference data and ratios are expected to help increase diagnostic accuracy in distinguishing normal and hydrocephalic third ventricles.

Venous Collagenosis as Pathogenesis of White Matter Hyperintensity.

OBJECTIVE: Periventricular white matter hyperintensities (pvWMHs) are commonly observed on MRI in older individuals and are associated with cognitive and motor decline. The etiology of pvWMH remains unknown. Venous collagenosis has been implicated, which may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). Here, we examine relationships between in vivo pvWMH volume and ex vivo morphological quantification of collagenosis and the PVS in veins and arteries. METHODS: Brain tissue from 25 Oregon Alzheimer's Disease Research Center subjects was selected to cover the full range of WMH burden. Tissue from white matter abutting the ventricle was stained with Masson's trichrome and smooth muscle actin. An automated hue based algorithm identified and segmented vessel into collagenized vessel walls, lumen, and PVS. Multiple linear regressions with pvWMH volume as the dependent variable and either collagen thickness or PVS width were performed with covariates of vessel diameter, age at death, sex, and interval between MRI and death. RESULTS: PVS width and collagen thickness were significantly correlated in both arteries (r = 0.21, p = 0.001) and veins (r = 0.23, p = 0.001). Increased venous collagen (p = 0.017) was a significant predictor of higher pvWMH burden while arterial collagen was not (p = 0.128). Neither PVS width in arteries (p = 0.937) nor veins (p = 0.133) predicted pvWMH burden. INTERPRETATION: These findings are consistent with a model in which venous collagenosis mediates the relationship between vascular risk factors and pvWMH. This study confirms the importance of changes to the venous system in contributing to MRI white matter lesions commonly observed with advanced age. ANN NEUROL 2022;92:992-1000.

Mechanisms of central brain atrophy in multiple sclerosis.

BACKGROUND: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients. OBJECTIVES: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA. METHODS: Fifty patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled. Lesional activity during 4 years of follow-up was analysed using custom-build software, which segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in mean diffusivity (MD). Volumetric change of lateral ventricles was used to measure CBA. RESULTS: During follow-up, ventricles expanded on average by 12.6% ± 13.7% (mean ± SD). There was a significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions. Correlation between volume of combined lesional activity and CBA (r2 = 0.67) increased when lesion volume was adjusted by the degree of tissue damage severity (r2 = 0.81). Regression analysis explained 90% of CBA variability, revealing that chronic lesion expansion was by far the largest contributor to ventricular enlargement. DISCUSSION: CBA is almost entirely explained by the combination of the volume and severity of lesional activity. The expansion of chronic lesions plays a central role in this process.

Surgical Treatment of IV Ventricle Calcifying Pseudoneoplasm of the Neuraxis (CAPNON) Operative Nuances.

Calcifying pseudoneoplasm of the neuroaxis (CAPNON) is a rare, slow growing, and generally benign fibro osseous mass that can emerge throughout the entire central nervous system (CNS). When diagnosed, prompt surgical treatment can determine a good neurological outcome and possibly curative resolution. The objective of the present work is to present a step by step technical report with its video. We present a 37 year old female presented with occipital headache and cervical pain associated with dysphagia, nausea, and gait disturbances. Computed tomography (CT) scan showed a focal calcified lesion on the floor of the IV ventricle projecting toward the vermis with associated supratentorial hydrocephalus and transependymal edema. The telovelar approach was chosen for the procedure. The outcome was favorable, with no complications. Postoperative CT was performed, which revealed no residual lesion. A step by step report of a IV ventricle CAPNON that manifested with hydrocephalus is described.

Accurate image-based CSF volume calculation of the lateral ventricles.

The size/volume of the brain's ventricles is essential in diagnosing and treating many neurological disorders, with various forms of hydrocephalus being some of the most common. Initial ventricular size and changes, if any, in response to disease progression or therapeutic intervention are monitored by serial imaging methods. Significant variance in ventricular size is readily noted, but small incremental changes can be challenging to appreciate. We have previously reported using artificial intelligence to determine ventricular volume. The values obtained were compared with those calculated using the inaccurate manual segmentation as the "gold standard". This document introduces a strategy to measure ventricular volumes where manual segmentation is not employed to validate the estimations. Instead, we created 3D printed models that mimic the lateral ventricles and measured those 3D models' volume with a tuned water displacement device. The 3D models are placed in a gel and taken to the magnetic resonance scanner. Images extracted from the phantoms are fed to an artificial intelligence-based algorithm. The volumes yielded by the automation must equal those yielded by water displacement to assert validation. Then, we provide certified volumes for subjects in the age range (1-114) months old and two hydrocephalus patients.

Periventricular magnetisation transfer abnormalities in early multiple sclerosis.

OBJECTIVE: Recent studies suggested that CSF-mediated factors contribute to periventricular (PV) T2-hyperintense lesion formation in multiple sclerosis (MS) and this in turn correlates with cortical damage. We thus investigated if such PV-changes are observable microstructurally in early-MS and if they correlate with cortical damage. METHODS: We assessed the magnetisation transfer ratio (MTR) in PV normal-appearing white matter (NAWM) and in MS lesions in 44 patients with a clinically isolated syndrome (CIS) suggestive of MS and 73 relapsing-remitting MS (RRMS) patients. Band-wise MTR values were related to cortical mean thickness (CMT) and compared with 49 healthy controls (HCs). For each band, MTR changes were assessed relative to the average MTR values of all HCs. RESULTS: Relative to HCs, PV-MTR was significantly reduced up to 2.63% in CIS and 5.37% in RRMS (p < 0.0001). The MTR decreased towards the lateral ventricles with 0.18%/mm in CIS and 0.31%/mm in RRMS patients, relative to HCs. In RRMS, MTR-values adjacent to the ventricle and in PV-lesions correlated positively with CMT and negatively with EDSS. CONCLUSION: PV-MTR gradients are present from the earliest stage of MS, consistent with more pronounced microstructural WM-damage closer to the ventricles. The positive association between reduced CMT and lower MTR in PV-NAWM suggests a common pathophysiologic mechanism. Together, these findings indicate the potential use of multimodal MRI as refined marker for MS-related tissue changes.

[Treatment for Hydrocephalus Caused by Intraventricular Tumors].

Intraventricular tumors often cause hydrocephalus because their location in the ventricles affect cerebrospinal fluid circulation. Even small tumors can lead to acute hydrocephalus when they block the cerebrospinal fluid flow. They may also be found as large tumors occurring in large spaces, such as in lateral ventricles. Since various histological tumors occur in ventricles, it is important to consider the treatment strategy according to the expected histological type before treating hydrocephalus in the early stage. In addition, it is beneficial to predict and evaluate the site and size of the tumor, the cause of hydrocephalus, and the effect of postoperative chemotherapy and radiation therapy. Some tumors are sensitive to chemotherapy and radiation therapy, so there is an advantage in performing a biopsy at the same time as hydrocephalus treatment. Ventricular drainage and ventricular peritoneal shunts for patients with high intracranial pressure are at risk of developing ascending hernias, so we should be careful with the procedure.

Pathogenesis and prevention of intraventricular hemorrhage.

Despite improvements in the mortality rates of preterm infants, rates of germinal matrix intraventricular hemorrhage (IVH) have remained static with an overall incidence of 25% in infants less than 32 weeks. The importance of the lesion relates primarily to the underlying injury to the developing brain and the associated long-term neurodevelopmental consequences. This clinical-orientated review focuses on the pathogenesis of IVH and discusses the evidence behind proposed prevention strategies.

Cerebral gray matter injuries in infants with intraventricular hemorrhage.

While intraventricular hemorrhage (IVH) predominantly damages the periventricular white matter, it induces substantial injury to the cerebral gray matter. IVH destroys the germinal matrix, suppresses neurogenesis, and disrupts corticogenesis, thereby reducing the number of neurons in the upper cortical layer and volume of the cerebral gray matter. The pathogenesis of gray matter injury is attributed to IVH-induced oxidative stress, inflammation, and mass effect damaging the germinal matrix as well as to post-hemorrhagic ventricular dilation (PHVD). The IVH-induced cerebral gray matter injury and PHVD contribute to cognitive deficits and neurobehavioral disorders. Neuroimaging has enhanced our understanding of cerebral gray matter injury and is a valuable predictor of neurodevelopmental outcomes. Evidence from therapies tested in preclinical models and clinical trials suggests that strategies to promote neurogenesis, reduce cerebral inflammation and oxidative stress, and remove blood clots from the ventricles might enhance the outcome of these infants. This review offers an integrated view of new insights into the mechanisms underlying gray matter injury in premature infants with IVH and highlights the imminent therapies to restore neurodevelopmental dysfunction in IVH survivors.