Neurodevelopmental Lesion Research Articles

Impaired pain in mice lacking first-order posterior medial thalamic neurons.

The thalamus plays an important role in sensory and motor information processing by mediating communication between the periphery and the cerebral cortex. Alterations in thalamic development have profound consequences on sensory and motor function. In this study, we investigated a mouse model in which thalamic nuclei formation is disrupted because of the absence of Sonic hedgehog (Shh) expression from 2 key signaling centers that are required for embryonic forebrain development. The resulting defects observed in distinct thalamic sensory nuclei in Shh mutant embryos persisted into adulthood prompting us to examine their effect on behavioral responses to somatosensory stimulation. Our findings reveal a role for first-order posterior medial thalamic neurons and their projections to layer 4 of the secondary somatosensory cortex in the transmission of nociceptive information. Together, these results establish a connection between a neurodevelopmental lesion in the thalamus and a modality-specific disruption in pain perception.

Pediatric Intraoperative Neurophysiologic Mapping and Monitoring in Brain Surgery.

Similar to adults, children undergoing brain surgery can significantly benefit from intraoperative neurophysiologic mapping and monitoring. Although young brains present the advantage of increased plasticity, during procedures in close proximity to eloquent regions, the risk of irreversible neurological compromise remains and can be lowered further by these techniques. More so, pathologies specific to the pediatric population, such as neurodevelopmental lesions, often result in medically refractory epilepsy. Thus, their successful surgical treatment also relies on accurate demarcation and resection of the epileptogenic zone, processes in which intraoperative electrocorticography is often employed. However, stemming from the development and maturation of the central and peripheral nervous systems as the child grows, intraoperative neurophysiologic testing in this population poses methodologic and interpretative challenges even to experienced clinical neurophysiologists. For example, it is difficult to perform awake craniotomies and language testing in the majority of pediatric patients. In addition, children may be more prone to intraoperative seizures and exhibit afterdischarges more frequently during functional mapping using electrical cortical stimulation because of high stimulation thresholds needed to depolarize immature cortex. Moreover, choice of anesthetic regimen and doses may be different in pediatric patients, as is the effect of these drugs on immature brain; these factors add additional complexity in terms of interpretation and analysis of neurophysiologic recordings. Below, we are describing the modalities commonly used during intraoperative neurophysiologic testing in pediatric brain surgery, with emphasis on age-specific clinical indications, methodology, and challenges.

Utility of Gadolinium-Based Contrast in Initial Evaluation of Seizures in Children Presenting Emergently.

The frequency and utility of gadolinium in evaluation of acute pediatric seizure presentation is not well known. The purpose of this study was to assess the utility of gadolinium-based contrast agents in MR imaging performed for the evaluation of acute pediatric seizure presentation. We identified consecutive pediatric patients with new-onset seizures from October 1, 2016, to September 30, 2021, who presented to the emergency department and/or were admitted to the inpatient unit and had an MR imaging of the brain for the evaluation of seizures. The clinical and imaging data were recorded, including the patient's age and sex, the use of IV gadolinium, and the underlying cause of epilepsy when available. A total of 1884 patients were identified for inclusion. Five hundred twenty-four (28%) patients had potential epileptogenic findings on brain MR imaging, while 1153 (61%) patients had studies with normal findings and 207 (11%) patients had nonspecific signal changes. Epileptogenic findings were subclassified as the following: neurodevelopmental lesions, 142 (27%); intracranial hemorrhage (traumatic or germinal matrix), 89 (17%); ischemic/hypoxic, 62 (12%); hippocampal sclerosis, 44 (8%); neoplastic, 38 (7%); immune/infectious, 20 (4%); phakomatoses, 19 (4%); vascular anomalies, 17 (3%); metabolic, 3 (<1%); and other, 90 (17%). Eight hundred seventy-four (46%) patients received IV gadolinium. Of those, only 48 (5%) cases were retrospectively deemed to have necessitated the use of IV gadolinium: Fifteen of 48 (31%) cases were subclassified as immune/infectious, while 33 (69%) were neoplastic. Of the 1010 patients with an initial noncontrast study, 15 (1.5%) required repeat MR imaging with IV contrast to further evaluate the findings. Gadolinium contrast is of limited additive benefit in the imaging of patients with an acute onset of pediatric seizures in most instances.

Lead-induced neurodevelopmental lesion and epigenetic landscape: Implication in neurological disorders.

Lead (Pb) was implicated in multiple genotoxic, neuroepigenotoxic, and chromosomal-toxic mechanisms and interacted with varying synaptic plasticity pathways, likely underpinning previous reports of links between Pb and cognitive impairment. Epigenetic changes have emerged as a promising biomarker for neurological disorders, including cognitive disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). In the present review, special attention is paid to neural epigenetic features and mechanisms that can alter gene expression patterns upon environmental Pb exposure in rodents, primates, and zebrafish. Epigenetic modifications have also been discussed in population studies and cell experiment. Further, we explore growing evidence of potential linkage between Pb-induced disruption of regulatory pathway and neurodevelopmental and neurological disorders both in vivo and in vitro. These findings uncover how epigenome in neurons facilitates the development and function of the brain in response to Pb insult.

Autophagic lipid metabolism sustains mTORC1 activity in TSC-deficient neural stem cells.

Although mTORC1 negatively regulates autophagy in cultured cells, how autophagy impacts mTORC1 signaling, in particular in vivo, is less clear. Here we show that autophagy supports mTORC1 hyperactivation in NSCs lacking Tsc1, thereby promoting defects in NSC maintenance, differentiation, tumourigenesis, and the formation of the neurodevelopmental lesion of Tuberous Sclerosis Complex (TSC). Analysing mice that lack Tsc1 and the essential autophagy gene Fip200 in NSCs we find that TSC-deficient cells require autophagy to maintain mTORC1 hyperactivation under energy stress conditions, likely to provide lipids via lipophagy to serve as an alternative energy source for OXPHOS. In vivo, inhibition of lipophagy or its downstream catabolic pathway reverses defective phenotypes caused by Tsc1-null NSCs and reduces tumorigenesis in mouse models. These results reveal a cooperative function of selective autophagy in coupling energy availability with TSC pathogenesis and suggest a potential new therapeutic strategy to treat TSC patients.

Histology Atlas of the Developing Prenatal and Postnatal Mouse Central Nervous System, with Emphasis on Prenatal Days E7.5 to E18.5.

Evaluation of the central nervous system (CNS) in the developing mouse presents unique challenges, given the complexity of ontogenesis, marked structural reorganization over very short distances in 3 dimensions each hour, and numerous developmental events susceptible to genetic and environmental influences. Developmental defects affecting the brain and spinal cord arise frequently both in utero and perinatally as spontaneous events, following teratogen exposure, and as sequelae to induced mutations and thus are a common factor in embryonic and perinatal lethality in many mouse models. Knowledge of normal organ and cellular architecture and differentiation throughout the mouse's life span is crucial to identify and characterize neurodevelopmental lesions. By providing a well-illustrated overview summarizing major events of normal in utero and perinatal mouse CNS development with examples of common developmental abnormalities, this annotated, color atlas can be used to identify normal structure and histology when phenotyping genetically engineered mice and will enhance efforts to describe and interpret brain and spinal cord malformations as causes of mouse embryonic and perinatal lethal phenotypes. The schematics and images in this atlas illustrate major developmental events during gestation from embryonic day (E)7.5 to E18.5 and after birth from postnatal day (P)1 to P21.

13. Parieto-occipital mapping-demonstrative cases

In this presentation, I will give an overview of how we can map different eloquent regions of parietal and occipital lobes. I will start with the anatomy with different cytoarchitecture and thus different functions of distinctive regions of these lobes. I will then present several neurophysiologic techniques that can be used for functional mapping, such as somatosensory evoked potentials (SSEPs) for intraoperative mapping and monitoring somatosensory cortex, visual evoked potentials (VEPs) for mapping striate cortex, direct electrical cortical stimulation for positive and negative cortical mapping. I will present specific tasks to be used during awake craniotomies for mapping of parietal functions. I will also present a case of visual mapping using VEPs and electrical stimulation in a case of intractable lesional epilepsy (from a parieto-occipital stroke). I will conclude with a case of mapping the sensorimotor cortex using exclusively median SSEPs recorded via a multicontact subdural grid electrode and in the absence of visual cortical inspection, in a patient with intractable lesional epilepsy from an extensive neurodevelopmental lesion in the pericentral regions.

A desperate search for biomarkers in schizophrenia. What is going wrong?

In their excellent review, Lawrie et al search for suitable biomarkers to establish the diagnosis of schizophrenia, and to predict the transition to psychosis and the response to treatment. They conclude that currently the diagnosis of schizophrenia by means of clinical criteria is reliable and that replacing this with another set of subjective criteria would be “comparable to rearranging deck chairs on the Titanic”. Despite their substantial effort to distil biomarkers out of the literature, the authors remain unsuccessful. What is the background and what can be done to change this lack? Concerning biomarkers, we seem to envy the rest of medicine. In cardiology, for instance, we have a wealth of markers like ECG or blood parameters, helping to establish a firm diagnosis. Even when we look at neurology, a discipline obviously working on the same organ we deal with, disease phenotypes like stroke, epilepsy or multiple sclerosis are easy to define. These disorders have a clear morphological substrate and often well identified etiological factors. Schizophrenia is a network disorder in which we find local abnormalities and a disconnection syndrome, but we are not able to discover a common neuropathological substrate or a set of established risk genes. The behavioural phenotype encompasses virtually all aspects of human behaviour. Therefore, we need to reduce the complexity of the phenotype under examination. Our task consists in designing simple experiments to answer a few questions or just one question. We need to focus on one “neurofunctional pathway” rather than leaving the interpretation of our data to “neuronal network hypotheses”. We can rely on sophisticated research tools, namely molecular genetics and brain imaging, but the differences to be detected in schizophrenia are exiguous and heterogeneous. And we still look for a static lesion explaining at least part of the psychopathology of schizophrenia. In a recent randomized trial, however, we could demonstrate that hippocampal volume reduction, one of the structural hallmarks of schizophrenia, is reversible with aerobic exercise over a period of three months 1. Therefore, our concept of a static neurodevelopmental lesion and/or degenerative brain process in schizophrenia might be wrong. We have to realize that any detrimental factor to the brain, such as obstetric complications, cannabis abuse or chronic psychotic symptoms, will lead to regenerative brain efforts. Therefore, it is vital to define the phase of illness of each patient under study. Interestingly, there is consistent evidence for a heterogeneous outcome in schizophrenia. About 20 to 30% of patients with schizophrenia show a very favourable, around 20% a fair and the remaining 50% a more unfavourable outcome 2. Despite this evidence, there are no studies trying to define the neurobiological basis of these different long-term outcomes. It would be a good start if neurobiological findings were interpreted on the background of the long-term outcome of the patients included in the study. In summary, Lawrie et al’s paper points to a wealth of neurobiological data from schizophrenia research, which currently are not helpful in identifying biomarkers for establishing the diagnosis, predicting the transition to psychosis or responding to treatment. This underscores the need to reduce the complexity of our observed phenotypes and to develop more focused study designs. Furthermore, in order to reach a better understanding of the neurobiological basis of schizophrenia, we need to focus on the different phases of illness, distinguishing prodromal, first- and multiple-episode cases. Finally, stratifying our findings on the background of the long-term outcome of the included patients could help us to develop a more sophisticated interpretation of our neurobiological data on schizophrenia.

Neurobiology of Schizophrenia

With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.

Ethanol sensitization in a neurodevelopmental lesion model of Schizophrenia in rats

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.

The Cells of Cajal-Retzius: Still a Mystery One Century After

Cajal-Retzius (CR) cells are an enigmatic class of neurons located at the surface of the cerebral cortex, playing a major role in cortical development. In this review, we discuss several distinct features of these neurons and the mechanisms by which they regulate cortical development. Many CR cells likely have extracortical origin and undergo cell death during development. Recent genetic studies report unique patterns of gene expression in CR cells, which may help to explain the developmental processes in which they participate. Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells. Emerging data show that these neurons are a critical part of an early and complex network of neural activity in layer I, supporting the notion that CR cells modulate cortical maturation. Given these key and complex developmental properties, it is therefore conceivable for CR cells to be implicated in the pathogenesis of a variety of neurological disorders.

Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences.

The evidence from structural imaging studies supports the notion that schizophrenia arises from an early abnormality in brain development. In this paper we review the timing of structural changes in schizophrenia and argue that schizophrenia is a neuro-developmental disorder with limited progressive brain changes occurring during the evolution and early phase of psychosis. The available cross-sectional and longitudinal studies are reviewed, along with data from our own research. The current literature, including our own data, suggests that structural brain changes are apparent premorbidly, consistent with a neurodevelopmental lesion. These are prominent in frontal and cingulate regions, and appear related to premorbid neuropsychological deficits in executive function. However, there appear to be additional brain changes over the transition to illness and beyond. We propose first, that an early neurodevelopmental insult interacts with either normal or abnormal postpubertal brain maturation to produce further (late neurodevelopmental) brain structural and functional changes; and second, that the effect of such neurodevelopmental lesions will have different consequences for functions that normally develop early in life, such as memory, compared with functions developing later, such as executive functions. A model is presented suggesting that the structural and functional abnormalities in schizophrenia can be understood as a consequence of the neurodevelopmental stage at which brain changes occur.

Does a Neurodevelopmental Lesion Involving the Hippocampus Explain Memory Dysfunction in Schizophrenia?

Abstract: Schizophrenia is a mental disorder that has been associated with structural abnormalities of the medial temporal lobes and with impairments of memory function. The evidence for this association is weak. Many analyses have not investigated whether the impairment of memory is over and above the recognized impairments of global cognitive function, attention or working memory, all of which are disturbed in schizophrenia. Another difficulty evident in studies to date is that the construct of memory has rarely informed the selection of neuropsychological tests used. Lastly, an understanding of the normal development of cognitive functions has not guided interpretation of results. In this review we examine the evidence for a hippocampal memory deficit in schizophrenia, and suggest that an appreciation of these three points can explain the impairments described. In particular, we propose that the effect of a neurodevelopmental lesion will have different consequences for functions that normally develop early in life, such as memory, compared with functions developing later, such as executive functions. The latter develop post-pubertally during the period of peak incidence of schizophrenia, and it is these functions that are most impaired in this disorder.

Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model.

Clinical, neuroimaging, neuropathological and neuropsychological evidence suggests that, in schizophrenia, there is structural and functional disturbance of the hippocampus. The purpose of this paper is to present published findings concerning the nature, timing and course of these putative disturbances of hippocampal function and the pathophysiological mechanisms involved, and to explore whether schizophrenia is a disorder of neurodevelopment, neurodegeneration or a combination of both processes. The available cross-sectional and longitudinal evidence for hippocampal involvement in schizophrenia is reviewed and a model of hippocampal involvement in this disorder, which derives from our own cross-sectional and longitudinal hippocampal imaging data, is described. We propose a three-hit model in which an early neurodevelopmental lesion renders the hippocampus vulnerable to further insult later in life during the transition phase to active illness. The available evidence suggests that the left hippocampus is particularly vulnerable during these early stages, while further insult involving the hippocampus bilaterally occurs in those who develop a chronic form of the illness. Intervention strategies should target the most vulnerable stages of the illness, in particular the transition phase to psychosis, when novel treatments may prevent the illness or ameliorate its effects.

Evidence for Progression of Brain Structural Abnormalities in Schizophrenia: Beyond the Neurodevelopmental Model

ObjectiveClinical, neuroimaging, neuropathological and neuropsychological evidence suggests that, in schizophrenia, there is structural and functional disturbance of the hippocampus. The purpose of this paper is to present published findings concerning the nature, timing and course of these putative disturbances of hippocampal function and the pathophysiological mechanisms involved, and to explore whether schizophrenia is a disorder of neurodevelopment, neurodegeneration or a combination of both processes.MethodThe available cross-sectional and longitudinal evidence for hippocampal involvement in schizophrenia is reviewed and a model of hippocampal involvement in this disorder, which derives from our own cross-sectional and longitudinal hippocampal imaging data, is described.ResultsWe propose a three-hit model in which an early neurodevelopmental lesion renders the hippocampus vulnerable to further insult later in life during the transition phase to active illness. The available evidence suggests that the left hippocampus is particularly vulnerable during these early stages, while further insult involving the hippocampus bilaterally occurs in those who develop a chronic form of the illness.ConclusionsIntervention strategies should target the most vulnerable stages of the illness, in particular the transition phase to psychosis, when novel treatments may prevent the illness or ameliorate its effects.