Transfer learning for cross-context prediction of protein expression from 5'UTR sequence.

Model-guided DNA sequence design can accelerate the reprogramming of living cells. It allows us to engineer more complex biological systems by removing the need to physically assemble and test each potential design. While mechanistic models of gene expression have seen some success in supporting this goal, data-centric, deep learning-based approaches often provide more accurate predictions. This accuracy, however, comes at a cost - a lack of generalization across genetic and experimental contexts that has limited their wider use outside the context in which they were trained. Here, we address this issue by demonstrating how a simple transfer learning procedure can effectively tune a pre-trained deep learning model to predict protein translation rate from 5' untranslated region (5'UTR) sequence for diverse contexts in Escherichia coli using a small number of new measurements. This allows for important model features learnt from expensive massively parallel reporter assays to be easily transferred to new settings. By releasing our trained deep learning model and complementary calibration procedure, this study acts as a starting point for continually refined model-based sequence design that builds on previous knowledge and future experimental efforts.

Role of sodium fluorescein in pediatric low-grade glioma surgery: an update.

PURPOSE: Complete surgical resection is still the mainstay in the treatment of central nervous system low-grade tumors, eventually resulting curative. The complete surgical removal of these lesions, however, may be difficult in some cases because of their infiltrative nature. Intraoperative adjuncts may be a game changer. Sodium fluorescein (SF) is among the ideal candidates as intraoperative tools to favor the actual recognition of the tumor extension, since it accumulates in areas of altered blood-brain barrier, a typical characteristic of pediatric gliomas, and has a low rate of adverse events. This work proposes an update of previous works about the evaluation of the feasibility and usefulness of a systematic use of SF in a low-grade lesion group of pediatric patients. METHODS: Pediatric patients operated on for a resection or a biopsy of a low-grade glial or glioneuronal lesion (WHO grade I and II) at our Institution between September 2021 and December 2023, with the intraoperative use of sodium fluorescein (SF), were enrolled in the study. We collected pre-operative and postoperative clinical and radiological data, intraoperative findings, and post-operative pathological diagnoses. RESULTS: No adverse events were registered related to the intraoperative use of SF. SF appeared useful for the localization of boundaries of tumors, especially when characterized by a high degree of infiltration or by a deep-seated location, and for the checking of possible tumor remnants at the end of surgery. A good tumor-to-healthy tissue contrast was registered when tumor visualization was in a range between 1 to 2 h and 30 min after SF injection. Possible "false positives" due to intraoperative vascular wall injury and clearance of SF from both tumor and healthy tissue were observed in some cases and still remain open issues. CONCLUSIONS: SF is a feasible and safe intraoperative adjunct tool in the surgical removal of pediatric low-grade tumors. SF may show its usefulness especially in selected cases, such as deep-seated lesions and infiltrating tumors. Its safety profile, user-friendly management, and potential utility in both tumor resections and neuronavigated biopsies favor its wider use in the surgical treatment of pediatric low-grade tumors.

Preoperative 11 C-Methionine PET-MRI in Pediatric Infratentorial Tumors.

PURPOSE: MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results. PATIENTS AND METHODS: Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification. RESULTS: Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15). CONCLUSIONS: Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors.

Bone Morphogenic Proteins in Pediatric Diffuse Midline Gliomas: How to Make New Out of Old?

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.

Studying the social mind: An updated summary of findings from the Vietnam Head Injury Study.

Lesion mapping studies allow us to evaluate the potential causal contribution of specific brain areas to human cognition and complement other cognitive neuroscience methods, as several authors have recently pointed out. Here, we present an updated summary of the findings from the Vietnam Head Injury Study (VHIS) focusing on the studies conducted over the last decade, that examined the social mind and its intricate neural and cognitive underpinnings. The VHIS is a prospective, long-term follow-up study of Vietnam veterans with penetrating traumatic brain injury (pTBI) and healthy controls (HC). The scope of the work is to present the studies from the latest phases (3 and 4) of the VHIS, 70 studies since 2011, when the Raymont et al. paper was published (Raymont et al., 2011). These studies have contributed to our understanding of human social cognition, including political and religious beliefs, theory of mind, but also executive functions, intelligence, and personality. This work finally discusses the usefulness of lesion mapping as an approach to understanding the functions of the human brain from basic science and clinical perspectives.

Brainstem tumors in children: a monocentric series in the light of genetic and bio-molecular progress in pediatric neuro-oncology.

Introduction: Brainstem tumors represent a challenge. Their management and prognosis vary according to anatomopathological findings and genetic and bio-molecular fingerprints. We present our experience with pediatric brainstem tumors. Material and methods: All patients admitted for a brainstem tumor at the Pediatric Neurosurgical Unit at Hôpital Femme Mère Enfant hospital between January 1997 and December 2019 were considered. Patients data were obtained through a retrospective review of the medical records; follow-up was from the last outpatient consultation. Results: One hundred and twelve patients were included. Eighty-five patients (75.9%) had open surgery or stereotactic biopsy. Thirty-five patients were treated for hydrocephalus. Sixty-six received an adjuvant treatment. Several protocols were adopted according to the SFOP and SIOP during this time period. The overall survival rate was 45% with a median follow-up of five years (range 1-18 year). However, the survival rate was very different between the diffuse intrinsic pontine gliomas (DIPG) and the others tumor types. If we exclude the DIPG (59 patients), of which only 1 was alive at 3 years, the survival rate was 90.6% (only 5 deaths over 53 patients) with a median follow up of 5 years. Conclusions: Our series confirms that benign tumors of the brainstem have a good survival when treated with surgical removal ± adjuvant therapy. Diffuse pontine gliomas continue to have a dismal prognosis. Individualized treatment based on molecular fingerprints may help to select the best adjuvant therapy and hence potentially improve survival.

Pineal cysts in children: a paediatric series treated over the last twenty years in Lyon.

BACKGROUND: Pineal cysts are a rare lesion of the pineal gland. Pineal cysts are benign lesions, generally asymptomatic, and are usually an incidental discovery on MRI performed for other problems. The management of pineal cysts in children remains a matter for debate. Here, we report our own retrospective paediatric cases that have been surgically treated and review the paediatric literature on this topic. METHODS: This is a retrospective monocentric study. All patients operated by the senior author (CM) for a benign pineal cyst from 2000 to 2021 were included. All other pineal region cystic lesions were excluded. Medical and surgical data were extracted from the hospital medical database. RESULTS: Twelve patients were included. The clinical symptomatology was characterized by headaches in seven patients, visual troubles in two patients, precocious puberty in one patient, signs of intracranial hypertension in two patients, seizures associated with headache in one patient, and headaches associated with behavioural troubles in another patient. No major post-operative complications were observed in this series. It is to noted that surgery was performed because a suspicion of a true pineal parenchymal tumour has been made. Histopathological study came back with the diagnosis of pineal cyst. CONCLUSIONS: Pineal cyst is rare. If the radiological diagnosis is clear, no surgery is advocated except in cases associated with hydrocephalus and rapid growth. In case of a suspicion of a true pineal parenchymal tumour, a surgery may be needed to confirm the diagnosis. Lastly, we stress that only cystic lesions of the pineal gland itself should be considered as pineal cyst.

The sub-occipital transtentorial approach for pineal region tumors: how I do it.

BACKGROUND: Two major approaches exist for the surgical removal of pineal region tumors: the supracebellar infratentorial and the sub-occipital transtentorial. METHODS: We present the Lyon's technique of the sub-occipital transtentorial approach for pineal region tumors and our tricks to avoid complications. The principle is to expose the pineal region under the occipital lobe and not through the interhemispheric fissure. CONCLUSIONS: The sub-occipital transtentorial approach is a direct, extra cerebral, safe, and effective way to access tumors of the pineal region.

Effective design and inference for cell sorting and sequencing based massively parallel reporter assays.

MOTIVATION: The ability to measure the phenotype of millions of different genetic designs using Massively Parallel Reporter Assays (MPRAs) has revolutionized our understanding of genotype-to-phenotype relationships and opened avenues for data-centric approaches to biological design. However, our knowledge of how best to design these costly experiments and the effect that our choices have on the quality of the data produced is lacking. RESULTS: In this article, we tackle the issues of data quality and experimental design by developing FORECAST, a Python package that supports the accurate simulation of cell-sorting and sequencing-based MPRAs and robust maximum likelihood-based inference of genetic design function from MPRA data. We use FORECAST's capabilities to reveal rules for MPRA experimental design that help ensure accurate genotype-to-phenotype links and show how the simulation of MPRA experiments can help us better understand the limits of prediction accuracy when this data are used for training deep learning-based classifiers. As the scale and scope of MPRAs grows, tools like FORECAST will help ensure we make informed decisions during their development and the most of the data produced. AVAILABILITY AND IMPLEMENTATION: The FORECAST package is available at: https://gitlab.com/Pierre-Aurelien/forecast. Code for the deep learning analysis performed in this study is available at: https://gitlab.com/Pierre-Aurelien/rebeca.

Bevacizumab as Single Agent in Children and Teenagers with Optic Pathway Glioma.

This is a retrospective study conducted on patients with OPG, aged less than 19 years, treated with bevacizumab as a single agent, since 2010 at IHOPe (Institute of Pediatric Hematology and Oncology). Efficacy of the treatment was evaluated on the tumor response rate on MRI with a centralized review basing upon RAPNO criteria and with visual assessment basing upon a 0.2 log change in the logMAR scale. Thirty-one patients with OPG have been included. From a radiological point of view, best anytime responses were: 1 major response, 6 partial responses, 7 minor responses and 14 stable diseases; achieving disease control in 28 (96%) out of 29 patients. Ophthalmological response was evaluated in 25 patients and disease control was achieved in 22 (88%) out of 25, with 14 steady states and 8 significant improvements. Among patients treated with chemotherapy after the bevacizumab course, nine relapsed and have been retreated with objective responses. Bevacizumab used as single agent seems effective in children and adolescents with OPG. Our work paves the way for a phase II study in which bevacizumab alone could be used as frontline therapy.

Clinical interest of molecular study in cases of isolated midline craniosynostosis.

In some cases of infants with apparently isolated single-suture synostosis, an underlying variant can be found. We aimed to determine the molecular substratum in isolated sagittal and metopic craniosynostosis. To this end, we included all infants who presented isolated midline synostosis (sagittal or metopic) and had undergone surgery at the craniosynostosis national reference center of Lyon University Hospital. All infants were examined by a multidisciplinary team including neurosurgeons, clinical geneticists and neuropsychologist. Among 101 infants tested, 13 carried a total of 13 variants; that is, 12.9% of the infants carried a variant in genes known to be involved in craniosynostosis. Seven infants carried SMAD6 variants, 2 in FGFR2, 1 in TWIST1, one in FREM1, one in ALX4 and one in TCF12. All variants were detected at the heterozygous level in genes associated with autosomal dominant craniosynostosis. Also, neurodevelopmental testing showed especially delayed acquisition of language in children with than without variants in SMAD6. In conclusion, a high percentage of young children with isolated midline craniosynostosis, especially in isolated trigonocephaly, carried SMAD6 variants. The interpretation of the pathogenicity of the genes must take into account incomplete penetrance, usually observed in craniosynostosis. Our results highlight the interest of molecular analysis in the context of isolated sagittal and/or metopic craniosynostosis to enhance an understanding of the pathophysiology of midline craniosynostosis.

A successful awake pediatric neurosurgery procedure following, 3 months after, a previous failure due to an emergence agitation: a case report.

Awake neurosurgery in children may sometimes require conversion to general anesthesia. We present here the case of a first failed awake procedure for epilepsy surgery. After adapting the anesthesia protocol (sedation + hypnosis) and acceptance by the patient, the surgeons operated the child in good conditions a few months later. We believe that it is possible to retry awake neurosurgery after a first failure if its analysis showed modifiable causes.

Sodium fluorescein in pediatric oncological neurosurgery: a pilot study on 50 children.

BACKGROUND: Sodium fluorescein (SF) is currently considered a valid intraoperative adjunct in the resection of high-grade brain lesions in adults. Experiences in pediatric groups and in low-grade gliomas and other low-grade lesions are still limited in literature, and subjective evaluation of fluorescence is still a limitation. MATERIAL AND METHODS: This study retrospectively reviewed all patients with brain or spine lesions operated on from September 2021 to July 2022 in the Pediatric Neurosurgery Unit of Hôpital Femme Mère Enfant, Lyon, who had received 5 mg/kg of 10%. Surgery was performed using a YELLOW560 filter at crucial times. At the end of surgery, the first operator completed a questionnaire, including his opinion on whether SF had been useful in tumor resection, recorded as a binary variable. Post hoc, surgical images were reviewed using ImageJ, an open-source Java image processing platform. In order to compare independent discrete variables, we applied the Student's t test, and we applied the Chi-square or Fisher exact test for binary variables. A threshold of p < 0.05 was set for statistical significance. RESULTS: We included 50 pediatric patients (0.2-17.6 years old). Forty/50 lesions showed SF uptake (80%). The differentiation between healthy and affected tissue, thanks to SF, subjectively evaluated by the surgeon, had as objective counterpart the statistically significant higher brightness of green in lesions, registered by the software (p < 0.001). SF overall allowed a good differentiation in 33/50 lesions, and overall utility of SF has been noted in 67% of them. When specifically considering gliomas, overall utility reached 75%. CONCLUSION: SF is a feasible, safe, and useful intraoperative adjunct in pediatric neurosurgery. In particular, it seems to have a promising role in some low-grade infiltrating glial tumors. The subjective evaluation of fluorescence seems to be reliable with respect to image analyses software.

Sodium fluorescein in pediatric neurosurgery: a systematic review with technical considerations and future perspectives.

BACKGROUND: Sodium fluorescein (SF) is routinely used in several centers as a valid intraoperative adjunct in adult oncological neurosurgery. Its use in pediatric neurosurgery is increasing, although its role is not yet well-defined in children. We reviewed the current literature in order to evaluate the use of SF in children with CNS and PNS lesions. METHODS: For this systematic review, we searched PubMed, Scopus, and Embase databases, and forward and backward citations for studies published between database inception and July 31st, 2022. We included any article type or congress abstract adding at least a new case, without restrictions of language or publication status, concerning the use of SF in neurosurgical procedures in patients under 18 years of age. We excluded studies concerning purely vascular cases and cerebrospinal fluid leaks. RESULTS: Of 4094 records identified, 19 articles were eligible and included for further analysis. As per July 31st, 2022, at least 119 patients aged from 11 months to 17.9 years underwent surgery with SF. No serious adverse events were reported. A large variety of tumor types was operated, in most cases resected under the specific YELLOW 560 nm filter after a low-dose SF injection (2-5 mg/kg) at the end of anesthesia induction. SF was reported particularly useful in gangliogliomas and pilocytic astrocytomas. DISCUSSION/CONCLUSION: Given its easy-to-use profile, low cost, and safety, SF seems to be a feasible and valid adjunct in the pediatric population when aiming at individuating a biopsy target or maximizing extent of resection, particularly in some tumor types. Further studies are required to strengthen the evidence on its impact on outcomes.

Results of the treatment of pineal tumors in children: the Lyon experience.

INTRODUCTION: Pineal tumors are rare and their incidence is of 1% among all pediatric tumors of the central nervous system. Patient survival depends on the histology, the extension of the surgical removal, and the efficacy of the complementary treatment (chemotherapy and cranio-spinal irradiation), as well as the age of the patient. MATERIALS AND METHODS: In this study, we analyzed 151 pediatric patients treated for pineal tumors from 1997 to 2020 in Lyon, France. All patients were recorded in the French Register of Pineal tumors, which has been centralized and maintained in Lyon since 2010. RESULTS: Our analysis shows that benign tumors have an overall positive prognosis with total surgical removal. Concerning pineal parenchymal tumors, pinealoblastomas have a poor prognosis , especially in children less than three years old. A new pathological classification system allows for a better stratification of patient risk within different groups of patients with pineal tumors. It is also important to note that the identification of DICER 1 syndrome in families with pinealoblastomas warrant further medical investigation. Patients with Germ Cell Tumors have more favorable outcomes, with a global survival rate of 87 % and a pure germinoma survival rate of almost 97%. When analyzing the prognosis of pineal gland gliomas, otherwise known as tectal plate gliomas, pilocytic astrocytomas had a promising prognosis. Otherwise, prognosis of other tectal plate gliomas are related to the grade of malignancy and the efficacy of complementary treatment. Lastly, papillary tumors need a complete removal for the best chance of survival, and Atypical teratoid/ rabdoid tumors (AT/TR) still have a bad prognosis, regardless of surgical resection. CONCLUSIONS: Our results show that, with regards to pediatric pineal region tumors, there are still areas in prognostic indicators that need to be improved. Similarly, these pathologies need to be treated via a multidisciplinary approach to improve a patient's survival rate and their quality of life.

Design and Analysis of Massively Parallel Reporter Assays Using FORECAST.

Machine learning is revolutionizing molecular biology and bioengineering by providing powerful insights and predictions. Massively parallel reporter assays (MPRAs) have emerged as a particularly valuable class of high-throughput technique to support such algorithms. MPRAs enable the simultaneous characterization of thousands or even millions of genetic constructs and provide the large amounts of data needed to train models. However, while the scale of this approach is impressive, the design of effective MPRA experiments is challenging due to the many factors that can be varied and the difficulty in predicting how these will impact the quality and quantity of data obtained. Here, we present a computational tool called FORECAST, which can simulate MPRA experiments based on fluorescence-activated cell sorting and subsequent sequencing (commonly referred to as Flow-seq or Sort-seq experiments), as well as carry out rigorous statistical estimation of construct performance from this type of experimental data. FORECAST can be used to develop workflows to aid the design of MPRA experiments and reanalyze existing MPRA data sets.

Pediatric Low-Grade Glioma Surgery with Sodium Fluorescein: Efficient Localization for Removal and Association with Intraoperative Pathological Sampling.

Low-grade gliomas are among the most common CNS lesions in pediatrics and surgery is often the first-line treatment. Intraoperative tools have been developed to maximize the results of surgery, and in particular dyes such as sodium fluorescein (SF) have been investigated in high-grade adult lesions. The use of SF in pediatric low-grade gliomas is still unclear. We retrospectively reviewed 22 pediatric CNS low-grade gliomas operated on with SF from September 2021 to October 2022. A total of 86% of lesions showed SF uptake, which was helpful intraoperatively (confirmation of initial localization of the tumor, or identification of tumor remnants) in 74% of them. The intraoperative fluorescence seems associated with gadolinium enhancement at the preoperative MRI. Interestingly, the extemporaneous pathological sampling (EPS) was informative in every case showing SF uptake, whereas in cases without SF uptake, the EPS was non-informative, although the tissue was later confirmed as pathological. These findings highlight the interest of SF for perioperative diagnosis of tumor tissue and may suggest in which cases the differentiation of tumor-healthy tissue could be especially blurred, posing difficulties for the pathologist.

Non-accidental head injury of infants: legal implications for the pediatric neurosurgeon.

BACKGROUND: Though the neurosurgeon's role in non-accidental head injury (NAHT) is the prompt recognition and care of the inflicted injuries, he/she should be aware of the possible legal implications related to this particular neurosurgical condition. MATERIAL AND METHODS: Based on published data and their own clinical and medico-legal practice, the authors review the role of the neurosurgeon in NHAT. RESULTS: Besides the contribution that can be given by the neurosurgeon to a correct differential diagnosis, he/she is likely to be involved in the interpretations of the pathological findings in the case where the judge may request for a medical opinion concerning etiology, circumstances, severity, and consequences. As a member of a multidisciplinary team, usually the neurosurgeon is only requested for information regarding the lesions he was called to recognize and treat. Nevertheless, such information may have a pivotal part in the evaluation process. Consequently, the neurosurgeon should be able to reach a correct differential diagnosis of NAHT among all the events that may share similar clinical and anatomo-pathological characteristics and be aware of the ongoing scientific controversies related to the diagnosis and pathophysiology. CONCLUSIONS: In practical terms, the pediatric neurosurgeon is called to individuate and record all the precise details of the condition to be eventually offered to the judge in case of controversy. Whereas the diagnosis of NAHT should be evoked at the initial phase in order not to leave the child unprotected, all possible alternative hypotheses should be ruled out "beyond reasonable doubt" for the court. The medical file should be maintained in the record carefully and be accessible even after a long time.

Recurrent Tethering in Conus Lipomas: A Late Complication Not to Be Ignored.

BACKGROUND: Recurrent symptomatic tethered cord (RTC) is a long-term complication of spinal cord lipomas, responsible for progressive motor deficits, urologic dysfunction, and aggravation of spinal deformities. We retrospectively analyzed all cases of recurrent tethering after spinal cord lipoma surgery, the clinical and radiologic features that led to the diagnosis, the surgical management, and the neuro-orthopedic outcome at the last follow-up. METHODS: The study was carried out over 20 years on 209 pediatric patients from a single institution, initially treated for a conus lipoma. RESULTS: Nine patients (4.8%) were surgically treated for an RTC. The age at retethering ranged from 2 to 12 years (median, 7.4 years). The time until the first and the second surgical procedure ranged from 19 to 140 months (median, 92 months [7.5 years]). The follow-up period after the second surgery ranged from 3 months to 13 years (median, 50 months). Regarding symptoms, pain responded well to surgery. Gait disturbances improved in 50% of patients after surgery. One patient with bladder dysfunctions also improved. The remaining patients maintained their presurgical status. CONCLUSIONS: When RTC is confirmed, the child should be referred to surgery as soon as possible, because we show that the postoperative clinical outcome improved and surgery did not worsen patients' condition. Follow-up should be as long as possible for these patients.

The shifting role of the cerebellum in executive, emotional and social processing across the lifespan.

The cerebellum's anatomical and functional organization and network interactions between the cerebellum and the cerebral cortex and subcortical structures are dynamic across the lifespan. Executive, emotional and social (EES) functions have likewise evolved during human development from contributing to primitive behaviors during infancy and childhood to being able to modulate complex actions in adults. In this review, we address how the importance of the cerebellum in the processing of EES functions might change across development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions. As a result of anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features. We suspect that this evolving role of the cerebellum has complicated the interpretation of its contribution to EES computational demands.