Inhibitory innate receptors and their potential role in transplantation.

The regulatory arm of the immune system plays a crucial role in maintaining immune tolerance and preventing excessive immune responses. Immune regulation comprises various regulatory cells and molecules that work together to suppress or regulate immune responses. The programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are examples of inhibitory receptors that counteract activating signals and fine-tune immune responses. While most of the discoveries of immune regulation have been related to T cells and the adaptive immune system, the innate arm of the immune system also has a range of inhibitory receptors that can counteract activating signals and suppress the effector immune responses. Targeting these innate inhibitory receptors may provide a complementary therapeutic approach in several immune-related conditions, including transplantation. In this review, we will explore the potential role of innate inhibitory receptors in controlling alloimmunity during solid organ transplantation.

Transanterior Limiting Sulcus of the Insula Approach: Novel Surgical Approach to the Ventral Striatum Region.

BACKGROUND: Lesions in the ventral striatum region (above the anterior perforated substance) are a challenge for neurosurgeons due to their direct relationship with the lenticulostriate arteries, which difficult the surgical access. The standard approaches for this region include the following: 1) transfrontal approach, 2) transanterior perforating substance approach, 3) transcallosal transventricular approach, and 4) pterional transsylvian-transinsular route. In this study, we aimed to describe a novel anatomical approach through the anterior limiting sulcus of the insula in order to access the ventral striatum. METHODS: We reviewed the literature and performed a detailed dissection of this region by using Klingler's technique with brain specimens injected with silicone, paying special attention to the white fibers and lenticulostriate arteries, and provided a description of an illustrative case of a cavernous malformation. RESULTS: Neuroanatomical dissections showed that the lenticulostriate arteries had an inverted C-shaped anterior concavity, leaving less significant vascular relationships in the depth of the anterior limiting sulcus of the insula. In the case we described, the cavernous malformation was completely resected and the patient was discharged without any neurological deficits. CONCLUSIONS: The transanterior limiting sulcus of the insula approach to the ventral striatum offers a safe access route for selected cases and can be performed on the basis of anatomical references. Three-dimensional understanding of the intrinsic brain architecture and its relationships with vascular structures in this specific area is important and can be acquired mainly through laboratory training.

ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit.

APOL1 risk variants are associated with increased risk of kidney disease in patients of African ancestry, but not all individuals with the APOL1 high-risk genotype develop kidney disease. As APOL1 gene expression correlates closely with the degree of kidney cell injury in both cell and animal models, the mechanisms regulating APOL1 expression may be critical determinants of risk allele penetrance. The APOL1 messenger RNA includes Alu elements at the 3' untranslated region that can form a double-stranded RNA structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting on RNA (ADAR)-mediated adenosine-to-inosine (A-to-I) editing, potentially impacting gene expression. We studied the effects of ADAR expression and A-to-I editing on APOL1 levels in podocytes, human kidney tissue, and a transgenic APOL1 mouse model. In interferon-γ (IFN-γ)-stimulated human podocytes, ADAR down-regulates APOL1 by preventing melanoma differentiation-associated protein 5 (MDA5) recognition of dsRNA and the subsequent type I interferon (IFN-I) response. Knockdown experiments showed that recognition of APOL1 messenger RNA itself is an important contributor to the MDA5-driven IFN-I response. Mathematical modeling suggests that the IFN-ADAR-APOL1 network functions as an incoherent feed-forward loop, a biological circuit capable of generating fast, transient responses to stimuli. Glomeruli from human kidney biopsies exhibited widespread editing of APOL1 Alu-dsRNA, while the transgenic mouse model closely replicated the edited sites in humans. APOL1 expression in mice was inversely correlated with Adar1 expression under IFN-γ stimuli, supporting the idea that ADAR regulates APOL1 levels in vivo. ADAR-mediated A-to-I editing is an important regulator of APOL1 expression that could impact both penetrance and severity of APOL1-associated kidney disease.

DGAT2 Inhibition Potentiates Lipid Droplet Formation To Reduce Cytotoxicity in APOL1 Kidney Risk Variants.

BACKGROUND: Two variants in the gene encoding apolipoprotein L1 (APOL1) that are highly associated with African ancestry are major contributors to the large racial disparity in rates of human kidney disease. We previously demonstrated that recruitment of APOL1 risk variants G1 and G2 from the endoplasmic reticulum to lipid droplets leads to reduced APOL1-mediated cytotoxicity in human podocytes. METHODS: We used CRISPR-Cas9 gene editing of induced pluripotent stem cells to develop human-derived APOL1G0/G0 and APOL1G2/G2 kidney organoids on an isogenic background, and performed bulk RNA sequencing of organoids before and after treatment with IFN-γ. We examined the number and distribution of lipid droplets in response to treatment with inhibitors of diacylglycerol O-acyltransferases 1 and 2 (DGAT1 and DGAT2) in kidney cells and organoids. RESULTS: APOL1 was highly upregulated in response to IFN-γ in human kidney organoids, with greater increases in organoids of high-risk G1 and G2 genotypes compared with wild-type (G0) organoids. RNA sequencing of organoids revealed that high-risk APOL1G2/G2 organoids exhibited downregulation of a number of genes involved in lipogenesis and lipid droplet biogenesis, as well as upregulation of genes involved in fatty acid oxidation. There were fewer lipid droplets in unstimulated high-risk APOL1G2/G2 kidney organoids than in wild-type APOL1G0/G0 organoids. Whereas DGAT1 inhibition reduced kidney organoid lipid droplet number, DGAT2 inhibition unexpectedly increased organoid lipid droplet number. DGAT2 inhibition promoted the recruitment of APOL1 to lipid droplets, with associated reduction in cytotoxicity. CONCLUSIONS: Lipogenesis and lipid droplet formation are important modulators of APOL1-associated cytotoxicity. Inhibition of DGAT2 may offer a potential therapeutic strategy to attenuate cytotoxic effects of APOL1 risk variants.

Gods and monsters: Greek mythology and Christian references in the neurosurgical lexicon.

BACKGROUND: Myths and religion are belief systems centered around supernatural entities that attempt to explain the observed world and are of high importance to certain communities. The former is a collection of stories that belong to a cultural tradition and the latter are organized faiths that determine codes of ethics, rituals and philosophy. Deities or monstrous creatures in particular act as archetypes instructing an individual's conduct. References to them in Greek mythology and Christianity are frequently manifested in the modern neurosurgical vernacular. METHODS: A review of the medical literature was performed using the PubMed and MEDLINE bibliographic databases. Publications from 1875 to 2021 related to neurosurgery or neuroanatomy with the medical subject headings (MeSH) terms mythology, religion, Christianity and Catholicism were reviewed. References pertaining to supernatural beings were classified to either a deity or a monstrosity according to their conventional cultural context. RESULTS: Twelve narratives associated with neurosurgery were identified, nine relating to Greek mythology and three associated with the Christian-Catholic faith. Eight accounts concerned deities and the remaining with monstrous creatures. CONCLUSION: This article explores the etymology of commonly utilized terms in daily neurosurgical practice in the context of mythology and religion. They reveal the ingenuity and creativity of early pioneers who strived to understand the brain.

Microbiome and oral squamous cell carcinoma: a possible interplay on iron metabolism and its impact on tumor microenvironment.

There is increasing evidence showing positive association between changes in oral microbiome and the occurrence of oral squamous cell carcinoma (OSCC). Alcohol- and nicotine-related products can induce microbial changes but are still unknown if these changes are related to cancerous lesion sites. In an attempt to understand how these changes can influence the OSCC development and maintenance, the aim of this study was to investigate the oral microbiome linked with OSCC as well as to identify functional signatures and associate them with healthy or precancerous and cancerous sites. Our group used data of oral microbiomes available in public repositories. The analysis included data of oral microbiomes from electronic cigarette users, alcohol consumers, and precancerous and OSCC samples. An R-based pipeline was used for taxonomic and functional prediction analysis. The Streptococcus spp. genus was the main class identified in the healthy group. Haemophilus spp. predominated in precancerous lesions. OSCC samples revealed a higher relative abundance compared with the other groups, represented by an increased proportion of Fusobacterium spp., Prevotella spp., Haemophilus spp., and Campylobacter spp. Venn diagram analysis showed 52 genera exclusive of OSCC samples. Both precancerous and OSCC samples seemed to present a specific associated functional pattern. They were menaquinone-dependent protoporphyrinogen oxidase pattern enhanced in the former and both 3',5'-cyclic-nucleotide phosphodiesterase (purine metabolism) and iron(III) transport system ATP-binding protein enhanced in the latter. We conclude that although precancerous and OSCC samples present some differences on microbial profile, both microbiomes act as "iron chelators-like" potentially contributing to tumor growth.

Diffuse large B-cell lymphoma of the central nervous system presenting as "lymphomatosis cerebri" and dementia in elderly man: Case report and review of the literature.

RATIONALE: Lymphomatosis cerebri is a rare form of PCNSL, characterized by diffuse infiltration of lymphoma cells in cerebral parenchyma, without mass-formation and mild or no contrast enhancement on magnetic resonance (MR) imaging. There are less than 50 cases described in the literature under the term Lymphomatosis cerebri. PATIENT CONCERNS: A 74-year-old man presented to our service with progressive dementia for 12 months and accelerated cognitive decline within the last two months. Brain magnetic resonance imaging showed areas of hyperintensity involving predominantly the white matter of frontal lobes and knee of the corpus callosum, along with areas of blood-brain barrier disruption and areas of restricted diffusion. Stereotaxy brain surgery was indicated into contrasting areas and histologically there was heterogeneous foci of discreet infiltration of rare medium-large lymphoid cells intermingled with inflammatory cells and these atypical lymphoid cells were placed on breakdown neuropil and did not form tumor mass or sheets of cells, but occasionally displayed perivascular distribution. Immunohistochemically, these atypical lymphoid cells expressed CD20, Bcl2, Bcl6 and, heterogeneously, IRF4/MUM1. DIAGNOSIS: The diagnosis of a primary CNS diffuse large B-cell lymphoma manifested as lymphomatosis cerebri was performed. INTERVENTIONS: The treatment of choice was: temozolomide 100 mg/m (D1 to D5), methotrexate 3 g/m (D1, D10, and D20) and rituximab 375 mg/m. OUTCOMES: The patient evolved with progressive neurological deterioration, regardless of the improvement on neuroimaging. LESSONS: We described the diagnostic dilemma we faced with an elderly man with rapid cognitive impairment and a myriad of differential diagnoses, diagnosed with primary CNS diffuse large B-cell lymphoma with a lymphomatosis cerebri-like pattern.

Understanding Anatomy of the Petrous Pyramid-A New Compartmental Approach.

BACKGROUND: Learning surgical anatomy of the petrous pyramid can be a challenge, especially in the beginning of the training process. Providing an easier, holistic approach can be of help to everyone with interest in learning and teaching skull base anatomy. We present the complex organization of petrous pyramid anatomy using a new compartmental approach that is simple to understand and remember. METHODS: The surfaces of the petrous pyramid of two temporal bones were examined; and the contents of the petrous pyramid of 8 temporal bones were exposed through progressive drilling of the superior surface. RESULTS: The petrous pyramid is made up of a bony container, and its contents were grouped into 4 compartments (mucosal, cutaneous, neural, and vascular). Two reference lines were identified (mucosal and external-internal auditory canal lines) intersecting at the level of the middle ear. The localization of contents relative to these reference lines was then described, and 2 methods of segmentation (the X method and the V method) were then proposed. This description was then used to describe middle ear relationships, facial nerve anatomy, and air cell distribution. CONCLUSIONS: This new compartmental approach allows a comprehensive understanding of the distribution of petrous pyramid contents. Dividing it into anatomic compartments, and then navigating this mental map along specific reference points, lines, spaces, and segments, could create a useful tool to teach or learn its complex tridimensional anatomy.

Microsurgical anatomy of the central core of the brain.

OBJECTIVE The purpose of this study was to describe in detail the cortical and subcortical anatomy of the central core of the brain, defining its limits, with particular attention to the topography and relationships of the thalamus, basal ganglia, and related white matter pathways and vessels. METHODS The authors studied 19 cerebral hemispheres. The vascular systems of all of the specimens were injected with colored silicone, and the specimens were then frozen for at least 1 month to facilitate identification of individual fiber tracts. The dissections were performed in a stepwise manner, locating each gray matter nucleus and white matter pathway at different depths inside the central core. The course of fiber pathways was also noted in relation to the insular limiting sulci. RESULTS The insular surface is the most superficial aspect of the central core and is divided by a central sulcus into an anterior portion, usually containing 3 short gyri, and a posterior portion, with 2 long gyri. It is bounded by the anterior limiting sulcus, the superior limiting sulcus, and the inferior limiting sulcus. The extreme capsule is directly underneath the insular surface and is composed of short association fibers that extend toward all the opercula. The claustrum lies deep to the extreme capsule, and the external capsule is found medial to it. Three fiber pathways contribute to form both the extreme and external capsules, and they lie in a sequential anteroposterior disposition: the uncinate fascicle, the inferior fronto-occipital fascicle, and claustrocortical fibers. The putamen and the globus pallidus are between the external capsule, laterally, and the internal capsule, medially. The internal capsule is present medial to almost all insular limiting sulci and most of the insular surface, but not to their most anteroinferior portions. This anteroinferior portion of the central core has a more complex anatomy and is distinguished in this paper as the "anterior perforated substance region." The caudate nucleus and thalamus lie medial to the internal capsule, as the most medial structures of the central core. While the anterior half of the central core is related to the head of the caudate nucleus, the posterior half is related to the thalamus, and hence to each associated portion of the internal capsule between these structures and the insular surface. The central core stands on top of the brainstem. The brainstem and central core are connected by several white matter pathways and are not separated from each other by any natural division. The authors propose a subdivision of the central core into quadrants and describe each in detail. The functional importance of each structure is highlighted, and surgical approaches are suggested for each quadrant of the central core. CONCLUSIONS As a general rule, the internal capsule and its vascularization should be seen as a parasagittal barrier with great functional importance. This is of particular importance in choosing surgical approaches within this region.

Surgical Approaches to the Temporal Horn: An Anatomic Analysis of White Matter Tract Interruption.

BACKGROUND: Surgical access to the temporal horn is necessary to treat tumors and vascular lesions, but is used mainly in patients with mediobasal temporal epilepsy. The surgical approaches to this cavity fall into 3 primary categories: lateral, inferior, and transsylvian. The current neurosurgical literature has underestimated the interruption of involved fiber bundles and the correlated clinical manifestations. OBJECTIVE: To delineate the interruption of fiber bundles during the different approaches to the temporal horn. METHODS: We simulated the lateral (trans-middle temporal gyrus), inferior (transparahippocampal gyrus), and transsylvian approaches in 20 previously frozen, formalin-fixed human brains (40 hemispheres). Fiber dissection was then done along the lateral and inferior aspects under the operating microscope. Each stage of dissection and its respective fiber tract interruption were defined. RESULTS: The lateral (trans-middle temporal gyrus) approach interrupted "U" fibers, the superior longitudinal fasciculus (inferior arm), occipitofrontal fasciculus (ventral segment), uncinate fasciculus (dorsolateral segment), anterior commissure (posterior segment), temporopontine, inferior thalamic peduncle (posterior fibers), posterior thalamic peduncle (anterior portion), and tapetum fibers. The inferior (transparahippocampal gyrus) approach interrupted "U" fibers, the cingulum (inferior arm), and fimbria, and transected the hippocampal formation. The transsylvian approach interrupted "U" fibers (anterobasal region of the extreme capsule), the uncinate fasciculus (ventromedial segment), and anterior commissure (anterior segment), and transected the anterosuperior aspect of the amygdala. CONCLUSION: White matter dissection improves our knowledge of the complex anatomy surrounding the temporal horn. Identifying the fiber bundles at risk during each surgical approach adds important information for choosing the appropriate surgical strategy.

Microsurgical anatomy and internal architecture of the brainstem in 3D images: surgical considerations.

OBJECT Brainstem surgery remains a challenge for the neurosurgeon despite recent improvements in neuroimaging, microsurgical techniques, and electrophysiological monitoring. A detailed knowledge of the microsurgical anatomy of the brainstem surface and its internal architecture is mandatory to plan appropriate approaches to the brainstem, to choose the safest point of entry, and to avoid potential surgical complications. METHODS An extensive review of the literature was performed regarding the brainstem surgical approaches, and their correlations with the pertinent anatomy were studied and illustrated through dissection of human brainstems properly fixed with 10% formalin. The specimens were dissected using the fiber dissection technique, under ×6 to ×40 magnification. 3D stereoscopic photographs were obtained (anaglyphic 3D) for better illustration of this study. RESULTS The main surgical landmarks and their relationship with the cerebellum and vascular structures were identified on the surface of the brainstem. The arrangements of the white matter (ascending and descending pathways as well as the cerebellar peduncles) were demonstrated on each part of the brainstem (midbrain, pons, and medulla oblongata), with emphasis on their relationships with the surface. The gray matter, constituted mainly by nuclei of the cranial nerves, was also studied and illustrated. CONCLUSIONS The objective of this article is to review the microsurgical anatomy and the surgical approaches pertinent to the brainstem, providing a framework of its external and internal architecture to guide the neurosurgeon during its related surgical procedures.

Three-dimensional digital projection in neurosurgical education: technical note.

Three-dimensional images have become an important tool in teaching surgical anatomy, and its didactic power is enhanced when combined with 3D surgical images and videos. This paper describes the method used by the last author (G.C.R.) since 2002 to project 3D anatomical and surgical images using a computer source. Projecting 3D images requires the superposition of 2 similar but slightly different images of the same object. The set of images, one mimicking the view of the left eye and the other mimicking the view of the right eye, constitute the stereoscopic pair and can be processed using anaglyphic or horizontal-vertical polarization of light for individual use or presentation to larger audiences. Classically, 3D projection could be obtained by using a double set of slides, projected through 2 slide projectors, each of them equipped with complementary filters, shooting over a medium that keeps light polarized (a silver screen) and having the audience wear appropriate glasses. More recently, a digital method of 3D projection has been perfected. In this method, a personal computer is used as the source of the images, which are arranged in a Microsoft PowerPoint presentation. A beam splitter device is used to connect the computer source to 2 digital, portable projectors. Filters, a silver screen, and glasses are used, similar to the classic method. Among other advantages, this method brings flexibility to 3D presentations by allowing the combination of 3D anatomical and surgical still images and videos. It eliminates the need for using film and film developing, lowering the costs of the process. In using small, powerful digital projectors, this method substitutes for the previous technology, without incurring a loss of quality, and enhances portability.

Head positioning for anterior circulation aneurysms microsurgery.

OBJECTIVE: To study the ideal patient's head positioning for the anterior circulation aneurysms microsurgery. METHOD: We divided the study in two parts. Firstly, 10 fresh cadaveric heads were positioned and dissected in order to ideally expose the anterior circulation aneurysm sites. Afterwards, 110 patients were submitted to anterior circulation aneurysms microsurgery. During the surgery, the patient's head was positioned accordingly to the aneurysm location and the results from the cadaveric study. The effectiveness of the position was noted. RESULTS: We could determine mainly two patterns for head positioning for the anterior circulation aneurysms. CONCLUSION: The best surgical exposure is related to specific head positions. The proper angle of microscopic view may minimize neurovascular injury and brain retraction.

Head positioning for anterior circulation aneurysms microsurgery / Posicionamento da cabeça para microcirurgias de aneurismas da circulação anterior

Objective To study the ideal patient's head positioning for the anterior circulation aneurysms microsurgery. Method We divided the study in two parts. Firstly, 10 fresh cadaveric heads were positioned and dissected in order to ideally expose the anterior circulation aneurysm sites. Afterwards, 110 patients were submitted to anterior circulation aneurysms microsurgery. During the surgery, the patient's head was positioned accordingly to the aneurysm location and the results from the cadaveric study. The effectiveness of the position was noted. Results We could determine mainly two patterns for head positioning for the anterior circulation aneurysms. Conclusion The best surgical exposure is related to specific head positions. The proper angle of microscopic view may minimize neurovascular injury and brain retraction. .

Objetivo Estudar o posicionamento da cabeça para a cirurgia de aneurismas cerebrais da circulação anterior. Método Dividimos o estudo em duas partes. Inicialmente, dez cabeças de cadáveres frescos foram posicionadas e dissecadas de modo a expor, de maneira ideal, os principais sítios de aneurismas na circulação anterior do cérebro. Posteriormente, 110 pacientes foram submetidos a microcirurgia para clipagem de aneurismas cerebrais da circulação anterior. Durante as cirurgias, as cabeças foram posicionadas de acordo com a localização específica de cada aneurisma e o resultado obtido no estudo dos cadáveres. Cada paciente teve sua posição avaliada quanto a sua eficácia. Resultados Obtivemos basicamente dois padrões de posicionamento da cabeça para cirurgias de aneurismas cerebrais da circulação anterior. Conclusão A melhor exposição cirúrgica está relacionada à posição específica da cabeça para cada localização aneurismática. O ângulo de visão microscópica adequado minimiza lesões neurovasculares e a excessiva retração cerebral. .

Alternative cost-effective method to record 3D intra-operative images: a technical note.

The educational value of stereoscopic imaging in neurosurgical training has increasingly been appreciated and its use increased during the last decade. We describe a technique that we developed to acquire and reproduce intra-operative stereoscopic images.

Nuevo reparo anatómico para la identificación del núcleo dentado en el abordaje suboccipital / New anatomical repair for the identification of the tooth nucleus in the suboccipital approach

Introducción: El abordaje suboccipital constituye una de las vías de acceso más frecuentes a la fosa posterior. Objetivo: La finalidad del presente estudio es definir un reparo anatómico reproducible en la superficie suboccipital del cerebelo que permita ayudar a localizar el núcleo dentado (ND) del mismo. Material y Métodos: Quince cerebelos de adulto fueron estudiados, previa fijación con formol y congelación. Se realizaron cortes axiales y sagitales, con medición de las relaciones entre la fisura horizontal (FH) y el ND. Resultados: La proyección en profundidad de la FH permitió identificar el núcleo dentado en casi todos ellos. Conclusión: La identificación del ND en la cirugía a partir de la FH puede ser considerada un método rápido y confiable. Su utilización pre y perioperatoria podría disminuir las complicaciones derivadas de la lesión de dicho núcleo cerebeloso.

Introduction: The suboccipital approach is one of the most common surgical routes to the posterior fossa.Purpose: The aim of this study was to define a reproductible anatomic landmark in the suboccipital surface of the cerebellum, allowing to localize the dentate nucleus (DN).Material and methods: Fifteen cadaveric specimens (adult brains) were studied, previously fixed with formaldehyde and frozen. Sagittal and axial cuts were performed in the specimens, measuring the relationships between the horizontal fissure (HF) of the cerebellum and the DN.Results: The projection in depth of the HF allowed to identify the DN in almost all of them.Conclusion: The identification during surgery of the DN using the HF maybe a safe and quick method and its usage pre and intraoperatively can lower complications related to lesions of the DN.

Study of fetal and postnatal morphological development of the brain sulci.

OBJECT: The surface of the developing fetal brain undergoes significant morphological changes during fetal growth. The purpose of this study was to evaluate the morphological development of the brain sulci from the fetal to the early postnatal period. METHODS: Two hundred fourteen brain hemispheres from 107 human brain specimens were examined to evaluate the timing of sulcal formation, from its appearance to its complete development. These brains were obtained from cadavers ranging in age from 12 weeks of gestation to 8 months of postnatal life. RESULTS: The order of appearance of the cerebral sulci, and the number and percentages of specimens found in this study were as follows: longitudinal cerebral fissure at 12 weeks (10/10, 100%); callosal sulcus at 12 weeks (10/10, 100%); hippocampal sulcus at 15 weeks (7/10, 70%); lateral sulcus at 17 weeks (20/22, 90.9%); circular insular sulcus at 17 weeks (18/22, 81.8%); olfactory sulcus at 17 weeks (18/22, 81.8%); calcarine sulcus at 17 weeks (14/22, 63.6%); parietooccipital sulcus at 17 weeks (11/22, 50%); cingulate sulcus at 19 weeks (16/20, 80%); central sulcus at 21 weeks (22/38, 57.9%); orbital sulcus at 22 weeks (9/16, 56.2%); lunate sulcus at 24 ± 2 weeks (12/16, 75%); collateral sulcus at 24 ± 2 weeks (8/16, 50%); superior frontal sulcus at 25 ± 2 weeks (5/6, 83.3%); rhinal sulcus at 25 ± 2 weeks (3/6, 50%); precentral sulcus at 26 ± 3 weeks (2/4, 50%); postcentral sulcus at 26 ± 3 weeks (2/4, 50%); superior temporal sulcus at 26 ± 3 weeks (2/4, 50%); central insular sulcus at 29 ± 2 weeks (4/4, 100%); intraparietal sulcus at 29 ± 2 weeks (2/4, 50%); paraolfactory sulcus at 29 ± 2 weeks (2/4, 50%); inferior frontal sulcus at 30 ± 3 weeks (2/4, 50%); transverse occipital sulcus at 30 ± 3 weeks (2/4, 50%); occipitotemporal sulcus at 30 ± 3 weeks (2/4, 50%); marginal branch of the cingulate sulcus at 30 ± 3 weeks (2/4, 50%); paracentral sulcus at 30 ± 3 weeks (2/4, 50%); subparietal sulcus at 30 ± 3 weeks (2/4, 50%); inferior temporal sulcus at 31 ± 3 weeks (3/6, 50%); transverse temporal sulcus at 33 ± 3 weeks (6/8, 75%); and secondary sulcus at 38 ± 3 weeks (2/4, 50%). CONCLUSIONS: The brain is subjected to considerable morphological changes throughout gestation. During fetal brain development the cortex begins to fold in, thereby increasing the cortical surface. All primary sulci are formed during fetal life. The appearance of each sulcus follows a characteristic timing pattern, which may be used as one of the reliable guides pertinent to gestational age and normal fetal development.